Bio Find Notes Spreadsheet

Module 2:
Welcome to Biology 100. The study of life is fueled by your sense of curiosity. This little body
is intrigued with some kind of "Life". You do not have to be a biological scientist to be a
biologist. Every aspect of your activities have a biological component. So stay curious and ask
questions about issues such as: What is Life? Death? Can zombies really exist? Is there life on
Mars? Why did he/she break up with me?
All the developments of our civilization, ranging from clothes to guns, and cars to medicines,
reflect mankind's insatiable curiosity. Other animals also use tools, but we are singular in the
types of tools that we have developed. Our ancestors used this curiosity and problem solving
ability for a very practical reason: food gathering (Figure 1). Protection from other human groups
and the elements resulted in other key developments such as animal husbandry, clothing, the bow
and arrow, to eventually weapons of mass destruction. What is different today, versus the
inventions of our ancestors, is that scientific studies require funds. In the past, scientific studies
were only conducted by rich people, since they had the time and money(!) to explore many
biological questions.
In this module, we will answer the following questions:
1. How do scientists find money to pay for their research?
2. Who pays for research?
3. What is the scientific method and why is it important?
4. Are there ways to make new discoveries?
5. How do ethics fit in?
It was in a large conference room in one of the major buildings in Bethesda, Maryland at the
National Institutes of Health (Figure 2) that scientists from major universities were evaluating
research proposals. Assistant professor Jim Smith's proposal from Harvard, which took him 6
months to write and submit through university channels, was under review. The primary
evaluator of Dr. Smith's proposal was not enthusiastically in favor of awarding the grant due to a
number of major issues he had with the proposal. As a result the grant proposal was not given a
good score. Dr. Smith was notified a month later that he would not receive funds for his research
but he was encouraged to reapply. Subsequently, Dr. Smith had to scramble to find funds to
support his laboratory crew of three post-doctoral fellows and two graduate students. The grant
also paid for 25% of Dr. Smith's salary. That was also gone. His research question which dealt
with the proposed genetic mechanisms of alcoholism was based on recent data he had
accumulated. He had published sufficient papers on this topic but his research was considered
pedestrian. Translated: Not breaking new ground in his research area.
The study of biology is not a nice neat world as is usually presented. Biomedical, ecological, or
space research produce new information that eventually will develop new insight in to various
biological questions, new vaccines, new approaches to diseases, etc. All scientific studies vary in
their sophistication, often according to the amount of funds that support them.

All countries conduct research: some more than others. The same goes with universities. Some
are more teaching-oriented, whereas others are research oriented institutions. Community
colleges are designed to be primarily teaching institutions, while institutions such as the
University of California, Stanford, Harvard, etc. are designed to be mostly research-oriented.
Others, such as San Diego State University, straddle the two areas of research and teaching.
Research, by nature, is competitive. If you think the super bowl is competitive, try going for the
Nobel Prize! There are limited funds to support important questions that affect various aspects of
our lives, ranging from making small robots that will be able to invade our computers to new
drugs that allow us to manage pain. Faculty that conduct research have two important functions:
they produce new knowledge, while bringing in additional funds to support research at the
Universities and they train future generations of researchers. The pursuit of new knowledge is
not for the faint hearted. It takes a driven personality that believes strongly in the value of
pursuing a research question: someone who is willing to find the funds, space, and graduate
students to publish findings. Scientists can be from any discipline: M.D. and Ph.D. and allied
areas of health, such as Nursing, Pharmacy, Physical Therapy, Chiropractic, etc. Many areas
of biomedical research include studies in fields as diverse as physics, chemistry, information
technology, and biotechnology.
Funding Sources: Sugar Daddy
Most biomedical research that is funded in the USA is supported by the National Institutes of
Health (NIH), which has an annual budget of $27.8 billion dollars (Figure 2). Another funding
agency is the National Science Foundation, which supports non-biomedical research on topics
such as global warming and development of engineering centers and has a budget of $5.6 billion
dollars. The Department of Defense supports research that deals with various aspects of weapons
development, human performance in extreme environments and national defense.
The National Aeronautics and Space Administration (NASA) supports research for the
exploration of space, such as improving life on this planet, searching for life on extraterrestrial
sites, engineering new materials for rockets or assessing human performance in space (Figure 3).
In addition, private pharmaceutical and biotechnology companies support their own private
research. There are also other private organizations that support research, such as the Bill and
Melinda Gates foundation.
Most of these organizations support research for new biomedical findings but, relatively small
amounts are spent on developing new ways to present the information. These agencies spend
limited funds on understanding the learning process in classrooms. NSF funds the majority of
these studies.
Associated with research support comes prestige. If a person brings in a grant for three years

valued at $300,000 per year, he does not have to teach and can write his papers so he can get
more funds. If he teaches, it is only for a couple of hours a year. In addition, his university will
receive additional funds ranging from 8-40% on top of the award for further development. This
process has been very effective in allowing faculty to become experts in their fields and arriving
at many new advances in medicine and in science.
Dr. Smith's proposal, and many of the others he is competing against, is based on the scientific
method. This method of critical observation leads to a hypothesis, which can be tested in the lab
with various kinds of experiments. It is the bedrock of research.
The scientific method consists of the following elements:
1. Observations- Observe a problem seeking a solution/explanation
2. Questioning- Analyze the problem and pose a hypothesis
3. Questioning- Investigate the premises of the hypothesis and condition necessary for the
premises
4. Hypothesis- Formulate the hypothesis into a question that can be verified
5. Testing- Perform a reproducible test
6. Testing- Analyze the data
7. Testing- Evaluate the validity of the results, tests and premises
8. Explanation- Accept or reject the hypothesis
Research at the highest level is supposed to be hypothesis driven, which means there is a
question that is being asked. For example, does Gatorade (Figure 4) increase performance in
football players? What indicators will you use to assess performance? How would you go about
showing that Gatorade is better than water? Would you want to use subjects who were trained
athletes or non-trained? What sport do you want them to perform? Do you want to exercise them
to the point of fatigue? If so, what kind of exercise? Where is the data, besides the nice ads on
television showing orange sweat?
Another example of a research question is: Does additional oxygen really help football players
on the field? You notice that football players are given oxygen masks after they make four or five
plays and return to the sidelines. Does it really enhance performance of the football players or
does it simply make them feel good? Where is the data? In many cases, the data does not support
various advertisements.
Being associated with research is the critical step in which the data must be reproduced in
separate laboratories and also have controls to verify that the experiment actually works. For
example, in Dr. Smith's research, he hypothesized that the individuals with a certain genetic

profile would respond differently to ethanol than would the general population. His method
would be to give ethanol to two groups of subjects: those with a certain genetic profile and a
sample of individuals from the general population.
He would then repeat the experiment with the same groups but he would substitute water for
ethanol. The reason for this would be to control if the response of the subjects was actually due
to the ethanol or simply to the ingestion of a liquid. Thus the second group in which the ethanol
would be substituted by water is the control group. If another scientist wanted to reproduce his
findings, they would have to have a similar group of subjects. What does that mean? Same age,
same gender distribution, same race, same exercise levels?
Although the scientific method is the most robust way to arrive at new understanding of
biomedical processes, it is difficult to put into practice with human research subjects. The human
is a complex set of interacting systems that influence each other. No two humans are identical.
Even identical twins have different fingerprints! (Figure 5). These observations are important
because medications do not work the same in various groups since people have different
chemical profiles. Although the scientific method is based on the premise that every experiment
can be repeated, very few experiments are actually repeated after their initial publication. The
reason? Money. Experiments require large outlays of funds and once a finding is published,
people assume it is correct. Another reason that experiments are often not repeated and published
is that scientific journals do not like to publish the same finding.
The use of animals such as rodents to understand complex systems like cancer is justified on the
basis of the ease of reproducing the experiment and getting a large sample to make sure the effect
is real. The downside is whether such results are translated to humans. Another downside is the
ethical debate over the humane treatment of animals.
Complicating the scientific world are the two major methods of reasoning: Deductive and
Inductive reasoning.
Deductive reasoning is based on a solid accepted premise from which particular conclusions can
be logically derived. For example, a solid premise would be:
1) All triangles have 180 degrees (premise)
2) A right triangle is a form of a triangle
3) Therefore, a right triangle has 180 degrees
Inductive reasoning starts with an observation which is not universally accepted. For example:
1) Priscilla likes men (premise)
2) Julius Caesar is a man
3) Therefore, Priscilla likes Julius Caesar.
Obviously this is a flawed conclusion. Most of biology is based on particular observations from
which general conclusions are derived. Another example:
1) DNA directs protein synthesis (premise)
2) Cells have proteins

3) Therefore, all cells have DNA.

Notice the premise is not completely accepted. Other molecules can direct protein synthesis, thus
the conclusion is flawed. The study of biological systems is based more on inductive reasoning
leading to continual modifications of conclusions.
For example:
1) Drug A minimized hypertension
2) Drug A is given to a patient with hypertension
3) Therefore, the patient has their hypertension under control.
Although this conclusion can be true in this patient's case, it may not be true in another patient.
Therefore this too shows a flawed conclusion.
Contributions of the Scientific Method
The scientific method has generated a large number of positive contributions for society. Some
examples of these contributions are: development of many antibiotics to kill various bacteria,
sterile technique, drugs to treat various mental diseases, artificial hearts and kidneys, support
systems that allow humans to exist in space for months, computers, the internet, cosmetics,
global positioning systems, etc. The list is endless. Each fact presented in the succeeding
modules is the result of many years of research and confirmation.
A young woman goes into a Chinese herbalist. Her complaint is that she has small breasts and
wants larger ones, but she does not want to have surgical implants. She does not like the way
they look on her friends. The herbalist gives her some special tea. In this case there is no control
group and no scientific evaluation of the herbs. However, there are many years of a tradition in
the culture about the breast enhancing qualities of certain plants and teas. Traditional medicine
has been around since the dawn of Homo sapiens.
People have used various plants and chemical concoctions to cure or treat all kinds of diseases or
conditions. One example is a plant, which has purported abortion properties used by indigenous
people in Mexico. Women would take the plant, soak it in water, and then drink the resulting tea
to induce abortions. In the USA, various natural products are used for everything from curing
baldness to alleviating hot flashes. Since these agents are not considered medicines, they are not
subject to the same scrutiny as are those sold by pharmaceutical companies. Whether these
agents work is hotly debated. Non-scientific remedies are not all bad. The use of acupuncture
(Figure 6) was at one time laughed at by American physicians. However, in the hands of trained
experts, it works on certain patient groups. Whether it is the exact positioning of the needles in
certain regions of the body or merely the act of placing needles into the body to cause it's effect
is not clearly understood. The scientific method is not the only way to arrive at knowledge.

Presently, the National Institutes of Health through its Center of Alternative Medicine is
supporting various studies to investigate the effectiveness of alternative medicine.
I have always been fascinated with Dr. Frankenstein (Figure 7). He epitomized, I thought, the
ultimate evil scientist. He took human parts and used them to create some form of life that
eventually he could no longer control. Eventually, he was killed by his creation. Of course he had
the necessary financial resources to employ his sidekick, Igor, and did not have to worry about
the electricity bills as he shocked his creation into life.
However, I met the real monsters of science when I reviewed how scientists in Nazi Germany
studied how humans survived or died in cold environments or at high altitude. The scientists who
conducted these experiments justified these experiments, since they claimed that they were
gathering data to protect pilots who were shot down over the North Sea and fell into cold water
in the battle to conquer England. In some experiments, prisoners were injected with various
lethal drugs or bacteria or exposed to cold water. As they died, their various physiological signals
were recorded.
The Nazi scientists were tried and convicted of mass murder. In addition, as a result of the trial,
international guidelines were developed that protected any prisoner of war from being used as a
scientific victim. These guidelines are laid out in the Geneva Conventions of 1949.
Today, experiments conducted on humans require that the subjects be informed of their rights
and the implications of the experiments, both good and bad. However, these guidelines are not
always honored. For example, a physician who owns the rights to a new drug that may cure
cancer gives the drug to a person who has the specific cancer, but the physician failed to tell the
patient that he owned the rights to the drug. Was this activity ethical? The physician may be
biased with the treatment of patients since he wants the data to support his claims about his drug.
One last case: a pharmaceutical company conducts research on human subjects and discovers the
drug does control the spread of cancer, but fails to mention that the drug has deleterious effects
on the liver. It causes liver failure! Ethical or not? Thus, if you are everinvolved in any kind of
clinical trial involving drugs, read all the fine print and make sure that the investigator cannot
personally gain from the results of the study.
Another aspect of ethics in the biomedical area is in the publishing of data. If a physician
publishes data in a journal that discusses how effective a drug is, should the author voluntarily
state that he was also paid by the drug company? Does the source of funds influence the data? It
does. If a scientist wants to continue to receive funds for his research, does he want to
report positive or negative data to his sponsor?
Although human subjects are protected, most animal groups are not. The use of animals in
biomedical research is hotly contested. In the past, animals have been used for various scientific
studies. In recent years, this has begun to change since many people contend that animals also
have feelings. Here are some of their questions: Why should medical students learn how
the cardiovascular system works by experimenting with anesthetized dogs (Figure 8)? Should

cats and monkeys be used for neurological studies? Should surgeons practice their techniques on
anesthetized pigs? Some medical schools have stopped using experimental animals in
teaching medical students about various drugs. This change in policy was due to intense political
pressure from various aspects of our society.
Another aspect of bio-ethics is in regards to data. Data presented in scientific journals should be
actual and not fudged. Due to great financial pressure or personal pride, scientists have been
caught manipulating or making up data. For example, a scientist recently claimed to have cloned
a human being. It was later discovered that he had not accomplished this and had made up
most of his data. Data that is reported in peer reviewed journals is at least critically evaluated.
Although, mankind has developed new tools and insights into many areas of biology and
biomedical sciences, the question remains as to whether he is capable of handling these
developments responsibly. The development of global warming, for example, is thought to be
due to the increased levels of carbon dioxide, resulting from our industrialized and
industrializing societies (Figure 9).
We as a species are at a crossroads. We have developed a sophisticated civilization that,
according to scientists, is causing massive changes in our environment that will eventually
influence us. What do we do? If we created the problem, hopefully we can correct it in time.
However, keep in mind that this story might not have a Walt Disney ending in which everyone
ends up happy and safe.
Frequently, scientists are portrayed as nerds: individuals with low to no social skills or with no
feelings (Figure 10). They seem to be different. They cannot give a simple answer to a
question. However, in reality, their personalities are no different than the general population.
They struggle to find the funds to continue and publish their research. Most scientists
are concerned about how "things" work. They often pursue the underlying mechanisms to
important clinical problems (Figure 11).
How does heroin cause addiction? How does HIV cause death? To answer these questions, the
scientist studies the micro events that occur in individual cells. They operate in a very controlled
environment necessary to ensure the validity of their data. To assess a heroin addiction, the
scientist may visualize the complex biochemical changes that are occurring in certain areas of
the brain. By training, scientists give complex answers to questions since they see the complexity
of the biological system. It is not easy to give a simple answer. Ask a football coach why the
team lost. If you get a simple answer, you can assume they do not want to spend the time to
explain to you the details of what is going on.
Scientists may also abuse their position. The use of knowledge they gather may be used in a
negative manner. A physician may have clinical trials to assess a drug that he is trying to get a

patent which eventually harms the patient or a microbiologist wants to spread a new form of
anthrax. Most scientists whether MD or PhD are conscientious and concerned about discovering
new ways to help mankind. However, a small majority will use unethical means to advance their
own agenda.
Who cares?!!!
Many of the research questions asked by scientists seem irrelevant to the nonscience world. Why
do we need to go to the moon? Who cares about other life forms in space? The non-science
argument is that we have plenty of problems that need our attention and perhaps we should focus
our efforts on more important issues. But science and our curiosity has always been the way in
which our species has advanced. All changes in our civilization occur due to the inventive genius
of mankind.
Besides discovering new knowledge, how is it dispersed? Who tells the world about the latest
way to grow sweeter tomatoes, minimize Alzheimers disease, etc. The major role of a teacher is
to act as the translator of the work conducted in the research labs and the various segments of our
society (Figure 12).
Frequently, researchers do not have the time to present their data to a class except for graduate
students. Why? The pressure to write papers and attract new funds to keep research going is a
full time job. There is another reason why people do not teach. The reward structure in research
Universities is geared towards the researcher not the teacher. Thus you have all kinds of persons
who teach: the dedicated researcher who still finds the time to teach, the person who likes to
teach but does not want to pursue funding for research, to the person who straddles both worlds
of research and teaching. This modules and the ones that follow are the legacy of many
dedicated researchers and teachers who want to understand various biological mechanisms and
educate future generations.
Science by nature is a process in which various views on a topic are studied and debated. This
data is used by industry to produce products. Whether the product is actually helpful or just a
waste of money requires a critical review. Read the warning label on any medicinal package. Be
aware that the data presented may affect you or a loved one. In most cases, there are no
simple answers to complex questions such as what causes obesity, human violence, etc. It is your
responsibility to educate yourself about the various aspects of biology.
Module 3:
Biological life is the coordinated interplay of various chemical and physical processes which are
used for two critical functions: energy gathering and reproduction. Associated with these two
functions in some biological forms is activation of special nerve cells causing "pleasure."
Pull the Plug?
You walk into the hospital room and see your friend who is in a coma. She has been there for six

months and her mother is always there, it seems. The physician is talking to the mother who is
constantly rubbing the arms of her daughter. He asks if he can stop the life support systems that
sustain her daughter's life. He quietly tells her that her daughter is clinically dead. Is your best
friend dead or not?
Since time immemorial, humankind has been studying life: animal, plant, and human. As far as
we can ascertain, only our species, Homo sapiens, has the ability to look both inward and
outward in order to seek the definition of life. We have a unique self-consciousness that is not
present in other living forms. For example, while I write this chapter, I am thinking abstractly
about myself and the human species.
There is universal agreement that all life forms ours included have two major functions:
reproduction and energy capture and utilization, or metabolism. Of these two properties, the
capture of energy has the highest priority since without it reproduction cannot occur. Metabolism
and reproduction are directed and orchestrated by molecules that are found in all living systems,
genetic material: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). These molecules
will be discussed in detail in a later module, but they are common to all biological systems.
Reproduction and energy capture and utilization are coordinated by DNA/RNA found in all
living systems.
In this module, we will discuss the following properties of life: energy capture and use,
reproduction, chromosomal change, homeostasis, and death.
All forms of life capture, ingest, and utilize energy from a source we call food. The entire
biological world involves the transfer of energy from one source or another. Nothing is sacred.
Food is everywhere! Bacteria thrive in our intestinal tract and get their energy from our
undigested food. Tyrannosaurus Rex, the fearsome and long since gone dinosaur, and you
eating your fish taco both used and use similar processes of mechanically breaking down food by
chewing it and then further breaking it down with chemicals produced within the intestine. So
what is the purpose of these processes? The purpose is to capture the chemical energy found in
hydrogen bonds. The bottom line is that all living systems ultimately strip hydrogen ions
and electrons from the food they ingest and use this energy to power their all chemical and
physical processes.
Stripping the energy from food is a chemical process. Whether you are a bacteria living in a
small pond, a hyena chewing on the remains of a kill on the plains of Africa, or a human eating
popcorn at the movies, the ultimate chemical processes are the same. A group of interconnected
proteins called enzymes strips hydrogen ions and electrons from the chemicals that make up our
food. These hydrogen ions and electrons indirectly produce Adenosine Triphosphate (ATP), a
molecule that powers all chemical reactions in every cell. The stripping or loss of electrons or
hydrogen ions is called oxidation and the addition of electrons or hydrogen ions is called
reduction. These terms may seem contradictory, but the reason that gaining an electron is called
reduction is because a change in electrons changes the electrical charge of the molecule. All life
activities depend on these two processes. We oxidize our food to make ATP. ATP powers the

neurons in your brain as you read this sentence. Energy capture and utilization depends on
oxidation and reduction (Figure 2).
Can you see the result of oxidation and reduction in real life? Absolutely. Although the concept
of hydrogen ions and electrons being accepted and stripped off of other molecules is difficult to
imagine, to see this process just walk in a parking lot near the beach and observe the rusted cars.
Notice the fender and body are reddish in color and may be full of holes. Another place you may
see rusted cars are in the colder parts of the world where salt is thrown on the roadways to melt
the snow or ice. If the salt from the road or from the beach air is not washed off the car, the parts
of the car exposed to salt and water will rust. Rusting is an example of oxidation. The salt
water strips electrons from the metal of the car, in essence slowly chewing through the metal in
the car (Figure 3). Living systems use all kinds of chemical processes to ultimately "rust" their
food. They oxidize the food by stripping hydrogen ions from the food. These hydrogen ions and
electrons power your body by producing ATP. All living systems use ATP to build up
(e.g. anabolism) and breakdown (e.g. catabolism) any substance they ingest.
Oxidizing and Reducing Agents
Table of Contents
1.
1. Oxidizing and Reducing Agents
2.
2. Applications
3.
3. Summary
4.
4. Problems
5.
5. Solutions
6.
6. References
7.
7. Contributors
Oxidizing and reducing agents are key terms used in describing the reactants in redox
reactions that involve transferring electrons between reactants to form products. Here, we will
look at what defines an oxidizing and reducing agent, how to determine an oxidizing and
reducing agent in a chemical reaction, and the importance of this concept in real world
applications.
Oxidizing and Reducing Agents
An oxidizing agent, or oxidant, gains electrons and is reduced in a chemical reaction. Also
known as the electron acceptor, the oxidizing agent is normally in one of its higher possible
oxidation states because it will gain electrons and be reduced. Examples of oxidizing agents
include halogens, potassium nitrate, and nitric acid.

A reducing agent, or reductant, loses electrons and is oxidized in a chemical reaction. A reducing
agent typically is in one of its lower possible oxidation states and is known as the electron donor.
A reducing agent is oxidized because it loses electrons in the redox reaction. Examples of
reducing agents include the earth metals, formic acid, and sulfite compounds.

Definitions
A reducing agent reduces other substances and lose electrons; therefore, its oxidation
state will increase.
An oxidizing agent oxidizes other substances and gains electrons therefore, its
oxidation state will decrease.
To help eliminate confusion, here is a mnemonic device to help you remember how to determine
oxidizing and reducing agents.
OIL RIG:
Oxidation Is Loss and Reduction Is Gain of electrons
Example 1: Identify reducing and oxidizing agents
Identify the reducing and oxidizing agents in the balanced redox reaction:
Cl2(aq)+2Br(aq)2Cl(aq)+Br2(aq)
Oxidation half reaction
2Br(aq)Br2(aq)
Oxidation States: -1
0
Reduction Half Reaction
Cl2(aq)2Cl(aq)
Oxidation States: 0 -1

Overview
Br loses an electron; it is being oxidized from Br to Br2, thus Br is the reducing
agent.
Cl2 gains one electron; it is being reduced from Cl2 to 2 Cl, thus Cl2 is the oxidizing
agent.

Common oxidizing agents

O2
O3
F2
Br2
H2SO4
Halogen metals (halogen metals tend
to gain an electron to get to noble gas
configuration)

Common reducing agents

H2
CO
Fe
Zn
Li
Alkali metals (alkali metals tend to lose
an electron to get to noble gas
configuration)

Applications
Oxidizing and reducing agents are important in industrial applications. They are used in
processes such as purifying water, bleaching fabrics and storing energy (such as in batteries and
gasoline). Oxidizing and reducing agents are especially crucial in biological processes such
as metabolism and photosynthesis. For example, organisms utilize electron acceptors such as
NAD+ to harvest energy from redox reactions as in the hydrolysis of glucose:
C6H12O6+2ADP+2P+2NAD+2CH3COCO2H+2ATP+2NADH
All combustion reactions are also examples of redox reactions. A combustion reaction occurs
when a substance reacts with oxygen to create heat. One example is the combustion of octane,
the principle component of gasoline:
2C8H18(l)+25O2(g)16CO2(g)+18H2O(g)
Combustion reactions are a major source of energy for modern industry.
Summary
Oxidizing Agents

Reducing Agents

Oxidation State

Decreases

Increases

# of Electrons

Gained

Lost

Substance is...

Reduced

Oxidized

By looking at each element's oxidation state on the reactant side of a chemical equation in
comparison to the same element's oxidation state on the product side, one can determine if the
element is being reduced or oxidized. Thus, one is able to conclude the oxidizing and reducing
agents of a chemical reaction.
Problems
1.
Identify the oxidizing agent and the reducing agent in the following redox reaction
MnO2(s)+4H+(aq)+2Cl(aq)Mn2+(aq)+2H2O(l)+Cl2(g)

2.
3.
4.
5.
6.
7.
8.
A.
B.
C.
D.
9.

1.

2.
3.
4.
5.
6.
7.
8.
9.

For the reaction, 2NO2(g)+7H2(g)2NH3(g)+4H2O(g), is hydrogen an oxidizing agent

or a reducing agent? Explain.
An element that is oxidized is a(n) __________ agent and an element that is reduced is
a(n) __________ agent.
What is the reducing agent in the following redox reaction:
5SO23+2MnO4+6H+5SO24+2Mn2++3H2O
What is the oxidizing agent in the following redox reaction:
Zn(s)+Cu2+(aq)Zn2+(aq)+Cu(s)
Determine the oxidizing and reducing agent of the following chemical equation for
aerobic respiration:
C6H12O6(s)+6O2(g)6CO2(g)+6H2O(l)
For a general redox reaction involving species A and B with A losing electrons
and B gaining electrons: Is A the oxidizing or reducing agent? Is B the oxidizing or reducing
agent? Which one is reduced and which one is oxidized?
In a redox reaction, there must be
an oxidizing agent and no reducing agent
a reducing agent and no oxidizing agent
a reducing agent and an oxidizing agent
no reducing or oxidizing agent
Which of the following will be a strong reducing agent, which of the following will
be a strong oxidizing agent?
NO3, NO, N2H4, NH3
Solutions
Cl is the reducing agent because it is oxidized and loses one electron (starting with an
oxidation state of -1 in the Cl ions and increasing to 0 in Cl2). Remember that gaining electrons
means it is "reduced". MnO2 is the oxidizing agent because it reduced by gaining two electrons
(starting with Mn in an oxidation state of +4 in MnO2 and decreasing to +2 in free Mn2+ ions).
Keep in mind that losing electrons means it is "oxidized".
In this reaction, hydrogen loses one electron. Hydrogen is oxidized, thus making it the
reducing agent.
An element that is oxidized is a reducing agent because the element loses electrons and
an element that is reduced is an oxidizingagent because the element gains electrons.
SO23 is the reducing agent because it lost two electrons, sulfur goes from an oxidation
state of +4 in SO23 to an oxidation state of +6 inSO24.
Cu2+(aq) is the oxidizing agent because it gains two electrons, going from an oxidation
state of +2 in Cu2+(aq) to an oxidation state of 0 in Cu(s).
The oxidizing agent is oxygen and the reducing agent is glucose. Oxygen is being
reduced, so it is an oxidizing agent. The glucose is being oxidized, so it is a reducing agent.
When A loses electrons, it is being oxidized, thus is a reducing agent. When B gains
electron, it is being reduced, thus is an oxidizing agent. A is oxidized and B is reduced.
The answer is C: In a redox reaction, there is always an oxidizing and reducing agent
NO3 is most likely to be a strong oxidizing agent. NH3 is most likely to be a strong
reducing agent. You determine the likelihood for oxidation or reduction by comparing the
oxidation numbers of nitrogen. Since NO3 has the highest oxidation number of +5, compared
to the other molecules, it will most likely be the oxidizing agent. Since nitrogen in NH3 has an
oxidation state of -3, it has the lowest oxidation state and will most likely be the reducing agent.

"Juiced": Catabolism and Anabolism

All living systems use their energy either to grow or maintain themselves. In the infamous case
of baseball player, Jose Canseco, he acknowledged that his muscle development was enhanced
by the use of anabolic steroids. These chemicals boosted the normal process of his skeletal
muscle growth, causing his muscle cells to enlarge. Anabolism happened when the chemicals in
his muscle cells gained electrons (were reduced) (Figure 4). In the case of someone who wants to
lose weight, they will be using the process of oxidation, losing electrons. They will want to
oxidize their stored food in their fat cells. This is called catabolism. The electrons lost in
the process of breaking down the food are used to power other reactions. In this case, it is
important to remember that energy never disappears. It is simply transferred from one cell to
another or expelled as heat.
Food: I Want Your Blood! Really means "I Want Your Electrons and Hydrogen Ions!"
We all know about the complex networks of the interdependence of animals in ecological niches.
The classic example is the cow eating grass. The cow breathes the oxygen that was produced by
the grass and plants, and subsequently it eats the grass. The digestion of the grass involves
oxidation and reduction. The vampire who strikes his victims and sucks their blood for nutrition
is "supposedly" using the blood as its food (Figure 5). Food is universally a source of hydrogen
ions and electrons to make energy. All living systems contribute energy (i.e. hydrogen ions and
electrons) to others. We are ultimately tied to the plants that produce the oxygen and
various biomolecules that we utilize to make energy. Bacteria, herbivores, and carnivores all
interact with each other to get their energy. Any major break in this linkage can have catastrophic
effects for the entire food chain.
Reproduction: Allows for Species Survival
Reproduction is such a fun topic. People snicker when the topic is introduced. They imagine
sexual intercourse. From a biological perspective, reproduction is the second most important
biological mandate after energy production. The world of biology is full of various ways that life
forms pass on their genetic information. Some reproductive behavior is triggered by the change
in seasons. The amount of sunlight at different times of the year triggers the release of hormones
in various animals so that they search for a mate. DNA/RNA molecules found in all living things
serve as the director of energy gathering and reproduction. The chromosomes found in the
nucleus dictate the physical and chemical expression of all living beings. These expressions are
the result of various proteins that control all of the chemical activities in all cells.
Chromosomal Change Promotes Evolutionary Change
1) Chromosomes are strands of chemicals called nucleotides.
2) Deoxyribonucleic acid (DNA) controls the expression of protein in all human cells. Changes

in some part of the sequence of protein production causes different plants and animals to form.
This important topic will be covered in greater detail in future modules.
Macro to Micro: Theme of Biology
A difficult concept for many students to grasp is the relationship between chemical reactions
such as oxidation and reduction and expressions of life. It requires energy for you to be able to
read this sentence, to turn the page in a book, to listen to your iPod, to kiss, to cry, etc. We see the
obvious: the macro expression of energy use, but what allows us to function are the
small chemical changes occurring in each of our cells millions of times a second. From the
muscle cell in your finger to the ones in your intestines, cell function is determined by chemical
and physical laws.
The chemical and physical changes that occur within us are expressions of the chromosomal
information coming from the nucleus of each cell. All physical expressions in living systems are
derived from the chemical and physical order of the nucleotides. Molecular commands from
chromosomes produce physical changes. We will discuss this more in the modules dealing with
evolution.
As a young premed student, I was very interested in shadowing various medical types. A number
of my friends and I were able to meet with a pathologist, an alumnus of our college, who let us
see an autopsy. The case was memorable. It was a suicide. A young woman, twenty-two years
old, had taken an overdose of sleeping pills (Figure 6). It was a tragic case. The pathologist had
exposed the esophagus and stomach and showed us the small white pills that she had ingested.
They were found in the middle of her esophagus, the antrum into the stomach, and in the
stomach proper. The pills were small in comparison to the person and yet they stopped the
energy making machinery in her brain.
If we wanted to help persons who attempt suicide, we would need to address two issues: the
micro, how the ingredients in the pills stopped her cellular machinery and the macro, why she
took the pills. The pathologist, who was a warm-hearted fellow and liked to educate students,
told us that the secret of understanding medicine was to understand the interaction between
macro and micro elements of biological systems. His comment was important for anyone who
wants to gain an understanding of how biological systems work. All biological systems involve a
chemical underpinning.
Communication: Feedback Loops and Homeostasis
For cells, tissues, and organs to interact with each other, there must be some form of
communication. This communication can occur by means of either physical or chemical signals.
Even inside our cells, the chemical networks that produce energy must interact with each other
and with the external environment. The term homeostasis has been used to state the obvious:
cells try to maintain a constant chemical/physical environment. The mechanism that cells utilize

to maintain homeostasis is called feedback. Every biological system performs some function.
Heart cells contract at a specific rate. If the rate becomes too slow or fast, neural and chemical
feedback systems will bring the rate back to their appropriate value. Your hormone levels are
preset to have certain fluctuations. This fluctuation is based on various feedback systems that
sense the concentration of the hormones and act to control their level. From individual cells to
the entire organism, feedback loops are the key to maintaining both chemical and physical
balance.
In the real world, we eat too much. The more we eat, the fatter we become, assuming that we do
not do any exercise. Why do we eat so much? Built into our system are a set of chemicals that
respond to food ingestion. If we eat too much food, we will produce chemicals to tell the body
that we are full. Thus more food will trigger the release of chemicals that will tell our brain
that we've had enough. This is a classic example of a negative feedback loop. The more you eat,
the faster you will shut off the desire to eat. If such feedback loops occur, why then are we as a
species so fat? (Figure 7)
Overriding Feedback Loops
Various feedback loops that control so many of our activities can be overridden. In humans, we
see fat people everywhere there is ample food available. What happened? In the process of
evolution, we have developed the ability to critically reason. This allows us to override our
normal instincts. We can override our survival instincts. Brave firefighters and police
officers stormed into the twin towers on September 11, 2001. They overrode an instinctive drive
for self-protection (Figure 8). A marine will charge into a hail of bullets to save his fellow
soldier. Their mental capacity to critically assess the situation, as well as a sense of ethics, allows
them to consciously decide which actions to take.
Death: Genetically Determined
All living systems have a defined period of existence. These systems grow at different rates,
reproduce, and die. Assuming no untimely lethal accident or infection, we should live to be in
our late eighties. However, sooner or later, we will lose the ability to trap energy and use it for all
our bodily functions. We will die. This period of existence is programmed into our genetic
code. Some of us will develop cancer, diabetes, etc. Although death is inevitable, we all have a
great instinct to live. Again, our systems are designed to maintain oxygen delivery and
production of energy to all our vital systems. The question of human life is not as simple as the
biological definition of life.
We obviously agree that we are more than just a reproductive and energy gathering organism.
After all, we have to get a job so we can eat and find a mate to start a family. In addition, we play
music, dance, connive to control people, build bridges, teach courses, etc. Imagine a scenario in
which the brain of a patient is severely damaged. For the person to survive, he requires oxygen
since he cannot breathe by himself. In this case, those areas of the brain that control breathing are
damaged, so machines called ventilators must be used to push air in and out of his lungs. Without

oxygen, the person will not produce enough ATP and die (Figure 9).
So the question is whether the person is alive. Since he cannot eat or breathe by himself, surely
he is not alive. However, as a society we maintain this person as being in some form of "life."
This scenario is a common one. What makes it more difficult is that we are asked if we want to
keep the person on the ventilator. Without it, they would surely die. Once, when this
situation was presented in class, a student raised her hand and said that the ventilator should stay
on. Why? She had been in a car accident and was comatose for six months. She was unable to
breathe, eat, talk, etc. The doctors recommended that the ventilator be discontinued since there
was minimal electrical activity in her brain. Her mother refused the advice of the physicians. Six
months later, she awoke. Regretfully, for every one case in which a person wakes up from a
coma, many more never will. The cost for this care is great. The bottom line? The biological
definition of life is straightforward. The sociological, religious definition is not. The
ultimate decision of whether or not a person is alive is made by society, not by biologists.
A Fascinating Science: Biology = You
Biology is a fascinating topic since many of the areas you study will ultimately impact you and
your loved ones directly. This is not a dead science. It ultimately deals with you from a chemical,
physical and behavioral point of view.
Module 4:
Your entire body is composed of cells which are floating in salt water. This image shows the USS
Cells ship as a "cell" with other "cells" approaching it. These "cells" may be invading bacteria
that USS Cells must kill or they maybe a group of cells that are going to transmit some product
required by the USS Cells. (Note: Even though our millions of cells are floating in salt water, the
inside of our cells are primarily saline (salt water) as well!)
The cell can be considered to be an organic, saline-filled balloon enclosed by membranes that
have various kinds of receptors. Inside the cell there are multiple chemical reactions that
maintain and trigger various functions of the cell. All cells have a number of key structures
called organelles that control energy production in form of ATP production and reproduction. In
this case of an animal cell, imagine small blood vessels bringing oxygen and food to the cell by
way of blood to make ATP and transporting carbon dioxide and other metabolic bi-products
away from the cell.
A public warning was sent out urging citizens on the island of Maui to stay away from certain
beaches. The beaches had a high level of E. Coli bacteria (Figure 1). Sewage with a high
concentration of E. Coli and other bacteria had been swept into the various waterways of the
island. Joe Smith is out late at night and gets into a fight with another person and is pushed into
the water. He swallows some of the contaminated water. After a day at home, he notices that he
is feeling sick, has diarrhea and a fever. He goes into the emergency room.
The cause of Joe's sickness is the E. Coli that entered his body as he swallowed the contaminated
water. The bacterium is a single cell that, like all cells, needs to get energy and reproduce.
Bacteria do these two things in many environments, from sewage, to meat or the human body. If
bacteria are reproducing within our body, we get an infection. Our body fights against this

bacterial infection with its own group of cells that forms the immune system. A man's body,
composed of millions of cells, is being attacked by bacteria smaller than the width of a strand of
your hair. Who wins? The story of biology is the interaction of various cell types from different
life forms. So what is a cell?
In this module we will explain what cells are and how they fit into the bigger picture of things.
We will also describe some of the components, or organelles, of a cell and discuss their most
important functions.
The cell is the basic unit of life (Figure 2). The story of biology includes how life has progressed
from individual cells to complex organisms involving multiple cell types. These multi-cellular
organisms are composed of cells that combine to form tissues which subsequently form organs.
Tissues contain cells of one kind. Muscle cells make up a tissue but not an organ. An organ is a
group of tissues. Your muscle has muscle cells, fat cells, blood cells, etc. Thus the heart is an
organ, not a tissue since it has multiple tissues. Organ systems are combinations of organs. The
organ systems are: nervous, skeletal, cardiovascular, respiratory, endocrine, immune,muscular,
digestive and skin or integumentary. Each organ system, organs and tissues are dependent
ultimately on the individual cells. Cells have different names depending on the organ system.
The neuron is the cell for the nervous system, meaning that its function must be maintained for
the nervous system to function.
What is usually not presented in most discussions about cells, tissues and organs is that they
cannot survive without a system to bring them food and oxygen. Cells need energy. In Homo
sapiens, all of our cells exist in conjunction with the small blood vessels, called capillaries,
which carry food and oxygen to the cells in the blood.
Cells and Castles: Division of Labor
Imagine each human cell is like a small castle placed close to a river (Figure 3). Each cell or
"castle" has its own internal operation and it communicates with other cells by way of chemicals
that travel in the blood or the "river" and by way of electrical signals. The castles therefore need
power cables to connect them. The cell has a number of operations that it has to perform
including gathering food, importing oxygen, making ATP, expelling metabolic products, and
reproducing. Also, just like a castle, it needs to repel invaders. In this case, bacteria or viruses.
To understand how the cell works to support an organ or repel invading cells, their structure and
function is important. In this section we will discuss the different structures, or organelles, within
the cell, and explain how they contribute to the life of the cell.

Castle Walls or Cell Membranes: First Line of Communication with the Outside World
Similar to a castle, the cell monitors its outside world and protects itself with an external barrier.
This barrier, called the plasma membrane, is made up of a phospholipid layer, with a negative
electrical charge on the inside and a positive electrical charge on the outside. Sensors called
receptors are embedded in the plasma membrane that can detect various incoming signals, much
as a submarine can monitor its surroundings using fancy equipment. These sensors are all
chemical structures such as proteins or protein carbohydrate groups (glycoproteins) that, when

perturbed, will trigger various reactions. These receptors respond to chemical signals that are
transmitted in the blood. For example, the cigarette that you smoke contains nicotine, which
eventually triggers a reaction on the nicotine receptor on the membrane of brain, heart, and
intestinal cells.
In addition to detecting various products, the cell membrane also controls the entry of various
chemicals. The entrance of various molecules and ions is dependent on their reaction to the cell
membrane. A substance such as water enters by certain specific channels called aquaporins. A
chemical like glucose requires a special carrier on the membrane to take it inside the cell. Small
ions, like sodium and potassium, also move through small holes or pores in the membrane.
The membranes of different cells vary. Thus a heart cell membrane will respond to nicotine,
which attaches to receptors on the surface, but fat cells will not respond since they do not have
nicotine receptors (Figure 4). The cell membrane is a vibrant structure. It is made of proteins and
lipids and is constantly being rebuilt. To control the import and export of various chemicals and
to develop new structures requires energy in the form of ATP molecules. Certain cells, such as
those in the intestinal tract are constantly being renewed. Movement of substances into the cell
through the membrane are categorized as either active or passive transport. Active transport
requires energy whereas passive does not. Active transport requires energy since the cell is
bringing in ions, for example, against a concentration gradient. Passive transport does not require
energy since the ions are flowing with the concentration gradient. This phenomenon will be
discussed in more detail in other modules as we study different organs.
Support Beams for the Castle Wall: The Flying Buttresses of the Cell Are Called Microtubules
The support beams for the cell are microfibers, which are made of actin, a protein also found in
muscle. These are the structures that give support to the plasma membrane. When microfibers
combine, they form microtubules. Microtubules have many roles in the cell.

Working Together for a Common Purpose

Cells that work together have a chemical "cement" called E-Cadherin. Cells may work together
to form a tissue or an organ, or to transmit electrical signals from your brain to your toe. Cell
collaboration may be compared to several castles forming an alliance to generate a larger harvest
or to defeat a band of invaders who are laying siege to the castle.
The Throne Room: The Nucleus Gives Orders That Must Be Obeyed
The control center of every cell is the nucleus (Figure 5). This structure has its own membrane,
which controls the exit and entry of molecules and ions. The nucleus contains the chromosomes
that dictate what the cell will do. The chromosomes are identical in all cells within an organism,
and various traits are expressed in different parts of the body. For example, you have skin cells,
intestinal cells, bone cells, hair cells, etc. Each of their nuclei contains chromosomes that have
identical chemical composition of DNA and RNA. The difference lies in that those parts of the

chromosome used to make a skin cell are activated only on the skin and nowhere else.
Each cell reproduces according to the direction given in the DNA or RNA of its nucleus. The
nucleus will go through an elaborate sequence, and eventually split in two, generating a copy of
itself and its own "new castle" in which to live.
The nucleus also directs the molecular signals for the production of proteins in the cytoplasm.
The molecular signals from the nucleus are sent out through the nuclear pores and into the
cytoplasm. Every protein in a cell has to be made under the direction of the molecules coming
from the nucleus. The key organelle for making the protein is the endoplasmic reticulum. The
Golgi complex then packages these proteins (Figure 6).
Endoplasmic Reticulum
Continuing our analogy of the castle, imagine that the castle has to make all of its own bricks and
constantly upgrade its internal structures. In essence, the castle has to have its own factory. These
factories receive their direction from the nucleus. These cellular factories are the rough and
smooth endoplasmic reticula.
The endoplasmic reticulum is a network of internal membranes that fold over each other to form
compartments. There are two types of endoplasmic reticula: rough and smooth. The rough
endoplasmic reticulum (ER) manufactures proteins and it has a "roughened" appearance since it
has ribosomes. In the adrenal cortical cells, it produces the steroidal hormones in conjunction
with another organelle, the mitochondria.
The smooth endoplasmic reticulum has different functions in various cells. In muscle cells, it
stores calcium ions that are used in one of the steps leading to muscle contraction.
Golgi Complex: Packaging the Protein
The factories in the cell produce items that need to be packaged. This process of packaging takes
place in the Golgi complex. The products from the endoplasmic reticulum go in to a set of
flattened, sac-like membranes, which sit on top of each other and are interconnected. When a
protein is produced in the ER, the protein is pinched off within part of the membrane. (Figure 8)
The protein that is being processed by the Golgi apparatus is enclosed in the second membrane
and pinched off. The resulting package is called a vesicle. What types of products are contained
within the vesicles from the Golgi apparatus? They are hormones, enzymes, etc. Some chemicals
that have multiple effects on your body are produced by the Golgi complexes in the neurons in
the brain and then are sent into the blood. This process of sending the vesicles outside the cell
and into the blood or elsewhere is called exocytosis.
Janitorial Service in the Cell: The Lysosome
Lysosomes are organelles that are also packaged by the Golgi apparatus. They contain powerful
digesting enzymes and are responsible for the breakdown and absorption of materials taken in by
the cells. In the case of Joe Smith, who is in the hospital fighting for his life, his white blood
cells are chasing down the E. coli bacteria that are in his body. Once the bacteria are ingested, the
lysosomes go to work to digest the bacteria, breaking down the E. coli's plasma membrane so
that the bacteria will die.
Energy Production in the Castle: The Mitochondria

In medieval times, power was derived from running water, which turned a waterwheel. The
waterwheel powered machines. In cells, mitochondria produce energy for the cell (Figure 9). In a
castle, activities such as manufacturing armor, building materials, clothes, and tools, required
energy. Energy came from waterwheels, fire, and lots of manual labor. Cells produce their own
energy from the nutrients we eat and the oxygen we breathe. Cells have two ways of producing
energy. They manufacture ATP (energy) in the cytoplasm from nutrients such as glucose through
a sequence of biochemical reactions called glycolysis. The second place that energy is
manufactured in cells is in specialized exos called mitochondria.
The mitochondria's well-being spells the difference between life and death for us. If the
mitochondria do not produce energy, none of the functions of the cell can continue and the cell
will die. When the life of a critical number of cells ceases, the life of the tissue, organ, and
organism may cease as well. The critical number of cells needed to maintain the life of a tissue
will depend on the type of tissue. For example, skin cells die and are replaced continually, but if
too many cells in the heart or brain die off from a heart attack or a stroke, the individual in
question will also die.
The Moat: Circulation
Many castles had moats to minimize a frontal attack by land as well as to be the lifeline for the
castle. Goods could be exchanged and transported on the water (Figure 10). In the case of the
cell, every cell floats in a three dimensional space, surrounded by water, both inside and out. The
solution inside the cell is called intracellular fluid, whereas the solution outside of cells is called
extracellular fluid. A subcategory of extracellular fluid is interstitial fluid which is between cells.
The cell is a water-filled balloon connected to other balloons floating in a sea of water.
Different Kinds of Cells
Some cells are stationary like castles. Others move or are transported in some way. WithinHomo
sapiens, the white blood cell is like a military "Special Forces unit" that travels in the blood
plasma to seek out "enemies", in this case invading bacteria or viruses. It moves in the blood and
then must leave through the capillary and engulf the attacking organism. In some cases, it spits
out a chemical to kill the invader (Figure 11).
The red blood cell is like a quiet "submarine". It floats in the blood, delivering oxygen to all cells
and picking up carbon dioxide. The actual process of oxygen delivery and accepting carbon
dioxide are chemical reactions.
Cardiac cells in the heart do not move from place to place, but they do contract. These cells
require a large amount of energy and therefore need a large blood supply. Every cardiac cell must
work together with other cardiac cells, which means that they are all connected physically.
Cardiac cells have "gap junctions", which enable the cells to share their cytoplasm. Imagine two
castles that share a common wall. There are holes in the wall to facilitate the transport of
materials and information.
Cell Suicide. I can't take it any longer!

All of our cells are programmed to die. Cell death is called apoptosis. This process is seen in
intestinal cells or skin cells that are constantly being replenished. Intestinal cells are actually
killed by their own lysosomes. By some unknown process, lysosomes will eventually open up
and their enzymes will devour the cell from the inside (Figure 12).
Battle of the Cells: Who Won?
So what happened to Joe Smith (introduced on page 4)? In this fictitious case, he was sick for a
number of days with diarrhea and itching. He eventually recovered. His white blood cells
managed to attack the E. coliand his lysosomes made sure that the invaders were destroyed.
Module 5:
Water! More precious than gold! It is the key chemical that supports all chemical reactions in
living systems. Where there is water, there is life. The current global warming will have an
impact on water levels that will directly impact you and all living systems.
The drive to curb your thirst has been known since time immemorial.
The following are two examples of how thirst has been used:
It was time for them to come to the water hole. The great Indian fighter, Geronimo, waited with
his soldiers as the American cavalry continued to search for them in the arid, hot Southwest. The
Apache Indians were superb desert fighters and excellent students of human biology. They
understood the body's demand for water and salt and how it would drive men crazy especially if
they did not get the precious fluid. The decrease in body's water level would have its major effect
on the central nervous system. The thirsty soldiers and their horses would attempt to slacken
their thirst by drinking all the water in their canteens especially when driven by unrealistic
demands to hunt Apaches in their desert homeland. Meanwhile, the sun would continue to heat
the soldiers causing them to lose the water and electrolytes. The Apaches would poison the water
holes so that the American cavalry would have to go further without water and would wait until
the American soldiers would come to an enclosed water hole. The Americans would see the
water and their horses would run toward the smell of water and dirt. As they slackened their
thirst, the Apaches would execute their carefully calculated ambush (Figure 1).
Joe Gomez was overweight on purpose. He was a nose tackle and he had built himself up to
handle the blows from the defense. He weighed 325 lbs on his 6' 4 inch frame. The game was
against Ohio University on a hot muggy Midwest day. The temperature was 95F and the
humidity was 85%. He was sweating as he semi-ran onto the field (Figure 2). He had to stay in
for three plays since some of the players were hurt. His tackles were not sharp. He was not able
to hit as well as he wanted. His muscles were cramping. He noticed that on the third play, he was
getting dizzy. He went off the field and looked for water. He could not catch his breath.

Joe sat down as he gulped down the Gatorade but the football was intercepted and he had to go
out again. His heart rate was increasing and he felt wobbly. He experienced severe muscle
cramps on the next play in his legs and thighs. He had to be pulled from the game.

The point of these two short examples: Both the American cavalry and Joe Gomez needed water.
Why is water so important? Where does it go when we drink it?
Body Composition of Water and Electrolytes
Approximately 60-70% of your body is water. Of this 60%, 35% is found inside cells
(intracellular space); 19% is found between cells (interstitial space); and 5% is in the plasma
(e.g. blood). (Figure 3) What is important to realize is that this distribution of water is associated
with various electrolytes. There are two kinds of electrolytes: those with a net positive charge
and those with a net negative charge. The major important positive and negative electrolytes,
their distribution and their functions are listed. We will discuss their functions in detail later
modules (See Tables 1 and 2).
Water is not only a molecule we need to live but it is also required as a solvent for chemical
reactions. Water and various important electrolytes are found in all cells and have essential roles
in promoting chemical reactions.
Cellular Priorities and Cell Membrane
All living things have certain requirements they must satisfy in order to remain alive. These
activities, to a large extent, are chemical reactions that include exchanging gases (usually
CO2 and O2), taking in water, minerals, and food, and eliminating wastes. These tasks ultimately
occur at the cellular/capillary level, and require that molecules move through the cell membrane
that surrounds the cell. This membrane is a complex structure that is responsible for separating
the contents of the cell from its surroundings, for controlling the movement of materials into and
out of the cell, and for interacting with the environment surrounding the cell.
Water is the universal solvent and as such promotes all chemical reactions in your cells. (Figure
4) There is a priority of need for water by certain cells. The neurons and other brain cells, the
cardiac cells, and the intestinal cells require a constant infusion of new water. Their chemical
reactions are occurring constantly and require water to maintain cellular chemical reactions.
Without water, an active person cannot last longer than three days. However, it is not really just
water but a solution of water and certain ions that are required for the normal functioning of
cells. As you drink water, it gets absorbed into the body, crosses the cell/capillary border, enters
the cells, and interacts with all the electrolytes in the cell.

Water, Electrolytes and the Heart - Volume

Although the importance of water and electrolytes deals with maintaining chemical reactions
essential for life, another role of this precious fluid is to maintain a critical volume of blood for
the heart to contract. In humans, if dehydration is too severe, the heart does not have enough
fluid to pump. Hence, the importance of giving patients adequate amounts of fluids is to:

1. Maintain cardiovascular health

2. Promote critical cellular chemical reactions
3. Promote overall health and well being of critical organs.
The Pathway for Water Input / Output
Water is a molecule made up of the elements, hydrogen and oxygen. Your body needs the
elements of sodium and chloride which it gets by ingesting a solution of sodium and chloride
plus water. The solution of water and ions is carried into your bloodstream by way of cells in
your intestinal tract. [The water goes from the intestines through the cells of the intestine into the
blood.] Notice, I said, the water and ions go through the cells in your intestine into the blood!!
From the blood, the water and ions are transferred to the cells. The cells can only get the solution
of water and ions at the capillary level. No where else. At the capillary level, the water goes
through holes in the capillary wall and enters the cells by way of various channels in the
membrane by two methods: diffusion and through water channels called aquaporins.
Both water and electrolytes are lost in the urine produced by the kidneys. Fluid is also lost from
the lungs and by sweat. Fluid is also lost in fecal material produced by the large intestine.
Depending on the situation of the organism, the body has various mechanisms for maintaining
normal water electrolytes.
Extracellular to Intracellular Movement Or Intracellular to Extracellular Movement
Remember that movement of water goes both ways: 1. From the outside of the cell to the inside
or 2. From the inside of the cell to the outside. Sooner or later, water must enter the cell. The
methods of movement of water need to address the fact that the water must cross the cell
membrane. The cell membrane is not a simple blob. It has electrical and physical dimensions that
control what moves in and out of the cell. Remember the castle wall. It has a major gate to allow
elements in and out. The same idea applies to the cell membrane in that it has physical and
chemical openings as well as electrical charges that determine what enters or leaves the cells. If
the molecule has no electrical charge and is small enough to move through the pores of the
membrane, it does not meet any resistance. Water, carbon dioxide and urea are examples of
small, uncharged molecules.
Since the membrane has a large amount of lipids, any molecule that is lipid soluble can enter the
cell through the membrane itself. Oxygen, nitrogen and certain kinds of anesthetic gases are
examples of lipophylic substances. Almost like ghosts, they would enter the castle wall by going
through the wall itself.
Water and Electrolytes Enter Cells either Passively Or Actively
Passive Transport
The principle means of passive transport is diffusion (Figure 5). Diffusion is the movement of
molecules from a region in which they are highly concentrated to a region in which they are less
concentrated. It depends on the motion of the molecules and continues until the system in which

the molecules are found reaches a state of equilibrium, which means that the molecules are
randomly distributed throughout the system. The movement of the molecules is dependent on all
those factors that influence molecular movement (e.g. temperature, pressure).
Active Transport - The Sodium/Potassium Pump
Active transport refers to the transportation of molecules against their concentration gradient.
Active transport can work against diffusion. If there is a higher intracellular concentration of
potassium than the interstitial fluid, based on diffusion, the ions will diffuse through the
membrane and out. However, to reverse this trend, energy in the form of ATP is used at the cell
membrane to keep the potassium ion inside the cell. It is similar to the castle having thousands of
people inside the courtyard wanting to leave. As they push to leave, big, burly guards grab them
and throw them back into the courtyard.
Active transport requires energy in the form of ATP which is formed by the mitochondria inside
the cell. The ATP is used to pump sodium outside the cell and bring potassium inside. Both these
processes are linked. Without either of these important components (ATP or electrolytes), the
cells will lose their chemical and electrical makeup and die. In practical terms, if you do not have
the proper concentrations of sodium and potassium as well as ATP, the nerve and heart cells will
not function. This will lead to death.
Active Transport - The Calcium Pump
This is another molecular pump. Calcium ion is pumped into muscle cells by way of ATP on the
muscle membrane. More than likely, this is the site and explanation of muscle cramps - the lack
of calcium ions.
Osmosis
Water in your body is a solution inside cells in the form of a slurry of molecules and ions.
Osmosis controls the movement of water in and out of the cells. Osmosis is most easily
demonstrated when you have two cells one in which the concentration of electrolytes is higher
than the other (Figure 6). Notice that if one cell has more electrolytes than the other, this means
that the water concentration is less. Put another way, the cell that has a lower concentration of
electrolytes has more water. Which way will the water go?
Water will always move from the cell that has more water, less concentrated solution, to the one
that has less water, more concentrated solution. (Figure 6) This is a osmosis. It is a physical event
which does not require energy. It is based on the physical attraction of the water molecule to
more solutes. Another very important point about osmosis: Osmosis only occurs when the two
solutions are separated by a membrane that allows only the movement of water in or out. In this
case, it is the cell membrane that separates the two different solutions. It is one of the most
primitive and important processes in life. Every living system uses this process to maintain the
proper hydration of its cells. Interestingly, even single cell organisms, such as bacteria, have
processes to protect themselves from dehydration using osmotic processes (Figure 6).
Hyper-Osmotic Vs. Hypo-Osmotic
Remember that the terms are relative to the solutions across the membrane. You are comparing

two solutions. A hyperosmotic solution is a solution that is more concentrated relative to another
solution, whereas a hypoosmotic solution is a solution more dilute relative to another. Remember
that the two solutions need to be separated by a membrane. If two solutions have the same
number of electrolytes and are separated by a membrane that only allows water to flow, there
will be no net movement of water. Why? Because the concentration of electrolytes is the same
meaning that the amount of water molecules is the same. Such solutions are isosmotic. If one
solution is hyper-osmotic relative to another, water always will flow from the hypo-osmotic to
the hyper-osmotic. Why? Water will flow from the compartment in which it is in higher
concentration to one which is lower.
Hypertonic versus Hypotonic - This is Us!
We have been using the term, osmotic. In humans, instead of describing blood as isosmotic, the
term isotonic is used. Instead of the blood being hyper-osmotic, the term hypertonic is used. The
water still flows from a hypotonic solution to a hypertonic solution as it would from a
hypoosmotic solution to a hyperosmotic solution (Figure 7). Lets consider the thirsty soldiers in
the desert. The concentration of water and electrolytes in their blood is falling, making the
blood hypertonic relative to the cells in the body. This is dangerous, since the hypertonic blood
will take water from cells in the body, thereby decreasing their function. Cells can only donate so
much water before you become dehydrated. As the cells lose their water to the blood, their
concentration increases in strength. (Figure 8)
As the cells loss their water, they will begin to shrink because they will lose their water. This
process of shrinkage of cells is called crenation. Interestingly, crenation becomes important for
survival. Certain cells in your brain are sensitive to changes in the osmotic forces in your blood.
As the blood loses some of its water, it becomes hyper-osmotic and causes certain cells in the
brain to shrink or crenate. As these cells crenate, they cause the release of a very important
chemical messenger called - the antidiuretic hormone (ADH).
A diuretic is an agent that promotes diuresis of urination, while an anti-diuretic hormone will
inhibit urination.
The antidiuretic hormone travels throughout the body in the blood. Its major function is to stop
further water loss. How can it do that? Will the soldiers stop sweating? No. Sweating keeps them
cool. The only way the ADH can help the body survive is to stop any further water loss. Thus it
has a major effect on the kidney. It basically shuts off the production of urine. Urine like blood is
60% water. So if the soldiers do not urinate, there is more intracellular water for their cells.
Various agents such as alcohol influence the release of ADH. ADH will cause a decrease in urine
production. Ethanol will inhibit the release of ADH, promoting an increase in urine production.
Osmosis Is Found in Both Plants and Animals
Water is found in both plant and animal life. Water is used in two ways in plants. It is not only a
solvent for chemical reactions but also the source of hydrogen ions that are used by the plant to
produce carbohydrates etc. Osmosis also occurs in plants. (Figure 9) Consider trees growing in
saltwater. Their roots are in salt water which makes the salt water hypertonic relative to the tree
roots. If this condition persisted, the tree cells would become dehydrated since the hypertonic salt

water would draw water from the roots. However, the trees have a way around getting
dehydrated. The cells in the water, hold onto more electrolytes so that the concentration of the
roots is hypertonic relative to the sea water and only water flows into the roots!
Water and control of body temperature
In humans, water is used as sweat to control body temperature. All chemical reactions in the cells
work at optimal temperatures. Chemical reactions will slow down or speed up depending on the
temperature. Sweating minimizes the development of high temperatures in cells but causes
dehydration. Water along with salt is secreted by certain cells close to the skin to cool the body.
The evaporation of water requires energy. This energy comes from the body's heat. As long as the
body can secrete water which then evaporates, the temperature of brain and heart cells can be
kept within a certain range (37C is normal). The term "secretion means that the cells must use
energy to have the fluid transported to the surface of the skin. This action of thermal sweating is
controlled by the nervous system. If you are not able to sweat in a hot environment, it is a very
dangerous sign. You either do not have any water left or the nervous system is not functional.
Some animals regulate their body temperature by behavior mechanisms as well. On a hot day,
before you begin to sweat, you try and stay out of the heat. Most animals do the same. Other
animals that do not sweat, control their body temperature by panting - demonstrating the amount
of water you can lose from the lungs!
Water and Gatorade
The use of Gatorade and other electrolyte solutions has become common practice in sports.
Human performance in hot environments requires replenishment of both water and electrolytes.
Previously, it was thought that giving dehydrated persons water would be sufficient. More
research showed that sodium and chloride were also required. Interestingly, in previous attempts
to minimize heat stress, soldiers were only given salt tablets. Salt tablets without adequate intake
of water resulted in the heat-stressed soldiers having many problems such as diarrhea. Dr. Bob
Cade -- Professor at the University of Florida -- accidentally discovered the formula used today
in Gatorade. He found that sugar, water, and electrolytes enhanced the performance of the high
school football teams who were playing in a hot, humid environment in Florida. Note: Any
effective solution that will minimize dehydration requires the use of sugar (Figure 10) which
promotes the uptake of water and electrolytes in the intestinal tract. (In essence, you could make
your own Gatorade - all you need is water, some sugar, salt and something for taste.)
Osmosis and Disease
Osmosis can be a potent mechanism in disease processes. Cholera is a major disease in countries
with poor water sanitation. Contaminated drinking water contains a bacterium called V. Cholerae
that produces an endotoxin whose action on the intestinal lining sets up an osmotic gradient. The
endotoxin causes the chloride ion transport mechanisms of the cell to transport the chloride ion
into the intestine. This action inhibits the movement of sodium into the cell creating a salt
solution in the intestinal cavity which is hypertonic relative to the intestinal cells in the intestine.
As a result, water flows from the cells into the intestinal cavity resulting in extensive diarrhea

which leads to dehydration. Depending on the degree of dehydration, death can result in several
days unless rehydration is instituted.
Electrolyte

Ions such as sodium and chloride that conduct electric currents in solution and
required to help maintain fluid balance between cells and within the body.

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Intracellular Space

The space inside the cell.

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Interstitial Space

The space between the cells.

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Cellular Level/Capillary Level

At the level of cells or capillaries. Located in the cells or in the capillaries.

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Diffusion

Tthe net motion of a substance from an area of high concentration to an area o

concentration.

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Aquaporins

Proteins that form pores or channels which allow for the passage of water.

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Passive Transport

Moving substances across membranes and does not require the use of energy.

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Equilibrium

A state of rest or balance between opposing forces within a system.

Active Transport

The transport of substances across a membrane and against a concentration gr

requiring the use of energy.

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Concentration gradient

The gradual difference in concentration of a solution between areas of high

concentration and low concentration.

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Osmosis

Diffusion of water molecules through a water-permeable-membrane from a p

high concentration to one of low concentration until equilibrium is reached.

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Hyperosmotic

A solution with a higher concentration of solute relative to a comparison solu

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Hypertonic

A cell that is surrounded by a higher concentration of solutes than are inside t

which causes water to leave the cell by osmosis.

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Isosmotic

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A solution that is in a state of equilibrium with its surroundings in terms of w

solute concentration.

Isotonic

A cell that is in a state of equilibrium with its surroundings in terms of water

solute concentration.

Module 6: Glycolysis
Glycolysis is a primitive chemical pathway that requires no oxygen to make small amounts of
ATP which powers chemical reactions in the cell such as muscle contraction. Glycolysis is
utilized by many life forms. Yeast utilizes glycolysis to make ATP and a by-product - ethanol.
A small Gazelle is being chased by a Cheetah (Figure 1). The race is fast and furious with the
Gazelle running for its life. The Gazelle does a right angle turn and jumps over a rock. The
Cheetah cannot follow as fast and cannot keep up with the Gazelle. The Cheetah fails to catch his
prey due to fatigue. He can only run for a limited period of time due to the constraints of
glycolysis. Maybe next time!
Overview of Cellular Respiration - ATP, Heat, H20
To garner energy for all our actions, food must be chemically manipulated so that hydrogen ions
and their associated electrons can be indirectly converted into Adenosine Triphosphate (ATP)
which facilitates all chemical reactions. Cellular metabolism refers to all the chemical reactions
that occur in cells to produce energy as well as to make and destroy various chemical and
physical products.
As you study this section, keep in mind two important points:
1. The carbohydrates, lipids and proteins must enter the cells to be metabolized. They therefore
must leave the capillaries and enter the cells facilitated by various hormones and membrane
processes.
2. As each metabolic pathway is presented, realize that each step requires one enzyme (protein)
that is produced by chemical commands from the nucleus of the cell. Since the cellular
mechanisms responsible for harvesting energy in food are not 100% efficient, heat is produced
which is used to maintain a proper temperature for chemical reactions to occur.
Glycolysis refers to a breakdown of sugar which does not require oxygen to produce ATP and is
therefore a form of anaerobic respiration. It is the most primitive of all metabolic systems. All the
enzymes for its nine chemical reactions are found only in the cytoplasm of the cells. Oxidative
phosphorylation which requires oxygen and harvests far more ATP from food than Glycolysis
occurs only in the mitochondria and is called aerobic respiration. Notice in Figure 2 that there are
three chemical processes that occur to make ATP: the first is Glycolysis which produces ATP by
way of substrate-level phosphorylation. This then leads to the Krebs Cycle (also known as the
Citric Acid Cycle) that produces ATP by substrate phosphorylation which, in turn, leads to the
electron transport chain that uses oxidative phosphorylation to make ATP.

Of these three processes that are all intertwined in animals, oxidative phosphorylation makes the
most ATP and is also dependant on oxygen. Notice that the krebs cycle is located in the
mitochondria. The mitochondria were more than likely a bacterium that was able to form a
relationship with another primitive cell to produce our animal cells. Supporting this point is the
fact that the mitochondria has its own unique DNA separate from that of the nucleus of the cell.
Glycolysis is the breakdown of a six carbon chain to a three carbon chain called pyruvate or
pyruvic acid. It is the chemical doorway to either aerobic metabolism or anaerobic metabolism
depending on whether oxygen is present. Glycolysis is the first chemical step needed to oxidative
phosphorylation. However, Glycolysis does not have to proceed to the krebs cycle and
subsequently to oxidative phosphorylation. If glycolysis does not advance to krebs cycle, it
produces chemical products as a result of fermentation. Fermentation is another term for
anaerobic respiration.
In aerobic respiration, glycolysis and oxidative phosphorylation are coupled. In anaerobic
respiration, they are decoupled, and the energy harvested from food ends with glycolysis
proceeding to fermentation. Some metabolic systems function efficiently using anaerobic
respiration. For example, your muscles rely on anaerobic respiration when you exercise very
hard for short periods of time. Sprint runners do not rely on oxygen to get their energy but on
anaerobic metabolism or glycolysis. The result of these chemical reactions is lactic acid. Yeast
cells can live in an anaerobic environment and produce ethanol as a by-product.
Certain organs such as the heart, brain, kidneys, intestine require oxidative phosphorylation to
survive. They cannot survive on the energy produced by glycolysis.
Notice that the end result of processes produces carbon dioxide and water (Figure 3). The carbon
dioxide has one consequence: it influences the degree of acidic pH produced.
Anaerobic Respiration: The Oldest Form of Cellular Respiration
When the Earth's atmosphere was primarily composed of carbon dioxide, primitive bacteria were
able to produce modest amounts of ATP without the use of oxygen. Methanogens are primitive
archaebacteria that use carbon dioxide instead of oxygen to produce ATP. Why bring up this
point? Although you will be exposed to a specific manner in which your cells make ATP from
food, there are other chemical reactions that also produce energy. Life can therefore exist in
environments that would be lethal to various forms of current animal life.
Glycolysis (The Breakdown of Sugar)
There are two ways to produce energy (ATP):
1. Substrate Phosphorylation: The first method for making ATP is by directly converting
adenosine diphosphate (ADP) to adenosine triphosphate (ATP). Phosphorylation is the addition
of a phosphate group onto the molecule ADP. This direct addition of a phosphate group to ADP is
called substrate-level phosphorylation, which is not effective in producing a large amount of
ATP, but does not require oxygen. the glycolytic pathway uses substrate phosphorylation to
produce energy.

2. Oxidative Phosphorylation: Reduction refers to the capture of Hydrogen

ions and its electron whereas oxidation is the release of the hydrogen ions and its electrons. In
this case, a phosphate ion is added to ADP by way of the food being oxidized. The hydrogen ions
from food indirectly add the phosphate ion onto ATP. Oxygen is required for this process. The
glycolytic pathway leads to another set of pathways that utilize oxidative phosphorylation.
Overview of Glycolysis
Glycolysis --- the process that harvests energy from glucose --- results in the break down of a 6carbon chain of sugar into two 3-carbon molecules each having an attached phosphate. This 3
carbon phosphorylated molecule subsequently donates the phosphate group to ADP making ATP.
This 3-carbon chain is called pyruvate. As Figure 4 shows, ATP is needed to break down the 6carbon chain so that there is a 3-carbon chain with a phosphate group attached. The 3-carbon
phosphate chains are then stripped of their phosphate group to form ATP and pyruvate. In the
process, ATP is regenerated. In addition, the hydrogen ion from this reaction is captured by a
molecule called NAD to form NADH.
So Where Is the Energy?
In Glycolysis, energy is transferred in two ways. First, electrons and hydrogen ions from the 3carbon sugar phosphate are transferred to the hydrogen ion/electron carrier NAD to form NADH.
Second, the phosphates are transferred directly to two ADP molecules to form two ATP
molecules. By way of substrate-level phosphorylation.
The bottom line is that glycolysis produces a net of two ATP molecules by way of substrate-level
phosphorylation, and another two ATP molecules if oxygen is present by way of oxidative
phosphorylation resulting from the production of NADH. If there is no oxygen present, pyruvate
will be converted to lactic acid. In addition to ATP production, water is also produced. The
metabolic end product of Glycolysis is pyruvate which is the metabolic doorway to either
fermentation or the Krebs cycle. If ATP is not needed, it will attach to the enzymes in the
glycolytic pathway and inhibit them, resulting in a decrease in cellular respiration and ATP. This
phenomenon is an example of negative feedback.
Fermentation
As you continue to read this section, you maybe snacking on some cheese pizza, pickles, and
crackers. The cheese and pickles are really nothing more than fermented milk and cucumbers!
Your muscles are still sore from your last workout since they have a certain amount of lactic acid
another example of fermentation, but this time in your muscles.
Fermentation is an anaerobic phenomenon whereby a chemical other than oxygen accepts the
hydrogen ion and electrons from NADH. Two examples of fermentation:
1. lactic acid fermentation in animals
2. alcoholic fermentation in yeast are presented in this section.
Lactic Acid Fermentation
For sprinters and weight lifters, whose muscles demand more energy than can be produced by

the oxygen available in their blood, glycolysis is the primary means in which these muscles get
energy (Figure 5). In these demanding conditions, pyruvate is the electron acceptor since oxygen
is not available. Pyruvate strips the electrons from NADH, subsequently being converted into
lactic acid. Lactic acid buildup was considered to be the major culprit in the development of
muscle fatigue. The lack of oxygen in the blood vessels of the muscle supposedly caused an
anaerobic state that produces lactic acid. Lactic acid was considered to be the cause of the
chemical burn associated with exercise (Figure 6). Whether lactic acid is the major chemical
responsible for muscle fatigue is still unclear (Figure 5). Recent research does not support the
idea that lactate causes skeletal muscle fatigue. In fact, some research reports that muscle uses
lactic acid for contraction. In the world of exercise, athletes should be very cynical about
advertisements reporting on various "magic" solutions that improve performance.
Alcoholic Fermentation and Applications
Alcoholic Fermentation refers to the glycolytic metabolism of yeast cells in an anaerobic
environment. Where does the sugar come from? For glycolysis to work, sugar must be present
(the sugar in the grapes if you are making wine). Any sugar source will work to make fermented
drinks. Yeast cells can live in both aerobic and anaerobic environments. In an anaerobic
environment, yeast cells produce NADH during glycolysis, and the electron acceptor for NADH
is pyruvate. Pyruvate is stripped of one carbon so that it becomes ethanol, and NADH is recycled
back into NAD+.
How does the yeast benefit from this reaction? The NADH is involved in making ATP! (Figure
7) Ethanol is only a by-product for the yeast. What becomes of the ethanol? It is released by the
cells into the environment. Eventually, when the ethanol concentration becomes too great, it kills
the yeast cells. This is the process that makes the ethanol from all kinds of sugar.
Ethanol
Alcoholic beverages are the natural result of anaerobic metabolism in yeast. Wine makers put
yeast and grape juice in a sealed wine vat, which is an anaerobic environment. The yeast
metabolizes the sugar in the grape juice by the processes of glycolysis and fermentation to make
wine. Historically, wine was more than likely used in place of water since water in many areas
was contaminated and resulted in many diseases. Wine was safe to drink (Figure 8). Fermented
drinks are as old as mankind. Fermented potatoes result in Vodka whereas
fermented maguey results in Tequila. Mankind has been able to ferment grapes and any other
form of vegetable that has sugar to make ethanol.
Metabolism of Ethanol
Ethanol has energy that can be utilized by the body. Beer is taken into the body and metabolized
by enzymes in the liver. The ethanol and associated chemicals in beer can be converted into ATP.
As is well known, beer drinkers have a "beer belly" which demonstrates the energy (calories) in
beer. A certain amount of ethanol is metabolized but not all of it. It circulates in your blood and it
has its effects on many cell types such as neurons. It inhibits basic functioning of the cell and in
high enough dosage can temporarily suppress brain cell function. This suppression can lead to
blackouts and in other cases to death. It may not only be ethanol per se but its metabolic products
such as acetaldehyde that cause damage to the neurons and liver cells.
Food Storage

Fermentation has been used throughout history to preserve food. Before refrigeration, it was used
to preserve food that was at times in short supply. Lactic acid minimizes the growth of harmful
bacteria. The result of fermentation is an acidic tasting product. Cheese and yogurt are both
fermented products of milk. In this case, bacteria --- not yeast --- ferment milk products and the
resultant lactic acid alters milk to make cheese. Sauerkraut and pickles are fermented cabbage
and cucumbers that are produced by anaerobic bacteria.
Glycolysis

Glycolysis is the breakdown of carbohydrates to produce ATP.

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Adenosine
Triphosphate (ATP)

Adenosine triphosphate (ATP) is a molecule that promotes chemical reactions within

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Adenosine Diphosphate
(ADP)

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Adenosine Diphosphate (ADP) is a nucleotide that is converted to ATP by the

addition of a phosphate group.

Cellular Respiration

Cellular respiration is the term given to the various metabolic reactions that ta
place in a cell through which ATP is produced by capturing the energy in food

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Anaerobic Respiration

Anaerobic respiration is the oxidation of molecules in the absence of oxygen

produce energy (ATP).

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Aerobic Respiration

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Aerobic respiration is the process of oxidative phosphorylation in which oxyg

required to produce ATP.

Oxidative Phosphorylation

Oxidative phosphorylation is a metabolic pathway that oxidizes NADH and

phosphorylates ADP to produce ATP.

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Substrate-level
phosphorylation
Citric Acid Cycle
(a.k.a. Krebs Cycle)

Substrate-level phosphorylation is the direct transfer of a phosphate group to

adenosine diphosphate (ADP) to form ATP.

This cycle is a series of chemical reactions that take place inside the matrix o
mitochondrion and is part of the process of converting food to energy.

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Pyruvate (Pyruvic Acid)

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Pyruvic acid is a water-soluble liquid that is important in many metabolic an

fermentation processes.

Fermentation

Fermentation is an anaerobic process that derives energy from the oxidation

compounds, often from sugars.

Module 7:
The sequence of chemical reactions labeled "Oxidative Phosphorylation" produces large
quantitites of Adenosine Triphosphate (ATP)/second, which powers all the chemical reactions
and mechanical movements of living systems ranging from sharks to humans. A key,
essential chemical for oxidative phosphorylation is oxygen. The bubbles coming from the diver
is an example of the absolute requirement of oxygen for oxidative phosphorylation. The school
of fish and the shark also use oxygen.

As I type this message, my fingers hit the keyboard keys clearly and accurately while I listen to
the latest Bob Dylan record. My eyes focus on the monitor and my heart beats a steady 60
beats/minute while my chest rises and falls in a slow steady rhythm. Life is good. Thanks to
mitochondria --- the organelle found in all my cells that produces ATP by the process of
oxidative phosphorylation --- I can appreciate Dylan's music and throughout my body, my
muscles respond to the motor commands of my brain.
The mitochondrion is king! It is the organelle that produces a chemical called ATP (adenosine
triphosphate). This important organelle was a primitive bacteria that millions of years ago
formed a symbiotic relationship with other cells to make the current eukaryote. The mitochondria
determine the life or death of cells since they produce ATP that powers all of our chemical
reactions.
Let us take a look at the structure of the mitochondria. Every cell has many mitochondria. Each
mitochondrion has two membranes --- an outer membrane and an inner membrane. The inner
membrane has inward folds called cristae. The space inside the inner membrane is called the
matrix. The matrix contains enzymes for aerobic respiration, also know as, oxidative
phosphorylation. The space between the inner membrane and the outer membrane is the
intermembrane space (Figure 2).
Metabolic Backbone of Oxidative Phosphorylation (Glycolysis, Citric Acid Cycle and Electron
Transport System)
Oxidative phosphorylation is a chemical process by which chemicals are oxidized and the results
of the oxidation cause another molecule to gain a phosphate group. Put another way, oxidative
phosphorylation is the oxidation of food resulting in production of ATP.
Three chemical pathways are connected to produce ATP during oxidative phosphorylation.
Glycolysis ends with pyruvate acid which is metabolized into acetyl-CoA which is the beginning
of the Citric Acid Cycle which produces hydrogen ions and electrons for the electron transport
system. The three processes (glycolysis, Citric Acid Cycle, electron transport system) form the
metabolic backbone for energy production. The carbohydrates, proteins, and lipids that you eat
must be metabolized by these three systems and all their associated enzymes to make ATP.
What about Fats and Proteins?
Our food, it is not pure glucose. Our biological systems ingest, mechanically breakup, and
eventually send molecular subunits of proteins, carbohydrates, and lipids to our cells. Where do
proteins and lipids enter into the various metabolic chains of glycolysis, Citric Acid Cycle and
electron transport system to produce energy? Notice in Figure 3, how the metabolic products of
proteins and lipids also enter into glycolysis and Citric Acid Cycle to produce energy. You can
survive for thirty days without eating any food since the fat and protein in your body can be
metabolized to give you the ATP that you need.
Of the molecules that are a pivotal towards taking the energy from food and converting it into
ATP, acetyl-CoA is most important. Acetyl-CoA is the transition molecule from glycolysis to the
Citric Acid Cycle. Carbohydrates, proteins and fats are all metabolized into acetyl-CoA which is
metabolized in the Citric Acid Cycle, eventually going to the electron transport system.

In future chapters you will be taught about the chemical structures of proteins, carbohydrates,
and lipids in greater detail. The bottom line is that these important molecules have energy in the
form of their hydrogen ions and their electrons to make energy.
What is the major function of Citric Acid Cycle?
Krebs cycle or the Citric Acid Cycle are the same. Krebs was the scientist who reported on this
chain of chemical events and citric acid is the name given for the first product formed. It
produces hydrogen ions and electrons that will be used to make ATP. This is a key point! It
produces the hydrogen ions and electrons that will be used to power the unique molecules in the
mitochondria that make ATP. Look at Figure 4. At different parts of the cycle, the hydrogen ion is
being picked up by two different molecules called NAD (nicotinamide dinucleotide) or FAD
(flavin dinucleotide).
As NAD and FAD picks up a hydrogen ion from the Citric Acid Cycle, it is reduced. Thus NAD
and FAD are reduced in the Citric Acid Cycle (Figure 5). Reduced NAD which is NADH and
FAD which is FADH are then carried to a set of proteins called the electron transport system.
Here, hydrogen ions and their electrons are separated. Notice: NAD and FAD do not carry
phosphate ion to join with ADP. They are not involved in substrate phosphorylation. Another
product of the Citric Acid Cycle is carbon dioxide. As the Citric Acid Cycle produces NADH and
FADH it also produces a large amount of carbon dioxide. Carbon dioxide has reached
historically high levels in the atmosphere, which leads to an increase in global temperature.
Humans and all living systems that use oxidative phosphorylation contribute to carbon dioxide
production.
The Function of the ETC is to Activate ATP Synthase
This section is the most important in terms of mastering what occurs at the inner mitochondrial
membrane to make ATP. There are basically two steps:
1. The NADH and FADH molecules lose their hydrogen ion or are oxidized, and a hydrogen ion
concentration difference is created across the cytochromes. These large protein structures are
responsible for transferring the hydrogen ion across the membrane resulting in a high
concentration on H+ on one side. For a hydrogen ion to be transported across the cytochromes,
its associated electron has to be in the mitochondrial matrix. The end result of NADH and FADH
at the electron transport system is that there hydrogen ion is on one side of the cytochrome and
the electron is on the other side.
2. Oxygen accepts the electrons in the mitochondrial matrix thus promoting a hydrogen ion
difference between the intermembrane space and the mitochondrial matrix. This oxygen is
derived from the air we breathe. It is carried to mitochondria by way of the capillary. Oxygen is
indirectly needed for ATP production. There is more hydrogen ions on the intermembrane space
than in the matrix-since oxygen is reduced by the electrons. What is the important consequence
of this large concentration of hydrogen ions in the intermembrane space?
3. Hydrogen ion concentration difference powers ATP synthase. Refer to Figure 6. This diagram
demonstrates the final stage for the production of ATP. The hydrogen ions that were received
from NADH and FADH from the Citric Acid Cycle are in a large concentration in the inner
mitochondrial membrane. By the sheer power of diffusion, the large number of hydrogen ions

will form a chemical equilibrium across the inner mitochondrial membrane. In other terms they
will diffuse. However, they can only do this by going through a huge enzyme called ATP
Synthase. Notice that the hydrogen ions or protons diffuse through ATP Synthase. This process
of the diffusion of hydrogen ion through ATP Synthase is called chemiosmosis. It has no
relationship with the concept of osmosis and the movement of water across a semi permeable
membrane.
4. ATP Synthase when activated by protons or hydrogen ions will combine inorganic phosphate
ion (phosphorylate) with ADP to form ATP! ATP synthase is a micromotor. It actually turns as
the protons enter it and in the process phosphorylation of ADP occurs so that it becomes ATP.
Oxidative phosphorylation refers to the phosphorylation of ADP by ATP associated with the
oxidation of NADH and FADH2 (Figure 7) and subsequent activation of ATP synthase.
Points to remember: We will start with the end of the process and work backwards!
9. ATP is produced when ATP Synthase is activated.
8. ATP Synthase is activated by the movement of hydrogen ions, also know as protons, through
its structure.
7. The hydrogen ions diffuse through the ATP Synthase because there is a chemical inequality of
these ions across the inner mitochondrial membrane.
6. The hydrogen ion inequality is produced by the cytochromes which accept the hydrogen ions
from NADH and FADH. NADH and FADH are oxidized in this process.
5. The hydrogen inequality at the cytochromes is produced by oxygen which accepts the
electrons associated with the hydrogen ions. Oxygen is reduced when it combines with the
electron.
4. NADH and FADH originate from the Citric Acid Cycle, which gets the hydrogen ions from
the catabolism of molecules found in food.
3. Carbohydrates, lipids, and proteins all contribute various amounts of hydrogen ions through
glycolysis and the Citric Acid Cycle. The greater the amount of hydrogen ions donated by these
food molecules, the greater the amount of energy or calories.
2. Carbohydrates, lipids, and proteins are all metabolized to end key metabolic pathways. They
are all converted to Acetyl CoA which leads to the Citric Acid Cycle.

1. Carbohydrates, lipids, and proteins are first metabolized in the intestine, transferred to liver,
and ultimately transferred to all cells. Cells will utilize their subunits for production of ATP.
Recycling of ATP
If ATP is used in various metabolic systems, and it subsequently becomes ADP which then must
be recycled back into ATP. All metabolic systems must continue to replenish the amount of ATP
being used otherwise the cells, tissues or organs will not function.
Various feedback loops exist that control the amount of ATP being produced at the organ and
cellular level. If ATP is not required, the energy that has been captured will be converted into fat.
Unanswered Questions
The story on energy in our biological systems is not complete. ATP powers your neurons to read
and comprehend this section. We think we know what powers neurons or brain cells to function
but not completely. Neurons utilize glucose for its energy, they cannot utilize brokendown
products of proteins and lipids. Why?
Mitochondria

A mitochondrion is a membrane-enclosed organelle that functions in energy (

production. It is found in the cytoplasm of cells. Mitochondria is the plural
mitochondrion.

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Oxidative Phosphorylation

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Oxidative phosphorylation is a metabolic pathway that oxidizes NADH and

phosphorylates ADP to produce ATP.

Cristae

Cristae are inward folds in the inner membrane of a mitochondrion that form
compartments.

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Mitochondrial Matrix

The matrix is the space inside the inner membrane of a mitochondria which c
enzymes for aerobic respiration (a.k.a. oxidative phosphorylation).

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Intermembrane Space

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The intermembrane space is the space between the inner membrane and the o
membrane of a mitochondrion.

Citric Acid Cycle

(a.k.a. Krebs Cycle)

This cycle is a series of chemical reactions that take place inside the matrix of
mitochondrion and is part of the process of converting food to energy.

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Nicotinamide adenine
dinucleotide (NAD)

NAD is a co-enzyme found in all living cells that is involved in reduction rea
in the Citric Acid Cycle.

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NADH

NADH is the reduced form of Nicotinamide adenine dinucleotide. It is reduced in the Citric Acid Cy
carries the hydrogen ion and its associated electron to the electron transport system.

Flavin adenine dinucleotide

(FAD)

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FAD is a coenzyme is involved in reduction reactions in the Citric Acid Cycle

FADH

FADH is the reduced form of Flavin adenine dinucleotide. It is reduced in the

Acid Cycle and carries the hydrogen ion and its associated electron to the elec
transport system.

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Electron Transport Chain

(ETC)

The electron transport chain functions to separate the hydrogen ion from its e
so that the high concentration of hydrogen ions activate ATP synthase to mak
The electron is picked up by oxygen.

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Cytochromes

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Cytochromes are large proteins that are responsible for separating hydrogen i
from its associated electron.

ATP Synthase

ATP synthase is the large protein that is also a micromotor that combines an
inorganic phosphate and ADP to form ATP when hydrogen ion activates it. H
ion is the gasoline for ATP synthase to work.

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Micromotor

A tiny protein motor.

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Chemiosmosis

Chemiosmosis is the diffusion of hydrogen ions through ATPsynthase which

subsequently causes ATP synthase to combine a phosphate ion with ADP.

Oxygen is critical for accepting the electrons at the cytochrome level to produce ATP. How does

the mitochondria promote more oxygen? Blood flow to the cells is the only way that the cells get
oxygen. Thus, when oxygen levels decrease in the mitochondria, certain chemicals called
reactive oxygen species are produced that cause the blood vessels to increase their diameter to
allow more blood flow and hence oxygen. Is there a negative feedback loop for shutting down
oxygen levels?

Module 8:

The victim has lost his ability to produce ATP. In this case, water entered his lungs and oxygen
cannot get to his cells to produce ATP. Pushing on his chest wall will "hopefully" assist the heart
to start pumping again to bring oxygenated blood to his heart and brain so they can begin to
function. Immediate resuscitation is critical since the longer the cells do not have Oxygen/ ATP,
the more likely they will die.

Troy was desperate. He had to lose 20 lbs to qualify for the team. He had not watched his diet
over the summer and now the coach gave him a month to shape up or ship out! Troy found a
new drug called DNP on the web that would raise his temperature but would make him lose
weight. He was into his second week and he noticed that his heart rate was much higher than he
remembered and he felt like he had a fever. But, Troy had lost 9 lbs. He had not told anyone
about DNP. What is going on with Troy's biology?
This module discusses what can go wrong in the process of oxidative phosphorylation. The end
result of oxidative phosphorylation is the development of ATP, for which there are three major
chemical pathways.
Figure 1. Notice that for 1 glucose molecule, you get the greatest number of ATP molecules from
the electron transport chain.
These three systems; glycolysis, Krebs and electron transport chain are intimately linked
together, but they can be selectively altered by various chemicals. Metabolic demanding systems
such as neural (brain), cardiac (heart), intestinal (intestines), and kidney tissue require the linked
cascade of glycolysis, Krebs cycle (also known as the Citric Acid Cycle) and the electron
transport chain (ETC) to function and survive. Any break in the linkage of these systems will
spell disaster for the cells and their organs. Even though the ETC produces the most ATP, it
cannot produce ATP if there is an alteration to the Citric Acid Cycle since it depends on the

products of the Citric Acid Cycle. In a similar way, if there is a problem with glycolysis, the
Citric Acid Cycle will not function as well. Thus these systems have to be considered as a
domino system. If one of the systems is affected, all of them are affected. Different cells have
varying demands on oxygen. Skeletal muscle can function the longest without oxygen due to
glycolysis for 20 minutes, whereas the heart cannot.
Poisons and How They Influence Various Metabolic Sites
Site 1: Disruption of the Citric Acid Cycle - Fluoroacetate Poison
Sodium fluoroacetate was discovered by German Scientists in World War II and was considered
very lethal since 0.1 grams could kill an adult male. However, it was considered difficult to
deliver to the enemy site, and was abandoned and then rediscovered as a pesticide.
Fluoroacetate is converted to fluorocitrate which prevents citrate or citric acid from being used in
the citric acid cycle. The ultimate result is the accumulation of citrate in the blood but no
production of ATP. The expression used to described this kind of poisoning is Suffocation from
within. See Figure 2.
Signs of poisoning included convulsions, and cardiac and respiratory collapse. These symptoms
are found in humans, dogs, and herbivores.
Treatment: What can you do?
There is no antidote. Symptoms show up after 30 minutes to 4 hours. Since it interferes with the
Krebs cycle, it is very difficult to treat. Muscle relaxants, anti-convulsants, and mechanical
ventilation are used as supportive measures. Few animals or persons respond to clinical treatment
after poisoning from Fluoroacetate.
Note: This poison is still used to control various herbivores such as the brushtail possum in
New Zealand. Brushtail possums are considered pests in certain parts of the world and they are
controlled by the use of various pesticides such as Fluoroacetate (Figure 3).
The Cytochromes
Many poisons have an effect on the cytochromes. These structures are responsible for
maintaining a proton imbalance as well as being the site in which oxygen ultimately accepts the
electrons. There are three major components to the ETC. Complexes I, III, and IV are complex
molecules that produce the proton gradient needed for ATP synthase activity. Any agent that
disrupts the sequence from Complex I to Complex II to Complex III seriously disrupts any
production of ATP.
Site 2. Disruption of proton gradient in Cytochromes in the Electron Transport Chain Dinitrophenol
Dinitrophenol was used as a weight reducing agent even though it had commercial uses such as
making dyes and wood preservatives. DNP stops the establishment proton gradient across the

cytochromes. As a consequence, the energy of the proton gradient is lost as heat. Cells produce
low amounts of ATP and consequently, they have to use carbohydrates and lipid reserves to
generate more ATP. This results in a weight reduction.
DNP was used as a diet pill but it was discontinued due to potential lethal effects. It is still used
by bodybuilders to rapidly lose body fat (Figure 4).
Symptoms of Use: The drug causes the patient to become hyperthermic. As a consequence,
patients sweat profusely, cannot sleep (insomnia), become dehydrated, and are lethargic (e.g.
they have no energy).
Treatment: What can you do?
DNP effects are removed within 24-36 hours after the patient stops taking the drug. HOWEVER,
there is no guarantee that all persons will survive DNP ingestion. Patients have died at reported
low dosages or safe dosages.
Site 3. Disruption of Electron Transport Chain - Cyanide
Cyanide kills all aerobic organisms by interrupting the process at the electron transport chain at
Complex IV. It competes with oxygen at this level so that oxygen cannot capture the electrons.
The result is no proton gradient and no ATP production.
Symptoms: Depends on the amount of exposure. Difficulty breathing and increased heart rate
progressing to coma and respiratory arrest.

Treatment: What can you do?

Since the cyanide binds so tightly to the cytochrome, another chemical is given to the patients
that attract the cyanide thus releasing it from the cytochromes. Sodium nitrite is given to the
patients and it converts hemoglobin to methemoglobin which is a more powerful attractant that
cytochrome oxidase.
A Little History
This metabolic poison was used in gas chambers in both Germany and USA. Interestingly, many
of the leaders of Nazi Germany died by cyanide poisoning including Adolf Hitler, Rommel,
Goebbels, and Goring (Figure 5). Other uses: Cyanide is also used in fishing! It is injected into
the water and kills the fish which are then caught and sent to market. Obviously, it kills all life
forms in the water, including coral reefs.
Site 4. Disruption of ATP Synthase: Oligomycin

This molecular motor is the primary method in which ATP is resynthesized from ADP. It has two
major components: F0 and F1 (Figure 6).
The antibiotic, Oligomycin works at the F0 unit by inhibiting its function. Antibiotics (anti-life
chemicals) in small amounts will kill various bacteria by affecting some part of the metabolic
pathway. In small amounts, its affects are more pronounced on the bacteria than on the host.
Site 5. Problems with low oxygen-Carbon Monoxide poisoning
Recall that for all cells to function, they need to have a close proximity to the blood so that
oxygen can be delivered to the cells and carbon dioxide removed. In addition, the blood carries
the chemical breakdown of food, (glucose, amino acids, and fatty acids) which also must be
transported into the cell. What happens when there is a loss of oxygen supply?
For this discussion, carbon monoxide will be used as an example of an inhibitor of oxygen
transport. Keep in mind, that other situations such as a severe blood loss (e. g. hemorrhage) will
have similar effects. That discussion will be held later in the course.
Carbon monoxide poisoning is due to the blocking of oxygen transfer to the cells. Carbon
monoxide has a significant affinity to the iron (or copper) sites in hemoglobin, the principal
oxygen-carrying compound in blood. The affinity between carbon monoxide and hemoglobin is
240 times stronger than the affinity between hemoglobin and oxygen. Once carbon monoxide is
inhaled, it binds much tighter to the heme component of hemoglobin than oxygen and as a result
hemoglobin cannot combine with oxygen. The overall result is that the lack of oxygen results in
cell death.
The end result of carbon monoxide poisoning at a metabolic level is as follows: 1. Limited
oxygen to the electron transport chain, 2. Severe decrease in ATP production, 3. Decrease in
function of oxygen demanding cells such as neurons or heart (cardiac). It is a little more involved
than these three points. Since the ETC does not produce ATP, the glycolytic pathway begins to
make lactic acid which leads to a lower pH in the patient and this in turn, leads to a clinical
condition called acidosis. The combined conditions of acidosis and lack of ATP leads to cell
death.
A sufficient exposure to carbon monoxide can reduce the amount of oxygen taken up by the
brain so that the victim becomes unconscious, and can suffer brain damage or even death from
anoxia. The brain regulates breathing based upon carbon dioxide levels in the blood, rather than
oxygen, so a victim can succumb to a decrease in oxygen (a condition called anoxia) without
ever noticing anything up to the point of collapse.
Carbon monoxide combines with hemoglobin to form a bright red color. It is often reported in
literature that patients with carbon monoxide poisoning are very pink cheeked. This cherry red
appearance is overrated and observed only in 2% of patients. Treatment: What to do? The best

treatment for a patient suffering from carbon monoxide poisoning is to give him 100% oxygen
since the oxygen accelerates the disassociation of carbon monoxide from hemoglobin.
Post Recovery: Problems
After acute poisoning, the patient eventually (2-28 days after the incident) develops movement
disorders so that they cannot move well and have symptoms similar to Parkinson's. In addition,
there are associated cognitive defects such as short term memory loss and speech disturbances
which remain and cannot be reversed. These signs signify the sensitivity of the brain tissue,
specifically, the mitochondria in the neurons to a loss of oxygen. Why the delay in the onset of
these signs? No one knows.
Oxidative Phosphorylation

Oxidative phosphorylation is a metabolic pathway that oxidizes NADH and

phosphorylates ADP to produce ATP.

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Hemoglobin

Hemoglobin is the principle oxygen-carrying compound in the blood.

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Acidosis

Acidosis is increased acidity in the blood and occurs when the blood pH falls
7.35.

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Anoxia

Anoxia is abnormally low oxygen levels in the body tissues.

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Cytochromes

Cytochromes are large proteins inside membranes that are responsible for
transferring hydrogen ions across the membrane.

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Cyanide

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Cyanide is a poison that kills by interrupting the processes of the electron tran
chain.

Oligomycin

Oligomycin is an antibiotic that inhibits ATP synthase by blocking its proton

channel.

2
ATP! The chemical that drives chemical reactions in living system. It is the "fireworks" of the
cell. However, it is not just not a flashy molecule. Its presence or lack therof defines life.

You receive a phone call. Your best friend's father is in the hospital. He has suffered a heart
attack and you rush to be with your friend at the hospital. The doctors think that the patient had
one of his major arteries blocked. Your friend states that his father was jogging with him and felt
a sharp pain in his throat and dropped right on the track. The emergency medical technician gave
the patient oxygen. One of them told your best friend that his father had suffered a heart attack.
Your friend wants to know what a heart attack really is.
All biological activities require energy in the form of a chemical molecule. ATP is required for
all anabolic and catabolic activities as well as physical movements and transport of molecules
across the cellular membrane. Its importance cannot be overestimated. To demonstrate the point each cell has one million ATP molecules which is sufficient for supporting a cell's activity for
only a few minutes. The ultimate source of energy for constructing ATP is food. If you can eat
2,500 calories, the body converts these calories into 400lbs of ATP. Obviously we do not gain
400lbs/day since the ATP is rapidly used for all kinds of activity. The phosphate are all
negatively charged and as such, they repel each other. The third phosphate group (gamma one) is
the one that is the most easy to separate from the other two phosphate groups.
ATP is composed of adenine and ribose and three phosphate groups: alpha, beta, and gamma
(Figure 1). ATP belongs to the family of nucleotides which also include DNA and RNA. In
addition, the basic structure of nucleotides are found in other important bio-molecules: NAD,
NADP, FAD, which are involved indirectly in producing ATP. NAD, NADP and FAD will be
discussed in future modules.
How is the energy contained in ATP utilized by the cell? The simple answer is that the energy
transmission occurs when the gamma phosphate is cleaved by hydrolysis. This process is called
ATP hydrolysis. The energy released by ATP hydrolysis drives biochemical reactions that would
not otherwise occur. But how does the cleaving of the gamma phosphate promote chemical
reactions? In every chemical reaction, there are the reactants and the products. The reactants

must reach a certain level of activation higher than the products to promote the chemical
reaction. The gamma phosphate attaches to one of the reactants and changes the physical
structure of the reactant increasing their level of activation - promoting the chemical reaction to
occur.
As an example, in the brain there is a molecule called glutamate which causes the cells to
become excitable. Glutamate has to be converted to Glutamine which is not excitatory to the
cells. How does this occur?
glutamate + NH4+ = glutamine (disfavored reaction)
But coupled with ATP hydrolysis, it is made to go forward:
glutamate + ATP + NH4+ = glutamine + ADP + Pi (favored reaction)
Figure 2. demonstrates the fundamental point about ATP. It combines with a chemical reactant
which promotes its interaction with another reactant so that the chemical reaction will occur. In
some sense, ATP is like a chemical reactant energizer.

A. The person cannot bowl uphill without a lot of energy. This is a disfavored reaction.
B. The person has no problem bowling the ball downhill.
C. ATP helps example A become more like example B. It decreases the amount of energy needed
for a reaction to proceed.
So how does ATP change the thermodynamics of the equation? In many cases it attaches its last
phosphate onto a reactant molecule which changes its properties. This is the important point. For
example, when the phosphate is attached to the protein, it causes a change in the shape of the
protein. This important step is called phosphorylation. The phosphorylated protein undergoes a
conformational change, meaning that it no longer has the same shape. As a consequence of the

conformational change, the thermodynamics have changed allowing a reaction to occur. The
bottom line is that ATP causes a conformational change in a molecule that then allows chemical
reactions to occur. Figure 3 (found on the following page) is an example of how ATP works in
making a protein change its thermodynamic property.
In brief, ATP can work to change the shape of the protein to allow a reaction to occur. Usually,
the terminal phosphate is used to modify the structure of the reactants, but in some cases, it is
adenosine products that can also do the trick. Thus ATP causes the reactants to be phosphorylated
which results in an active reactant that promotes the chemical reactions.
Please note: In most textbooks, the major point about ATP is that the last phosphate group
directly imparts its energy to the chemical reaction when it detaches from ATP. It is not so. The
gamma phosphate group becomes part of the reactants which changes the molecular structure of
the protein and increasing the energy in that system so it can proceed.
Enough of chemistry, how about some examples. The best example of ATP use is in terms of
skeletal muscle activation and relaxation at the molecular level. So how does ATP play a role in
this function? Oxidative phosphorylation produced ATP needed for muscle contraction. The ATP
diffuses to the muscle cells. Then what happens? Consider Figure 4 on the following page.

In a resting non-contracted state, myosin is not able to bind to actin. When ATP is available it
attaches to the myosin head. Subsequently, the ATP is split into two products ADP and inorganic

phosphate by way of hydrolysis. When these products break from myosin, myosin attaches to
actin and pulls the actin. This is similar to a person pulling on a rope in a hand over hand
maneuver. Subsequently another molecule of ATP attaches to the myosin causing it to detach
from the actin. This process is repeated until the desired contraction is accomplished. Thus, ATP
is used in contraction at two points - contraction and relaxation. Most textbooks emphasize the
contraction phase of muscle contraction, but the controlled relaxation phase is the hallmark of a
superbly trained athlete. It gives smoothness to the motion. The cell and multicellular organisms
have two major functions: energy gathering and reproduction. ATP generation is critical for both.
In future modules, you will study how ATP is used in protein production and also how it is used
in cellular replication during mitosis and meiosis.
The Heart Attack
Figures 5 & 6 on the following page demonstrate the sequence of events that explain the heart
attack mentioned in the anecdote in the beginning of this module. The oxygen needed for
indirectly promoting the development of ATP is carried to the heart muscle cells by the molecule
hemoglobin which is encased in the red blood cell. The combination of oxygen and hemoglobin
is called oxyhemoglobin.
When oxyhemoglobin reaches the capillaries of the heart muscle, it releases its oxygen which
diffuses from the capillary to the mitochondria. In the mitochondria, the oxygen combines with
the electrons from the electron transport chain which allows the protons to enter ATP synthase.
This activated ATP synthase produces ATP from ADP. The ATP diffuses from the mitochondria
and powers the contraction of the heart muscle. In mammalian cells, the mitochondria accounts
for 25% of cell volume. This fact demonstrates the importance of mitochondria in replenishing
ATP to promote chemical reactions.
In the case of the heart attack, the cardiac muscle does not contract due to a failure of ATP
replenishment. This failure is due to the lack of oxygen reaching the mitochondria in the heart
cells. The red blood cells carrying the oxygen are not able to reach the capillaries of the heart
muscle. Oxidative phosphorylation does not occur and as a consequence, the heart muscle no
longer contracts and oxygen carrying blood cannot reach other oxygen demanding organs. If not
treated, the patient will die. The term "heart attack is used to describe the failure of heart cells to
contract. Although this module emphasized the importance of ATP on muscle contraction, ATP
promotes most biological chemical reactions.
Adenosine
triphosphate (ATP)

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Adenosine triphosphate (ATP) is a molecule that promotes

chemical reactions within cells.

ATP Hydrolysis

ATP Hydrolysis is the process by which energy stored in the

high-energy bonds within ATP is released to produce work.

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Thermodynamics

Thermodynamics is the study of the effects of work, heat, and

energy on a system.

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Conformational
Change

A shape-change within a molecule.

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Phosphorylated

Phosphorylation is the adding of a phosphate (PO4) group to a

molecule.

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Oxyhemoglobin

The combination of oxygen and hemoglobin carried in the

bloodstream.

Photosynthesis
Products of photosynthesis include dynamic plant colors, street drugs (i.e. marijuana and
cocaine), medicines (e.g. digitalis, maybe caffeine?) , proteins, lipids, and most importantly
oxygen which is used by animals to generate ATP. Plants are amongst the oldest living systems
since they make ATP from water and sunlight.

Introduction
Photosynthesis is the most important set of chemical reactions in the world. The result of
photosynthesis is oxygen, the metabolic end product of a complex set of plant chemical reactions
that ultimately support aerobic metabolism. In addition, plants are also the mainstay of all
civilizations. Indigenous people in Peru grew potatoes, in Mexico they grew corn, in the Middle
East (Iran and Iraq) they grew wheat, and in China, they grew rice. The biological importance of
photosynthesis cannot be overestimated nor can its current financial weight. Huge multinational
industries are designed around cultivating these important produce (flour, rice, beans, and
potatoes) to support the world's exploding population.
The term photosynthesis is somewhat misleading. It literally means making light, which
plants do not do. Photosynthesis is a set of chemical reactions that occur in plants to produce
energy for the plant in the form of ATP, which is used to power all the anabolic and catabolic
activities of the plant cell (Figure 1). What is most remarkable about this process is that the plant
cell is able to grow by using only carbon dioxide, water, and sun light. It is the ultimate solar
gathering system. The ability of plants to take certain wavelengths of sunlight, carbon dioxide,
and H20 and subsequently use them to produce all of its chemical needs is a remarkable
chemical feat and is called photosynthesis.
The plant cell is the functional unit of plants. It differs from animal cells in that it has a cell wall
in addition to a plasma membrane. It serves a variety of functions from protecting the cell to
regulating the life cycle of the plant. In addition, plants have chloroplasts which are the
structures that convert light energy into electrical energy (Figure 2). Interestingly, the plant cell
also has mitochondria which produce energy when light is not available for the chloroplasts.
Each plant cell has a large single vacuole that stores compounds, helps in plant growth, and plays
an important structural role. Notice that all the cellular machinery that was noted in the animal

cells to make proteins is also in the plant cell. The nucleus, nucleolus, nuclear envelope, rough
endoplasmic reticulum, golgi bodies, and ribosomes are all present.
The critical energy producing organelles of the plant cell are the chloroplasts. All of the green
structures in plants, including stems and un-ripened fruit, contain chloroplasts, but the majority
of photosynthesis activity in most plants occurs in the leaves. On an average, the chloroplast
density on the surface of a leaf is about one-half million per square millimeter. We will discuss
plants that do not have leaves, such as cacti, later in this module.
The chloroplast, basically, is the organelle responsible for photosynthesis. It is very similar to the
mitochondrion in structure. It contains a permeable outer membrane, a less permeable inner
membrane, an intermembrane space, and an inner section called the stroma. However, the
chloroplast is larger than the mitochondria. It is larger in size because its membrane is not folded
into cristae. Also, the inner membrane is not used for the electron transport chain. Instead it
contains the light-absorbing system, the electron transport chain, and ATP synthase in a third
membrane that forms a series of flattened discs, called the thylakoids. In addition, the
chloroplasts of the mitochondrion have its own unique DNA separate from that of the plant
nucleus.
Where Does The Plant Get Its Source of Hydrogen Ion?
So how does photosynthesis occur in a plant? (Figure 3) Van Helmont took a tree, measured its
length as a sapling and the amount of soil that it was in, gave it water, and watched how the plant
grew and ended up weighing 170 lbs, but the amount of soil lost was only 2 ounces. The
conclusion of the experiment was that the plant grew using primarily water and something in the
air--carbon dioxide. Using certain wavelengths of light, water, and carbon dioxide from the air,
plants are able to grow and reproduce.
The chemical reactions that the plant undergoes are divided into two distinct phases: the light
dependent phase (LDP) and the light independent phase (LIP) (Figure 4). The LDP takes certain
wavelengths of light and water to form oxygen, ATP, and NADPH. Figure 4 does a great job of
presenting this overall complexity of photosynthesis wavelengths in a straightforward manner.
The LDP split water into oxygen and hydrogen ion in the LIP. The hydrogen ion is used to
reduce NADPH which generates ATP. ATP and carbon dioxide from the air are used to make
sugars and other products, such as cocaine, in the dark reaction.
Photosynthesis = Photophosphorylation
The energy generating component of photosynthesis has the same end result as does oxidative
phosphorylation in mitochondria. Photosynthesis results in the phosphorylation of ADP to form
ATP. There are two distinct kinds of photosynthesis: Noncyclic photophosphorylation and Cyclic
phosphorylation. Cyclic photophosphorylation is the oldest of the two forms and the emphasis of
this module will be on the noncyclic form of photophosphorylation.
The Light Dependent Phase: The Role of the Chlorophyll Molecule
Chlorophyll gives plants their green color but more importantly it captures electrons from the
various wavelengths of light coming from the sun. It has a major role in the capture of a small

part of sun's energy which is then transferred to all living systems in the world.
A chlorophyll molecule has a hydrophobic "tail" that inserts the molecule into the thylakoid
membrane. The "head" of a chlorophyll molecule is a ring called a porphyrin. The porphyrin ring
of chlorophyll, which has a magnesium atom at its center, is the part of a chlorophyll molecule
that absorbs light energy. It has striking similarities to the hemoglobin molecule with the
exception that its center has a magnesium center whereas the hemoglobin molecule has an iron
center (Figure 5).
Light Reactions Produce NADPH and ATP
What occurs in the light reactions is shown in Figure 6. Light activates Photosystem II first and
subsequently Photosystem I. Photosystem II, when activated by sunlight, will separate hydrogen
from oxygen. Oxygen is expelled into the atmosphere and hydrogen powers ATP synthase by
chemiosmosis.
Recall that in the mitochondria, hydrogen ions and their associated electrons are the chemicals
that power ATP synthase to make ATP. The system is the same in plants. The only difference is
that the hydrogen ion in plants come from water. Water, in essence, is the food for plants. It is
oxidized and the resulting hydrogen ions are used to energize the ATP synthase pump.
NADP = Ultimate Electron Acceptor
Recall how in the animal mitochondria oxygen was the ultimate electron acceptor promoting the
proton imbalance that powered the ATP synthase pump. In plants, the ultimate electron acceptor
is NADP which is reduced to NADPH in LDP. If NADP is not available, the ATP synthase pump
will not function and as a consequence the plant will die. Another view of the same phenomenon
is in Figure 6 and 7.
So how is ATP produced? During the electron movement from photosystem I to photosystem II,
the electron that is removed from photosystem II is replaced by electrons from water. Water is
oxidized so that the electron and its associated proton is separated from oxygen. Thus oxygen is
produced as a result of the oxidation of water. The electron from water is used to replace the
electrons that are activated in photosystem II. The hydrogen ion is used to power ATP synthase to
make ATP.
The hydrogen ion will not power ATP synthase unless the electron is ultimately captured by
NADP. Thus NADP acts in a similar fashion to oxygen in oxidative phosphorylation in animals
in that oxygen picks up the electron associated with the proton.
Cyclic Photophosphorylation
Cyclic photophosphorylation involves only photosystem I in which ATP is not generated by
NADPH. It is considered to be a very primitive system since photosynthetic bacteria use this
approach. Since there is no NADPH produced, complex carbohydrates are not produced and
more importantly, the system itself does not produce much ATP. Also, cyclic

photophosphorylation does not oxidize water - thus it can survive during periods of drought
(Figure 8).
LIP Or Dark Reactions
The LIP reactions are those that do not require light but do not have to take place in the dark. To
put it in other terms, these are chemical reactions that are powered by ATP and NADPH. The end
result of the dark reaction is that carbon dioxide from the atmosphere is combined to an organic
compound using ATP and NADPH. This process is called CO2 fixation which is catalyzed by the
most abundant protein in the world, called rubisco. The one carbon from carbon dioxide
combines with the five carbons of a molecule called ribulose bisphosphate to form the six carbon
compound a carbohydrate. This reaction is catalyzed by rubisco.
The end result of the LIP is the production of 3-phosphoglyceric acid which is then synthesized
into proteins, lipids, and carbohydrates. The carbon dioxide comes from the atmosphere and is
the basis of all organic molecules that the plant uses.
Insecticides: Cocaine, Nicotine, Caffeine, Heroin, Marijuana
The end result of photosynthesis is the production of many organic products. These products
include hormones for the plant to direct its growth and various chemicals to ward off or kill
insects. The development of these chemicals has been used by mankind for his use and abuse.
Cocaine is an insecticide. It causes a number of reactions in invading insects such as shakiness
etc. What is important to stress is that the cocaine produced by plants coincidently activates our
pleasure center while being a poison.
The reaction to the insecticide on humans varies depending on a number of factors such as
dosage, tolerance, method of introduction, gender, age, race, etc. From a biological point of view,
the insecticides produced by plants that have an effect on our pleasure center have their effect by
activating specific nerve cells in an area of the brain called the nucleus accumbens.
This site gives us the sense of well being and being happy. Once activated by a happy chemical
stimulus, the nucleus accumbens ends signals to various parts of our brain. The neurons release a
chemical called dopamine that gives the sensation of pleasure. This chemical is similar to the
neurochemical called octopamine in insects which is the target of cocaine. Thus, cocaine
produced by the LIP in plants will affect the chemical metabolism of octopamine in insects as
well as the dopamine in humans.
In another example, marijuana's active ingredient, THC, affects the pleasure center of the brain.
The nucleus accumbens, with its metabolism of the neurochemical dopamine, is the main site of
many addictive drugs produced by plants.

From an evolutionary viewpoint, the use of various plant products by humans ensures their long
term survival. So, by accident, many plants that benefit man are maintained by mankind.

Photosynthesis

A set of chemical reactions that occur in plants to produce energy for

the plant in the form of ATP which is used to power all the anabolic and
catabolic activities of the plant cell.

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Chloroplasts

A plant organelle that contains the pigment chlorophyll that is the site
of photosynthesis.

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Stroma

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A fluid filled area in chloroplasts that is enclosed by the inner

membrane.

Thylakoids

Disk shaped membrane sacs inside chloroplasts that contain

chlorophyll and enzymes for the light dependent reactions of
photosynthesis.

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Chlorophyll

Light Dependent
Reactions

Green photosynthetic pigment found in plants, algae, and

cyanobacteria.
A mechanism whereby electrons are energized and
subsequently used in ATP and NADPH synthesis.

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Dark Reactions
(aka Calvin Cycle)

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These are chemical reactions that are powered by ATP and

NADPH. The end result of the dark reaction is that carbon
dioxide from the atmosphere is combined to an organic
compound using ATP and NADPH.

Cyclic
Photophosphorylation

The oldest of the two forms and noncyclic is the newer

version and most common.

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Rubisco

The most abundant protein on earth, which catalyzes the first

step in the Calvin Cycle.

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Porphyrin

A ring on the "head" of a chlorophyll molecule.

Digestive System, Liver, Molecules of Life

Gorging -- Eating to Excess. One of the primordial drives is to eat. Now, when do we stop
eating? Eating is a complex biological, psychological and social activity. The body is superbly
designed to take in a lot of food and store it or to survive on limited amounts. "Enjoy?"

Digestive System
The next 6 modules will present the chemistry and metabolism of protein, carbohydrates, and
lipids. These are the sole sources of ATP that you just learned about. Metabolism also includes
the ingestion of vitamins and electrolytes. Those topics will not be discussed in these modules.
This current module is designed as an overview of the gastrointestinal (GI) system (Figure 1).
The challenge is to master both the anatomy and biology of the digestive tract. So, some
concepts presented in this overview will be repeated in subsequent modules.
The human digestive system or gastrointestinal (GI) tract ranges from 21 - 30 feet of specialized
regions subdivided into the mouth, pharynx, esophagus, stomach, small intestine, large intestine
(or colon), rectum, and anus (see figure). Glandular organs that have accessory roles in digestion
and absorption include the salivary glands, liver, gallbladder and pancreas.
For the most part, the entire length of the GI tract has the same structure to its wall. The inside
layer facing the gut lumen is the mucosa consisting of a surface epithelial layer and an
underlying layer of connective tissue. The mucosa is surrounded by a layer of connective tissue
that is meshed with blood and lymph vessels. The next layer toward the outside of the tube is
muscle tissue divided into two sub layers; smooth muscle which is arranged in longitudinal and
circular directions. The outermost layer of the digestive tract is the connective tissue serosa.
Back to Basics
The digestive system has four basic functions which include motility, secretion, digestion, and
absorption. These functions have many levels of control ranging from the nervous system to
individual cells. The nervous system is specifically very important since there are thought to be
more neurons in the gastrointestinal system than the brain!
Motility involves contractions in the muscle layers that mix food material with secretions and

moves it through the gastrointestinal tract. The two common types of movement are peristalsis
and segmentation.
Peristalsis is when rings of circular muscles contract behind a mass of food material and relax in
front of it to advance it forward (Figure 2). The forward motion expands the tube wall thus
stimulating peristalsis further down the digestive system.
Segmentation only happens in the intestines. Rings of smooth muscle contract and relax creating
a back and forth movement that constantly mixes the contents of the lumen and forces them
against the absorptive surface of the intestinal wall. The flow of material is controlled by
sphincters, rings of smooth muscle which normally prevent backflow from one region of the
digestive system to another. Sphincters are located at the beginning and end of specific regions
like between the esophagus and the stomach (i.e. gastroesophageal sphincter) or the stomach and
the small intestine (i.e. pyloric sphincter).
Chewing and Swallowing -- Mouth/Esophagus
Mechanical reduction of food and the digestion of polysaccharides begin in the mouth (Figure
3). The teeth and the tongue mechanically reduce food and mix it with saliva, a fluid secretion
from the salivary glands. Salivary amylase is the enzyme in saliva that takes part in the initial
breakdown of starch.
Saliva also consists of bicarbonate ions which act as pH buffers and mucins that are
glycoproteins which bind bits of food together into a softened, lubricated ball called a bolus. The
tongue then moves toward the roof of the mouth and forces the bolus into the pharynx where it
stimulates mechanoreceptors that cause contraction of the walls of the pharynx and the
esophagus. The contraction initiates swallowing, which can be voluntary, but swallowing is a
reflex controlled by a region of the brain called the brain stem.
The swallowing reflex opens a sphincter at the top of the esophagus and closes the trachea while
food is moving into the esophagus, so that no food enters the respiratory system. Neither the
pharynx nor the esophagus contributes to digestion but their peristaltic movements propel the
food to the stomach.
Stomach
The stomach is a muscular, distensible sac that has three main functions:
1. Stores and mixes food received from the esophagus
2. Secretes substances that help dissolve and degrade food
3. Helps control the rate at which food moves into the small intestines
Cells in the stomach release hydrochloric acid (HCl), pepsinogens, mucus, and hormones.
The HCl secreted into the stomach dissolves food and produces a solution called chyme. HCl
also, kills most of the microbes entering the body in food.
Pepsinogens are enzymes that break proteins into smaller pieces, sometimes called peptides.

Peristaltic waves in the stomach mix the chyme and build up force as they approach the pyloric
sphincter (#10 in Figure 4) between the stomach and small intestine. Only a small amount of
chyme moves into the duodenum, the first part of the small intestine, with each strong peristaltic
contraction.
Factors such as stomach distension, increases in acidity, osmotic pressure, fat, and emotional
states control how fast the stomach empties into the small intestines.
The Small Intestine: Its not the size of the intestine that counts its the motion of segmentation
Digestion is completed in the small intestines where most nutrients are absorbed (Figure 5).
The small intestine is divided into three parts:
The duodenum, jejunum and ileum.
Most proteins, fats and carbohydrates in the chyme have been broken down into amino acids
(proteins), fatty acids, monoglycerides (fats) and monosaccharides (glucose) by the time they are
halfway through the small intestine. These small organic molecules move across the epithelial
cells of the intestinal mucosa which is densely folded into absorptive structures called villi. The
villi greatly increase the surface area available for interactions with the chyme.
The small molecules move across the epithelial cells into the circulatory system. Blood
containing the absorbed nutrients is carried away from the small intestine via the hepatic portal
vein and goes to the liver for filtering, removal of toxins, and nutrient processing. The small
intestine also absorbs some water and dissolved mineral and ions.
As a side note: small intestines (preferably non-human) can be prepared as tasty treats (Figure 6.
Fried pork small intestines).
We all really love our... Pancreas?!
Ducts from the pancreas and liver join to form a common duct that empties into the duodenum
(Figure 7). The pancreas contains exocrine cells that secrete enzymes into this duct which digest
carbohydrates, fats, proteins, and nucleic acids.
The stomach secretes pepsin to digest proteins and the pancreas secretes trypsin and
chymotrypsin (other digestive enzymes) to digest proteins into peptide fragments.
The pancreas also secretes bicarbonate ions to neutralize the HCl that arrives from the stomach.
This neutralization is necessary for the pancreatic enzymes to function.
The pancreas also has an endocrine function by which it produces hormones. The pancreas
secretes insulin and glucagon from cells called the Islets of Langerhans (Figure 8).
Large Intestine, Colon
Contractions in the small intestine force the chyme into the large intestine, or colon (Figure 9).
One function of the colon is to store and concentrate the feces which are a mixture of undigested
and unabsorbed material, water and bacteria.

The bacteria in the large intestine live on unabsorbed nutrients. The colon is about 1.2 meters (3'
11'') long, with the ascending part extending upward on the right side of the abdominal cavity,
the transverse part cutting across to the other side and the descending part extending down
the left side.
The colon is continuous with a small tube called the rectum which expels material from the body
through the terminal opening of the gut, and the striated muscle sphincter called the anus. The
large intestine has an extensive colony of different species of bacteria that are thought to be
essential to the well being of the host.
The Liver
The liver is the largest and most versatile glandular organ in the vertebrate body (Figure 10). Its
functions include storage of fats and carbohydrates for energy, regulation of blood glucose levels,
synthesis of blood proteins, storage of iron and some vitamins, conversion of toxic ammonia into
urea, and detoxification of other harmful substances such as nicotine and alcohol.
The liver produces bile, a complex mixture composed of bile salts, water, other salts and
cholesterol. Bile is synthesized in the liver from cholesterol and amino acids. It is stored and
concentrated in the gallbladder where it is released into the small intestines through the bile duct.
Bile salts assist in the breakdown of lipids by acting as a detergent or emulsifying agent. It
disperses globs of fat in the chyme into microscopic particles thus exposing their large surface
area to lipases, the lipid-digesting enzymes produced by the pancreas.
What does this red panda have in common with the plant it is eating? I'll give you a few hints: it
is not its cuteness or taste. Think smaller. Like molecular small.

Biological Molecules: The Chemistry of Life

The molecules of life are macromolecules that typically consist of carbon, hydrogen, oxygen,
and nitrogen atoms. These atoms combine to form a series of large molecules (hence the term
macromolecule) with a given purpose that can be found in every organism.
These macromolecules have multiple functions. They are a source of chemical energy (muscle
energy), give structure to cells and tissue, store information (your genetic material, Figure 1), and
carry out molecular work (fight diseases, transport nutrients, etc.).
Why are we Carbon-based Lifeforms?
Carbon atoms form the backbone of these macromolecules. These atoms can make stable
molecules by sharing electrons with other atoms.
Atomic Bookkeeping
Carbon wants to have 8 electrons in its outer electron shell even though it comes with only 4.
Therefore, a carbon atom needs to form four covalent bonds by sharing electrons with other
carbon atoms to make it stable. Carbon atoms can form either single, double, or triple bonds
with some atoms which can link multiple atoms together in chains, branches or rings.
Oh no... chemistry! How in the world do I read a chemical structure?
Most of the time atoms of a given element are listed with their 1- or 2-letter abbreviation
(Carbon = C; Hydrogen = H; Oxygen = O; etc.).
Lines between atoms, like in methane (Figure 2), represent covalent bonds. In this example
carbon has 4 single covalent bonds to 4 separate hydrogen atoms.
Often times, due to laziness and to save on time, however, many scientists when drawing a large
chemical structure will not write in the hydrogen atoms on the main carbon backbone and will
use ends and corners to represent carbon atoms. Based on this shorthand notation the glucose
molecule has a total of 6 carbons (5 form the ring), 12 hydrogens, and 6 oxygens (Figure 3).
Macromolecules have mono...mers
Small molecules are used as subunits with which to synthesize macromolecules. These individual
subunits are called monomers that assemble into long chains called polymers (aka
macromolecules).
Large polymers are made when the monomer subunits are joined together in a chemical reaction
called dehydration synthesis (also known as a condensation reaction). It is called dehydration
because 1 water molecule is removed and set free for every two monomers that bind together.
Energy is required to break the chemical bonds when water is extracted from the monomers,
therefore cells must supply energy in order to assemble polymers. Nothing in life comes free.
So what specifically do the red panda and the plant share? (Figure 5)
Or in other words what biological molecules do they have in common that give them life?

The answer is the four main types of macromolecules. These molecules can be broken up into
four groups (including their monomers):
1. proteins (e.g. enzymes, muscle, hair) which are made of amino acids
2. lipids (e.g. fat, oils, cholesterol, cell membranes) which are made of fatty acids
3. carbohydrates (e.g. sugar, starch, potato chips) are made of glucose molecules
4. nucleic acids (e.g. DNA, RNA) which are made from nucleotides:
Adenine, cytosine, guanine, and thymine for deoxyribonucleic acid
Adenine, cytosine, guanine, and uracil for ribonucleic acid
The next few modules after this one will discuss each of these macromolecules and their
biological roles in greater detail.
Bile

A bitter yellow or green alkaline fluid secreted by hepatocytes from the l

bile is stored in the gallbladder between meals and upon eating is discha
where the bile aids the process of digestion of lipids. In other words it m
insoluble in water, soluble so they can be absorbed and transported in th
by the liver.

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Chyme

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The semifluid mass of partly digested food expelled by the stomach into

Colon

The colon is a storage tube for solid wastes. The main function of the co
extraction of water and salts from feces.

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Connective Tissue Serosa

The outermost layer of the digestive tract.

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Duodenum

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The first part of the small intestine.

Emulsifying Agents

Substances that are soluble in both fat and water and enable fat to be uni
water as an emulsion. Foods that consist of such emulsions include butt
dressings, mayonnaise, and ice cream. Stabilizers maintain emulsions in
Emulsifying agents are also used in baking to aid the smooth incorporati
and to keep the crumb soft.

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Human Digestive System or

Gastrointestinal (GI) Tract

The digestive tract (also known as the alimentary canal) is the system of
multicellular animals that takes in food, digests it to extract energy and n
remaining waste. The major functions of the GI tract are ingestion, dige
defecation.

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Hydrochloric Acid (HCl)

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The solution of hydrogen chloride (HCl) in water. It is a highly corrosiv

and therefore a major industrial chemical. It is found naturally in gastric

Islets of Langerhans

The endocrine (i.e., hormone-producing) cells of the pancreas are groupe

Langerhans.

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Liver

The largest and most versatile glandular organ in the vertebrate body. Its functions include storage of
for energy, regulation of blood glucose levels, synthesis of blood proteins, storage of iron and some vi
toxic ammonia into urea, and detoxification of other harmful substances such as nicotine and alcohol.

Motility

Involves contractions in the muscle layers that mix food material with se
forward through the gastrointestinal tract. The two common types of mo
and segmentation.

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Mucosa

Mucus-secreting membrane lining all body cavities or passages that com

exterior.

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Muscle Tissue

Contractile tissue of the body and is derived from the mesodermal layer
Muscle cells contain contractile filaments that move past each other and
cell. They are classified as skeletal, cardiac, or smooth muscles. Their f
force and cause motion.

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Pancreas

A gland organ in the digestive and endocrine system of vertebrates. It is

pancreatic juice containing digestive enzymes) and endocrine (producing
hormones, including insulin, glucagon, and somatostatin). It also produc
that pass into the small intestine. These enzymes help in the further brea
carbohydrates, protein, and fat in the chyme.

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Pepsins

Protease enzymes that break proteins into smaller amino acids called pep

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Peristalsis

When rings of circular muscles contract behind a mass of food material

advance itforward.

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Saliva

A fluid secretion from the salivary glands.

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Salivary Amylase

The enzyme in saliva that takes part in the initial breakdown of starch.

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Sphincters

Rings of smooth striated muscle which prevent backflow from one regio
to another.

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Stomach

Villi

A muscular, distensible sac that has three main functions. It stores and m
the esophagus, it secretes substances that help dissolve and degrade food
rate at which food moves into the small intestines.
They increase the absorptive area and the surface area of the intestinal
food is absorbed at a considerably fast rate so as to allow more food to

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Covalent Bonds

Bonds that form between atoms as a result of sharing electrons.

Dehydration Synthesis
(Condensation reaction)

A reaction between monomers that results in producing a polymer and

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Hydrolysis

A chemical reaction in which a large molecule is split by a water molec

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Monomer

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The simple starting unit from which a polymer is made.

Polymer

A large molecule made of repeating smaller units called monomers.

Teacher: What is the definition of a protein?

Student: A protein is something that is made up of mean old acids.
"Hello! You mean amino acids?"

Life, Love, Health, and Death: The World of Proteins

What is so special about proteins anyway?
What is an enzyme?
After completing this module these are questions that you will hopefully be able to answer if
someone (friend, family, exam, etc.) were to ask you.
The following sums up the importance and influence that proteins have on us and life for that
matter:
Protein... its whats for dinner (Figure 1).
Protein... the other white meat.
Protein... its in you (Figure 2).
Protein... it makes you who you are.
Given that our body weight is about 90% water and fat, without proteins we would be a giant
puddle of water and fat/oil. Proteins give us shape and hold us together. They allow us to move
(skeletal muscle), provide structure (cartilage and bone), help us fight disease
(immunoglobulins), and digest the food we eat (enzymes).
Proteins are also instrumental in carrying the digested nutrients all through our body and control

just about every process that occurs inside of us.

Of all biological molecules, proteins are one of the most diverse. Perhaps the most important
proteins are enzymes, which are capable of speeding up specific chemical reactions and lowering
the energy required to activate or start a chemical reaction. Some enzymes work to digest the
foods we eat and break large macromolecules into smaller molecules that our body can use.
Other enzymes play important roles in controlling the entire spectrum of chemical and molecular
processes that take place in our body.
Proteins can function as cell signaling molecules, membrane receptors, and structural elements in
cells. Proteins are also regulatory molecules in the nucleus and cytoplasm.
For example if you get an insect bite (Figure 3). Proteins will recognize the intrusion and will
signal other proteins to cause swelling, which will signal other cells to release histamine (that
wonderful itching sensation). As well as a number of other events that all lead to you getting that
nice itchy red bump on your skin (Figure 4).
They serve as markers to identify every cell in our body as self so that our immune system can
recognize any intrusion by a cell, bacteria, or virus that is not self. A list of important protein
functions is listed at the end of this module.
Computer Analogy:
If DNA is the hard drive, then proteins are the rest of the computer (CPU, monitor, printer, RAM,
USB drives, etc.)
Okay, so a protein is important. But what exactly is a protein?
How would I be able to describe a protein to someone if they asked?
Proteins are large, complex macromolecules that have a structural function. Keratin, for
example, which makes up hair, nails, and collagen, is found in all types of connective tissue
including ligaments, cartilage, bone, and tendon. The horns or antlers on animals also consist of
durable proteins. Muscles contain proteins that contract and subsequently move our body. Even
our skin is made from proteins that protect everything on the inside from the environment that is
outside.
Proteins are polymers of amino acids; they may be composed of one or more chains of amino
acids (Figure 5).
What is an amino acid? (not to be confused with the fictional mean old acid)
An amino acid consists of a central carbon atom bonded to four different groups (Figure 6). The
four groups are a nitrogen containing amino group (-NH2) (hence the amino part of the name),
a carboxylic acid group (-COOH) (the acid part of the name), a hydrogen atom (H) and a
functional "side group designated R (R is a variable here like X is for Algebra).
R can be any of 20 different side groups that give each amino acid its own distinctive chemical
property. The way that each amino acid affects the shape of a protein depends on the chemical

nature of the amino acid's side group. The exact type, position, and number of different R groups
of the amino acids of a protein determine both the structure of the protein and its biological
function.
The 20 different amino acids can be roughly put into two groups: hydrophilic or hydrophobic.
Hydrophilic or water loving amino acids contain atoms (typically oxygen and nitrogen) that
are polar which make the R-groups soluble in water. These amino acids can form hydrogen
bonds with nearby water molecules.
Hydrophobic or water fearing amino acids contain atoms (typically carbon) that are non-polar
which make the R-groups insoluble in water.
Life is meaningless without structure...
Protein chains found in living cells vary in length from three to thousands of amino acids. The
exact sequence of amino acids dictates the structure and function of each protein.
Proteins are formed by dehydration synthesis. The amino group of one amino acid forms a
covalent bond with the carboxylic acid group of another. The bonding of the two amino acids
forms a molecule of water from the loss of hydrogen from the amino group and the loss of the
OH from the carboxylic acid group. The bond between the two amino acids is called a peptide
bond (Figure 7).
The chain of two amino acids is a dipeptide; three or more amino acids linked together form a
polypeptide chain.
The process of hydrolysis (or condensation reaction) breaks polypeptide chains into the
individual amino acids by the addition of a water molecule that breaks the peptide bond.
Levels of understanding the structure of a protein:
Or in other words, how scientists view and study protein structure
There are 4 different ways or levels that scientists use to understand a protein and its function.
Primary (1'), Secondary (2'), Tertiary (3'), and Quaternary (4')
Primary
The sequence of amino acids that make up a particular polypeptide chain constitutes the primary
sequence of a protein (Figure 8).
Secondary
Each amino acid of a polypeptide interacts with its neighbors thus forming hydrogen bonds.
These interactions cause the protein to fold spontaneously into coils that are termed alpha-helices
or beta-pleated sheets. The folding patterns are referred to as the protein's secondary structure
(Figure 9).
Tertiary

The disulfide bonds allow the protein to take on a three-dimensional shape which is referred to as
the tertiary structure (Figure 10). A protein dissolved in water folds into an irregular glob,
influenced by the tertiary structure, with the hydrophilic amino acids facing the outside watery
environment and the hydrophobic ones clustered in the center of the molecule.
Quaternary
Quaternary structure is the fourth level of protein architecture, resulting from interactions
between two or more polypeptide chains in some proteins (Figure 11). As a result, the protein
can be globular, fiber like, or some combination of the two shapes.
Proteins are the molecular workhouse of the cells (Figure 12). The following are the
major functions of proteins.
1. Proteins are a critical component of cellular membranes and their organelles.They are the
major component of various kinds of connective tissue. Hair, nails, fur, etc, are all composed of
proteins.
2. Proteins compose all enzymes. Every chemical sequence is dependent on enzymes. Without
people's enzymes, chemical sequences will be retired leading to disruption of biological function.
3. Proteins act as "taxis" or shuttles in the membrane to move various molecules and ions from
one side of a membrane to another.
4. Proteins act in plasma transfer ions and molecules throughout the body. For example, globulin,
a protein, transports Thyroxine, a hormone, to all cells.
5. Proteins control osmotic forces. For example, albumin determines the toxicity of blood. It
normally causes the blood to be hypertonic thus drawing water from extracellular space.
6. Proteins influence the pH of systems by binding H+ which can be used to minimize changes in
pH.
7. Proteins compose all antibodies which are critical for killing invading bacteria.
8. Proteins compose hormones. Both proteins and its metabolites regulate cell metabolism and
permeability of cells. For example, insulin, human growth hormone
(HGH), vasopressin (antidiuretic hormone), etc. are all proteins.
9. Proteins act as a source of fixed nitrogen for other molecules who need nitrogen.Heme, a
major component of hemoglobin which transfers oxygen to the tissue gets nitrogen from
proteins.
10. Proteins are a major source of energy. Once the nitrogen has been removed the leftover
carbon skeleton is shuttled into acetyl CoA to make ATP. In starvation proteins in the body are
used as the last source of energy. Starved persons have no
muscle mass since the muscles have been catabolized into energy.
Proteins... so how exactly are they made?
DNA / RNA and Proteins
All proteins are generated by molecular commands from DNA and RNA. In later modules, you
will study the processes of Transcription and Translation which result in the production of
proteins.
Which classes of proteins are produced by Transcription and Translation?
All are!

When alteration occurs in the Transcription/Translation processes (i.e. mutations) various critical
proteins are not produced resulting in many chemical disorders. As stated earlier, the importance
of protein structure and function cannot be over-emphasized (Figure 13).
The wide variety of functions that proteins perform requires that they come in many different
shapes and sizes because each one is specific to the job it must do.
Our knowledge of protein structures can help us understand how they work. Sometimes we want
to STOP a protein from working.
This may be because it is no longer working correctly and is causing damage to the body or it is
no longer responding to proper controls due to a disease or infection from bacteria or a virus
protein.
Many medications that people take are prescribed to correct problems associated with faulty
proteins in the body.
Thus...
Protein... its whats for dinner (Figure 14).
Protein... the other white meat.
Protein... its in you.
Protein... it makes you who you are.
Prions:
When Proteins go Bad... the case of the infectious protein?!
A prion is an infectious agent that is composed of protein (i.e. is not a virus, bacteria, or other
microbe). To date, all such agents that have been discovered propagate by transmitting
a misfolded protein state; the protein does not itself self-replicate and the process is dependent on
the presence of the polypeptide in the host organism.
The misfolded form of the prion protein has been implicated in a number of diseases in a variety
of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow
disease") in cattle and Creutzfeldt-Jakob disease (CJD) in humans (Figure 15).
All known prion diseases affect the structure of the brain or other neural tissue, are collectively
called transmissible spongiform encephalopathies (TSEs), and are untreatable and fatal.
Current research suggests that the primary method of infection in animals is through ingestion.
Waste not want not... may not be the best idea here.
As a way to save money on animal feed some farmers mix in dead matter from other cattle with
the normal feed (Figure 16). It is thought that many cases of prion disease in livestock were
caused from the animals being fed from feed containing the brain matter of other livestock that
were carriers of the disease. Yikes!

Proteins: Albumin... the water keeper

Why does it look like some starving children have big/protruding/swollen abdomens?
The explanation ties together protein metabolism and osmosis. The liver makes plasma proteins
- the most important being albumin - which is a protein that maintains the osmotic pressure in the
blood.
The liver needs the amino acids from food to make albumin. With starvation, the essential amino
acids are not available for the liver to make albumin. This condition is called Kwashiorkor,
when children ages 1-4 do not get enough protein in their diet (Figure 17).
Albumin is a powerful osmotic agent at the capillary level that draws fluid from the interstitial
space. If the albumin is not present, the interstitial space acts as the major osmotic force and
water from the blood enters into the interstitial space.
The result of these physical forces is that the fluid enters the interstitial space and causes it to
expand which results in the abdomen being bloated. It is not the stomach that is bloated nor is
their fat in the abdomen it is fluid from the the plasma moving into the interstitial space.
For the baby to lose this expanded stomach, protein must be introduced into the diet.
Regretfully, persons not aware of this biology assume the starving person is okay since he has a
bloated abdomen, which they think is a stomach full of food.
Protein Metabolism: What happens to proteins when they are consumed?
When we eat any food source, most people are completely unaware of what is taking place with
that morsel of a meal once it is swallowed (Figure 18). For proteins, the journey to assimilation
begins in the stomach. After ingestion of a protein food, it is broken down mechanically by the
peristaltic motion of the gastrointestinal tract and chemically by the release of enzymes and
hormones that take part in digestion (Remember that ol' module on digestion?). The process of
digestion reduces the macromolecules into particles small enough to cross the lining of the gut
and reach the internal environment. The digested nutrients are passed from the gut lumen into the
blood or lymph, which distributes them through the body.
When we consume either vegetable or animal proteins in our meal, the simple chemical bonds
(e.g. hydrogen bonds) holding the molecules together are broken by specific digestive enzymes
and other enzymes involved in dehydration synthesis will disassemble the long polypeptide
chains into individual amino acids (Figure 19).
These amino acids are then absorbed through the lining of the intestines and carried by the blood
stream throughout the body. All of the cells in our body are surrounded by a fatty cell membrane
to keep the contents separate from the rest of the body. These membranes have special proteins
inserted in them that allow certain molecules like amino acids to enter. Once inside, the cells
then use these amino acids to assemble the proteins that our bodies make by following the
blueprint in our genes.

Protein Metabolism:
Delivering the muscles and then some...
In the stomach, proteins are broken down by digestive enzymes and hydrochloric acid into short
chains of amino acids (often called peptides or polypeptides), which pass to the small intestines
(Figures 20 & 21).
When peptides reach the small intestines they are broken down further into individual amino
acids (monomers) by the pancreatic digestive enzymes (e.g. trypsin, chymotrypsin, and
carboxypeptidase).
After which, the majority of the amino acids are carried from the small intestine to the liver by
way of the hepatic portal vein (Figure 22).
Nothing like a little fava beans and some liver...
The human liver can synthesize 9 out of the 20 different amino acids used in proteins (Figures 23
& 24). The amino acids that cannot be synthesized are called essential amino acids and must be
supplied by the diet in the foods we eat (Figure 25).
Proteins that are stored in the liver or circulating in the blood stream are transported to the tissues
of the body. These proteins are rapidly exchanged into the unique proteins needed by the
specific tissue or transformed into other substances like hormones.
Some proteins are temporarily stored until they are needed. All tissues in the body use the
available amino acids in proteins that are specifically required for building or repairing their own
characteristic proteins.
The Urea Cycle... something you do not necessarily ride
When absorbed amino acids are carried to the liver they are used to synthesize proteins which are

either stored or transported through the blood to various tissues in the body. Excess newly
synthesized amino acids are broken down into keto acids and transformed into glucose to be used
for energy or stored as glycogen or fat. In this process the amino group is separated from the
amino acid and becomes ammonia.
Amino acids that are not absorbed pass through to the large intestines where bacteria remove the
nitrogen from the amino acids (deamination) to form ammonia.
Unfortunately, ammonia is highly toxic to living things and must be eliminated in a way that
does no harm. Unlike fish we do not have enough available water to adequately dilute and
remove ammonia. So our bodies convert ammonia to ammonium ion which then enters the urea
cycle where it becomes urea (Figure 26). Urea is non-toxic and easy for our body to dispose of.
The urea cycle occurs only in the mitochondria of the liver. Urea is excreted from the body by
way of the urine through the kidneys.
Examples of Metabolic Diseases
Phenylketonuria (PKU) is characterized by a deficiency in the enzyme necessary to metabolize
the amino acid phenylalanine to the amino acid tyrosine (Figure 27).
Left untreated, this condition can cause problems with brain development, leading to progressive
mental retardation, brain damage, and seizures. PKU, however, is one of the few genetic diseases
that can be controlled by diet. A diet low in phenylalanine and high in tyrosine can be a very
effective treatment. There is no cure. Damage done is irreversible so early detection is crucial.
Maple Syrup Urine Disease (MSUD) gets its name from the distinctive sweet odor of affected
infants' urine (Figure 28). It is caused by a deficiency in the enzyme that breaks down the amino
acids leucine, isoleucine, and valine (Figure 29). This leads to a buildup of these amino acids
and their toxic by-products in the blood and urine.
Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage,
and eventually die.
Albumin

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Protein that maintain the osmotic pressure in the blood.

Carboxypeptidase

An enzyme that hydrolyzes the carboxy-terminal (C-terminal) end of a p

animals, and plants contain several types of carboxypeptidases with dive
from catabolism to protein maturation.

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Chymotrypsin

A digestive enzyme that can perform proteolysis. In other words it chew

smaller pieces. Chymotrypsin cleaves peptides at the carboxyl side of ty
phenylalanine because these three amino acids contain aromatic rings, w
'hydrophobic pocket' in the enzyme.

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Dipeptide

A protein composed of 2 amino acids.

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Enzyme

A protein that catalyzes a chemical reaction.

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Hepatic Portal Vein

(AKA Portal Vein)

A portal vein in the human body that drains blood from the digestive sys
glands. It is one of the main components of the hepatic portal venous sy

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Hydrogen Bonds

A type of chemical bond formed between a hydrogen (H) atom of one m

(O), nitrogen (N), or sulfur (S) atom of another molecule (or in the same
your life to them.

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Hydrophilic

Molecules that dissolve in water. They can be called water loving.

Hydrophobic

Molecules that do not dissolve in water. They can be called water feari

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Keto Acids

Organic acids containing a ketone functional group and a carboxylic acid

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Pepsin

A digestive protease released by the chief cells in the stomach that funct
proteins into peptides.

Polypeptide

A protein composed of 3 or more amino acids.

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Primary Structure

The amino acid sequence of a polypeptide.

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Secondary Structure

The folding of a polypeptide in to alpha-helix or beta-pleated sheets.

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Tertiary Structure

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The way in which the alpha-helices or beta-sheets (secondary structures)

folded or arranged into a three-dimensional configuration.

Quaternary Structure

The fourth level of protein architecture, resulting from interactions betw

polypeptide chains in some proteins. Association of two or more folded
functional problem.

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Trypsin

Secreted into the duodenum, where it acts to hydrolyze peptides into its
named amino acids (these peptides are the result of the enzyme pepsin b
proteins in the stomach). This is necessary for the uptake of protein in th
peptides are smaller than proteins, they are still too big to be absorbed th
ileum.

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Urea

A waste product for your bodies excess nitrogen from the amino groups
found and retracted from urine. It also, howev

Carbohydrates
One of America's favorite carbohydrate feasts usually enjoyed while viewing sports events.
Pizza, buffalo wings, beer, fried onion rings are great "comfort" foods and your biological system
will store the calories for a rainy day.

Awww sugar sugar...

Carbohydrates (saccharides) are the most abundant of the four major classes of biomolecules.
They fill numerous roles in living things, such as the storage and transport of energy (e.g., starch,
glycogen; Figure 1) and structural components (e.g., cellulose in plants and chitin in animals;
Figures 2 and 3).
Carbohydrates are the most common source of biochemical energy.
In a list of ingredients, any word that ends with "-ose" (such as "glucose", "dextrose", "fructose",
etc.) will likely denote a sugar (carbohydrate).
With this ring I thee wed...
Monosaccharides (from Greek monos: single, sacchar: sugar) are the most basic unit of
carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble,
crystalline solids. Some monosaccharides have a sweet taste.
Examples of monosaccharides include glucose (dextrose), fructose, galactose, xylose, and ribose.
Monosaccharides are the building blocks of disaccharides such as sucrose and polysaccharides
(such as cellulose and starch).
Most monosaccharides you will encounter in your food and elsewhere have a cyclic-like
structure (Linear monosaccharides will cyclize in water to form a ring stucture; Figure 3).
Two joined monosaccharides are called a disaccharide and these are the simplest polysaccharides
(e.g. sucrose and lactose). They are composed of two monosaccharide units bound together by a
covalent bond known as a glycosidic linkage formed via a dehydration reaction. This results in

the loss of a hydrogen atom (H) from one monosaccharide and a hydroxyl (OH) group from the
other.
Sucrose, also known as table sugar, is the most abundant disaccharide, and the main form in
which carbohydrates are transported in plants (Figure 4).
Poly wants a cracker (salty carbohydrate)
Polysaccharides are polymeric carbohydrate structures that are formed of repeating units (either
mono- or di-saccharides) joined together by glycosidic bonds. These structures are often long
straight chains, but may contain various degrees of branching. Polysaccharides are often quite
heterogeneous, containing slight modifications of the repeating unit.
Examples of polysaccharides include storage molecules such as starch and glycogen, and
structural molecules such as cellulose and chitin (Figure 5).
Depending on the structure, these macromolecules can have distinct properties from their
monosaccharide building blocks. They may be amorphous (non-crystalline) or even insoluble in
water.
Saccharides and polysaccharides play many other integral roles in biology in addition to being a
source of biochemical energy.
Ribose and its relative 2-deoxyribose are both 5-carbon sugars and act as chemical messengers in
the body and are integral components in the macromolecules RNA and DNA (Figure 6).
Proteins that contain short carbohydrate chains are known as glycoproteins. These molecules
have important functions on the surfaces of all cells. Glycolipids, carbohydrates bonded to
lipids, are essential in cell membranes.
The Sugar Store
Starches, also known as complex carbohydrates, are glucose polymers in which glucose units are
linked to each other with glycosidic bonds in long chains.
It is made up of a mixture of Amylose (15-20%) and Amylopectin (80-85%) (Figures 7 and 8).
Amylose consists of a long straight (linear) chain of several hundred glucose molecules and
Amylopectin is a highly branched molecule made of several thousand glucose units (every chain
24-30 glucose unit).
Starches are insoluble in water. They can be digested by hydrolysis and catalyzed by the enzyme
called amylase, which can break the glycosidic bonds. Humans and other animals have
amylases, so they can digest starches.
Potato, rice, wheat, and maize are major sources of starch in the human diet. The formation of
starches are the way that plants store glucose.
Glycogen is a polysaccharide that is found in animals and is composed of a branched chain of

glucose residues (Figure 9). In other words, it is the animal version of starch. It is stored mostly
in the liver and some in muscles.
Bloody Carbohydrates
Did you know that your blood type (A, B, AB, and O) is defined by carbohydrates?
Almost a century ago, scientists discovered that human blood can be classified into four blood
group types: A, B, AB, and O. This classification results from the presence on the surface of red
blood cells of three different oligosaccharide units, designated A, B, and O. A and B are just
modified versions of O (Figure 10). Individuals with type AB have both A and B
oligosaccharides displayed on the same cells.
Selecting a matching blood type is vitally important in choosing blood for transfusions because a
major component of the body's immune system is a collection of proteins called antibodies that
recognize and attack foreign substances (e.g viruses, bacteria, potentially harmful
macromolecules, and foreign blood cells).
Among the targets of these antibodies are cell-surface molecules that are not present on the
individual's own cells and are thus considered foreign blood cells. For example, if Boba Fett
(a student from a galaxy far far away) has blood type B, his plasma will contain antibodies to the
type A oligosaccharide. If he gets a transfusion of blood type A, the type A blood cells will be
recognized as foreign and his immune system will attack them (i.e. clumping of cells, blocking
of capillaries, and possibly death).
People with blood types A, B, and AB all lack antibodies to type O cells. Therefore individuals
with type O blood are known as universal donors and those with type AB blood are known as
universal acceptors (Figure 11).

In the beginning ...

The digestion of carbohydrates begins in the mouth by action of the salivary enzyme amylase
into smaller saccharide molecules (Figure 12).
Saccharides like starch continue to be catabolized in the stomach by the enzyme ptyalin and in
the small intestines by the pancreatic enzymes amylase and maltase.
The metabolism of polysaccharides generates monosaccharides like glucose, fructose, and
galactose. These simple sugars are then absorbed into the small intestines and are carried by the
hepatic portal vein to the liver.
Sugar is partially metabolized in the liver, but the sugar in the blood is subsequently transported
to the heart and then to all parts of the body. Glucose reserves are stored as glycogen in the liver
and skeletal muscle.
Glycolysis: The ATM for biochemical energy
Most carbohydrates will eventually undergo glycolysis for use as metabolic energy. When
glucose is oxidized it releases energy in the form of 2 ATPs and 2 NADHs. Its quick and easy
like an ATM, but also like an ATM you are limited in the amount you can withdraw (Figure 13).
As in this case only 2 ATPs can be immediately generated. Larger withdrawals or more ATP
have to be handled by the body's bank: Fatty acid oxidation and the Krebs cycle.
The product of glycolysis, pyruvate, can be further processed for energy under either anaerobic
or aerobic conditions. It is during aroebic conditions that pyruvate is made into the common
metabolite acetyl-CoA (involved in Krebs cycle, lipid metabolism, and protein metabolism). The
acetyl-CoA is used in tissues (e.g. muscle) to enter the Krebs cycle to generate ATP. However,
when oxygen supply runs low, this metabolism produces pyruvic acid and lactic acid (anaerobic).
During fasting or starvation, the body mobilizes fat reserves for ATP synthesis to supply the body
with energy. Fat metabolism products (by way of acetyl-CoA) can be converted directly into the
metabolic pathways of glucose (Figure 14). This process is called gluconeogenesis which refers
to the production of glucose from non carbohydrate sources.
In overeating, however, sugars and starches like those in potato chips, beignets, and candy can be
converted into fats for energy storage when energy supply is in excess (by way of acetyl-CoA).
When sufficient stores of ATP are available, acetyl-CoA is used to make fatty acids.
Glucose that is not needed to generate energy can also be converted to glycogen for storage.
Insulin and Glucagon: Yin and Yang
Plasma glucose levels regulate insulin secretion from pancreatic -cells by way of feedback
loops. The greater the amount of glucose in the blood the greater the amount of insulin
secretion. Conversely, the smaller amount of glucose in the blood, the less insulin is secreted.
The major functions of insulin are to counter the action of a number of hormones that increase
glucose in the blood and to maintain low blood glucose levels. In addition, insulin causes cells
to absorb glucose ceasing a decrease in blood glucose. Insulin stimulates the conversion of

carbohydrates into fat, diminishes the breakdown of fat, and increases amino acid uptake. In the
liver, glucose is stored as glycogen. Insulin activates the receptors on the liver cell surfaces
causing 1. an increase in the storage of glucose as glycogen and 2. a decrease in the release of
glucose into the circulation by liver cells. In other tissues of the body, insulin increases glucose
uptake by increasing the number of plasma membrane glucose transporters on the cell surface
(Figure 15).
Insulin effects are countered by the hormone glucagon which does the opposite of insulin.
Glucagon, a hormone, also secreted by the pancreas will cause blood glucose levels to increase.
When blood sugar levels are low, glucagon is released causing blood glucose levels to increase.
The release of glucagon is another example of a feedback system to regulate blood glucose.
Besides insulin and glucagon, another hormone can control blood glucose levels. When you get
excited before an athletic event, adrenaline (epinephrine) is secreted and it has multiple effects
on your body. One of those effects is to increase the amount of glucose in the blood. Thus in
any situation of excitement, the blood glucose levels increase which generates quick energy for
fight or flight (Figure 16).
Phosphorylated incarceration...
As you recall, glycolysis is a series of enzyme-catalyzed reactions that breaks down each glucose
molecule into two pyruvate molecules, and yields two ATPs and two NADHs. Glucose can
easily enter and exit cells. So what keeps glucose in a cell long enough for it to be used for
glycolysis or glycogenosis?
Phosphorylation. Glucose is carried in blood to cells where it is transported across the cell
membrane. As soon as it enters the cell, glucose is phosphorylated using a little ATP. From here
on, all intermediates are sugar phosphates and are trapped within the cells because phosphate
(very polar and hydrophillic) cannot cross cell membranes (Figure 17).
Prison break!
Glycogen forms an energy reserve that can be quickly mobilized to meet a sudden need for
glucose and only the glycogen stored in the liver can be made accessible to other organs. About
four hours after a meal, glycogen begins to be broken down and converted again to glucose. For
the next 812 hours, glucose derived from liver glycogen will be the primary source of blood
glucose to be used by the rest of the body for fuel. So how can glucose that is trapped in liver
cells be released into the blood stream?
Liver cells possess an enzyme (glucose-6-phosphatase) which removes the phosphate group from
phosphorylated glucose (glucose-6-phosphate) produced during glycogenolysis or
gluconeogenesis. Free glucose can then be sent into the bloodstream for uptake by other cells.
Obesity Epidemic
Many parts of the world (e.g. USA) are suffering from an obesity epidemic.
The reason for the placement of the topic obesity in the carbohydrate section is that it is the most
inexpensive form of food and is thought to be a major food source for low income persons who

become obese.
The problem with eating primarily carbohydrates is that it is deceptive how many calories are in
any giving serving. Also, they typically do not leave a person with a fulfilled/full sensation like
other foods that contain more fats, proteins, or water. Junk-food vegetarians, people who eat
pastas, chips, and other easy-to-prepare carbohydrate-rich foods, tend to be
more overweight than other vegetarians and omnivores.
The Body Mass Index or BMI is a measure of body fat based on height and weight that applies to
both adult men and women. BMI provides a reliable indicator of body fatness for most people
and is used to screen for weight categories that may lead to health problems, such as obesity. Go
to this site to calculate your BMI. Is your BMI normal?
The values for an overweight person in terms of BMI are 25.5 -29 whereas for an obese person it
is a BMI value of 30 and above (Figure 18). Obesity puts an individual at high risk for many
cardiovascular diseases including high blood pressure, sleep apnea certain kinds of cancer,
insulin resistance and Type II Diabetes.
peaking of diabetes...
Diabetes (diabetes mellitus) is a metabolic disorder in which there is an inability to oxidize
carbohydrates due to disturbances in insulin function.
There are two types of Diabetes: I and II. Type I Diabetes is a condition in which the pancreas no
longer produces insulin. On the other hand, Diabetes II is a condition in which the pancreas
continues to produce insulin, however, the insulin has no effect on the cell so that carbohydrate
intake is inhibited. Diabetes II can be caused by being overweight and lack of exercise. It is a
major outcome of the obesity epidemic. In a normal condition, insulin promotes the intake of
glucose by the cells. The earlier an individual is diagnosed with diabetes, the better the chance
he has of protecting himself from some of its negative consequences such as kidney failure,
blindness, and limb amputation due to circulatory problems (Figure 19).
Early diagnosis of diabetes hopefully leads to weight reduction increased exercise and most
importantly a change in lifestyle. This simple approach can eventually lead to a situation in
which insulin's effects on cell receptors is increased. It should be emphasized that persons with
type I diabetes will always need insulin (Figure 20). Even though being thin is fashionable,
humans who have fat reserves can survive hard times in circumstances when slender people may
succumb to starvation.
Modern society has generated a regular agricultural surplus and cultural induced inactivity to
lead to obesity, and has placed our population at risk for long-term serious obesity-related health
issues.
Acetyl Coenzyme A (Acetyl
CoA)

Acetyl CoA is an important molecule in metabolism which is used in many re

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Beta-cells

Beta cells are a type of cell found in the pancreas that produce insulin. They
up a large portion of the islets of Langerhans.

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Body Mass Index (BMI)

A measure of body fat based on height and weight that applies to both adult m
women. BMI provides a reliable indicator of body fatness for most people an
used to screen for weight categories that may lead to health problems, such as
obesity.

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Catabolism

The set of metabolic pathways that break down molecules into smaller units a
release energy.

Disaccharide

Two monosaccharides linked together.

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Fatty Acids

Are generated by a series of reactions that are essentially the reverse of fatty a
break down. Normally fatty acids are synthesized in the liver, but fat storage
the fat cells that are primarily distributed around the waist and hips.

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Gluconeogenesis

A metabolic pathway that results in the generation of glucose from non-carbo

carbon substrates such as pyruvate, lactate, glycerol, and glucogenic amino ac

Glycogen

A polysaccharide of glucose (Glc) which functions as the primary short term

storage in animal cells. It is made primarily by the liver and the muscles.

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Insulin

Stimulates cells to take in glucose. It is involved in the conversion of carbohydrates into fat, diminis
the breakdown of fat, and amino acid transport into cells. Insulin also modulates protein transcriptio
stimulates growth, DNA synthesis and cell replication.

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Monosaccharide

A carbohydrate consisting of only one sugar molecule.

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Oligosaccharide

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A saccharide polymer containing a small number (typically 3 to 10) of compo

sugars, also known as simple sugars.

Plasma Glucose Levels

(AKA Blood Sugar)

Concentration of glucose in the blood. Glucose, transported via the bloodstre

from the intestines or liver to body cells, is the primary source of energy for t
body's cells.

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Polysaccharide

A Polysaccharide is two or more monosaccharides linked together.

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Saccharide
(AKA
Carbohydrates)

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The most abundant of the four major classes of biomolecules, which also include proteins
and nucleic acids. They fill numerous roles in living things, such as the storage and transp
energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals
Additionally, carbohydrates and their derivatives play major roles in the working process
immune system, fertilization, pathogenesis, blood clotting, and development.

Salivary Amylase

An enzyme that breaks starch down into sugar. Amylase is present in human
where it begins the chemical process of digestion.

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Sugar

A basic food carbohydrate compound in which carbon, hydrogen, and oxygen

are combined in about a 1:2:1 ratio. Table sugar is known as sucrose.

Lipids
The biological molecules that contain the most energy are lipids. Food cooked with saturated fats
give a distinctive, delightful flavor but also a lot of ATP potential via calories. Saturated lipids
love to line the inside of your arteries decreasing the amount of oxygenated blood that can be
transmitted to the vital organs. Unsaturated fats such as olive oil do not have as much ATP
potential but they do not play a major role in clogging your arteries.

Lipids: The fat of the land

Our bodies receive nearly all of the energy they need from the oxidation of carbohydrates and
lipids. Carbohydrates are a quick source of available energy, while lipids function mostly for
energy storage (Figure 1).
Lipid reserves in the fat deposits of a male who weighs 154 lbs and has 100,000 kcal of energy
can maintain human body functions without food for 30-40 days as long as sufficient water is
available. Lipids provide the sole source of energy in hibernating animals and migrating birds.
Lipids are more compact and contain more energy per gram than glycogen, the stored form of
carbohydrates found in skeletal, muscle, and liver. Body weight would increase approximately
110 pounds if glycogen replaced fat as the energy reserve in our bodies.
Lipids are beautiful... well at least chemically they are.
Lipids are stored as fat throughout the body in specialized connective tissue called adipose tissue
(Figure 2). Adipose tissue cells consist of fat globules which can occupy up to 90% of the cell
volume.
Many cells contain phospholipids as a structural component in the bilayer of biological
membranes (Figure 3).
Other functions of lipids include providing a waterproof covering on plants and some animal
bodies.

Lipids and lipid derivatives serve as a precursor to vitamins and hormones. For example,
athletes who do not have enough fat lose their secondary sexual characteristics since their sex
hormone levels are decreased. Adipose tissue serves as a protective physical cushion and
provides structural support to help prevent injury to vital organs such as the heart, liver, kidneys,
and spleen.
Fat also insulates the body from heat loss and extreme temperature changes. Fat deposits are
buoyant so that animals who need buoyancy usually have high amounts of fat.
Chemistry of Lipids
Lipids contain large regions composed almost entirely of hydrogen and carbon with nonpolar
carbon-carbon or carbon-hydrogen bonds. Nonpolar water-fearing regions make lipids
hydrophobic and insoluble in water but they do dissolve in nonpolar solvents like ether. Lipids
are classified into three major groups:
1. Phospholipids: structurally similar to oil and contain phosphorous and nitrogen as well as
carbon, hydrogen, and oxygen. They are hydrophobic in their tails and hydrphilic in their
phosphate group. Phospholipids make up a major component of the cell membrane (Figure 4).
2. Steroids: fused-ring structures. Example are hormones. Cholesterol is the key molecule in
steroids since it is found in all steroids (Figure 5). It is the precursor to sex hormones and
vitamin D. It is also found in cell membranes.
3. Oils, fats, and waxes: similar in structure and contain only carbon, hydrogen, and oxygen.
Plant oils are commonly used for cooking (Figure 6). Fat is produced by adipose cells.
What does it mean for a fat to be unsaturated?
Fatty acids may be either saturated or unsaturated:
Saturated fatty acids - When all carbons in a fat molecule are bonded to the maximum number of
hydrogen atoms, it is considered saturated (i.e. saturated with hydrogen). Pork lard is a great
example of a saturated fat (Figure 8).
Unsaturated fatty acids - There are double bonds between some of the carbons in the
hydrocarbon tail which cause kinks in the molecule. This feature means that unsaturated fatty
acids have less calories since they have less hydrogen atoms. Monounsaturated fats have only
one carbon-carbon double bond and polyunsaturated fats have more than one of these double
bonds. Canola oil is an example of an unsaturated fat (Figure 9).
Notice how butter is solid at room temperature while canola oil or most vegetable oils are not?
Well it has to do with the saturated and unsaturated fat content. Figure 10 shows the amounts of
saturated, monounsatured, and polyunsaturated fats in canola oil versus butter. What is the
difference between butter and canola oil? Hydrogenation and Health
Hydrogenation of an unsaturated fatty acid refers to the addition of hydrogen atoms to the double

bonds. The addition of hydrogen bonds results in fat that is solid at room temperature but melts
easily with minimal heat (e.g. shortenings and margarine, Figure 11) What is interesting is that
the standard method of hydrogenation increases the number of Trans fats. Overall Trans fats
should be avoided to minimize cardiovascular problems such as strokes or heart attacks due to
formation of Trans fat plaques.
Glycerides
Fats and some oils are formed by dehydration synthesis from one molecule of glycerol and three
fatty acid subunits. Glycerides are the most abundant lipids and the richest source of energy in
the body. The terms mono-, di-, and tri-glyceride refer to the number of fatty acid tails that are
attached. When three fatty acid subunits are attached the chemical name for these molecules is a
triglyceride (Figure 12). They have a high concentration of chemical energy since they have a
large number of hydrogen atoms and are used for semi-permanent energy storage.
Waxes
Waxes have fatty acids linked to large, long-chain alcohols rather than to glycerol. Waxes are an
important component of cutin, a secretion that forms a waterproof coating over leaves, stems,
and certain fruits of some terrestrial plants. Animals synthesize waxes as a waterproofing agent
for mammalian fur and insect exoskeletons. Western honey bees produce wax to build
honeycomb cells to raise their young and to store honey and pollen (beeswax, Figure 13).
Fat free cells? Impossible...
Phospholipids
Phospholipids are similar to a triglyceride except that in phospholipids, one of the fatty acids is
replaced by a phosphate group. This phosphate group is polar, charged, and soluble in water. A
molecule or portion thereof becomes polar when it contains atoms that interact with water
molecules and are water-loving. The two dissimilar ends of the phospholipid, a polar
hydrophilic head and a nonpolar hydrophobic tail, are crucial for the structure of the cell
membrane (Figure 14). When the phospholipid molecules assemble into a membrane all of the
polar heads are arranged to protect the nonpolar tails from the extracellular aqueous
environment as well as the aqueous intracellular cytoplasm. The bilayer is interspersed with
protein molecules that interact with the external and internal environment of the cell to serve as
signaling receptors, transport molecules, and ion channels.
Steroids
Steroids are composed of four carbon rings fused together with various functional groups
protruding from them (Figure 15). These rings of carbon include cholesterol, male and female
sex hormones, hormones that regulate salt levels in the body, others that assist in fat digestion,
and insect hormones that stimulate the shedding of exoskeletons.

Cholesterol: The Good, The Bad, And The Ugly

Cholesterol is an important component of membranes and is used by cells to synthesize other
steroids (Figure 16). Abnormally high levels of triglycerides and cholesterol are thought to be
involved in the "hardening" of the arteries. As a result of lipids not being soluble in blood,
excess intake of saturated fat can cause plaques or plugs of molecules containing cholesterol to
develop and deposit on artery walls. This may lead to blockage, high blood pressure, stroke, or
heart attack. Limiting dietary intake of saturated fats, like those found in animal fats, can
prevent these plaques from forming. Fats derived from vegetables, such as corn oil and canola
oil, are better choices for protecting arteries from plaque buildup.
Cholesterol is a steroid that has many important functions. It is the precursor to male and female
hormones, it is a major ingredient in the cell membrane, it is a precursor to bile salts involved in
fat metabolism. Keep in mind that cholesterol is formed from acetyl-CoA, an important
molecule in the Krebs cycle.
Who framed cholesterol?
LDL, a molecule with a chip on its shoulder
Because cholesterol is hydrophobic it is transported in the blood by a molecule called a
lipoprotein which is a chemical combination of a lipid and a protein. There are two kinds of
lipoproteins: high density and low density lipoproteins.
High density lipoproteins (HDL) 1. carry cholesterol away from the blood vessels and 2.
transport it to the liver. They are protein dense and are considered to be a molecular transport
device to minimize the amount of cholesterol in the blood. Normal values are 35-135 mg/dl with
adults being 85mg/dl. The good cholesterol.
Low density lipoproteins (LDL) get deposited in blood vessels. They are considered to be a key
player in the development of plaques in blood vessels in conjunction with other factors such as
inflammation. LDL levels range in value of 62-130 mg/dl with a normal adult being 81 mg/dl.
The bad cholesterol.
For good health, HDL should be in high concentration and LDL should be low. Exercise is a
major way to increase HDL (Figure 17). Better than any medicine, it increases HDL and
lowered LDL. However, genetic background in certain groups of people requires the use of
medicine. Besides exercise, niacin is reported to cause a 10-30% increase in HDL levels.
Conversely, statins which are a class of drugs that lower LDL, are considered to be effective
(Figure 18). Although these medications are effective, they do have their downside. For niacin
to be effective, it has to be taken in large amounts and this results in flushing of the skin and
nausea. Statins are effective in decreasing cholesterol levels but side effects may affect muscle
and nerve function.

You want
ATP? Eat butter!
No matter what your body size or type everyone has some fat storage in their body (Figures 19
and 20). These fat stores are used by the body during fasting or starvation to make ATP by way
of the TCA cycle and electron transport chain.
All dietary lipids pass through the stomach to the small intestines for digestion by the pancreatic
enzyme lipase.
Fatty acids aggregate on the wall of the intestines and are reassembled into complex chemical
structures called chylomicrons (Figure 21, phospholipids = green head/yellow tail, T =
triglycerides, C = cholesterol). These structures are kind of similar to a lipid bilayer with the
exception of not having that second layer of phospholipids. Having only a mono-phospholipid
layer allows the structure to be filled with hydrophobic molecules like lipids.
Chylomicrons are then passed directly into the lymph to the blood and rest of the body.
Oh my, omega fats are essential for our health?!
Essential fatty acids (EFAs) are fatty acids that cannot be constructed within humans from other
components by any known chemical pathways, and therefore must be obtained from the diet.
The term refers to fatty acids involved in biological processes (e.g. phospholipids), and not those
which may just play a role as fuel.
There are two families of EFAs: omega-3 or omega-6. Fats from each of these families are
essential, as the body can convert one omega-3 to another omega-3, for example, but cannot

create an omega-3 from omega-6 or saturated fats. They were originally designated as Vitamin F
when they were discovered as essential nutrients in 1923, but have since then been labeled as a
fat.
The end of the polyunsaturated fatty acid is called Omega (last letter in greek alphabet). Omega3 fatty acids, have a carbon-carbon double bond 3 carbons from the omega-carbon. Omega-3 is
found in "fatty" fish such as salmon that is involved in preventing the build-up of fat deposits in
arteries (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) (Figure 22). It
therefore minimizes the incidence of strokes and heart attacks. Polyunsaturated, unsaturated, and
saturated fats are all found in the same product.
Some of the food sources of omega-3 and omega-6 fatty acids are fish and shellfish, flaxseed
(linseed) (Figure 23), hemp oil, soya oil, canola (rapeseed) oil, chia seeds, pumpkin seeds,
sunflower seeds, leafy vegetables, and walnuts.
Salvation from starvation is the backbone of obesity
Lipogenesis (fatty acid biogenesis) is the process by which simple sugars such as glucose are
converted to fatty acids, which are subsequently esterified with glycerol to form the
triacylglycerols that are packaged in VLDL (very low density lipoproteins) and secreted from the
liver.
Fatty acid biogenesis starts with acetyl-CoA (one of the last products of glycolysis and fatty acid
oxidation) and builds up by the addition of two carbons units.
In us, fatty acids are predominantly formed in the liver, adipose tissue, and mammary glands
during lactation.
Adipose tissue is located beneath the skin, around internal organs, and in the bone marrow.
Adipose tissue is found in specific locations which are referred to as 'adipose depots.'
For most females, a high percentage of the subcutaneous adipose (fat) tissue surrounds the areas
of the breasts, waist, hips and buttocks.
Most males have a high percentage of their subcutaneous fat distributed around the fat areas of
the chest, abdomen, and buttocks regions (Figure 24).
Insulin
Insulin is an indicator of the blood sugar level of the body, as its concentration increases
proportionally with blood sugar levels.
Thus a large insulin level is associated with the fed state. As one might expect it is involved in
the signaling of metabolic pathways for storage, such as fatty acid biosynthesis and
triacylglycerides (TAGs) biosynthesis.
Insulin, a protein and hormone, causes cells in the liver, muscle, and fat tissue to take up glucose
from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an
energy source. When insulin is absent (or low), glucose is not taken up by body cells, and the

body begins to use fat as an energy source, for example, by transfer of lipids from adipose tissue
to the liver for mobilization as an energy source.
Therefore, if someone is always in the fed state (e.g. eats frequently or continually eats large
portions) their body will typically be producing and storing TAGs. Typically an increase in waist
size is observed (Figure 25).
Conversely, if someone is always in the starved state (e.g. eats infrequently or eats very small
portions) their body will not produce or store as many TAGs.
The bitter truth of bile...
Bile is a bitter yellow, blue, and green fluid secreted by hepatocytes (liver cells) from the liver.
Typically, bile is stored in the gallbladder (Figure 26) between meals and upon eating is
discharged into the duodenum where the bile aids the process of digestion of lipids by
emulsification (i.e. make water-soluble).
When fat is in the intestine, it triggers release of bile. Bile acts to some extent as a
surfactant, helping to emulsify fats, and thus aids in their absorption in the small intestine.
Bile salts combine with phospholipids to break down fat globules in the process of emulsification
by associating its hydrophobic side with lipids and the hydrophilic side with water (Figure 27,
looks kind of like cholesterol, doesn't it?).
The phospholipids have a charged "head" which prevents two fat droplets from recombining.
Pancreatic lipase acts on the triglyceride material of the fat in the small intestine and breaks them
down into two fatty acids and a monoglyceride, which are absorbed by the villi, rebuilt into
triglycerides, arranged into chylomicrons, and can then be transported in the blood.
Acetyl
Coenzyme A
(AcetylCoA)

An important molecule in metabolism, used in many biochemical reactions. Its main use is
to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for
energy production.

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Adenosine triphosphate

The main energy storage and transfer molecule in the cell.

(ATP)

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Adipose Tissue

Loose connective tissue in which fat cells accumulate.

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Cholesterol

A steroid that serves as the basis for steroid hormones and is also a key
component of membranes.

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Eicosapentaenoic acid
(EPA) and
Docosahexaenoic acid
(DHA)

Are omega-3 fatty acids found in fish oil. They are polyunsaturated fatty
acids used in the biosynthesis of hormones, phospholipids, and
prostaglandins.

Essential fatty acids (EFAs)

Fatty acids that cannot be constructed within an organism from other

components (generally all references are to humans) by any known chemical
pathways; and therefore must be obtained from the diet.

Glycerides

An ester formed between one or more acids and glycerol. Fatty acid esters
with glycerol are found in plant oils and animal fats.

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Lipase

A water-soluble enzyme produced by the pancreas that catalyzes the

hydrolysis of ester bonds in hydrophobic lipid molecules. Lipases perform
essential roles in the digestion, transport, and processing of dietary lipids
(e.g. triglycerides, fats, oils) in most if not all living organisms.

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Phospholipid

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A molecule containing glycerol, two fatty acid tails, and a phosphate head.
Found in the cell membrane (lipid bilayer) and in chylomicrons.

Plaque

Deposition of lipids in arterial walls.

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Saturated fatty acid

A fatty acid with no double bonds that contains the maximum number of
hydrogen atoms possible.

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Steroids

Lipids derived from cholesterol that contain four fused rings.

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Triglycerides
(triacylglycerides, TAGs)

Lipids composed of one glycerol and three fatty acids.

DNA

What does dogma have to do with molecular biology? Does it not refer to religion? Or are we
talking about that Kevin Smith movie?
Actually, dogma is simply an established opinion among a group of people. The central
dogma of molecular biology is an established opinion held among molecular biologists
pertaining to the flow of cellular information from the three main macromolecules of molecular
biology, DNA, RNA, and proteins. These molecules are different forms of the same information
required to run the cell.
DNA is the molecule that stores information long-term. It is also the molecule that transmits
information to new cells so all cells carry the same information.
RNA is the molecule that acts as a messenger carrying the information from DNA to protein.
Messenger RNA, known as mRNA, is a mobile short-term storage of cellular information.
Proteins are the molecules that perform the functional form of the information.
Simply stated, the central dogma says that the flow of cellular information (the information
required for a cell to live) flows from:
DNA --> RNA --> Protein
It also states this process is unidirectional meaning it NEVER flows from protein to RNA or
RNA to DNA.
DNA

What is all the fuss about DNA, anyway? Well, DNA holds all of the information required to run
a cell. It is also the molecule that is passed down from cell to cell so that every cell has the same
information.
In this module we will discuss this storage molecule, DNA , in detail and address the following
questions:
1.What are the molecules that make up DNA?
2.What is the difference between a molecule of DNA, a chromosome, and a genome?
3.How are new copies of DNA made?
4.What can cause DNA mutations?
5.How is DNA actually storing cellular information?
What are the molecules that make up DNA?
DNA and RNA belong to a class of macromolecules known as nucleic acids. DNA stands
for DeoxyriboNucleic Acid, and RNA stands for RiboNucleic Acid. As with other
macromolecules that you have learned about, DNA and RNA are made up of monomers, which
in the case of nucleic acids, are called nucleotides. There are three parts that make up a
nucleotide: a 5 carbon sugar, a phosphate group, and a nitrogenous base.
1. 5 Carbon Sugar (Pentose)
Both DNA and RNA have a 5 carbon sugar (also known as pentose) as the center of their
nucleotides. The 5 carbons of the sugar ring are labeled 1', 2', 3', 4' and 5' based on their position
in the ring with respect to the central oxygen (O). Using this numbering system we can indicate
the location on the carbon ring where other molecules are attached. The major difference
between a DNA nucleotide and an RNA nucleotide is the group attached to the 2' carbon of the
sugar ring (see Figure 1). In an RNA nucleotide the sugar is called Ribose andhas an OH group
on its 2' carbon, while in DNA the sugar is calledDeoxyribose and the 2' carbon only has a
hydrogen (H). Thus the sugar is called deoxy, because it is missing that oxygen (O).
2. A Phosphate Group
Each nucleotide of DNA or RNA contains a phosphate group on the 5 carbon. This group is
important for the formation of DNA or RNA polymer chains from individual nucleotides. The
phosphate group on the 5' carbon of one nucleotide can react with the OH group on the 3' carbon
of the sugar ring of a different nucleotide to form a bond between two nucleotides to make single
stranded DNA or RNA. See Figure 2 for an example of the phosphate group binding two
nucleotides together.

3. A Nitrogenous Base
The last piece of a nucleotide we need to discuss is the nitrogenous base, which is attached to the
1 carbon of the sugar. There are four different types of nitrogenous bases that can bind
a deoxyribose sugar to make a nucleotide. These four bases fall into two groups (Figure 3):
1. Pyrimidines nitrogenous bases with one carbon ring
Cytosine C
Thymine T
2. Purines nitrogenous bases with two carbon rings
Adenine A
Guanine G
Base Pairing
While the phosphate groups and sugar ring help bring together nucleotides to create a single
stranded chain of DNA, it is the nitrogenous bases that are used to create a double stranded DNA
molecule. This is referred to as base pairing (See Figures 4 and 5).
There are a few rules of base pairing that we must discuss in order to understand the structure of
DNA and how DNA can carry out its function.
Rule 1: Double stranded DNA contains two anti-parallel single strands. This means the two
strands are side by side in opposite directions. One runs from the 5' carbon to 3' carbon while the
second lays in the opposite 3 to 5' direction.
Rule 2: Base pairing always occurs between a purine and a pyrimidine.
This rule has two further specific parts:
Adenine ALWAYS pairs with Thymine (A-T)
Guanine ALWAYS pairs with Cytosine (G-C)
The formation of double stranded DNA by these rules creates a larger DNA structure known as
the double helix (Figure 5 left). The two strands intertwine like a twisted ladder with the 5' to 3
interactions of the nucleotides on the outside like the rails of a ladder and the base pairing
between the nitrogenous bases occurring on the inside forming rungs. Figure 4 shows a
simplified image of base pairing between two single strands of DNA while Figure 5 shows a
more detailed view with the double helix.

What is the difference between a molecule of DNA, a chromosome, and a genome?

Now that we know what makes a DNA molecule, lets discuss how its packaged within a cell.
Lets quickly review the building blocks first:
Nucleotide - a single monomer
Single stranded DNA - the linking of 5' and 3' carbons between nucleotides to create one strand
of DNA
Double stranded DNA (double helix) - two DNA strands running in opposite directions
connected by base pairing
You can imagine that an organism has a whole lot of double stranded DNA to store all of the
information needed to live, so how does all of that DNA fit into a tiny cell? Long double strands
of DNA are wrapped around proteins to form chromosomes (Figure 6), and this packaging of
DNA allows all of the DNA to fit within a single cell. A genome is a full set of chromosomes.
This organization is consistent between organisms, but the size of the genome and number of
chromosomes varies between species. The human genome is made of 3 billion base pairs that are
separated on 23 chromosomes (Figure 7). For an interactive explanation, click here (Figure 8).
How are new copies of DNA made?
Each cell in your body has a complete copy of your genome (see Figure 7). Actually, all of your
cells, except for the reproductive cells (eggs and sperm), have two complete sets of your genome
(two versions of every chromosome). When the first cell of your body was created, an egg (with
one set of chromosomes) came together with a sperm (with one set of chromosomes) to create a
cell with two copies of the genome. Each new cell that is derived from the first cell has the exact
same genome- the exact same information. How does every cell in your body have this same
information? Well, every time a cell divides it first makes a new copy of every chromosome in
that cell.
The process of making new DNA strands is called DNA replication. During DNA replication
every chromosome in a cell is copied by taking advantage of base pairing between single strands
of DNA.
Generally speaking, a copy of DNA is made by unwinding the double helix to create a single
stranded template that is copied using base pairing. The first step of unwinding the double strand
is done by a protein called helicase(Figure 9). The two single strands can now act as a template
for making the opposite strand and a copy of DNA.
DNA Replication and Base Pairing

Once the template for replication is made through unwinding the double helix, DNA is replicated
using base pairing.
Remember there are specific rules to base pairing:
1. Purines only pair with pyrimidines
2. Adenine ALWAYS pairs with Thymine (A-T)
3. Guanine ALWAYS pairs with Cytosine (G-C)
Because of this rule if you have one strand of DNA you can make the second strand by adding
the correct partner nucleotide one at a time to a new opposite strand. If there is an A in the
template strand, then a T is added to the new strand, if there is a G then a C will be added, and so
on. This process of creating a new strand from a template strand of DNA is performed by a
protein known as a DNA polymerase. The name of this protein comes from the fact that the
function of a DNA polymerase is to take individual nucleotides and put them together to make a
new polymer (or strand) of DNA. Figure 10 shows DNA polymerase creating a new DNA strand
from a template strand.
When DNA replication is complete one double stranded piece of DNA will have been separated
and from each single strand the opposite strand will have been made. The result is two new
double helicies each containing one strand from the original molecule (Figure 11, red) and one
newly synthesized strand (Figure 11, blue). This pairing between old and new strands is known
as semi-conservative replication.
DNA Replication Regulation by the Cell Cycle
DNA replication does not happen spontaneously. It only happens when the cell is preparing to
divide during a process called the cell cycle. A cell needs to make a copy of DNA when the cell
is getting ready to divide so that each cell has an identical copy of the genome. You will learn the
details about cell division and the cell cycle in upcoming modules, and you will learn that DNA
replication occurs at a specific part during the cell cycle.
Right now we will generally discuss how the cell cycle regulates DNA replication. There are four
phases of the cell cycle that are tightly regulated by CELL CYCLE CHECKPOINTS and certain
CELL CYCLE PROTEINS. The proteins are the sensors and signal to the cell cycle
checkpoints (the comparator) that the cell cycle can progress to the next phase. Once the
checkpoints get the go ahead from the cell cycle proteins to proceed to the phase where DNA is
replicated, DNA replication takes place to make 2 DNA molecules through the processes we just
learned about. As you will learn in future modules, once the cell cycle has committed to making
DNA, the cell continues through the cycle to divide and the process starts over again.
When the cell cycle proteins signal that the cell is ready to proceed through the cell cycle, the

loop is turned ON and DNA replication moves forward. If the cell cycle proteins do not signal to
proceed, the loop is OFF and DNA replication does not occur.
What can cause DNA mutations?
Now that we have learned the basics of DNA structure and replication, lets discuss what can
cause errors in DNA. A mutation in DNA is caused by modifications of one or more nucleotides
in the DNA. Mutations can occur during replication, but here we will briefly discuss two ways in
which DNA can be damaged from extracellular factors leading to DNA mutations.
1) UV light
Ultraviolet light can harm the DNA molecules of living organisms in different ways. In one
common damage event, adjacent Thymine bases bond with each other instead of across the
"ladder". This makes a bulge, and the distorted DNA molecule does not function properly. Figure
12 shows a cartoon example of this type of DNA damage.
2) Mutagenic chemicals
Molecules of a certain size and chemical nature can fit themselves in between base pairs of
DNA. Figure 13 shows a chemical that has disrupted the DNA double helix.
Both of these types of changes can affect two important processes; the making of a new copy of
a DNA molecule (replication) and the transfer of information from a DNA molecule to an RNA
molecule (transcription). You will learn in later emodules the role of mutations in different
diseases and even cancer.
How does DNA store information?
So far we have discussed the many levels of DNA structure, how DNA structure allows for easy
replication, and how this structure can be disrupted. However, we have yet to hear how this
molecule is storing information!
The ability of DNA to act as a store of information comes from its nucleotide structure. As we
have learned, there are four distinct nucleotides that can be used to make a molecule of DNA,
Adenine (A), Thymine (T), Guanine (G) and Cytosine (C). The order of nucleotides in a strand
of DNA is not random; the A,G,C and T nucleotides act as a molecular alphabet. A particular
sequence of these nucleotides within a strand of DNA creates a gene, thus you may have also
heard of DNA containing a genetic code or genetic information. These genes contain the
information necessary to make a protein.
In our next emodule we will learn how to read this alphabet, understand how genetic information
is transferred from a DNA molecule to an RNA molecule and how from an RNA molecule a
functioning protein is produced.

Base Pairing

interaction between nitrogenous bases on nucleotides to form double str

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Chromosome

long strands of double stranded DNA packaged around proteins

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Deoxyribose

5 carbon sugar of DNA nucleotides that lacks an oxygen on the 2 carbo

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DNA

short for Deoxyribonucleic acid, a polymer of nucleotides that stores cel

DNA polymerase

the protein responsible for synthesizing new DNA strands through base

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DNA replication

the process by which new copies of DNA are made. The basic steps incl
stranded DNA by helicase to make a template strand and synthesis of a n
addition of nucleotides by DNA polymerase

Double helix

another name for double stranded DNA

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Genome

a full set of chromosomes

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Helicase

the protein that unwinds double stranded DNA during DNA replication

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Nitrogenous base

group attached to the 1 carbon of DNA and RNA. There are 4 bases in D
cytosine (C), guanine (G), and thymine (T)

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Nucleotide

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monomer of DNA and RNA that consists of a 5 carbon sugar, a phosphate group, and a nitrogen

Phosphate group

Protein

attached on the 5 carbon of the central sugar of DNA and RNA, it can interact with the 3
other nucleotides for form a single strand of DNA
The functional form of cellular information encoded by DNA

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Purine

nitrogenous base with two carbon rings (guanine and adenine)

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Pyrimidine

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nitrogenous bases with one carbon ring (cytosine and thymine)

Ribose

5 carbon sugar of RNA with an OH group on the 2 carbon (compared to

that lacks an oxygen on the 2 carbon

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RNA

short for Ribonucleic acid, it is a polymer of nucleotides that acts as a me

DNA and proteins

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Semi-conservative replication

the term to describe the nature of DNA replication. Two new DNA molec
one original molecule. Each new DNA molecule has one strand from the
a new strand.

Gene Expression:

Last emodule we learned about DNA, the curator of all of our cellular information, but how does

all of that information get expressed? In other words, how does all of the information stored in
DNA get out and manifest itself into proteins, the functional form of cellular information?
It all comes back to the central dogma we learned about last time. Lets recall that the central
dogma states the flow of cellular information flows from DNA to RNA to protein. How does this
happen?
The information in our DNA is turned into protein through 2 separate processes: transcription
and translation. First, the information stored in DNA is copied into RNA through transcription in
the nucleus using RNA polymerase. Second, the genetic message in RNA is converted into
proteins through translation in the cytoplasm by the ribosome. Therefore, the flow of information
flows from DNA to RNA via transcription and from RNA to protein via translation (Figure 2).
In this emodule we will learn more about the genetic code stored in our DNA, how RNA acts as
a messenger and why it needs to, and lastly, how proteins are made from the genetic code.
The Genetic Code
The nucleotide sequence in DNA is the molecular alphabet that encodes the amino acid
sequence of proteins. This is also known as the genetic code. How do we get from this alphabet
on DNA to amino acid sequences? It turns out DNA and proteins do not speak the same
language, so the cell needs to translate the nucleotide sequence into amino acids.
Remember that DNA is made up of 4 different nucleotides, Adenine (A), Cytosine (C), Guanine
(G), and Thymine (T), and there are 20 different amino acids that make up proteins. How do 4
nucleotides encode for 20 amino acids? If each nucleotide encoded a single amino acid, there
would only be 4 possible amino acids. Would pairs of nucleotides encode enough amino acids? A
two nucleotide code would only account for 16 amino acids (42). A triplet nucleotide code would
provide at least 64 different amino acids (43) more than enough possibilities for the 20 amino
acids, and thus scientists discovered the triple nucleotide code known as a codon.
A codon is simply a word in DNA and RNA language that a protein can understand.
One codon encodes for one amino acid. Because there are 64 possible codons, this also means
that one amino acid can have more than one three letter code. Figure 3 shows all of
the codons that encode for the different amino acids.
From Genes to Proteins and the Messenger
So if a codon is a DNA word that encodes an amino acid, how are these words put together to
make a full protein? In comes the gene. A gene is a segment of DNA (see Figure 4), and the
nucleotides within thisone segment of DNA encode one protein. One gene is essentially a series
of codons, or you can think of it as several nucleotide words strung together into a sentence. If
you translate all of the codons of one gene you would make one protein.
Recall that there are 3 billion base pairs in the human genome. The tricky part to remember is
that this DOES NOT mean that there are 1 billioncodons in the human genome. Rather within

each chromosome there are many genes, but there are also nucleotides between the genes that
serve functions other than specifically being used to code for a protein (notice the spaces in
between genes in Figure 4). In fact only 2% of the human genome is composed of genes, which
is approximately 30,000 genes.
Now that we understand the language, how is this language actually made into proteins? DNA
needs both a messenger AND a translator in comes RNA, messenger RNA (mRNA), to be
more specific. DNA is located in the nucleus wrapped up as chromosomes, and protein synthesis
occurs in the cytoplasm. In the nucleus, mRNA decodes the DNA words that make one protein
and then takes this message to the cytoplasm where it is translated into an amino acid sequence,
the primary protein structure. We will spend the rest of this module discussing how mRNA is
made as a copy, or transcript, of the DNA in the nucleus through transcription, and how that
transcript is translatedinto a protein in the cytoplasm.
Transcription - The Basics
Before we get into the complicated details of transcription, let us go over the basics.
First, mRNA is a copy of a single gene made from DNA. The process by which mRNA is made
from DNA is called transcription. In linguistics, transcription means conversion of a written
source into another medium. In biology it means converting information from a DNA source into
RNA. Both DNA and RNA use the nucleotide language, and the information is simply
transcribed, or copied, from one molecule to the other. There are three major differences between
an mRNA and DNA:
1) The 5 carbon sugar used to make up a mRNA nucleotide is ribose (RNA) instead
of deoxyribose (DNA)
2) While DNA is composed of A, G, C, and T nucleotides, RNA uses A, G, C and U. The U
stands for Uracil. Wherever you would see a T in DNA it would be a U in an RNA molecule
(see Figure 5 of mRNA).
3) While DNA is primarily found in the double stranded form, mRNA is single stranded.
The Template Strand
Because mRNA is single stranded, it is very important to understand which strand of the double
stranded DNA is used to make mRNA. Each of the two DNA strands is given a name:
1) The Coding Strand: the coding strand contains the nucleotide
codons in the correct order to be read. However, the coding strand is NOT the one used to make
mRNA.
2) The Non-Coding Strand also known as the Template Strand: because double stranded DNA is
anti-parallel this strand has the nucleotide codonsequence opposite of the coding strand.
This strand is the one used to make mRNA. (See Figure 6 for an example).

These descriptions may seem counter-intuitive. Why not use the coding strand to make mRNA?
This is because the process of mRNA transcription is similar to DNA replication. It makes use of
base pairing to create the new mRNA strand. That means that when mRNA is made using the
non-coding DNA strand, the resulting mRNA strand will actually have the same sequence
(except U instead of T) as the DNA coding strand
Transcription: Structure of a Gene
The process of transcribing mRNA from DNA is performed by a protein calledRNA
polymerase (See Figure 7 for an example). Remember transcription happens in
the nucleus because that is where DNA that is being transcribed is located.
So how does RNA polymerase know where to start and stop making an mRNA? As mentioned
earlier, the entire genome is not made up of codons. Instead only certain regions on a
chromosome known as genes are individually transcribed. The part of the genome that is read
to make proteins is called anopen reading frame. The open reading frame contains all of
the codons to make a protein (Figure 8).
Directly before the open reading frame is a promoter region that tells RNA polymerase where to
bind. Within the promoter, there is a transcription start site that tells RNA polymerase where to
start transcription. Promoters are also used to regulate when a gene is transcribed as well as in
which cell type a gene is expressed.
Following the promoter, the first codon of every gene is always the same, ATG (in the coding
strand, so TAC in the non-coding template strand). This is known as the start codon. The end of a
gene is indicated by one of three codons, which do not translate into an amino acid and instead
function as stop signals. These stop codons are TAG, TAA, and TGA (ATC, ATT, and ACT in
thenoncoding strand).
Shortly after the stop codon is the terminator region that tells RNA polymerase to stop
transcription. See Figure 8 for a simple schematic of gene.
Transcription: The Steps
Now we know the players involved in transcription and the structure of a gene, how does this
actually happen? There are three main steps in transcription: Initiation, Elongation, and
Termination (Figure 9).
Initiation
Transcription begins with RNA polymerase binding to the promoter. RNA polymerase unwinds
double stranded DNA and starts RNA synthesis.
Elongation

An mRNA molecule is synthesized using base pairing rules to make a complementary strand to
the template strand (which is a copy of the codingstrand with U instead of T).
REMEMBER base pairing rules! They are the same for DNA base pairing:
Purines only pair with Pyrimidines
G pairs with C
and
A pairs with U (instead of T)
RNA polymerase moves along the DNA elongating the mRNA molecule based on the
nucleotides present in the DNA.
Termination
When RNA polymerase reaches the terminator, RNA polymerase dissociates from DNA, and an
mRNA molecule has been created. Transcription is complete.
See Figure 9 for an overview of these steps and Figure 10 for a close up of how all of this
happens.
How is Protein Made from mRNA?
Remember that genetic information is stored inside the nucleus as DNA, but proteins are made in
the cytoplasm. That is why DNA needs mRNA to act as a messenger to carry the genetic
information from the nucleus where DNA islocated to the cytoplasm where it can be used to
make proteins. After transcription has been completed in the nucleus, mRNA is transported to the
cytoplasm.
Once in the cytoplasm, mRNA is ready to convert the DNA language into protein language
(amino acids) through a process called translation.
Translation uses two other types of RNA, ribosomal RNA (rRNA) and transfer RNA
(tRNA). rRNA along with oproteins make up the ribosome, the site of translation. tRNA acts as
the interpreter reading the codons of mRNA and translating them into the amino acid language
to make proteins. tRNAs bind their specific amino acid from the cells pool of free amino acids
in the cytoplasm and brings the amino acid to the ribosome to be added to the growing amino
acid chain.
tRNA
Let us examine the structure of tRNA a little further.
Another way to remember the name of a tRNA is that its 3D shape roughly resembles a lower
case t. Each tRNA has two specific features that makes them unique (see figure 11):
1) The anti-codon: a three base region within a tRNA which specifically complements a

particular nucleotide codon.

2) Amino acid binding site: each type of tRNA can only bind one particular amino acid.
Because of these properties, tRNA can interpret and translate the nucleotide language into
protein language. The anti-codon recognizes a codon in the mRNA and the amino acid that is
attached specifically to that tRNA is added to the growing amino acid chain.
The next few slides will go over a step-by-step example of translating mRNAcodons into an
amino acid chain.
Translation
1) mRNA binds the ribosome.
2) The ribosome scans the mRNA until it finds the AUG start codon.
3) The tRNA with the corresponding UAC anti-codon binds to the AUG start codon in the
mRNA.
This tRNA brings with it the amino acid methionine (Met). The first amino acid of every protein
is always methion.
4) The second codon of the mRNA is recognized by the tRNA with the corresponding anticodon.
This tRNA brings along its specific amino acid.
5) The ribosome begins to build the protein by adding the methionine from the first tRNA to the
amino acid on the second tRNA. This pair of amino acids is now attached to the second tRNA.
6) The ribosome moves three nucleotides down the mRNA to the next codon.
7) The first tRNA leaves the ribosome to pick up another amino acid.
8) The third codon of the mRNA is recognized by the tRNA with the corresponding anti-codon.
ThistRNA brings along its specific amino acid.
9) The ribosome begins to build the protein by adding the two amino acids from the
second tRNA to the amino acid on the third tRNA. Thus all three amino acids are now attached
to the third tRNA.
10) This process continues until the ribosome reaches one of the three stop codons. There are
notRNAs with an anti-codon to the stop codons. Thus these codons efficiently stop the process of
making a new protein and synthesis of the new protein is complete.
11) The newly synthesized protein is released from the ribosome to go off and perform its
function in the cell. Translation is complete.
Overview of Gene Expression: Simple Feedback Loops

Let us take a step back and look at gene expression as a whole. Simply stated, gene expression is
taking the genetic code from the DNA, transcribing it into mRNA, and then translating the
mRNA into protein. So when a cell gets a signal from the environment or other cells that it needs
more of a given protein, it must first make a copy of the gene that encodes that protein through
transcription. Once the transcript is made, the mRNA leaves the nucleus and enters the cytoplasm
where it is translated into protein.
As simple as all of this sounds, this is a highly regulated process, and in some cases the
expression of a gene results in feedback either resulting in further transcription of a given gene or
dampened transcription. To keep it simple, you can think of gene expression as a simple
feedback loop. We will first go over two very simple feedback loops, and then describe a more
detailed feedback loop.
Remember the structure of a gene with the promoter region before the open reading frame. Well,
the promoter controls gene expression. The promoter tells the system whether or not to start
transcription. Figure A is a simple view of aNEGATIVE feedback loop. In this example, the
promoter tells transcription to begin. After the mRNA is made, the transcript is translated into
protein. The presence of the protein (represented by the line) tells the promoter to stop
transcription. Because the protein is present, the cell no longer needs to make additional protein,
so transcription is stopped.
Figure B shows a simple POSITIVE feedback loop of transcription. In this example, the presence
of the protein actually activates transcription and tells the promoter to turn transcription on.
Transcription Initiation
In this more complicated feedback loop, we will take a closer look at what controls transcription
initiation.
In this example, we will learn two new terms: the ACTIVATOR and the INDUCER.
The INDUCER senses signals from the environment or the cell. An inducer could be a protein or
it could be an energy source like glucose or lactose. The INDUCER senses the environment and
binds to the ACTIVATOR. When the INDUCER and ACTIVATOR are bound together, they bind
to a region of the promoter called the operator and signal that transcription should start. See the
figure to the left for a schematic of the inducer and activator
After this emodule you are now familiar with how the cellular information stored in our DNA is
made into protein with the help of a messenger, mRNA. You have learned how DNA is
transcribed into mRNA inside the nucleus and how mRNA is then transported into the cytoplasm
where it is translated into an amino acid chain the primary structure of proteins. See Figure 12
for a summary of everything we have covered in this emodule.
But what does gene expression mean?? Well, your cells do not go through this process for
every single protein encoded in your DNA all of the time. In fact, not all cells express (or make)
the same proteins at a given time even though they have the DNA to make it. Which proteins are
made is tightly regulated within a cell.

Gene expression simply means that a gene encoded in DNA is transcribed into mRNA that is
then translated into a protein. When a cell needs a particular protein product, that gene will be
expressed meaning it will go through all of the processes discussed in this emodule.
These principles are essential for understanding many topics in biology including cancer,
development, and evolution.
Anti-codon

three letter code on tRNAs that complement three letter

codon on mRNAs

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Coding strand

the single strand within a DNA double helix that

contains the nucleotide codons in the correct order to be
read. This DNA strand has the same sequence as the
transcribed mRNA (given U in RNA and T in DNA).

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Codon

Words of the DNA/RNA language, sets of three

nucleotides that code for a particular amino acid

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Gene

A series of codons within a DNA sequence; also

includes regulatory regions of DNA such as a promoter

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Genetic Code

Sets of three nucleotides that specify amino acids or

stop codons during the process of translation at the
ribosome; the set of rules by which information encoded
in genetic material (DNA or RNA sequences) is
translated into proteins (amino acid sequences).

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Gene Expression

The process by which information from a gene (DNA)

is made into a functional gene product (protein) using
mRNA.

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mRNA (messenger
RNA)

A molecule of RNA encoding the information for a

protein product. mRNA is transcribed from a DNA
template, and carries coding information from the
nucleus to the sites of protein synthesis in the
cytoplasm, the ribosomes

Non-coding strand

The DNA strand that forms the template for the

transcribed mRNA. This strand is the opposite strand of
the coding strand.

Open Reading
Frame

A sequence of nucleotide codons (from start to stop) that

encodes one protein

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Promoter

A portion of a gene found before the open reading frame

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Ribosome

Site of protein synthesis where proteins are translated

from mRNA

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RNA polymerase

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The protein enzyme that creates an mRNA from the

template strand of DNA

rRNA (ribosomal
RNA)

RNA molecule that makes up the ribosome

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Start codon

The first three nucleotides (or codon) of any gene. This

codon helps indicate where the ribosome should begin
translating an RNA into a protein

Stop codon

Nucleotide codon that signals the end of an open reading

frame and causes the termination of transcription because
there is no tRNA with the corresponding anti-codon

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Terminator

A portion of a gene after the open reading frame that

signals the end of transcription

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Transcription

The process of creating an mRNA from DNA using the

protein enzyme RNA polymerase

Translation

The process by which the ribosome uses tRNAs to make a

protein from an mRNA by translating the nucleotide
codons into amino acids

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tRNA (transfer
RNA)

A small RNA that transfers a specific amino acid to a

growing amino acid chain at the ribosomal site of protein
synthesis during translation

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Uracil

Nitrogenous base with one ring that is found in RNAs

instead of Thymine

In the last two emodules we have discussed the properties of DNA in detail and how the cellular
information is stored in DNA is translated into protein following the Central Dogma of molecular
biology. Let us quickly review the steps in the Central Dogma one more time. DNA stores all of
the information to make every protein in our bodies in the nucleus of all of our cells. A DNA
segment of one gene is transcribed (or copied) into mRNA, which is then transported to the
cytoplasm. In the cytoplasm, mRNA is translated into proteins, which then go on to perform their
function within the cell. This process occurs for every single protein produced in a cell. Some
proteins are enzymes, for example the helicases and polymerases involved in transcription and
replication. Other proteins are structural creating the architecture of the cell.
But what happens when something goes wrong? If a protein is not made correctly it can have
disastrous effects on not just the cell, but also the surrounding tissue and the organism as a
whole, often the resulting in disease.
In this module we will discuss what happens when there are errors in the DNA sequence and the
downstream effects of these errors. We will learn about the different types of DNA mutations,

how they lead to abnormal proteins that can lose function and ultimately how these mutations
can lead to a disease.
DNA Mutations
Let us first talk about the different types of DNA mutations that can lead to changes in proteins.

Substitution: This type of mutation occurs when one nucleotide is replaced by another (Figure 1).
Sometimes substitutions do not affect the amino acid sequence because multiple codons can
encode for a given amino acid. These are called silent mutations. In other cases, the substituted
nucleotide can change thecodon to encode for a different amino acid that can affect the resulting
protein. Substitutions can also change the codon to a STOP codon causing the production of a
truncated and likely nonfunctional protein.
Insertion/Deletions: These mutations are as they sound an extra nucleotide or multiple
nucleotides are inserted into a DNA sequence, or one or many nucleotides are missing from a
nucleotide sequence (Figure 2).
Frameshifts: Insertion and deletions can lead to a shift in the way the nucleotide sequence is
read. Remember, nucleotides are read in sets of three as codons. Therefore, if nucleotides are
inserted or deleted, it can change the way the nucleotides are read. See the sentence in Figure 3.
If one of the letters is deleted, the sentence does not make much sense just like
the codon sentence does not always make sense when nucleotides are inserted or deleted (see
Figure 4 for an example). Figure 5 gives additional examples of frameshifts causing mutations.
We will spend the rest of this emodule learning how these types of mutations lead to loss of
protein function and ultimately disease by learning about two genetic disorders, sickle cell
anemia and cystic fibrosis. Genetic Disease
Sickle Cell Anemia
Sickle-cell anemia is a serious blood disease in which red blood cells (RBC) take on a sickle or
C shape instead of the normal round shape (Figure 6). The major function of your red blood
cells is to carry oxygen to all of your organs and tissues via the protein hemoglobin. In this
disease, the abnormal shape of the RBCscauses the RBCs to clump in blood vessels blocking
blood flow to various organs and tissues (See how sickle cells can block blood flow in Figure 7).
The blockage of blood vessels can cause severe pain in the blocked area, a condition referred to
as a sickle cell crisis. A crisis is marked by sudden pain throughout the body particularly
affecting bones, lungs, abdomen, and joints. There are several complications associated with this
disease including anemia (a condition when your blood has lower than normal red blood cells or
your RBCs have low levels of hemoglobin marked by fatigue, shortness of breath, and
weakness), hand-foot disease (swelling of the hands and feet due to blocked blood vessels),
infections, acute chest syndrome (pneumonia-like infection caused by sickle cells getting trapped
in the lung), and stroke. Sickle cell anemia primarily affects people from or with decedents from
sub-Saharan Africa or other areas where malaria is prevalent. Sickle-shaped cells are more
resistant to malaria infection and arose as an adaptation to the disease. Sickle cell anemia is the
result of a single nucleotide mutation leading to a change in one amino acid in one of the proteins

that make up hemoglobin.

Genetic Disease
Cystic Fibrosis (CF)
CF is a progressive disease that affects the mucous glands of the lungs, small intestine, and
pancreas as well as the sweat glands. CF patients often lose excessive amounts of salt when they
sweat leading to an imbalance of minerals in the blood and abnormal heart rhythms. Mucous in
the lungs of CF patients is also very thick and sticky. Having a thin layer of mucous lining the
lungs and intestines is important for lung and digestive function, but when the mucous becomes
too thick to be removed regularly, it serves as a playground for bacterial infections. CF patients
typically have chronic bacterial infection that are difficult to fight and can lead to lung damage.
The thick mucous found in the pancreas can block the pancreas from secreting digestive enzymes
into the intestine leading to malnutrition. Other complications of CF include sinusitis
(inflammation of nasal sinuses), clubbing of fingers and toes (rounding of the fingers and toes),
coughing up blood, and liver disease. Lung disease is often the cause of death in CF patients and
the average lifespan of a CF patient is 30 years. CF is most common among caucasians with
ancestors from Northern Europe. The most common CF mutation is the result of a deletion of
three nucleotides resulting in a loss of one amino acid in the coded protein.
Specific DNA Mutations
Let us take a closer look at the mutations of these diseases and how they cause a given protein to
lose normal function.
Sickle Cell Mutation
The most common gene mutation leading to sickle cell anemia is a single
nucleotide substitution that changes one amino acid in the hemoglobin beta gene (or HBB).
There are two protein chains that make up hemoglobin, the protein that carries oxygen
throughout the body via red blood cells, alpha chains and beta chains. The HBB gene makes up
the beta chains. The most common HBB mutation is called Hb S, which is a point mutation that
leads to an amino acid substitution of a valine instead of a glutamic acid (Figure 10). This single
substitution causes the hemoglobin protein to bind together abnormally forming long fibers,
which cause the red blood cells to sickle (see Figure 7 again).
Cystic Fibrosis Mutation
Seventy per cent of the mutations involved in CF are the result of a threenucleotide deletion leading to the deletion of one amino acid in the cystic
fibrosistransmembrane conductance regulator (CFTR) gene. The normal CFTR protein is a
chloride channel protein in the membrane of cells that line the lungs, liver, pancreas, intestine,
and reproductive organs. This protein is essential in maintaining the balance between sodium and
chloride ions in these cells. The most common mutation associated with CF is the deletion of the
three nucleotides that encode for phenylalanine (see Figure 11). The deletion of phenylalanine
causes the protein to misfold and it is marked for degradation. Thus the protein never makes it to
its proper place within the cell and it has lost its function.

The main complication of Sickle Cell Anemia is that the sickle-shaped cells can clump up and
block blood vessels leading to several symptoms that we have discussed, but how does that ONE
mutation in the HBB gene actually cause the disease?
- As we saw in the previous slide, the single nucleotide substitution changes one of the amino
acids in the protein sequence.
- This amino acid substitution causes hemoglobin proteins to bind together to form long fibers
inside the RBC.
- This abnormal binding of hemoglobin proteins inside ofRBCs lead to the sickle shape of RBC
cells.
- The sickle shape of the RBCs are sticky and can block blood vessels.
- Blockage of blood vessels lead to most of the symptoms and complications of the disease
- Therefore, this single nucleotide mutation has a profound affect on the normal function of the
protein, which leads this disease
How do mutations lead to disease?
Cystic Fibrosis
The production of thick mucous in the lungs and digestive system leads to the complications of
CF. How does a mutation in a chloride channel protein create thick, sticky mucous?
-The deletion of three nucleotides in the CFTR sequence leads to the deletion of one of the
amino acids in the CFTR protein (phenylalanine).
- The CFTR protein is misfolded and loses function.
- The membranes of the cells that line the lungs, pancreas, etc. lacks a functional chloride
channel protein (See Figure 13).
- These cells lose the ability to maintain the balance between sodium and chloride ions within the
cell. This balance maintains the usual healthy thin layer of mucous in the lungs and digestive
track.
- The sodium/chloride imbalance leads to the build up of thick mucous.
As we have discussed, this thick mucous is at the core of the symptoms and complications of CF
that is marked by chronic lung infections and lung damage (See Figure 14 for an overview).
CFTR channel
Another way to think about this is through a feedback loop. The cell must maintain a balance of
chloride ions between the inside and outside of the cell to keep a healthy layer of mucous lining

the lungs and digestive tract. The CFTR channel is responsible for maintaining the flow of
chloride ions out of the cell, which in turn keeps the intracellular and extracellular chloride ions
at equilibrium. Let us take a closer look at how the CFTR channel regulates this balance.
First of all, what causes the CFTR channel to open to allow chloride ions to pass through? On the
left side of the figure, the CFTR channel is closed (note the brown, blue, and green structures all
make up the channel). In order for the channel to be open, or activated, it must bephosphorylated,
which just means an enzyme adds a phosphate group to the channel protein. Phosphorylationis
represented by the pink Ps in the circles. The channel also requires energy in the form of ATP to
actively pump chloride ions outside the cell. When the channel isphosphorylated and ATP binds
to the channel, the channel is open, and chloride ions are pumped to the outside of the cell.
How does the channel know when to open? There is a region inside the pore that senses the
chloride concentration outside of the cell, and this sensor will put the activation of the channel
into action.
Treatment options
Currently, there is no cure for either of these terrible diseases, and treatment focuses primarily on
managing painful symptoms to keep patients as comfortable as possible. For sickle cell anemia,
blood transfusions are a common treatment to replenish the bodys red blood cells and may help
decrease strokes. Constant doses of oral antibiotics to prevent acute chest syndrome is prescribed
for infants and children until age 5. More recently, the anti-cancer drug, hydroxyurea, has been
used to manage sickle cell crises.
As for CF patients, the main goals are to keep bacterial infections in the lung to a minimum and
keep the mucous levels low. To help clear mucous from the lungs, patients go through a
bronchial draining therapy which involves the patient being put into a position for optimal
clearing and someone clapping on their back to loosen and dislodge mucous from the lung.
Medications are also used to open airways and decrease mucous. A specific diet is used to
counteract the digestive complications.
Although there are no current cures for these and other genetic diseases, there is a therapy on the
horizon thanks to our understanding of the human genome that may provide cures in our
lifetime.
Gene Therapy
We have just learned about two devastating diseases that are the result of mutations in the DNA
that lead to proteins that have abnormal functions within the cell. These diseases are the result of
a mutation in that SPECIFIC gene. A mutation in another gene results in a different disease. We
are gaining a better understanding of genetic based diseases with the sequencing of the human
genome. Many of these genes have been mapped to specific chromosomes that you can examine
further on this website.
Because of our increased understanding of the genetic basis of these diseases, there are new
developments in treatment. Most treatments of the two diseases discussed today manage the
symptoms of the disease but do not offer cures for the disease. A newly emerging treatment takes

advantage of the knowledge of which gene causes the disease and what is wrong with the given
gene.
Gene therapy is a technique that attempts to correct the mutated genes responsible for the
production of an abnormal protein and the development of a genetic disease.
There are mutiple general approaches used to counteract a mutant gene by gene therapy:
1. Introduce a normal (unmutated) copy of the gene to another location in the genome (other than
where the gene normally resides in the genome)
2. Swap the abnormal gene with a normal copy of the gene
3. Alter the regulation of the mutated gene
The simplest method used to introduce the therapeutic DNA into target cells is direct injection.
This approach is limited in its application because it can be used only with certain tissues and
requires large amounts of DNA. Typically for gene therapies to be performed a carrier
orvector must be used to introduce the normal gene into a patient's cells. The most common
vector used in gene therapy are disabled viruses. The viruses used are modified so they cannot
cause disease when used in people. Viruses are used because they have a unique ability to
recognize certain cells and insert genetic material into them. You can think of the virus as a
molecular delivery truck which unloads its DNA cargo (the normal copy of the gene) into the
cell. The vector can be injected directly into a specific tissue in the body or given intravenously
(by IV), where it is taken up by individual cells.
Alternatively, a sample of the patient's cells can be removed and exposed to the vector in a
laboratory setting. The cells containing the vector are then returned to the patient. Once the new
gene is introduced to the cell in this manner, it can produce the normal protein to counteract the
problems created by the abnormal protein. See an image of this process in Figure 14.
While in theory gene therapy is a powerful and promising method to counteract genetic disease,
to date the Food and Drug Administration has not yet approved any human gene therapy product
for sale. Currently gene therapy is only used in clinical trials. This means that scientists and
doctors are still in the process of determining the best methods of delivery and gene expression
as well as making sure that their therapies do not cause other major side effects in their patients.
Despite these challenges, gene therapy is a promising method to offer possible cures for difficult
and devastating genetic diseases.
Summary
In these last 3 modules, we have learned the foundation of molecular biology how the
information in our cells is stored in DNA and how that information is turned into protein through
transcription and translation of the messenger, mRNA.
In this module we discussed different types of DNA mutations and how these changes in

nucleotide sequence alter protein function and sometimes lead to disease.

In the next several modules you will learn about cancer, development, and evolution, all of
which involve the regulation of gene expression and to some extent DNA mutations. These
concepts will also apply to topics later in the semester, so make sure you keep the central dogma
in the back of your mind the rest of the semester.
Acute Chest
Syndrome

A symptom associated with sickle cell anemia

where sickle cells get trapped in the lung and
cause infection

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Anemia

A condition when your blood has lower than

normal red blood cells or the red blood cells
are low in hemoglobin

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CFTR

Cystic Fibrosis Transmembrane conductance

Regulator protein; it is the gene that is
mutated to cause cystic fibrosis.

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Clubbing

A symptom associated with cystic fibrosis

where the fingers and toes have a rounded

appearace.

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Cystic Fibrosis
(CF)

A genetic disease affecting the mucous glands

of the lungs and digestive system.

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Deletion

A type of DNA mutation that occurs when

one or more nucleotides is removed from the
nucleotide sequence. These mutations often
result in frameshifts.

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Disease

An abnormal condition that impairs normal

bodily function and is associated with certain
symptoms

Frameshift

A DNA mutation that leads to a shift in the

way the nucleotide sequence is read; often the
result of insertion and deletion mutations

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Gene therapy

A technique that tries to correct a mutated

gene that is responsible for a genetic disease

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Hand-foot
disease

A symptom associated with sickle cell anemia

where the hands and feet swell due to
blockage of vessels by sickled cells

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HBB gene

Hemoglobin beta gene that is mutated to

cause sickle cell anemia

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Hemoglobin

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The protein inside red blood cells that carries

oxygen throughout the body

Insertion

A type of DNA mutation that inserts extra

nucleotides in a nucleotide sequence;
insertions often lead to frameshits

Mutation

A change in a nucleotide sequence; common

mutations are insertion, deletions,
substitutions, and frameshifts

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RBC

Red blood cells

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Sinusitis

A symptom associated with cystic fibrosis

which is characterized by inflammation of
nasal sinuses

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Substitution

A DNA mutation where one nucleotide is

replaced by another; it can result in coding for
a different amino acid or a STOP codon

Vector

In gene therapy, vectors are carriers of DNA

into a patients cell

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Virus

An infectious agent that requires a host; it is

used in gene therapy to deliver DNA to a
target cell or organ

Cell Division
A journey of a thousand miles must begin with a singlestep. - Laozi, founder of Taoism
Each of us is made of an estimated 100 trillion cells, yet we begin from the fusion of just two
cells. How are so many cells derived from so few?
The two cells that initially fuse are from our parents, withour mothers supplying the egg and our
fathers supplying the sperm. These cells provide our genetic blueprint, yet we are not identical
clones of our parents, nor are we a perfect 50-50 hybrid of each parent. Further, we are often
very different than our siblings. How does sexual reproduction generatesuch human diversity?
The answer to both of these questions is heavily steeped in the processes of cell division. In this
module, we will learn about two types of cell division: mitosis and meiosis.
Mitosis is the process by which somatic cells divide. Somatic cells are cells of the body (non sex
cells). Cell division is slightly different in germline cells or gametes. These are the sex cells;
males produce sperm while females produce eggs, also known as ova. Gametes divide by
meiosis.
In this module we will learn about the requirements for, the stages of, and the regulation of cell
division.

Purposes of cell division

Growth
Cells are generally quite small. The diameter of the average human cell is around 10 microns.
To put this in perspective, you would need over 2500 cells in a line to measure just 1 inch**.
Cells do not grow in proportion to our bodies; instead, we produce more cells as we grow (Figure
3). Cell division is our only mechanism of making new cells, thus without cell division, we
would not grow taller and wider as we mature, nor would our hair and fingernails grow
throughout our life cycle.
Repair of tissues
The body has an incredible ability to heal itself. Whether you cut yourself cooking dinner or
break a bone playing football (Figure 4), your body will invoke repair processes involving cell
division to fix the problem. Some animals can even regenerate entire limbs that have been
removed!
Reproduction
Most cells have two copies of each chromosome. If these cells combine, the resulting cells

would have four copies of each chromosome. The number of chromosomes would double each
generation! Instead, a specialized process of cell division called meiosis takes place in gametes
(sperm and eggs) to prevent this from happening. This process also contains a critical step that
increases genetic diversity in offspring (Figure 5).
**For more biological size comparisons:
http://learn.genetics.utah.edu/content/begin/cells/scale/
Requirements for Cell Division
1. Signal - Cell division is a highly regulated process. Cells must receive signals, either
internal or external, to divide.
2. Replication After a division, each daughter cell has anequal amount of DNA to each other
as well as to the parent cell. For this to occur, the parent cell must first duplicate its DNA.
3. Segregation The DNA of the parent cell is equally allocated to each of the daughter cells
4. Cytokinesis The cytoplasm and organelles must be divided between the daughter cells.
These events consistently occur in the same order, called the cell cycle (Figures 6 & 7). The cell
cycle can be partitioned into several phases. In the most general sense, it consists of the mitotic
phase (M), when segregation and cytokinesis take place, and interphase, a long period of
growth. Interphase can be further broken down into three subphases: Gap1 (G1), Synthesis (S),
and Gap2 (G2).
DNA is double helix. The helix is wrapped around proteins called histones to make increasingly
complicated structures. Ultimately, DNA forms a supercoiled chromosome with two identical
sister chromatids bound together at a centromere.
Ploidy refers to the number of sets of chromosomes in a cell. Humans have 23 chromosomes.
These exist in a haploid state in gametes (top), meaning each cell has one copy of each
chromosome. In contrast, somatic cells are diploid (bottom), with 2 copies of each chromosome,
for a total of 46.
The cell cycle is the process by which cells divide. It can be divided in many ways, but is
commonly broken down into interphase and mitosis, each of which can be subdivided further.
Strictly speaking, mitosis refers to the portion of the cell cycle when chromosomes are separated
from each other. However, the word mitosis is also commonly used to refer to the complete cell
cycle in somatic cells.
INTERPHASE
Interphase is the part of the cell cycle when the cell grows by synthesizing proteins, cytoplasmic
organelles, and DNA (Figure 10).
Gap 1 (G1): The G1 or first gap marks the beginning of interphase. During G1, the cell begins
to grow. Many enzymes are made that are needed for DNA synthesis. During this phase, each
chromosome exists as a single, unpaired chromatid. Cells that are not currently dividing are
most likely to pause the cell cycle during the G1 phase.
Synthesis (S): The S phase is when DNA synthesis takes place. At the end of S phase, each

chromosome has two sister chromatids

Gap 2 (G2): The G2 or second gap is the final portion of interphase. Cells continue to grow and
make proteins. Importantly, microtubules are synthesized during this phase, which are necessary
for mitosis.
MITOSIS:
After interphase is complete, the mitotic phase can proceed. Mitosis(Greek "mitos" = thread) is
the process bywhich a eukaryotic cell separates its chromosomes into two pairs.
Like interphase, mitosis can be subdivided into several stages (Figure 11):
Prophase (Greek "Pro" = before): As its name suggests, this step happens before mitosis. The
chromatin fibers of DNA get moretightly coiled, condensing into discrete chromosomes that are
visible with a microscope (Figure 12).
Prometaphase: The nuclear envelope degrades. Thread like structures called microtubules
extend towards the middle of the cell, where some bind to the DNA via a central structure called
a kinectochore.
Metaphase: (Greek "Meta" = between). The chromosomes have lined up in the middle of the
cell(remember: M for middle!). Each sister chromatid is attached to microtubules that are
anchored at opposite ends of the cell.
Anaphase (Greek "Ana" = up): During anaphase, the sister chromatids are pulled to opposite
ends of the cell by the microtubules (remember: A for action!). The cell takes on an elongated
shape. By the end of anaphase,each pole of the cell has a complete (and equivalent) set of
chromosomes.
Telophase (Greek "Telo" = end): The cell continues to elongate and nuclei form around the sets
of chromosomes found at each pole of the cell. The DNA becomes less tightly coiled.
Cytokinesis, the division of the cytoplasm, generally occurs during this time, dividing one cell
into two daughter cells.
For an animation of mitosis:
http://www.youtube.com/watch?v=AhgRhXl7w_g
Mitosis has multiple phases. The DNA condenses during prophase, aligns in the middle of the
cell during metaphase, gets pulled apart during anaphase, and forms new nuclei in each of two
genetically identical daughter cells during telephase.
The series of events that comprise interphase and mitosis must take place sequentially in order to
be successful. For example, DNA synthesis must take place before the microtubules can bind to
each of two paired chromatids. Furthermore, microtubule binding must take place before the
chromatids can be separated from each other. To ensure that these events proceed in the proper
order, a series of checkpoints exist in the cell cycle. These checkpoints provided the
necessary signals for the cell cycle to proceed.
There are multiple checkpoints spread throughout the cell cycle (Figure 13). These transitions

are governed by a family of enzymes known as cyclin-dependent kinases (CDKs). There are
several types of CDK that are responsible for progression through different stages of the cell
cycle. Kinases are a family of proteins that add phosphate groups to other molecules through a
process known as phosphorylation. In most cases, phosphorylation serves to activate the target
protein. However, CDKs do not phosphorylate target proteins unless they themselves are
activated. CDKs are activated after being bound to proteins known as cyclins. The cyclins
themselves have no effect on the target proteins, rather they serve to activate the CDKs. Once
cyclin-CDK complexes are formed, the CDK is activated and able to phopshorylate its target
protein. CDKs have multiple targets that they interact with at different steps of the cell cycle,
each of which may require different cyclin/CDK combinations.
CDKs are always present at about the same level within a cell, but this does not lead to aberrant
cell cycling because they inactive unless bound to the appropriate cyclins. The amount of cyclin
molecules present, and which cyclins are present, varies throughout the cell cycle in response to
a variety of factors (Figure 14). For instance, a molecular cue exists to alert the cell that
microtubules have attached to the kinetochores, making it okay to proceed to anaphase. This is
an example of an internal signal that comes from within the cell. External signals also exist,
such as the presence of growth factors. Each of the cyclin-CDK complexes functions to sense
whether or not the required conditions have been met before sending a signal for the cell cycle to
continue.
Some cell populations develop mechanisms to ignore these cues and escape cell cycle
regulation. These cells divide excessively and may migrate to other tissues. Loss of proper cell
cycle regulation is a hallmark of cancer, a topic we will learn more about in the next module.
The cell cycle is carefully regulated at multiple steps by molecules called cyclin-dependent
kinases (CDKs).
The cell cycle is regulated by CDKs. Several CDKs are present within the cell at all times,
however they are only active when they associate with the appropriate cyclin. Expression of the
appropriate cyclin is triggered by the appropriate cues, causing CDKs to only be active when the
cell is ready to proceed to the next step of the cell cycle.
Fertilization takes place when specialized cells called gametes fuse together. The genome
supplied by each gamete combines together to provide the genetic basis for a new individual.
If gametes were created by mitosis, each would be diploid (two complete sets of chromosomes)
and the fusion of two gametes would yield 4 sets of chromosomes. If this were the case, the
number of chromosomes would double with each generation. This would be incompatible with
life. Therefore, a different process of cell division called meiosis (Greek "meio" = less) is used to
generate gametes.
The male gamete is sperm, and the female gamete is the egg (Figure 15), these cells are produced
exclusively in the testes and ovaries, respectively, by the process of meiosis.
Gametes are produced by the process of meiosis.
Meiosis shares many steps with mitosis, but the end result is different. While mitosis generates
diploid cells (2n), meiosis results in haploid cells (n).

Meiosis includes one DNA replication and two separate cell divisions, meiosis I and meiosis II.
Like mitosis, each cell division of meiosis consists of prophase, metaphase, anaphase, and
telephase (Figures 16 & 18).
Meiosis I: This process separates homologous chromosomes into two haploid daughter cells.
Interphase I: DNA is replicated, producing 4n cells.
Prophase I: Sister chromosomes pair together through a process unique to Prophase I
calledsynapsis. At various places along the chromosomes, the chromatids from sister
chromosomes exchange DNA with each other at X-shaped structures called chiasmata(singular:
chiasma). At these chiasmata, portions of the sister chromatids are exchanged with each other by
a process known ascrossing over or homologous recombination (Figure 17). If homologous
recombination did not occur, each gamete would contain 23 chromosomes, some of which would
be exact copies of those you received from your mother, and others exact copies of those you
inherited from your father. The process of homologous recombination produces new gene
combinations, creating unique chromosomes. Each meiotic cycle may result in different
recombination events, thus producing unique gametes. For this reason, homologous
recombination is essential for generating population diversity.
Metaphase I: Chromosomes line up at the middle of the cell and are bound by microtubules
Anaphase I: The chromosomes are pulled apart from each other. Sister chromatids are kept
together, while homologous chromosomes move to opposite poles. This is different from
mitosis, where sister chromatids are separated.
Telophase I: Each pole now has a haploid set of chromosomes with two sister chromatids each.
Cytokinesis generally occurs during this stage.
Meioisis II: This process serves to separate sister chromatids, ultimately generating 4 haploid
cells from the original cell.
Prophase II: Microtubules form
Metaphase II: Chromosomes are positioned in the middle of the cell, as in mitosis. Microtubules
bind the kinetochores of the sister chromatids.
Anaphase II: The sister chromatids are pulled to opposite poles of the cell.
Telephase II: Sister chromatids are localized to opposite poles, cytokinesis usually occurs. There
are now 4 haploid cells with unreplicated chromosomes.
For an animation of meiosis:
http://www.youtube.com/watch?v=D1_-mQS_FZ0&feature=related
Meiosis is the process by which gametes are produced. Take note of the exchange of genetic
material between the blue and red chromosomes during prophase I. This process, called

homologous
During Prophase I of meiosis, sister chromosomes are paired together through a process called
synapsis. The actual sites of DNA exchange are called chiasmata. This allows the chromatids to
exchange genetic material (notice the blue genes on the red chromosome and vice versa),
ultimately generating unique chromosomes in the gametes. This process is critical for the
generation of population diversity.
Like all biological processes, meiosis does not always function as it should. In some meiotic
events, the chromosomes do not properly separate from each other. This is called meiotic
nondisjunction (Figure 19).
Meiotic nondisjunction can occur during either Meiosis I or Meiosis II. If it occurs during
Meiosis I, all gametes will be affecting having either too many or too few chromosomes. If it
occurs during Meiosis II only 2 out of the 4 gametes produced will be abnormal.
If a disjunction event occurs during gamete development, the resulting offspring will more than
likely be abnormal. Trisomy 16 (3 copies of chromosome 16) is the most common disjunction
event in humans, occuring in 1% of all pregnancies. As one of the body's many feedback
mechanisms, this is normally detected and miscarriage is induced during the first trimester.
You are likely more familiar with trisomy 21, or Down's syndrome (Figure 20). Down's
syndrome, and other trisomy of autosomes (non-sex chromosomes) is associated with birth
defects, mental retardation, and reduced life expectancy.
Meiosis can go wrong when a nondisjunction event occurs, meaning a chromosome fails to
separate. This can happen during either Meiosis I or Meiosis II.
Meiosis does not always function properly. Sometimes, one daughter cell ends up with too many
or too few chromosomes. If a gamete has 2 copies of chromosome 21, the resulting offspring
will have 3 copies, called trisomy 21, also known as Down's Syndrome. This image shows a
karotype, or a picture of an individuals chromosomes. You can clearly see 3 copies of
chromosome 21, while a normal individual would have 2 copies. Note the presence of an X and
a Y chromosome, indicating this a male.

Cell Cycle

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also known as cell-division cycle is the series of events that

take place in a cell leading to its division and duplication
(replication).

Kinases

a type of enzyme that transfers phosphate groups from highenergy donor molecules, such as ATP, to specific target
molecules (substrates); the process is termed phosphorylation
(the addition of a phosphate group to a protein or other organic
molecule).

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Chromatin

is the complex combination of DNA, RNA, and protein that

makes up chromosomes; and its found inside the nuclei of
eukaryotic cells (organism whose cells contain complex
structures enclosed within membranes), and within the
nucleoid in prokaryotic cells. It is divided between
heterochromatin (condensed) and euchromatin (extended)
forms. The functions of chromatin are to package DNA into a
smaller volume to fit in the cell, to strengthen the DNA to
allow mitosis and meiosis, and to serve as a mechanism to
control expression and DNA replication

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Histones

are the chief protein components of chromatin. They act as

spools around which DNA winds and they play a role in gene
regulation, and without histones, the unwound DNA in

chromosomes would be very long.

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Nucleosomes

form the fundamental repeating units of eukaryotic chromatin,

which is used to pack the large eukaryotic genomes into the
nucleus while still ensuring appropriate access to it (in
mammalian cells approximately 2 m of linear DNA have to be
packed into a nucleus of roughly 10 m diameter). They are
folded through a series of successively higher order structures
to eventually form a chromosome; this both compacts DNA
and creates an added layer of regulatory control which ensures
correct gene expression.

Prophase

is a stage of mitosis in which the chromatin condenses into a

highly ordered structure called a chromosome (it is at this
stage giemsa staining - used for the pathological history
diagnosis of malaria and other parasites - can be applied to
elicit G-banding in chromosomes) in which the chromatin
becomes visible.

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Prometaphase

is the phase of mitosis following prophase and preceding

metaphase, in eukaryotic somatic cells.

Metaphase

a stage of mitosis in the eukaryotic cell cycle in which

condensed chromosomes, carrying genetic information, align
in the middle of the cell before being separated into each of the
two daughter cells. Microtubules (one of the components of
the cytoskeleton) that had formed in prophase have already
found and attached themselves to kinetochores in metaphase.

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Anaphase

the stage of mitosis when chromosomes separate in a

eukaryotic cell. Anaphase begins abruptly with the regulated
triggering of the metaphase-to-anaphase transition; and at this
point the anaphase becomes activated.

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Telophase

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a stage in either meiosis or mitosis in a eukaryotic cell

reversing the effects of prophase and prometaphase events.

Gamete

is a cell that fuses with another gamete during fertilization

(conception) in organisms that reproduce sexually. A female is
any individual that produces the larger type of gamete, called
an ovum (egg) and a male produces the smaller tadpole-like
type, called a sperm.

Cancer

Cancer! Uncontrolled cell division indicating that the processes of transcription and translation
are no longer being controlled in certain cells in certain organs. The trigger for cancer can be
internal or external. (Please put on the suntan lotion.!)
Cancer is a disease that will affect nearly all of us in our lifetimes, either directly or through the
diagnosis of a friend or family member. Cancer accounts for 1 in 4 deaths in the United States,
only heart disease is more deadly.
Cancer can occur in people of all ages, though the risk increases with age. While our increased
understanding of the biology of cancer has greatly improved physicians ability to treat cancer
patients, cancer remains one of the leading causes of death in the United States and worldwide.
By the end of this module you will be able to answer the following questions:
1. What are the characteristics of cancer cells?
2. How does the body protect itself against cancer?
3. When the body fails to fight cancer, how can physicians intervene?
4. What are the risk factors for cancer?

Cancer is a category of diseases involving uncontrolled growth and spread of abnormal

cells. Cancerous cells have escaped the precise regulatory mechanisms of the cell cycle (see
previous module for review). This allows cells that would otherwise be deemed unhealthy and
thus not be able to divide, to continue to grow without restriction.
As a result of uncontrolled growth, most cancers form tumors, solid lesions formed by abnormal

growth of cells (Leukemia, a form of blood or bone marrow cancer, is one exception). Tumors
may be eitherbenign or malignant. Benign tumors are self-limited in size, do not invade adjacent
tissue, and do not spread throughout the body. This is different from malignant tumors, which
grow uncontrollably, invade adjacent tissues, and spread throughout the body. Only malignant
tumors are considered to be cancerous.
The physical appearance of cancer cells
As cancerous cells continue to divide, their appearance gets more and more unhealthy. This is
known asdysplasia from the Greek word for malformation. They develop ragged edges and lose
their normal pattern of organization. Additionally, cells may develop large, abnormally-shaped
nuclei, lose their size uniformity, appear disorganized, have a small amount of cytoplasm
relative to the nucleus, and lose cell-type specific features.
Getting nutrients to a tumor
Physical properties can limit the size of tumors. If a tumor grows too large, the cells on the
inside will not get enough oxygen or nutrients and will die. This begins to happen when tumor
diameter is around 1-2 mm. To escape this phenomenon, cancerous tumors produce signals
causing blood vessels to grow into the tumor, providing oxygen and nutrients for its cells to
continue their uncontrolled growth. This is a process known as angiogenesis (Greek: angio =
blood vessel, genesis = origin or beginning), that is a natural part of growth and healing, but has
been co-opted by cancer.
A second feature of cancer is its ability to spread to other tissues. This process is
called metastasis. Metastasis has several stages. First, cancer cells from the primary tumor
spread to the surrounding tissues. The cancer cells produce digestive enzymes and begin to
break down the healthy tissue around the tumor. Eventually, the cancer cells will reach a blood or
lymphatic vessel. The cells enter these vessels, facilitating transport throughout the entire body.
Many of the cancer cells will die in the blood vessels. The surviving cancer cells may ultimately
leave the vessels and take residence in a new tissue, where a secondary tumor may form.
Cells from the primary tumor breakdown surrounding tissue to gain access to a blood vessel,
which enables them to migrate to another part of the body where they can form a secondary
tumor. Image from www.websters-online-dictionary.org
The major hallmark of cancer cells is rapid, uncontrolled division. As you learned in the last
module, there are many checkpoints in the cell cycle to ensure that new cells are only generated
when needed. Under normal circumstances, a series of conditions must be met before the cell
cycle proceeds to the next step. Cancerous cells have developed mechanisms to escape the
careful regulation of the cell cycle.
There are two distinct mechanisms by which this can occur:
Some genes involved in cell cycle regulation send a Gosignal for the cell cycle to proceed
when a series of conditions have been met. If these genes mutate, they can change to send a
go signal regardless of the conditions. When this occurs, the genes become known
as oncogenes (Greek: on co = tumor). By analogy, these signals are the gas pedal of the cell
cycle. It should only be pressed when the traffic light turns green, but in the case of mutation to

an oncogene,the gas pedal is stuck to the floor. The mechanism of cancer development is quite
common, nearly 30% of human cancers have an oncogenic mutation in a gene named ras.
Just like in a car, the cell cycle has brakes to counteract the accelerator. These mechanisms tell
the cell cycle to stop. In biological terms, these proteins are made by tumor suppressor genes.
If these genes mutate, the cell does not receive signals to stop. To continue with the car analogy,
it is as if someone has cut the brake line, disabling them. This is also a very common mechanism
of cancer development. Nearly 60% of all cancers involve a mutation in a tumor suppressor gene
called p53.
If you were driving a car with the gas pedal stuck to the floor or without brakes, the result would
be the same; you would be driving at an unsafe speed. The same is true of cancer, the cell cycle
proceeds rapidly, and cells accumulate at an abnormal rate, generally forming tumors.
Keep in mind, that because of the numerous regulatory mechanisms in the body, mutation of a
single gene is unlikely to cause cancer. Generally, at least one oncogene must appear and
multiple tumor suppressor genes must lose their activity for cancer to develop.
What medical treatments are available for cancer?
If a patient is diagnosed with cancer, a variety of treatment options exist. The best medical
intervention depends on a number of factors including the size and location of the tumor, how
much the cancer has spread through the body, and the patients general health.
If a cancer has not metastasized and the tumor is accessible, surgery may be sufficient to
eradicate the cancer. Early detection is key, the longer cancer has been present, the greater
chance that it has spread through the body. Its easy to find and remove cancer when all the cells
are grouped in a tumor. Once cancer has begun to metastasize, physical removal of all cancerous
cells is impossible. Instead, chemotherapy and radiation therapy may also be required.
Apoptosis is a major reason why chemotherapy and radiation therapy work. Radiation therapy
and many chemotherapy agents cause profound DNA damageenough to induce
apoptosis.Unfortunately, these treatments do not discriminate between cancer cells and normal
cells. Any cell that is dividing is a potential target. In fact, the apoptosis of normal cells produces
most of the side effects of chemotherapy and radiation therapy, including nausea and hair loss.
Given the connection between p53 and apoptosis, can you see a potential problem for physicians
treating a patient who has cancer? In many cancers, the p53 gene is defective, but p53 is needed
for efficient induction of apoptosis in response to DNA damage. Thus, for those cancers caused
by cells with defective p53, chemotherapy and radiation therapy may be less effective than for
other cancers. Indeed, examining the p53 gene in a particular cancer can help physicians decide
on appropriate courses of therapy.
Fair skinned people and those who spent a lot of time outdoors are at risk for skin cancer. Early
detection is critical for successful treatment of cancer. Image from Irish Cancer Society
Mutations that produce oncogenes or reduce tumor suppressor gene function can lead to the
development of cancer. Where do these mutations come from?

Natural mutations:
Every time a somatic cell passes through the cycle cell, it must replicate its DNA. The human
genome is around 3.1 billion nucleotides, each of which is copied individually. Due to the
massive amount of replication events that occur, mistakes are bound to occur. The cell checks
the accuracy of DNA replication and repairs as many mistakes as it can. Over time, more and
more mutations build up, it becomes more difficult to repair them all. For this reason, age is a
risk factor for cancer.
As was stated previously, it generally requires the mutation of multiple tumor suppressors and at
least one oncogene to cause cancer. Some families and even whole populations are born with
mutated copies of genes, reducing the number of mutations needed to develop cancer. For
example, mutations in the tumor suppressor genes BRCA1 BRCA2 (Breast Cancer) are often
inherited, making these individuals more susceptible. In the event of known inherited mutations,
it is important to have frequent screening for early detection and to make healthy lifestyle
choices to reduce other risk factors.
Carcinogen-induced mutations:
Chemicals, known as carcinogens, can induce mutations (changes in DNA), some of which may
cause cancer. Known carcinogens include chemicals present in tobacco smoke, alcohol,
ultraviolet light from the sun (and tanning booths!), and radiation from sources such as X-rays.
Different carcinogens may promote different cancers, generally influenced by the route of
exposure. For instance, tobacco smoke is more likely to cause lung cancer than ultraviolet light,
which can promote skin cancer. Our knowledge of carcinogens is constantly expanding and it
should be noted that this list now includes many chemicals that were once thought to be safe.
Just as in the past, chemicals that we are now exposed to daily may one day be known
carcinogens.
Diet and exercise:
People who have a poor diet, do not get enough physical activity, or are overweight are at risk for
certain types of cancer. It is thought that cancer protective diets include many fruits and
vegetables, whole grains, and some proteins (meats, beans, etc.), while avoiding fatty foods and
processed meats.
Dysplasia

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from the Greek word malformation. As cancerous cells continue to

divide, their appearance gets more and more unhealthy.

Angiogenesis

cancerous tumors produce signals causing blood vessels to grow into

the tumor, providing oxygen and nutrients for its cells to continue
their uncontrolled growth. This is a natural part of growth and
healing, but has been co-opted by cancer.

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Apoptosis

programmed cell death as a clean way for cells to delete themselves

and recycle many of its valuable components.

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Metastasis

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the ability for cancer to spread to other tissues.

Oncogenes

the process in which certain genes that send out a "go" signal become
mutated and the "go" signal is turned even when it is not suppose to.

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Tumor suppressor
genes

the process in which genes that send out a "stop" signal become
mutated and the cell does not receive signals to stop.

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Carcinogen

chemicals that can induce mutations such as smoke, alcohol,

ultraviolet light from the sun, etc.

Genetics:
Genetics is the study of how genes bring about characteristics, or traits, in living things and how
those traits are passed on from one generation to the next. To put simply, genes are portions of
our genetic code (DNA) that make proteins. While each of us generally has the same types of

proteins, there may be slight variations from person to person in either how the protein is made
or how much of the protein is made. Genetics seeks to explain these variations. Amazingly,
while genetics studies how DNA tells our body to make proteins and how these instructions are
passed on to our offspring, many of the major concepts of genetics were described before DNA
was discovered.
Epigenetics is the study of how modifications to DNA or histones, but not to the DNA sequence
itself, alter expression of genes. The two major types of epigenetic modifications, methylation
and deacetylation, can repress or activate genes, respectively.
After reading this module, you will be able to answer the following questions
1. What is the difference between dominant and recessive genes?
2. What is the relationship between genotype and phenotype?
3. How do both genetics and epigenetics relate to human disease?

Genes are segments of DNA (Figure). As you learned, DNA is made of a string of four different
nucleotides (Adenine, Guanine, Thymine, Cytosine) that can be combined in any order. The
nucleotides are transcribed from DNA to RNA. The RNA is organized in nucleotide triplets
called codons. Each codon is then translated into a specific amino acid. Proteins are composed of
these amino acids. Therefore, genes encode proteins
Humans are diploid organisms, meaning we have two copies of each chromosome, one inherited
from our mother and one from our father. Each gene can be found at a specific place on a

chromosome, thus we have two copies of each gene. While each gene encodes for the same
protein, there may be differences in this protein based on the genetic variation between
individuals. Each copy of a gene represents an allele, which is an alternate form of a gene. If
both of your alleles are identical, you are said to be homozygous (Greek: homo = same, zygous =
paired). If the alleles differ from each other, then you are known to be heterozygous (Greek:
hetero = different). A description of the zygosity of our alleles, that is to say, how they are written
in our genetic code, is known as a genotype. The expression, or production of proteins from
DNA, of the alleles within our DNA determines our outward appearance. This can be determined
by the output of one gene or that of multiple genes. This is described as an
individual's phenotype, or the observable traits of an organism.
For example, humans have a gene that determines whether or not the earlobes are attached.
Someone could have two copies of a gene that code for attached earlobes, two copies of a gene
that code for free earlobes, or one of each gene. Thus, there are three possible genotypes, but
only two possible phenotypes, attached or free earlobes. We will discuss this in more detail on
the next slide. The two different forms of the gene, in this case, free and attached earlobes, are
the alleles.
These concepts are critical to the understanding of genetics, but amazingly, they were not yet
known when many of the principles of genetics were first described.
Mendelian Genetics: Mendel's LawsHow We Inherit Our Genes
In 1866, Gregor Mendel studied the transmission of seven different pea traits by carefully testcrossing many distinct varieties of peas. He spent an enormous amount of time crossing different
types of these plants and carefully observing and documenting the results. His observations led
to a great understanding of how genes are passed on from generation to generation.
Studying garden peas might seem trivial to us who live in a modern world of cloned sheep and
genetically modified crops, but Mendel's simple approach led to fundamental insights into how
genes are inherited, known today asMendel's Laws. At the time, the molecular mechanisms
behind these laws of inheritance were completely unknown. Nonetheless, Mendel demonstrated
his understanding of the principles of genetics by correctly predicting the behavior of traits and
how they are transmitted. From his experiments in breeding garden peas, Mendel developed
three major underlying principles of genetics.
Mendel's Principles of Genetic Inheritance
Mendel's observations led him to create three rules regarding how our traits are passed on from
generation to generation. Mendel's principles are:
1. Law of Segregation: Each of the two inherited factors (alleles) possessed by the parent will
segregate and pass into separate gametes (eggs or sperm) during meiosis, which will each carry
only one of the factors.
Think back to the description of meiosis in the cell division module. In Meiosis I, sister

chromosomes are paired and then separated from each other. Because of this separation,
maternal and paternal genes are distributed to different gametes. This process provides the
mechanism for the law of segregation.
2. Law of Independent Assortment: In the gametes, alleles of one gene separate independently of
those of another gene, and thus all possible combinations of alleles are equally probable.
Again, think back to what you learned about meioisis. During Meiosis I, the process of
homologous recombination occurs. This makes it so that genes that are on the same chromosome
do not necessarily end up in the same gamete. Without homologous recombination, each
chromosome would be passed down as it was received from your mother or father. Instead, new
gene combinations are made that combine alleles from each parent. Thus, homologous
recombination provides the mechanisms for law of independent assortment.
3. Law of Dominance: Each trait is determined by two factors (alleles), inherited one from each
parent. These factors each exhibit a characteristic dominant, co-dominant,
or recessive expression, and those that are dominant will mask the expression of those that are
recessive.
In the previous slide, there was an example of attached versus free earlobes. Free earlobes are
the dominant allele, while attached earlobes are recessive. It is conventional to capitalize the
dominant allele and make the recessive allele lowercase. We shall call the free allele "F" and the
attached allele "f." You have two copies of this gene, one from each parent. Thus, the possible
genotypes are FF, Ff, and ff. Because F is dominant, the presence of one F allele is sufficient to
give a free earlobe phenotype. Therefore, individuals with FF or Ff genotypes has the free
earlobe phenotype. The recessive allele can only exert its phenotype if it is not masked by the
dominant allele, and thus the attached ear phenotype is only observed when an individual's
genotype is ff.
These three laws have provided the fundamental basis for our understanding of genetics. Our
current knowledge of the molecular basis for genetics has led us to understand that inheritance is
far more complicated than it was initially described by Mendel. Nonetheless, Mendel's laws
generally hold true to this day.
One of Mendel's famous crosses was between green and yellow peas. He determined
experimentally that yellow (Y) was dominant over green (y). Our current knowledge of genetics
tells us that yellow plants can be YY or Yy, while a green plant must be yy. One of the strengths
of Mendel's work was that he was able to accurately predict the outcome of various crosses he
setup.
If the genotypes of both parents are known, it is possible to determine the potential genotypes of
the offspring. This is accomplished by the use of a Punnett Square. A Punnett square is a
diagram that provides a summary of every potential allele combination that would result in
offspring. In it's simplest form, it is a 2 X 2 square with the maternal and paternal genotype
listed outside the box (Figure 1). You simply transfer the parental alleles to the boxes below or
to the right of them. The resulting four new combinations of alleles are the potential genotypes

of any offspring. In this example, two heterozygous parents (Bb) mate, which can yield
offspring that are either homozygous dominant (BB), heterozygous (Bb), or homozygous
recessive (bb). There is a 25% chance of BB, 50% chance of Bb, and 25% of bb. These are
known as simple mendelian ratios.
Let's try it for ourselves. We start with a green plant, which we know to be recessive, its
genotype is yy and its phenotype is green. We cross it to a yellow plant. We know the yellow
plant has a yellow phenotype, but we do not know whether it's genotype is YY or Yy. For the
sake of this exercise, let's assume it is Yy. What colors would the offspring of the two plants be
and in what ratios would we expect them? The Punnett square (Figure 2) shows that 50% of the
offspring would have a Yy genotype resulting in a yellow phenotype, while 50% would have a
yy genotype and a green phenotype.
You could use this same methodology to work backwards and figure out the the genotypes of the
parents. Let's say Mendel crossed a green pea with a yellow pea of unknown genotype (based on
phenotype we know it is YY or Yy). This cross resulted in yellow peas, but no green peas. Use
a Punnett square to determine the genotype of the yellow parent.
While many human traits are quite complex and controlled by several genes (such as eye color),
we also have genes that are easily described by simple mendelian inheritance of a single gene.
These include cheek dimples, facial freckles, free earlobes, and a widow's peak, all of which are
dominant. On the other hand, hitchhiker's thumb and albinism are simple reccessive traits.
There are many examples of inheritance that appear to be exceptions to Mendel's laws. Usually,
they turn out to represent complex interactions among various allelic conditions. For example,
co-dominant alleles both contribute to a phenotype. Neither is dominant over the other. Control
of the human blood group system provides a good example of co-dominant alleles.
There are four basic blood types, and they are O, A, B, and AB. We know that our blood type is
determined by the alleles that we inherit from our parents. For the blood type gene, there are
three basic blood type alleles: A, B, and O. We all have two alleles, one inherited from each
parent. The possible combinations of the three alleles are OO, AO, BO, AA, BB and AB. Blood
types A and B are "co-dominant" alleles, whereas O is "recessive". Like a dominant allele, the
presence of a single co-dominant allele is sufficient to influence the phenotype; a recessive
phenotype is apparent only if two recessive alleles are present. Because blood type O is
recessive, it is not apparent if the person inherits an A or B allele along with it. So, the possible
allele combinations result in a particular blood type in this way:
OO = blood type O (recessive)
AO = blood type A (A is dominant, masking O)
BO = blood type B (B is dominant, masking O)

AA = blood type A
BB = blood type B
AB = blood type AB (co-dominant, both alleles involved in phenotype)
You can see that a person with blood type B may have a B and an O allele, or they may have two
B alleles. If both parents are blood type B and both have a B and a recessive O, then their
children will either be BB, BO, or OO. If the child is BB or BO, they have blood type B. If the
child is OO, he or she will have blood type O.
As mentioned earlier, the laws that Mendel came up with opened the way to understanding how
genes are transmitted and regulated. But there are still many questions that remain unanswered.
For example, if all cells in the body have the same exact DNA (except for gametes, of course),
then how are they so different and how can they perform such different functions? Think about
the cells in your skin, and how different they are from the neurons in your brain. For a more
striking example, think about the life cycle of a butterfly or moth (Figure)
The answer lies in part in how the expression of genes is controlled. In other words, having the
DNA sequence which encodes for a gene does not help you if this gene is not being expressed.
And that is what epigenetics means: changes in DNA expression that are not related to the DNA
sequence, but rather to the "signals" that allow a gene to be expressed.
In order to understand how epigenetic control of gene expression works, we must first review
how DNA is "packaged" inside the cell. DNA does not exist as naked molecules in the cell; it is
associated with proteins called histones to form a complex substance known as chromatin
(Figure).
Chemical modifications to the DNA or the histones alter the structure of the chromatin without
changing the nucleotide sequence of the DNA. Such modifications are described as epigenetic.
Changes to the structure of the chromatin have a profound influence on gene expression. If the
chromatin is condensed, the factors involved in gene expression cannot get to the DNA, and the
genes will be switched off. Conversely, if thechromatin is 'open', the genes can be switched on if
required.

Epigenetics refers to non DNA factors that influence transcription and translation which is
transmitted to new generations. A person who gets skin cancer due to UV radiation but does not
pass it on to the next generation is not an example of epigenetics. An obese person whose
succeeding offspring have obesity is an example of epigenetics. Some chemical factor associated
with obesity is transmitted to succeeding generations.
Epigenetics may occur at the histone/DNA junction due to environmental factors or

environmental factors may also influence some process of transcription or translation.

Keep in mind that the term: environmental factors can be any physical change in DNA caused
by chemicals in or around the cells or factors external to animal itself such as sunlight.
The tobacco hornworm (Manduca sexta) has three stages of its life cycle: larvae (green), pupae
(brown), and the adult gypsy moth. This provides an example of how an organism can have the
same DNA but yield very different outcomes through differential gene silencing and activation.
Similarly, cells throughout your body have very different functions and appearances. Image
from http://zebra.sc.edu/
A Punnett square is a diagram that allows you to predict the ratio of genotypes (and thus
phenotypes) that will result from any combination of parental alleles. The simplest Punnett
squares are 2 X 2, but can be much more complex for traits controlled by multiple genes.
Crossing a green pea (yy) with a heterozygous yellow pea (Yy) will yield offspring that are
either Yy (yellow) or yy (green) in a 50:50 ratio.
The ability to hyperextend the thumb joint is a condition known as hitchhiker's thumb. This is a
recessive trait encoded by a single gene and thus follows simple mendelian ratios.
Gregor Mendel was a monk whose simple breeding experiments with peas provided the
foundation for much of our current understanding of genetic inheritance.
Having attached or free earlobes is a simple Mendelian trait. You must inherit recessive alleles
from both parents (genotype: ff) for you to have attached earlobes (phenotype)
Genotype is the genetic basis of a trait, a description of each copy, or allele, of a gene.
Phenotype is the observable traits that result from genotype. Image from www.bbc.co.uk
For transcription to occur, RNA polymerases must bind to regions upstream of the gene called
promoters. If methyl groups are added to the promoter, it blocks the polymerase from binding,
thus preventing transcription.
When histones are acetylated , the chromatin structure is loose, allowing transcription. If
histones are deacetylated, it causes the chromatin to become more compact, preventing
transcription, by presenting a physical barrier for the transcriptional machinary.
A hallmark of cancer is loss of cell cycle regulation. This can happen through the silencing of
cell cycle regulators or the activation of cell cell promotors.
While many heritable disorders in humans are caused by DNA sequence changes (mutations)
that abolish gene expression or alter protein function, a number of human diseases are caused by
inappropriate gene silencing brought about by epigenetic modifications. Indeed, most cancers
involve the epigenetic silencing of genes that normally regulate cell proliferation. The major
forms of epigenetic gene silencing occurring in human tumors are DNA methylation and
histonedeacetylation.
DNA methylation is a chemical modification of the DNA molecule itself; it is carried out by an
enzyme called DNA methyltransferase (DNMT). Methylation, the addition of a -CH3 group, can
directly switch off gene expression by preventing transcription factors from binding
to promoters, segments of DNA that promote expression of a particular gene. DNA methylation,
or adding a methyl group to the DNA molecule, is like adding a stop light at an intersection. The
cars will stop while the red light is there, and the red light can be removed to allow the cars to
continue, or the gene to be expressed.

Histone deacetylation refers to the function of enzymes called histone deacetylases (HDACs),
which function to chemically modify histones and change chromatin structure. Chromatin
containing acetylated histones is open and accessible to transcription factors, and the genes are
potentially active.
Histone deacetylation causes the condensation of chromatin, making it inaccessible to
transcription factors and the genes are therefore silenced. Certain diseases can also be caused by
inappropriate gene silencing. For instance, if the p53 gene were methylated or deacetylated, what
would the result be?
In the last module we discussed how carcinogens can mutate your DNA, which can lead to the
development of cancer.
Some carcinogens can cause cancer without mutating DNA, these are known as epigenetic
carcinogens. Examples of epigenetic carcinogens include hexochlorobeneze (fungicide),
diethylstilbestrol (synthetic estogren), arsenite, and nickel compounds.
Genes that promote cell cycle progression are often deacetylayted as a mechanism to control
their production and thus keep the cell cycle tightly regulated. If one of these compounds
acetylates a histone that is associated with one of these genes that is normally silenced, such as a
gene called MYC, cancer may result. While deactelyated, MYC is produced at low levels and is
generally inaccessible for transcription. Due to its tight chromatin structure, histone acetylation
leads to gene expression. Overexpression of a gene that promotes the cell cycle allows the cell to
escape the careful regulatory mechanisms in place, thus causing cancer.
An alternative route to cancer is to silence genes that are normally active. This includes tumor
suppressor genes such as BRCA1. These genes are normally active to ensure the cell cycle is
properly regulated. Silencing of these genes leads to an overactive cell cycle progression.
For many years, debates raged in the fields of biology and psychology regarding
whether nature (genes) or nurture(environment) governed our development as individuals.
Eventually, it became accepted that both nature and nurture were important. Our understanding
of epigenetics provides the mechanism by which nature exerts its influence.
One interesting example of this suggests that a mother's behavior can affect the chemistry of
DNA in her offspring. It is often stated that children need parental love and nurturing for
successful development as people. But how does love promote mental health?
In a research study, scientists showed that maternal care was correlated with methylation of the
gene encoding the glucocorticoid receptor. Glucocorticoids are stress hormones produced by the
body. In order to feel the effects of the hormones, a receptor is needed. Once a sufficient
amount of hormone is bound to the receptor, the brain sends signals to shut down the
glucocorticoid production, thus ending the stress response.

Rats that received lots of maternal care had less methylation of this gene, while rats that received
less maternal care had more methylation. The result is that rats with methylated glucocorticoid
receptor genes lacked the ability to properly respond to stress responses and thus felt the effects
of stress for longer.
The methylation of genes can be long lasting. So, when these rats reached adulthood, those that
received more parental care had more stress hormone receptors, and thus were better at
responding to stress, leaving them relaxed. In contrast, poorly-nurtured rats had methylated
glucocorticoid receptor genes, leaving them capable to responding to stress, thus making them
anxious.
Many factors can reverse epigenetic modifications, so these effects are not necessarily
permanent. Despite their reversibility, epigenetic changes can be passed on to offspring.
If the researchers inject a well-nutured pup with epigenetic carcinogens that methylate genes, the
pup mature into a anxious mother that takes poor care of her offspring. This shows the effect is
epigenetic and not genetic. The researchers went on to show that this effect was linked to the
methylation of a stress hormone receptor.
The type of upbringing that rat pups receive dictates what type of parent they will become.
Female rats will be the same type of mother as their own. On its own, this seems like a genetic
effect.
Epigenetics

the study of how modifications to DNA or histones alter expression

of genes that is not related to the DNA sequence.

Turn flashcard

Allele

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represented by each copy of a gene and is an alternate form of a gene.

Homozygous

both alleles are identical.

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Heterozygous

the alleles differ from each other.

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Genotype

how the alleles are written in our genetic code.

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Phenotype

the observable traits of an organism.

Early Embryonic Development:

Good News? Unexpected News? What happened? The body is superbly designed for
reproduction. The chemical signals that are found in body fluids that indicate conception are
discoveries based on scientific discovery.

Human Development

Kate had everything a modern woman wants in life a successful career as a lawyer, an adoring
husband, a large house in the suburbs and yearly vacations in exotic places. Everyone was
jealous of her, but inside she felt empty. Kate wanted a child. She and her husband, Jim, had
decided against having children so they could pursue their high-powered careers. However, her
biological clock could not be ignored and Kate persuaded Jim to start a family. After a year of
trying, Kate still couldnt get pregnant. She and Jim consulted a fertility doctor, who
recommended the couple try in vitro fertilization. She got pregnant on the first attempt, but the
pregnancy ended in a miscarriage. On the second try, Kate was able to carry the baby to term.
But there was an unforeseen problem their baby had a heart defect. After years of trying why
couldnt something go right?!?
While Kate and Jim were struggling in the suburbs, Valerie had quite the opposite problem. She
was knocked up. She was so drunk at a party a few weeks ago that she barely remembered
hooking up with that guy...what was his name again? She was 20 years old, pregnant and an
alcoholic. Val went into labor two months early. Her premature baby boy weighed only 3 pounds
and had trouble breathing. After he stabilized in the hospital, Val decided to give him up for
adoption. At first the boy seemed to be doing okay, but his adoptive parents noticed that it took
longer for him to learn how to talk and he always seemed so hyper! What was wrong with this
poor child?
These examples highlight just a few of the many things that can go wrong during human
development. Development is not a trivial process, it is a complex web of interactions at the
molecular, cellular, and organ levels. The topic of developmental biology brings together many
topics you have already studied, such as cell division, genetics, and gene expression. It also will
provide the foundation for topics you will cover later in the semester, such as cell
communication, organ systems, and evolution.
Most people know they started off as a single cell, but have you ever taken the time to think
about what that means? Just one cell! How did that single cell turn into the trillions of cells that
make up your body today? And did you know that every one of your cells contains the same
DNA sequence? If that is the case, why do you have eyes in your head but not on your toes?
Why do islet cells in the pancreas know to produce insulin, while cardiac myocytes in the heart
know to beat rhythmically? How are these identities established if all cells have the same DNA,
the same genes? We will answer these questions over the next three modules by discussing the
following specific challenges that are faced by a developing embryo.
In order for an embryo to properly develop, it must:
1. Originate from the union of egg and sperm(Fertilization).
2. Grow via cell division to increase total cell number(Cleavage).
3. Organize cells to establish the body plan(Gastrulation).
4. Specialize cells to perform diverse functions(Differentiation).
5. Rearrange cells to build tissues and organs(Organogenesis).
We will cover the first three steps in this module and tackle the final two steps in the next
module. Take a quick look at Figure 1 to get a broad overview of the early steps of embryonic

development that we are going to cover today.

1.How is an embryo created? Fertilization
The first step of embryonic development is fertilization which is the fusion of a haploid (1N)
sperm and a haploid (1N) egg to create a diploid (2N) zygote (Figure 2). Lets start by taking a
closer look at the players involved. These reproductive cells called gametes.
Sperm lean, mean, fertilizing machines
The sperms role in fertilization is fairly simple, they travel through the female reproductive
tract, find the egg and deposit chromosomes. Sperm are much smaller than female eggs (see
Figure 2) and there is a very good reason for this. Human males release over 250 million sperm
during each ejaculation. Since so many sperm are continually produced, the male body cannot
afford to invest a lot of energy or resources in something that is quickly discarded. So each
sperm cell is designed to be a compact and efficient package that contains only the resources it
needs to get the job done (Figure 3):
(1) A haploid (1N) nucleus containing the fathers chromosomes.
(2) A tail that propels the sperm on its journey to the egg.
(3) Mitochondria that generate energy (ATP) to power the tail.
(4) A sac, called the acrosome, containing enzymes that allow the sperm to enter the egg.
Egg fertile grounds
While the sperm is a lean, mean, motile machine, the female egg provides a rich, nurturing
environment that supports the embryo until it starts producing proteins on its own and is able to
obtain nutrients from the mother. The egg contains a haploid (1N) nucleus and a huge volume of
cytoplasm where many of the proteins and mRNAs the embryo needs to survive early
development are stored. Two protective barriers surround the egg to regulate sperm entry are the
cumulus cells and the zona pellucida (Figure 4). Unlike sperm, which are continuously produced,
all the eggs a female will ever need are present in ovaries at birth. Eggs remain inactive until
triggered by menstrual hormones and one egg is released during each menstrual cycle. The
menstrual cycle will be discussed in more detail in upcoming modules.
Journey to the center of the womb
Following intercourse, sperm deposited in the females reproductive tract start swimming
upstream with their motile tails (similar to salmon swimming upstream to spawn) using ATP as
an energy source. If the timing is right, the sperm will encounter a freshly ovulated egg in the
fallopian tube (also called the oviduct) (Figure 1). Good timing is essential since the sperm need
to be in the female reproductive tract long enough to become activated, or capacitated, but not so
long that they die. Sperm are usually capable of fertilizing an egg anywhere from several hours
to 5 days after intercourse. In contrast to long-lived sperm, the egg has only 24 hours to
encounter a sperm before it dies.
Sperm-egg binding love at first sight
Of the 250 million sperm that begin the race to the egg, only 200 sperm successfully make the
journey. That is about the same chance as winning the lottery! But the journey does not stop

there. After the handful of lucky sperm make it to the egg, they still have to breach the two
barriers surrounding the egg (Figure 5). The cumulus layer acts as a first line of defense. It lets
capacitated sperm through, but holds back inactivated sperm. If sperm are able to pass through
the first barrier, they next try to attach to the zona pellucida, the tough coating surrounding the
egg. Evolution has created many safeguards to make sure successful reproduction only occurs
between males and females of the same species (there is a reason that centaurs and mermaids are
mythological creatures!). One of these safeguards is sperm-egg binding, which works much like
a lock and key system. The egg can only be unlocked if the sperm displays a species-specific
protein on its surface (the key), which recognizes a species-specific protein on the zona
pellucida (the lock). If the key does not match the lock, fertilization will not happen.
Sperm fusion breaking down the door
If sperm binding is successful, the acrosome releases enzymes that chew a hole through the zona
pellucida (Figure 5). The hole allows the sperm to contact the plasma membrane of the egg.
Fusion of the plasma membranes allows the sperm nucleus to enter the egg, creating a singlecelled embryo called a zygote. The zygote is diploid (2N) since it results from the fusion of two
haploid (1N) gametes. Fertilization releases the egg from its suspended state, triggering
production of new proteins and initiation of the cell cycle (mitosis).
Block to polyspermy getting rid of the competition
Within seconds of fertilization, the zygote is already in danger. The single sperm that fertilized
the egg is probably not the only sperm in the vicinity. What might happen if more than one
sperm were allowed to enter the egg? In a previous module you learned about Down syndrome,
a devastating disorder caused by three copies of chromosome 21. What do you think might
happen if all 26 chromosomes were present in three copies, or even four? One word Disaster.
Fertilization by multiple sperm, called polyspermy, always results in embryonic death. Luckily,
the zygote reacts quickly to prevent polyspermic fertilization by releasing enzymes to modify the
protein lock on the zona pellucida so additional sperm are no longer able to bind. No binding
means no fertilization. Disaster averted. The prevention of polyspermy is a negative feedback
loop.
Medical applications of fertilization research
Research on mammalian fertilization has allowed society to address fertility problems that
prevent nearly 15% of couples from having babies naturally.
2. How does the embryo grow? Cleavage
The single-celled zygote will not make it very far in development unless it undergoes cell
division. The next stage of development, called cleavage, lasts nearly one week and is
characterized by a rapid and exponential increase in cell number. These are the first signs of
differentiation and uterine implantation.
Cell division
Fertilization triggers initiation of the zygotic cell cycle, resulting in cell division and a rapid
increase in cell number. The single celled zygote divides into a 2-cell embryo, which divides into
the 4-cell embryo, and so on (Figure 6). Cleavage is known as a period of cell division in the
absence of cell growth. Without cell growth, the total amount of cytoplasm in the embryo does
not change, cells get progressively smaller at each division and the developing embryo remains

the same size as the original zygote.

Cell division during the cleavage stage generates special embryonic cells called blastomeres.
Blastomeres are undifferentiated, meaning that all cells are exactly alike and have not yet
become specialized. In fact, this is how identical twins form blastomeres divide into two
separate cell masses. Since all cells are identical, each cell mass has the ability to develop into a
complete person.
Cell cycle differences
So why, exactly, do blastomeres get successively smaller during cleavage? The answer is simple
blastomere cell cycles are different than normal cell cycles (Figure 7). As you may recall, a
normal cell cycle consists of DNA synthesis (S) and mitosis (M) separated by two Gap phases
(G1 and G2) that allow the cell to grow. Blastomeres going through cleavage skip the G1 and G2
phases, so they do not have time to grow in size or double the amount of cytoplasm before
dividing into two new cells.
Blastocyst
Cleavage ends with the formation of a hollow ball of cells called the blastocyst (Figure 8). The
center cavity is called the blastocoel. The blastocyst contains two types of cells. (1) The outer
trophoblast cells help form the placenta and other extra-embryonic tissues, but do not contribute
to the embryo itself. (2) Cells of the inner cell mass are the precursors of all future cells of the
embryos body and are more commonly known as embryonic stem cells. The separation of
function between the trophoblast and inner cell mass is the first evidence of differentiation, or
specialization, in the embryo. We will discuss differentiation in more detail in the next module
since it is so important during embryonic development.
Implantation
During development, the growing embryo will need a steady supply of nutrients and oxygen, and
will need to discard waste materials like carbon dioxide. These needs are met through a constant
connection with the bloodstream of the mother via the umbilical cord and placenta. To build this
connection, the embryo implants itself into the wall of the mothers uterus. Implantation usually
takes place a week or so after fertilization when the embryo is at the late blastocyst stage. The
embryo hatches from the zona pellucida and the trophoblast cells bind the uterine wall.
Enzymes released from the trophoblast break down uterine tissue and the embryo burrows inside
(Figure 9). Descendants of the trophoblast grow outward and form the embryonic half of the
placenta (the other half comes from the mother). Blood vessels grow into the placenta, forming
the umbilical cord that allows exchange of nutrients and gasses. You can still see remnants of this
previous connection to your mother your belly button is a section of the umbilical cord that
was tied off at birth! After implantation the blastocyst secretes human chorionic gonadotropin
(hCG), the hormone detected by home pregnancy tests and one of the causes of morning
sickness.
Medical application of cleavage stage blastomeres
Following closely on the heels of fertilization research, scientists quickly realized that the
undifferentiated blastomeres of the inner cell mass can be removed and used as embryonic stem

cells. We will talk more about how stem cells are being used to find cures for diseases and the
ethics involved in stem cell research in the third developmental biology module Development
and Society.
3. How does the embryo begin to take shape? Gastrulation
At the end of cleavage, blastomeres of the inner cell mass are non-descript and unorganized.
During gastrulation, a rough body plan starts to emerge. Dynamic cell movements set up the
inner and outer layers of the embryo, along with the body axes.
Gastrulation
During gastrulation, the inner cell mass rearranges into three germ layers that will form the
outside, middle, and inside layers of the embryo. Movement of cells during gastrulation is
similar to what happens if you push your finger into an inflated balloon the cells migrate
downward into the embryo (Figure 10). The first cells to move inward form the most internal
layer of the embryo, the endoderm. The next group of cells to move inward, the mesoderm,
situate themselves on top of the endoderm but underneath the outer layer, forming the middle
cell layer. The cells that remain on top of the embryonic disc will form the outer layer of cells,
the ectoderm. Each of the germ layers will form different tissues and organs later in development
(Figure 11):
1. Endoderm (inside): lining of digestive and respiratory systems
2. Mesoderm (middle): circulatory system, reproductive system, kidneys and urinary system,
bone, muscle, tendon
3. Ectoderm (outside): skin, pigment cells, nervous system including brain, and spinal cord
Body Axes
While gastrulation determines which cells will form internal vs. external structures, the body
plan must be further refined by setting up three body axes: the anterior-posterior, dorsal-ventral
and left-right axes (Figure 12).
1. Anterior-posterior axis: the imaginary line extending from the top of your head to the tip of
your toes. Anterior is toward the top, posterior toward the bottom.
2. Dorsal-ventral axis: the imaginary line extending from your back to your belly. The dorsal fin
of fish, dolphins, and whales got its name because this fin is located on their backs. Your spinal
cord is a dorsal structure, while your belly button is a ventral one.
3. Left-right axis: the imaginary line between the two lateral sides of your body. Even though
humans look symmetrical along this axis from the outside, inside we are asymmetric. Your heart
is on the left side of your body, while your liver is on the right.
Segmentation
A long axis, such as the anterior-posterior axis that runs from head to tail, can be further
subdivided into segments. Think about the vertebrae in your spinal column cervical vertebrae
are located in your neck, thoracic vertebrae run down the majority of your trunk and have ribs,
lumbar vertebrae are in your lower back and sacral vertebrae fuse to form your pelvis (Figure
13). Each of these regions represents a different segment of the vertebral columns anteriorposterior axis and each has a specialized function. The segmentation is exact and precise all
humans have the same number of cervical, thoracic, lumbar and sacral vertebrae. How does the

embryo know how many vertebrae to include in each segment? Instructions are provided by the
homeobox (Hox) gene family. Hox genes are some of the master regulators of differentiation
during embryonic development and we will continue discussing them in the next module.
Summary of Concepts
1. Embryonic development begins at the point of fertilization the fusion of a haploid sperm and
haploid egg to create a diploid zygote. Sperm must overcome many barriers to successfully
fertilize an egg, including a long-distance swim, capacitation, and species-specific recognition of
the egg. The egg prevents polyspermy by modifying proteins on its zona pellucida, preventing
the binding of additional sperm.
2. The newly fertilized embryo undergoes mitotic cell divisions known as cleavage. Cleavage
results in an exponential increase in cell number, but the embryo does not grow in size
(blastomeres get smaller at each division). The end result of cleavage is a blastocyst, which
implants into the uterine wall. Trophoblast descendants form the placenta and establish a
physical connection to the mothers blood supply, while the inner cell mass (also known as
embryonic stem cells) continues dividing and will give rise to all embryonic tissues.
3. The inner cell mass begins to organize and take shape. Cells undergo gastrulation and
rearrange into three germ layers (endoderm, mesoderm and ectoderm). The three body axes are
established anterior-posterior, dorsal-ventral, and left-right. Further subdivision of the axes is
accomplished through segmentation, a process regulated by masters of differentiation the Hox
genes.
4. Developmental biology has important medical implications. Infertility treatments, genetic
testing, and stem cell research were all made possible because of the progress made by
researchers studying early embryonic development.
Embryo

Name given to a developing organism; in humans the embryonic

stage lasts from fertilization through the first 8 weeks of development

Fetus

Name given to a developing human from 8 weeks post-fertilization

until birth

Fertilization

Fusion event between egg and sperm that creates a new embryo

Zygote

Specific name for a single-celled embryo that is fertilized but has not
yet divided

Gamete

Reproductive cell, such as an egg or sperm, formed during meiosis;

carries a haploid (1N) set of chromosomes

Acrosome

Compartment in sperm head containing enzymes that penetrate the

zona pellucida during fertilization

Zona pellucida

Protective barrier surrounding the egg; contains species-specific

recognition proteins

Capacitation

Sperm activation within in the female reproductive tract

Polyspermy

Fertilization by multiple sperm; lethal for the embryo

Cleavage

Blastomeres

Early embryonic stage characterized by cell division in the absence of cell growth

Early embryonic cells at the cleavage stage

Undifferentiated
cell

Blastocyst

Immature cell that has not yet acquired special structure or function; for
example a stem cell

Hollow ball of cells formed during cleavage; first evidence of differentiated

embryonic cells

Blastocoel

Hollow cavity in the middle of the blastocyst

Trophoblast

Outer layer of cells of the blastocyst; some of these cells will help
form the embryonic component of the placenta

Inner cell mass (ICM)

Collection of blastocyst cells known more commonly as embryonic

stem cells; will divide to form all future cells in the embryos body

Differentiation

Transformation of a cell into a more specialized role through the

acquisition of genetic changes and physical characteristics; for
example from a stem cell into a blood cell or neuron

Pluripotent stem cells

Undifferentiated cells that have the ability to form every cell type
that will be present in the future embryo

Gastrulation

Stage of embryonic development following cleavage, hallmarked by movement

of cells through the primitive streak to establish the three germ layers

Germ layers

Three layers of the embryo established during gastrulation; ectoderm

(outer), mesoderm (middle), and endoderm (inner) cell layers

Hox genes

Genes required for patterning the anterior-posterior axis; master

regulators of differentiation

A negative feedback loop prevents multiple sperm from fertilizing a single egg. Fro fertilization
to occur, a sperm must recognize and bind to proteins on the egg's surface. If binding occurs and
the sperm successfully fertilizes the egg, the egg responds by releasing enzymes that irreversibly
modify the sperm-binding proteins. These changes make the protein unrecognizable to sperm and
additional sperm can therefore no longer bind the fertilized egg.

Development of Organ Systems:

Embryos go through dramatic transformations during early development. After only eight weeks

the embryo has grown and differentiated considerably, forming limbs, eyes, and all the organ
systems. Of course this sweet bundle of joy takes up a lot of room.

Dare to be Different
Remember when adults used to ask you what you wanted to be when you grew up? The process
of choosing a career path is much the same as a cell becoming specialized during embryonic
development. When you were a young child, you had limitless potential to be anything an
astronaut, a concert pianist or even President of the United States. In elementary and high school,
your interests were likely shaped by natural aptitude and external influences. Now that you are
in college, you are pursuing and refining your natural interests further, for example by majoring
in political science rather than chemistry. After graduation, your interest in public policy may
lead you to law school, where you will specialize in environmental law. At this point, you will
have acquired defining traits and characteristics of a highly trained lawyer, but your career
choices will be very limited. You can no longer be an astronaut like you dreamed about as a
child. Now think about what your 10-year high school reunion will be like. You will have
chosen one career path, but your many classmates will have gone down alternate paths to
become teachers, construction workers and doctors. Society needs people of different professions
in order to run smoothly, much like an embryo needs specialized cells to form the many organ
systems that will allow the body to function properly (Figure 1).
Differentiation and Organogenesis
Let us recap what we learned about embryonic development in the last module. In order for an
embryo to properly develop, it must:
1. Originate from the union of egg and sperm (Fertilization)
2. Grow via cell division to increase total cell number (Cleavage)
3. Organize cells to establish the body plan (Gastrulation)
4. Specialize cells to perform diverse functions (Differentiation)

5. Rearrange cells to build tissues and organs (Organogenesis)

We covered fertilization, cleavage, implantation and gastrulation in the last module and we will
now tackle differentiation and organogenesis.
Soon after gastrulation, cells continue to migrate and rearrange, signaling the beginning of
organogenesis (Figure 2A). First, cells become specialized by acquiring characteristics that set
them apart from other cells, a process called differentiation (Figure 2B). Differentiation is a
gradual process where cell function becomes more and more restricted over time. Next, related
cells group together to form a tissue that carries out a specific function (Figure 2C). Finally,
different tissues assemble into a working unit called an organ (Figure 2D).
4. How are specialized cells created? Differentiation
The adult human body has over 50 trillion cells. Are all of these cells identical? Clearly not
cardiac myocytes in the heart beat rhythmically, red blood cells carry oxygen throughout the
body, pancreatic beta islet cells produce insulin to regulate blood glucose levels, and
photoreceptor cells in the retina process what you see and deliver that information to the brain.
Each of these cell types performs a specific function in the human body. Amazingly, each of
these specialized cells descended from the single cell created at fertilization. This incredible
transformation where cells acquire characteristic changes in size, shape, and function in order to
perform a special role in body maintenance is called differentiation.
Stem Cells and Potency
Stem cells are the foundation of embryonic development for two important reasons: (1) they can
replenish themselves in a process called self-renewal that guarantees a continual population of
stem cells and (2) they can divide to form subsets of cells able to differentiate. This balance
between maintenance of non-committed cells and formation of specialized cells drives
development forward. As the embryo develops, stem cells become more and more restricted in
their ability to form different cell types. The stages of progressive differentiation are described
below and illustrated in Figure 3.
1. Totipotent stem cells have unlimited potential and can form every type of cell. In humans,
totipotent cells are present from the point of fertilization (the zygote) through the first several
cleavage divisions. These cells can form any cell type in the future embryo, as well as the extraembryonic tissues like the placenta.
2. Pluripotent stem cells can give rise to most, but not all, cell types. A perfect example is the
inner cell mass of the blastocyst. These cells can form all cell types of the future embryo, but
cannot contribute to the placenta (which is the job of the outer trophoblast cell layer). Human
pluripotent cells are commonly referred to as embryonic stem cells since they can form
ectoderm, mesoderm, endoderm, and all the cell types derived from these germ layers.
3. Multipotent stem cells can form limited cell types. They are partially differentiated, giving
rise to cells that have related functions or will form parts of the same organ system. For example,
hematopoietic stem cells form all types of blood cells (red blood cells, T-cells, B-cells,
neutrophils, macrophages, etc.) but, they cannot form brain cells or muscle cells. Human
multipotent cells are more commonly known as adult stem cells. They are found in several

organs and self-renew to replenish old and damaged cells.

4. Unipotent stem cells can only differentiate into a single cell type their own. Unipotent cells
are still considered stem cells since they can self-renew. An example of unipotency is skin cells,
which divide to replace the millions of dead skin cells we slough off every day.
5. Terminally differentiated cells are the end product of differentiation. They have acquired all
the characteristics necessary to perform a specific function and are not capable of self-renewal.
Neurons, cardiac muscle cells, and red blood cells are examples of terminally differentiated cells
(Figure 4). Differentiated cells with the same characteristics group together to form tissues.
Differentiated cells express tissue-specific proteins
What makes differentiated cells unique? What enables a muscle cell to contract, or a skin cell to
repel bacteria? The answer is tissue-specific proteins. Muscle cells contain actin and myosin, two
proteins that allow the cell to lengthen and shorten. Skin cells release antimicrobial proteins that
kill bacteria before they can invade our bodies. Muscle-specific myosin is not found in skin cells,
while antimicrobial proteins arent present in muscle cells. Each differentiated cell type
expresses a unique combination of proteins that allows it to carry out its specific function (Figure
5). Tissue-specific proteins are the basis of differentiation!
Differentiation is driven by tissue-specific mRNA expression
How do unique proteins become expressed in differentiated cells? In a previous module you
learned the Central Dogma DNA is transcribed into mRNA, which is translated into proteins.
So if unique proteins expressed in different cell types, there must be an inherent difference
between those cells at either the DNA level or the mRNA level. Let us start with DNA. Is the
genome of a muscle cell different than the genome of a skin cell? Are chunks of DNA removed
from certain cells when that DNA is no longer needed? No all cells in our body contain the
exact same DNA sequence since they all derive from the same original cell (the zygote). Since
differences do not lie at the level of DNA, they must occur at the mRNA level. This is precisely
what happens differentiated cells arise because tissue-specific mRNAs are expressed (which
are translated into proteins).
Gene expression is driven by transcription factors
How is tissue-specific mRNA expression achieved? In the Gene Expression module, you learned
that a gene is transcribed when RNA polymerase binds the genes promoter. Every genes
promoter contains instructions indicating where and when that gene should be active. The
instructions are read by transcription factors that bind the promoter (Figure 6). Transcription
factors flag down RNA polymerase and help it bind when the gene needs to be turned on, and
they prevent it from binding when the gene should be turned off. When a cell differentiates,
transcription factors turn on genes that are required for that cell to function properly. For
example, a muscle cell forms when a gene like myosin is turned on by muscle-specific
transcription factors, while genes required for brain cell function will be turned off in muscle
cells. The feedback loop to the left shows how cell differentiation is a negative feedback loop.
Hox genes encode transcription factors
Remember the Hox genes we discussed during the last module that were important for
establishing segments along the anterior-posterior axis? Can you guess what the Hox genes are?
Yes, you are right they are transcription factors! They help the developing embryo

differentiate. When the anterior-posterior axis is relatively undifferentiated, various Hox genes
are turned on in specific regions of the anterior-posterior axis. For example, Hox5 is turned on in
regions that will form cervical vertebrae, while Hox6 is activated in regions that will become
thoracic vertebrae (Figure 7). When Hox5 is present, it acts as a transcription factor and turns on
the expression of more genes that will help cells differentiate into cervical vertebrae. Those
target genes will then go on to activate more genes, and so on. Transcription factors often act in a
cascade, activating increasingly larger numbers of genes that will help a cell acquire tissuespecific proteins, leading to differentiation.
Cell communication also drives differentiation
While transcription factors regulate what is happening inside a cell, additional information on
how a cell should differentiate is also provided from the outside environment. Any given cell in
an embryo is not isolated, but rather is surrounded by many other cells that are in constant
communication. Signals are sent between cells so they can instruct each other. These signals can
be bound to a cells surface, or floating around in the extracellular space (Figure 8). You will
discuss cell communication in more detail later in the semester, but for now, just understand that
communication and interaction between neighboring cells can provide cues for cells to
differentiate. Signals from the outside of a cell are converted into information inside the cell. As
with transcription factors, this information leads to tissue-specific gene expression, which
produces proteins required for differentiation.
Medical applications of embryonic differentiation
As you may have guessed when reading this section, differentiation is an essential part of stem
cell research. When embryonic stem cells are used to grow neurons to treat Parkinsons patients,
correct transcription factors must be present to allow neuronal differentiation to occur. We will
talk more about stem cell research in the next module, Development and Society.
. How do differentiated cells assemble into organs? Organogenesis
The purpose of differentiation is to generate specialized cells that can group together to form
tissues. Different tissues combine to form organs. Interestingly, many organ systems form by
combining tissues derived from two separate germ layers. For instance, your skin is made up of
the outer epidermis (derived from ectoderm) and inner dermis (derived from mesoderm) layers.
The lining of the digestive system derives from endoderm, but the muscles required for
peristalsis come from mesoderm. Oftentimes there is direct communication between ectoderm
cells and mesoderm cells, or between mesoderm cells and endoderm cells. Signals sent back and
forth help cells identify where they are in the body and are essential for proper differentiation.
We will now talk about some of the organ systems you will learn about later in the semester.
Hopefully this will give you a good background on how the organ systems form, and why they
behave the way they do.
Nervous system
The nervous system is the first organ system that begins to form, but one of the final ones to
complete. The nervous system is derived from ectodermal cells (the outside germ layer) and
forms on the dorsal (back) side of the embryo. The first step of nervous system formation is
called neurulation (Figure 9). Neurulation begins when the notochord (a mesodermal structure)
sends signals to ectodermal cells above it, telling them to form the neural plate. The neural plate
is a strip of stem cells that runs down the entire back of the embryo. The neural plate folds in on

itself, pinching off to form the neural tube. The upper (anterior) section of the neural tube will
differentiate into the brain, while the lower (more posterior) sections will form the spinal cord.
Can you guess which genes are turned on during differentiation of the anterior neural tube? You
guessed it Hox genes!
Circulatory system
The circulatory system includes the heart, blood vessels and blood cells, and is derived entirely
from mesoderm. The workhorse of the circulatory system, the heart, is the first fully functional
organ in the embryo. Just 21 days after fertilization, two tubes fuse together forming a singlechambered heart capable of beating (Figure 10)! It takes a few more weeks to fully form the
four-chambered heart. Blood vessels do not sprout out from the heart, but originate elsewhere in
the embryo. They grow longer, eventually connecting to the heart. Once the first circulatory loop
is completed, the heart can pump blood through the embryo. The circulatory system is the lifeline
of the embryo and performs functions not normally carried out by an adult circulatory system.
For example, the embryo must obtain nourishment and oxygen before the intestine and lungs
develop, and must get rid of waste before kidneys form. The embryonic circulatory system
performs all these functions by connecting the embryo to the mothers circulatory system via the
placenta.
Digestive system
The digestive system derives from endoderm and arises from the primitive gut, a long tube that
forms around the same time as the single-chambered heart (Figure 11). The most anterior region
of the gut forms the pharynx, which is shared between the digestive and respiratory systems.
Moving from anterior to posterior, the foregut differentiates into the esophagus, stomach and
intestines. Remember when we discussed how cells communicate with each other to drive
differentiation? This is how the digestive system differentiates mesoderm surrounding the
esophagus is different than mesoderm surrounding the stomach. Signals sent out from the
different regions of mesoderm instruct the gut to become different structures along the length of
the tube. Accessory organs, including the liver, gallbladder and pancreas, form by budding off
from the main gut tube.
Respiratory system
When you choke on food or water, do you ever explain to your worried friends or family that it
went down the wrong pipe? The origin of this expression comes from the fact that the
digestive and respiratory systems are intimately connected. Normally the pharynx is open to the
trachea so that you can breath freely. But when you swallow, a flap of tissue (called the
epiglottis) folds down and covers the opening to the trachea, diverting the food into the
esophagus. This prevents you from choking.
Why are breathing and swallowing so closely connected? It turns out that the respiratory and
digestive systems have the same origin the foregut tube! During development, the foregut tube
projects outward just below the pharynx and forms a new tube that develops into the trachea
(windpipe) and lungs (Figure 12). This new tube branches at the bottom to form the left and right
sides of the lungs. The lungs are one of the last organs to fully form and differentiate, which
explains why many premature babies have trouble breathing. In order for a baby to breathe on its
own, the lungs must secrete a substance called surfactant, which is produced toward the end of
pregnancy. Premature babies are often put on ventilators to help them breathe, and artificial

surfactant can be delivered until the lungs are developed enough to produce surfactant on their
own.
Transition from embryo to fetus
After only eight weeks of development, the embryo has formed all the major organ systems
(Figure 13). It has hands, feet, eyes, eyelids and even fingerprints. All of the most dramatic
transformations have taken place, and the chance of miscarriage drops sharply. For the remaining
30 weeks of pregnancy, the embryo is called a fetus. During the fetal stage, the organ systems
continue to grow and develop, becoming more functional every week.
Normal gestation time for human babies is 36-40 weeks post-fertilization. Thanks to incredible
advances in medical technologies, more than 50% of premature babies can now survive even if
they are born after only 24 weeks of pregnancy. One recent case saw survival after 22 weeks, but
this was a rare occurrence (Figure 14). Because the lungs and brain are the last organs to fully
develop, many premature babies have immediate problems with breathing, and later problems
with cognitive function. There are many causes of premature delivery. In some cases the mother
makes unhealthy choices during pregnancy, including smoking, alcohol use, drug use, or poor
nutrition. In other cases, the causes are out of the mothers control, including hormone
imbalances or illness.
Summary of Concepts
During development, stem cells undergo differentiation to produce specialized cells that
perform specific functions. When stem cells divide, they can either produce more of themselves
(self-renewal) or can differentiate further. Differentiation is gradual, with stem cells passing
through totipotent, pluripotent,multipotent, and unipotent stages before reaching terminal
differentiation.
Cell differentiation is driven by internal and external factors. Internally,transcription
factors (including Hox genes) activate genes at the right time and place. The genes are
transcribed into mRNA and translated into tissue-specific proteins. Externally, cells
communicate with each other by sending instructional signals that turn on tissue-specific proteins
that guide differentiation. Each differentiated cell type expresses a unique set of tissue-specific
proteins.
Differentiated cells with a common function group together to form tissues, which assemble into
organs. This process is called organogenesis. Many organ systems arise due to communication
and interaction between cells originating from two different germ layers (e.g. skin forms from
ectodermal epidermis and mesodermal dermis).
The nervous, circulatory, digestive, and respiratory systems all form from primitive tubular
structures. Signals from different mesodermal cell populations help organize anterior-toposterior differentiation along the length of the tube.
The embryonic stage ends at the 8th week of development when all the major organ systems have
formed, at which point it is called a fetus for the remainder of the pregnancy. Normal
development takes 36-40 weeks.

Differentiation

Specialization of a cell through acquisition of cell-specific proteins

and characteristics; for example from a stem cell into a blood cell or
neuron

Stem cells

Undifferentiated cells that have the ability to form many cell types

Self-renewal

Stem cell characteristic describing the ability to divide repeatedly

while retaining an undifferentiated state in daughter cells

Totipotent

Potential to differentiate into every cell type, including extra-embryonic tissues

like the placenta

Pluripotent

Multipotent

Potential to differentiate into every cell type except extra-embryonic

tissues

Potential to differentiate into many, but limited, cell types; an example is

hematopoietic stem cells

Embryonic stem cells

Pluripotent stem cells derived from the inner cell mass of the
blastocyst

Adult stem cells

Multipotent stem cells with the ability to replace damaged or dying

cells in an organ; able to differentiate into several cell types present
in the organ

Unipotent

Potential to differentiate into a single cell type; an example is skin stem cells

Tissue

Group of differentiated cells sharing a common origin that come

together to carry out a specific function; multiple tissues assemble
into an organ; an example is cardiac muscle tissue that allows the
heart to contract and pump blood

Promoter

Region of DNA near a gene containing instructions for when and

where a gene should be expressed

Transcription factors

Proteins that bind promoters and instruct RNA polymerase as to

whether the gene should be transcribed or not

Hox genes

Class of genes encoding transcription factors responsible for

patterning the anterior-posterior body axis

Neurulation

First stage of nervous system formation where the neural plate folds
up to form the neural tube

Neural plate

Region of dorsal ectoderm running the length of the embryo (from

anterior to posterior) that will form the neural tube

Neural tube

Hollow structure formed during neurulation that is the precursor for

the brain and spinal cord

Primitive gut

Long, hollow tube of endodermal cells that will form the lining of the
digestive and respiratory systems

Surfactant

Substance secreted in fetal lungs that prevents the lung air sacs from
collapsing

Fetus

Name given to a developing human from 8 weeks post-fertilization

until birth

Development and Society

"Mom! Look what I found!" We are products of our DNA and social surroundings. The
interaction of humans has a biological basis that plays a major role in cooperation and
competition. Easier to quantify is the fact that our DNA is affected by environmental products
whether it is "Agent Orange" sprayed in the jungles of Vietnam or the medicine that your mother
took while he was pregnant with you.

We will now discuss the impact the field of developmental biology has had on society. Drugs
and chemicals that cause horrible developmental deformities have been identified, resulting in
public programs dedicated to their prevention. Cures for human disease might be on the horizon
thanks to research on stem cells and differentiation. And finally, as humans we have always been
intrigued in by the question of who we are and where did we come from? Studying
developmental biology from an evolutionary perspective is starting to answer some of those
questions.

Environmental Influences on Development

When we think about the environment, images of the sun, trees, and the ocean normally come to
mind. But in the context of developmental biology, environment takes on a different meaning. An
embryos environment is mainly influenced by its connection to the mothers blood stream
through the umbilical cord and placenta. If beneficial things like nutrients and oxygen can pass
from the mother to the embryo, so can harmful things like teratogens. A teratogen is any
chemical or environmental factor that can cause birth defects in an embryo. Teratogens include
radiation, viruses, alcohol, retinoic acid, and many other drugs. Let us take a quick look at a few
of these.
Alcohol
Alcohol is probably the most devastating teratogen because of how many children it affects.
When a mother drinks alcohol during pregnancy, her infant has a chance of developing Fetal
Alcohol Syndrome (FAS). Any amount of alcohol at any stage of development can negatively
affect the embryo, but the severity of FAS increases proportionally with the amount and duration
of alcohol exposure. Children with FAS have characteristic facial defects like wide set eyes, a
flat face, and a small head (Figure 1). But the most serious problem is the potential for mental
retardation. Alcohol can cause neurons to die during fetal brain development, explaining why
children with FAS have below-average IQs and reading and math abilities. These mental
problems carry over into adulthood, since many adults born with FAS have problems handling
money, learning from experiences, and coping with the demands of normal life.
Retinoic Acid / Vitamin A / Accutane
Retinoic acid is an interesting teratogen it is required in small doses for normal development,
but in high doses can cause facial deformities, including cleft palate (Figure 2). Retinoic acid is
a form of vitamin A, which explains why women are warned to limit vitamin A intake during
pregnancy. The normal function of retinoic acid is to activate Hox genes, which as we learned
earlier, are essential for setting up the anterior-posterior axis of the embryo. Scientists believe
some birth defects caused by excess retinoic acid are due to improper expression of Hox genes at
times or places they would not normally be activated. Isotretinoin, the active ingredient in the
acne drug Accutane, is also a vitamin A derivative. Women should be especially careful to
prevent pregnancy if they are taking Accutane.
Thalidomide
Thalidomide is a perfect example of why pharmaceutical drugs should be thoroughly tested by
the Food and Drug Administration (FDA) before entering the market. Fifty years ago,
thalidomide was prescribed to pregnant women around the world to prevent morning sickness
and as a sleep aid. Sadly, the devastating effects of thalidomide on embryonic development were
not realized until 10,000 children were born with missing or deformed arms and legs (Figure 3).
Fortunately, the impact on the United States was minimized thanks to an observant FDA
reviewer who prevented the distribution of thalidomide in the U.S., saying it needed more
testing. Soon after, Congress passed laws requiring that drugs be tested during pregnancy before
being approved by the FDA.
Environmental Chemicals
The widespread use of agricultural pesticides can also cause developmental defects. For
example, in the 1950s and 1960s, methylmercury was used to kill fungus in wheat and grain
fields. Mothers who ate bread or drank water contaminated with methylmercury gave birth to

children with decreased mental functioning.

Some animals are more sensitive to teratogenic agents than humans, and can serve as
biosensors telling us when harmful chemicals are present. For example, 5 miles from my
hometown in Minnesota, a group of school kids exploring a pond found that 40% of the frogs
had missing or extra limbs (Figure 4). Scientists descended upon the town to identify the cause
of the deformities. No definitive cause has been found yet, but some research suggests that a
pesticide used by local farmers can cause limb deformities in laboratory frogs by either
interfering with the retinoic acid pathway or enhancing the ability of parasites to infect the frogs.
It has not been determined whether the teratogenic agent has affected humans in the area, but a
local resident noticed that at least one person in every household surrounding the wetland has
cancer.
Cloning
When you think of the word cloning, what comes to mind? Agent Smith in The Matrix (Figure
5)? Ewan McGregor and Scarlett Johansson almost having their organs harvested in The Island?
A futuristic army of cloned soldiers designed for super-human strength and speed? Cloning has
been a popular theme in science fiction for ages, and at times has been a dirty word in public
policy. There are two main types of cloning, reproductive and therapeutic. Each with its own
advantages and ethical concerns. We will discuss some of these differences to help you
understand more about cloning and its place in current scientific inquiry and public policy.
Reproductive Cloning
The purpose of reproductive cloning is to create a new organism that is genetically identical to an
existing one. In 1997, Scottish researchers reported the first successful cloning of a mammal a
sheep named Dolly. Reproductive cloning uses a technique called somatic cell nuclear
transfer(SCNT), where the nucleus from a donor cell to be cloned is transferred into a recipient
egg whose nucleus has been removed (Figure 6). The egg is tricked into thinking it is fertilized
and the embryo is implanted into the uterus of a surrogate mother. Since the embryo has the
exact same DNA as the donor cell, the embryo will be a genetic clone of the adult. Reproductive
cloning has been reported for sheep, cows, mice, dogs, monkeys, and many other animals, and
could be beneficial for the agricultural and pharmaceutical industry. Private speculators have
even tried to cash in one company (now out of business) offered to clone your favorite pet cat
for $50,000! While a few rogue scientists claim they are trying to clone humans, nearly all
scientists have no desire to clone human beings for reproductive purposes. It is illegal in many
countries, including the United States, because of the ethical issues it raises.
Therapeutic Cloning
While the goal of reproductive cloning is to recreate an entire organism, therapeutic cloning
generates stem cells to be used in the laboratory to study cell differentiation and to develop
treatments for diseases. It stops well short of creating a whole new organism. There are a number
of methods used to create therapeutic stem cells, which we will discuss below. The field of stem
cell research is still fairly new and has a long way to go before cures for human disease can be
found, but much progress has already been made. While some religious and political groups
oppose therapeutic cloning because it can involve destruction of a blastocyst-stage embryo, most
of the general public and scientists support it because of the therapeutic potential.
Stem Cell Research

Stem cell research is a hot topic both in the scientific community and in current public policy.
Stem cells hold great potential for treating Parkinsons, Alzheimers, diabetes, and heart disease,
or in reversing paralysis due to spinal cord injury. They are also incredibly useful as general
research tools (Figure 7). However, many challenges face stem cell research, including how to
obtain stem cells, how to get them to differentiate, whether they are actually capable of treating
disease, and whether it is ethically responsible to pursue this line of research.
How are stem cells isolated? The abortion debate revisited.
Stem cells have been isolated from three main sources: (1) pluripotent stem cells from the
blastocyst inner cell mass (a.k.a. embryonic stem cells), (2) multipotent stem cells from adult
organs, and (3) skin cells that were de-differentiated to resemble embryonic stem cells.
(1) Embryonic stem cells
Human embryonic stem cells (ES cells) have traditionally been considered the gold standard for
stem cell research because they have the greatest potential to form virtually every cell type.
However, they also generate the greatest controversy since creation of new ES cell lines requires
that an embryo be destroyed to harvest the inner cell mass (Figure 8). On one hand, pro-life
advocates say this constitutes abortion since a human life is destroyed, and therefore the practice
is unethical. On the other hand, ES cell advocates say blastocyst-stage embryos cannot be
considered true humans yet because they have not differentiated and are not able to survive
without being implanted into a womb.
Could the whole debate be avoided if stem cells were obtained from embryos destined to die
anyway? There are currently 400,000 embryos being stored at in vitro fertilization clinics around
the country, with 12,000 of these scheduled for destruction. Rather than destroying the embryos,
should they be donated to stem cell research? Who should decide? Even if the embryos were
destined for destruction anyway, does it devalue human life by using ES cells from these
embryos for research purposes?
In 2001, President Bush allowed the use of federal taxpayer money to fund stem cell research for
the first time, with the stipulation that research was limited to existing ES cells lines. The money
would not fund creation of new ES cell lines, nor research using ES cell lines created after 2001
with private funding, since he believes in the sanctity of human life. In response, California
passed Prop 71 in 2004, providing $3 billion for ES cell research that was not eligible for federal
funding (Figure 9). This has made California one of the leading centers for stem cell research. In
more recent news, the Obama administration has reversed some, but not all, of Bushs limitations
on stem cell research.
(2) Adult stem cells
While ES cells hold the most promise in terms of differentiation potential, quite a bit of progress
has already been made with adult stem cells. Adult stem cells are generated from multipotent
cells in organs, such as hematopoietic stem cells from bone marrow or cardiac stem cells from
the heart (Figure 10). Most adult organs contain multipotent stem cells to help replace
differentiated cells that are old, injured, or dying. They are hard to isolate and are extremely rare,
with less than 1 stem cell for every 1000 differentiated cells. But when they are isolated, they
can be very useful. For example, neural stem cells can be differentiated into dopaminergic
neurons, which could potentially be used to treat Parkinsons patients. The use of adult stem

cells is of great interest to stem cell researchers because it helps avoid the controversies
surrounding ES cells.
(3) Induced pluripotent stem cells
The newest fad in stem cell research is induced pluripotent stem cells (iPS cells). Since ES cells
are surrounded by controversy and adult stem cells are difficult to isolate, researchers wanted to
find a way to get the best of both worlds cells with unlimited potential that are easy to isolate
and avoid ethical problems. This was accomplished in late 2007 when two different research
groups transformed skin cells into pluripotent stem cells (Figure 11). This amazing feat was
accomplished by turning on the expression of four transcription factors commonly present in ES
cells, causing the skin cell to revert back to its original undifferentiated state. iPS cells are nearly
identical to ES cells, and no embryos are destroyed in the process. Much work still needs to be
done to determine whether iPS cells are going to be useful and safe, but at the moment the future
looks bright!
How do stem cells differentiate in the lab?
Once stem cells are created, how are they transformed into the differentiated cells that can be
used to treat disease? Think back to what we learned in the last module. Cell communication
and tissue specific gene expression is key! Thanks to decades of research, many of the proteins
required for differentiation of specific cell types are known. Scientists can bathe stem cells in
these proteins, which instruct the cell to differentiate in a certain way. Rigorous tests are
performed to make sure the cells display all the expected characteristics of the desired cell type.
Will stem cell therapies really work?
In short, we do not know yet. The only concrete example of successful stem cell therapy so far is
bone marrow transplantation, which has been used for 40 years to treat leukemia, immune
system disorders, and other blood-related diseases. Bone marrow transplants repopulate a
patients defective or destroyed marrow with adult hematopoietic stem cells, which are able to
form every type of blood cell. Other therapies using adult stem cells are currently in clinical
trials, but none have been approved for general use.
Embryonic stem cell therapies are even further behind. In January of 2009, the FDA approved
the very first clinical trial of a treatment involving ES cells. The study will treat paraplegic spinal
cord injury patients with ES cells coaxed to differentiate into cells that help neurons to function.
Scientists have been somewhat hesitant to try ES cell therapy in humans since similar treatments
in animal models (like mice) have, on occasion, caused tumors. The very characteristics that
make stem cells useful self-renew and pluripotency could also be a major problem during
treatment. If some of the injected cells do not follow their differentiation path, they could grow
uncontrollably into a tumor. This is a major concern for ES cell therapy that is currently being
addressed.
Another problem facing stem cell therapies is genetic compatibility. As with bone marrow
transplants, stem cell treatments may need to be a genetic match. In the case of a non-match, the
patient could reject the injected cells, or the cells could mount an immune response against the
patient as in graft versus host disease. The recent success of iPS cells may help circumvent this
problem by generating patient-specific stem cell therapies. A patient would have a skin biopsy,
the cells would be dedifferentiated in the laboratory into iPS cells, which could then be used to
generate any given stem cell treatment. Since the cells originally came from the patient himself,

the treatment would be an identical genetic match!

Is stem cell research (and cloning) ethical?
This is for you to decide!!! Read about it, think about it, decide for yourself, and tell your
elected government representatives what you want them to do about it!
Here are just a few questions to get the juices flowing:
1.Does human life begin at conception, implantation, the fetal stage, or birth?
2.Does ES cell research devalue human life?
3.How can society balance curing disease and the sanctity of life?
4.If a female donates eggs for the purpose of making ES cells, should she be financially
compensated? Would this create a black market for eggs? Would it exploit poor women who
find it an easy way to make money?
5.Should we use reproductive cloning to bring back extinct animals like dinosaurs, the woolly
mammoth, or Michael Jackson (Figure 12)?
4. The Evolution of Development
2009 marked the 150th anniversary of Charles Darwins pinnacle work on evolution, On the
Origin of Species. In honor of Darwin, let us spend a couple minutes talking about how
developmental biology has helped us understand the evolutionary relationships between humans
and other animals.
Evolution of the body plan
It is easy to tell the difference between humans, chickens, and fish, right? Instead of considering
their adult forms, what if you looked at their embryonic forms instead? Take a look at the top
row of Figure 13. Would you have been able to tell which animal was which if their names were
not listed at the bottom of the figure? Likely not they all look pretty similar.
Most animals that share a common evolutionary history tend to look very similar during early
development. For example, humans, chickens, and fish are all classified as vertebrates (having a
backbone), and they all have notochords, spinal cords, and primitive hearts in the very early
embryo. Features that make the animals unique, such as hair, feathers, or scales, emerge at later
developmental stages. These observations have led scientists to hypothesize that similarities
between early embryonic body plans are reminiscent of the body plan of a common ancestor,
while unique characteristics that appeared after species diverged do not appear until later in
development. Basically, what makes us human does not necessarily become evident until later
in development. Until then, we are hard to distinguish from other animal species.
Molecular evidence for common origins
Why do early embryonic body plans look so similar, and what allows them to diverge to create
new species? Let us return to our old friends, the Hox genes. There is a reason Hox genes are so
important for many of the developmental processes we have discussed they make up an ancient
gene family present in all animal species. They also carry out the same function which is to
pattern the body plan of the early embryo. Hox genes required for anterior structures in the fruit
fly are also required for anterior structures in the human; the same holds true for Hox genes
required for posterior structures (Figure 14). Hox genes lie right next to each other on the
chromosome in a cluster, with genes at the 3 end being required for anterior patterning, and

genes at the 5 end for posterior patterning. It is highly unlikely that Hox gene sequence,
chromosomal arrangement, and function would be so highly conserved unless all animals shared
a common ancestor. Hox genes therefore provide excellent support for the theory of evolution.
During evolution the Hox gene clusters duplicated. For example, fruit flies have one copy of the
cluster, while humans have four copies (Figure 14). The duplication of Hox genes might help
explain why an ancestral body plan could diverge along separate paths, with one path leading to
the fruit fly and another to humans. Early anterior-posterior patterning in the embryo requires
Hox genes, which is why they are conserved. However, in humans there are four copies. One
copy would stay unchanged to perform the conserved function, leaving the other three copies
free to experiment with new roles, such as forming vertebrae, a structure not present in flies.
Keep in mind that these ideas are theories and need to be tested in a scientific manner.
Teratogen

A chemical or environmental factor that causes birth defects in an

embryo

Retinoic acid

Vitamin A derivative required in small doses for anterior-posterior

patterning in the embryo; activates transcription of Hox genes; acts as
a teratogen in large doses

Hox genes

Gene family that encodes transcription factors required for anteriorposterior differentiation

Accutane

Treatment for severe acne that acts as a teratogen; active ingredient is

a vitamin A derivative

Reproductive cloning

Cloning approach used to create an organism genetically identical to

another

Somatic cell nuclear

transfer (SCNT)

Cloning technique involving transfer of a nucleus from an adult

somatic cell into an enucleated egg

Therapeutic cloning

Cloning approach that generates stem cells for use for medical and
research purposes

Stem cells

Undifferentiated cells that have the ability to form many cell types

Embryonic stem cells

(ES cells)

Pluripotent stem cells isolated from the inner cell mass of the
blastocyst

In vitro fertilization

Infertility treatment where an embryo is created by combining egg

and sperm in a petri dish

Adult stem cells

Multipotent or unipotent stem cells isolated from adult organs

Induced pluripotent
stem cells (iPS cells)

Pluripotent stem cells created by reversing differentiation of a nonpluripotent cell; virtually identical to embryonic stem cells;
circumvents the need to destroy embryos

Hox gene cluster

Linear arrangement of Hox genes on a chromosome; the order of

genes on the mirrors their progressive anterior to posterior expression
patterns

Evolution:
Evolution! A controversial topic. Over time our ideas of swimsuits has evolved. In a similar
manner, DNA changes over millions of years has developed different life forms.

Evolution can be defined in simple terms: it is descent with modification. Not just any type of
change over time, like the erosion of a mountain or seasonal cycles. Descent with modification
refers to change over time through genetic inheritance. The fact that all life forms on earth share
a common ancestor represents the central theme of evolution. It is through change with
modification that common ancestry is responsible for the magnificent diversity that now exists
on this planet. In other words, evolution tells us that humans and other life forms are all distant
cousins. The idea of descent with modification was present for a time. However, none of the
thinkers put forward anything we now recognize as a satisfactory theory to explain why species
change. The main interest was in the factual possibility that one species might change into
another.
Darwin wrote On the Origin of Species by Means of Natural Selection, or the Preservation of
Favored Races in the Struggle for Life (Fig. 1) in 1859 and presented a mechanism for
evolution. He proposed the mechanism, natural selection, by which evolution occurs. The fact
that evolution occurs became accepted by the scientific community and much of the general
public in his lifetime. However, it was not until the emergence of the modern evolutionary
synthesis from the 1930s to the 1950s that a broad consensus developed that natural selection
was the basic mechanism of evolution that led to neo-Darwinism or the synthetic theory of
evolution.
Lets start with Darwin and his time
Charles Darwin was born to an aristocratic family. His grandfather was a famous scientist and
philosopher named Erasmus Darwin, who questioned the idea of species as a fixed entity.

In 1827, Darwin (Fig. 2) enrolled at Cambridge to study for the clergy, the most popular major at
the time. Then he got the chance of a lifetime, he was asked to join an exploratory voyage around
the world on a boat called "The Beagle". He observed many natural phenomina during this
voyage and made collections. He kept a journal of his observations. This became Darwins first
book. It is a great travel book titled Voyage of The Beagle (1839). If you like travelling and
seeing new things, this is a must read. One of his collections during this time were the finches of
the Galapagos Islands. These finches were to become known as Darwins finches (Fig. 3). We
will return to them later in our discussions.
Two examples of observations that intrigued Darwin are:
1. Similar species were found on isolated islands. Could they have descended from a common
ancestor?
E.g. Mockingbirds on the Galapagos (Fig. 5).
2. Fossil animals that resemble animals still present in the same area (Fig. 6). You will hear more
about fossils later in this module.
Two central ideas about change and population growth by two naturalists of the time were also
important in shaping Darwin's thinking:
Charles Lyell
The first was Charles Lyell (1797-1875, Fig. 7), who wrote Principals of Geology. The central
argument in "Principles" was that the present is the key to the past. Lyell wrote that geological
remains from the distant past can, and should, be explained by reference to geological processes
now in operation and thus directly observable. His interpretation of geologic change as the
steady accumulation of minute changes over enormously long spans of time was a powerful
influence on the young Charles Darwin.
Thomas Malthus
Meanwhile, Thomas Malthus (1766-1834, Fig. 8) wrote an essay titled,An Essay on
the Principle of Population saying that if everyone had a lot of children and every one survived
to adulthood we would have a huge population, and this does not happen because there is
regulation. He argued that population growth generally expanded in times and in regions of
plenty until the size of the population, relative to the primary resources, caused distress and
populations collapsed due to war, disease, famine etc. Darwin built upon the works of others as
well as his own observations during the time of the voyage and experimentation after returning
home.
Darwin came up with the idea of natural selection as a mechanism that can explain biological
evolution as descent with modification in 1838. But he returned home to his farm and lived his
life as a family man, with an ever-active interest in biology. Among other works, he wrote a large
volume on barnacles at this time. But he did not write about natural selection. He had this big
idea and waited a long time before publishing it. On November the 22nd 1859 his "Origin of

Species" is published.
In his book he wrote, As many more individuals of each species are born than can possibly
survive; and as, consequently, there is a frequently recurring struggle for existence, it follows
that any being, if it vary however slightly in any manner profitable to itself, under the complex
and sometimes varying conditions of life, will have a better chance of surviving, and thus be
naturally selected. From the strong principle of inheritance, any selected variety will tend to
propagate its new and modified form. Charles Darwin, 1859.
Why would he wait that long to publish his idea?
He wanted to gather evidence through further observation and inquiry. He knew that the idea was
controversial. The final occurrence that pushed Darwin to publish his masterpiece was that
another scientist, a young man by the name of Alfred Russell Wallace (Fig. 9), wrote Darwin a
letter with much of the same ideas on natural selection that Darwin had. So finally, in 1859
Darwin published On the Origin of Species.
Other ideas about evolution before Darwin
Before Darwin, the French naturalist Jean-Baptiste Lamarck (1744 1829, Fig. 10) also argued
that species change over time into new species. Historians prefer the contemporary word
'transformism' to describe Lamarck's idea. Lamark proposed two mechanisms that could explain
how organismal change or evolution takes place. He argued that species' lineages persisted
indefinitely, changing from one form into another. Lamarck explained that species changed
because of 'internal forces that he described as some sort of an unknown mechanism within an
organism causing it to produce offspring slightly different from itself. The changes accumulated
over many generations became visible transformations and if enough changes took place, this
transformation would result in new species. This was the first mechanism that he put forth to
explain how species changed or evolved. The second is the one we today remember him for. He
said that as an organism develops, it acquires many individual biological characters because of
the organisms history of diseases, the way in which the organism uses its body and also due to
accidents. He further argued that species can then become transformed if these individually
acquired modifications were inherited by the individual's offspring, and further modifications
were added through time. This is called the inheritance of acquired characteristics.
The famous example he used was the giraffes neck (Fig. 11). Lamarck argued that ancestral
giraffes had stretched to reach leaves higher up trees that caused caused their necks to grow
slightly longer. These longer necks were inherited by their offspring who then were more likely
to grow even longer necks than their parents. Using the giraffes neck, he explained that after
many generations of neck-stretching the giraffes became long necked as we find them today. The
way in which he thought species changed with his idea of inheritance of acquired characteristics
was importantly different from Darwin's and our modern idea of evolution.
Evidence for evolution
Here we will consider the four significant lines of evidence for evolution:
1. The fossil record
2. Common structures and behavior
3. Biogeography

4. Molecular evidence
We will begin with fossils.
1. Fossil Record:
What is a fossil?
A fossil is the preserved remains of an organism from a remote past. Whether a plant or an
animal, an organism is only fossilized when they are buried by sediment (or volcanic ash)
immediately after death. This is a rare process because most organisms are eaten by scavengers
or subjected to decay though the rages of time. In addition, most fossils are extremely fragile and
easily destroyed through natural phenomena such as earthquakes, tornados, floods, hurricanes, or
rigid weather conditions. Further, only a fraction of fossils are located on the Earths surface.
Most fossils are deeply buried beyond the reach of paleontologists, scientists who study
prehistoric life forms. So, next time you visit the Natural History Museum at Balboa Park and
witness the Smilodon Saber-toothed tigers fossil (Fig. 12), take into account all the factors that
came into place for you to appreciate such a magnificent specimen that used to roam in North
America approximately 2.5 million to 10,000 years ago.
How do scientists know the precise age for a fossil?
Scientists take advantage of a radioactive clock provided by nature. Basically, the age of any
fossil can be measured if the geological stratum where it was found is known. Certain rocks,
particularly lavas and other volcanic deposits, contain radioactive minerals which decay at a
constant rate over time. For example, uranium has a half-life of 4.5 million years and produces
lead in this long process. Therefore, a ratio between uranium and lead can determine the age of
any given rock where a fossil is found. The totality of fossils with their placement in rock
formations and sedimentary layers is called the fossil record. The fossil record is a direct
testament of how the history of life unfolded on Earth. The minimum age to distinguish a fossil
from an ordinary remain is set arbitrarily at 10,000 years from the present.
How does the fossil record support Darwins thinking on evolution?
Example: The fossil record contains evidence for simple to complex forms of evolution of the
eye (Fig. 13). Darwin wrote, To suppose that the eye, with all its inimitable contrivances for
adjusting the focus to different distances, for admitting different amounts of light, and for the
correction of spherical and chromatic aberration, could have been formed by natural selection,
seems, I freely confess, absurd in the highest possible degree. Yet reason tells me, that if
numerous gradations from a perfect and complex eye to one very imperfect and simple, each
grade being useful to its possessor, can be shown to exist; if further, the eye does vary ever so
slightly, and the variations be inherited, which is certainly the case; and if variation or
modification in the organ be ever useful to an animal under changing conditions of life, then the
difficulty of believing that a perfect and complex eye could be formed by natural selection,
though insuperable by our imagination, can hardly be considered real. Charles Darwin, 1859.
Let us remind ourselves where we are:
Multiple lines of evidence come together to explain the story of life through the passage of time.
We consider four significant lines of evidence for evolution: The first is the fossil record. Lets

look at the second line of evidence, common structures and behavior.

2. Common Structures and Behavior
What are homologies?
If all life forms on earth share a common ancestor, then evolution predicts that related organisms
will have similar characteristics, or homologies. Comparative anatomists dedicate their entire
careers to investigating evolutionary relationships in bone structures. Homologous anatomical
structures are those that evolved from the same structure in a common ancestor. Take, for
example, the bones in mammalian forelimbs. Although a humans arm is used to grasp, a horses
foreleg to walk, a whales flipper to swim, and a bats wing to fly, the bones are homologous to
each other because they share the same physical and functional characteristics within the overall
structure of a forelimb (Fig. 14). Similarly, homologies can be established for the functions of
different organs, in the development of embryos, or behaviors among different types of living
forms.
What is the difference between homologies and analogies?
Homologous structures are not to be confused with analogous structures. In some cases, separate
evolutionary lineages evolved similar features that are the result of common environments rather
than common ancestry. This is called convergent evolution. The resulting structures that look
similar but were not present in the last common ancestor are called analogous features. Dolphins,
an aquatic mammal that evolved from terrestrial mammals over the past 50 million years,
evolved a body that closely resembles that of a shark. However, a dolphin is more closely related
to a human than it is to a shark because dolphins are mammals. Similarly, bats and birds can both
fly but their forelimbs are not homologous because they do not share a common ancestor that
gave rise to the forelimb. The bat's wing was independently derived from the bird's wing. They
are analogous structures. Scientists thus face the difficult task of distinguishing whether physical
and behavioral similarities are the result of common descent or are independent responses to
similar environmental challenges.
In Figure 15, a shovel, a mole paw, a human hand, and a mole cricket forelimb are shown
clockwise.
Which structures are homologous? Which share functional constraints?
Here we will consider the third significant line of evidence for evolution: Biogeography.
3. Biogeography
Biogeography is the study of the distribution of life forms over geographical areas.
Biogeography not only provides significant inferential evidence for evolution and common
descent, but it also provides testable predictions. Biogeography is split into two areas: ecological
biogeography, which is concerned with current distribution patterns, and historical biogeography,
which is concerned with long-term and large-scale distributions.
How does Biogeography support Evolution?
Species are distributed around the globe largely in relation to their genetic relationships to one
another, with some understood exceptions. For example, marsupials (Fig. 16) are found almost
exclusively in Australia, whereas placental mammals (not counting those brought there by
humans) are very rare in Australia. The opossums in the Americas can be explained by the

connectivity of Australia to South America via Antarctica during the supercontinent of

Gondwana (up to about 167 million years ago, Fig. 17).
How does Biogeography support Evolution? Continued
Science proceeds by the ability to create predictions on the basis of a theory or suggested
explanation. The degree to which the predictions are successful tend to point to the strength of
the theory or explanation. The prediction which is made possible by biogeography is this: if
evolution were in fact the case, we should generally expect species that are closely related to be
found near each other, unless there are good reasons for them not to be, such as great mobility
(for example, sea animals, birds, and animals distributed by humans, or over longer time frames,
plate tectonics). If, however, we found that species were distributed in an effectively random
geographic manner, with closely related species no more likely to be located close to each other
than not, this would be strong evidence against evolution and common descent. If life forms
arose independently, for example, it would make as much if not more sense for them to exist
wherever an environment could support them, as opposed to being distributed according to their
apparent relationship to other life forms.
How can we explain discontinuity in biogeography in the fossil record?
The fossil, Mesosaurus (Fig. 18), is found both in South America and in South Africa, continents
that are separated by the sea today but were closer to each other historically. Mesosaurus was
significant in providing evidence for the theory of continental drift (movements of continental
plates around the world), because its remains were found in southern Africa and eastern South
America, two far away places. As Mesosaurus was a freshwater animal, and therefore could not
have crossed the Atlantic Ocean, this distribution indicates that the two continents used to be
joined together (Fig. 19).
What about discontinuity in current distribution patterns?
There are cases of living organisms where there is a break or a gap in their current distribution
pattern. An example to consider is that of camel family (Fig. 20). True camels are mainly found
in Asia and Africa while their close relative, the llamas, are native to South America. Can
evolution explain why the ranges of the existing members of the camel are widely spread?
Certainly. If one takes into account that evolution is continuous through time and space, together
with Earths continental drift, then one can predict that North America should be the link
between these the two isolated areas where the camel family is found. However, we all know that
there are no camels in North America. The proof for this prediction came with the discovery in
North America of a large fossil fauna of Tertiary camels. Based on the age of this fossil record,
the llamas may have originated from the central plains of North America about 40 million year
ago and migrated to South America and Asia about 3 million years ago (Fig. 21). In addition, it
appears that camels became extinct in North America by the end of the last ice age (10,00012,000 years ago).
Evidence for evolution

Now, let us look at the molecular evidence, our fourth significant line of evidence for evolution.
4. Molecular Evidence.
How do Hox genes explain the recurring pattern of basic body parts and common ancestry?
As you have learned from previous readings in this course, all living organisms are made of
cells. Cells, in turn, are composed of a lipid membrane encasing a cytoplasm filled with
organelle structures such as mitochondrion, endoplasmic reticulum, golgi apparatus, vacuoles,
granules, and a nucleus, among others. The nucleus contains the cells genetic material,
organized as multiple long linear DNA segments in chromosomes that carry genetic information
to make RNA molecules and proteins that are called genes (Fig. 22). As far back as the 19th
century, it was apparent to some biologists that a simple, repeated pattern underlay the differing
body structures of animals. It could be seen in the segmented bodies of worms, in the vertebrae
of animals with backbones, and in the head-thorax-abdomen construction of insects. In all of
these, modular units like Lego blocks were arranged in a front-to-back line down the center of
the body. Yet, it was a complete mystery how the blueprints in the developing embryo of these
creatures guided the assembly of these complex parts. Only in the past two decades has the
answer begun to emerge. The development of body plans in all animals is controlled by a
remarkably small number of genes called the Hox genes and are virtually identical in all animals
(Fig. 23). The DNA code in Hox genes directs the cell to make chemical sequences, which
regulate other genes that affect the positioning of cells in the embryo.
4. Molecular Evidence. Contd
How do Hox genes explain the recurring pattern of basic body parts and common ancestry?
Clues came from instances in which the pattern is marred by mutations in these crucial genes. In
fruit flies, for example, a malfunctioning body-plan gene can produce a fly with legs sprouting
from where the antennae should be on the head. Or, the fly has an extra set of wings or no wings
at all. In 1994, Walter Gehring (Fig. 24) discovered the eyeless gene, which guides formation of
fruit fly eyes. As an experiment, Gehring put a mouse's eyeless gene into a fruit fly, resulting in
normal fruit fly eyes (Fig. 25). The same holds true for Hox genes for wings, legs, and even
heads. This discovery indicates that animals descended from a single common ancestor that
passed along to them a set of Hox genes, used to build a wide variety of forms from just a few
basic body plans. While this sounds complicated, it is a far more elegant and simple mechanism
than scientists thought could possibly be responsible for the enormous variation we see when we
survey the animal kingdom.
Knowledge about Hox genes explained the discontinuous jumps in body form found in the
evolution of species because a mutation in one gene could result in large changes in the organism
from one generation to the next.

The Human Genome Project

Scientists are able to characterize the DNA sequence of the entire genome of a whole organism.
Do you remember when the human genome project was completed in June 2000?
Similar to humanitys first step on the moon in 1969, the completion of the human genome
project represents one of the major advancements in human history (Fig. 26). Likewise, different
genome projects have been completed for organisms such as the bacterium, yeast, nematode,
fruit fly, newt, lungfish, and flowering plants. The analysis of similarities between DNA
sequences from different organisms holds a tremendous potential to frame many evolutionary
questions at the molecular level. Now we can begin to establish evolutionary relationships
between organisms by comparing their cell organelles, development of their embryos with body
plans, and the vertebrate immune systems, among other cellular and molecular aspects. It is
predicted that various pending questions about similarities and differences between humans and
our closest relatives will be addressed by data from the field of genomics.
As we have seen, the fossil record, common structures and behavior, biogeography, and
molecular evidence are the main four lines of evidence that support evolution as a natural
process.
But there were three main objections to Darwins theory of evolution.
1. He could not explain how characteristics were inherited.
2. There are situations in which gradual evolution can not explain the changes seen.
3. It is sometimes difficult to explain that evolution can happen by chance.
Then there was the question of origin of man. In 1859, Darwin had only said "Light will be
thrown on the origin of man. After Darwin published The Descent of Man in 1871, he was
depicted in caricature with an ape body (Fig. 27), identifying him in popular culture as the
leading author of evolutionary theory.
The three criticisms for Darwins theory of evolution were later reconciled because of
Mendel's theory of heredity.
Gregor Mendel (1822-1884, Fig. 28), an Austrian monk, discovered the laws of heredity in about
1856 1863. Mendelism has been the generally accepted theory of heredity since the 1920s and
is the basis of all modern genetics. It was destined eventually to allow a revival of Darwin's
theory, but its initial effect in the first two decades of the century was the exact opposite. The
early Mendelians all opposed Darwin's theory of natural selection. The combination of these two
ideas, natural selection and Mendelian genetics, gave rise to Neo-Darwinism but only with later
support from other scientists work.
The second major addition to support Darwins theory of evolution came in 1918 when R. A.
Fisher (Fig. 29) demonstrated that the continuous variation in real populations could be derived
from Mendelian principles. Fisher (1890-1962) along with J.B.S. Haldane (1892-1964, Fig. 30)

and Sewall Wright (1889-1988, Fig, 31) demonstrated that Mendelian heredity and natural
selection are compatible. The synthesis of the two ideas, Darwins theory of evolution and
Mendelian genetics, is called Neo-Darwinism or the synthetic theory of evolution.During the
1930s and 1940s, Neo-Darwinism gradually spread through all areas of biology and became
widely accepted. It unified genetics, systematics, paleontology, classical comparative
morphology, and embryology. We will look at applications of evolutionary biology in a future
module. But before that, let's find out how natural selection works.
Evolution

decent with modification; change over time through genetic inheritance.

Fossil

preserved remains of an organism from a remote past.

Fossil record

The totality of fossilized artifacts and their placement in rock formations

layers.

Homologous

anatomical structures that have evolved from the same structure in a curre

structures share the same physical and functional characteristics.

Analogous

structures that look similar but were not present in the last common ances
have different ancestors but similar functions.

Biogeography

the study of the distribution of life forms over geographical areas.

Hox

a gene that controls the development of body plans in all animals.

neo-Darwinism

the synthesis of Darwin's theory of evolution and Mendelian genetics, als

synthetic theory of evolution.

Natural Selection
Natural Selection, everything is someone's lunch. All living systems require ATP that will be
found in some form of protein, carbohydrate or lipid.

In the module Evolution we learned that evolution can be simply defined as descent with
modification. We then went on to discuss the circumstances of the publication of On the Origin
of Species by Charles Darwin.
We then learned that there are four significant lines of evidence that supports Darwins theory of
evolution:
1. The fossil record
2. Common structures and behavior
3. Biogeography
4. Molecular evidence
Our final learning concept for the evolution module was that the blending of Mendelian heredity
and natural selection resulted in neo-Darwinism or the synthetic theory of evolution as we know
evolution today.
In this module we look at how Evolution works and gives rise to the living world around us.

We will first look at the process of natural selection as Darwin proposed it, using the example of
natural selection in Galapagos finches (Fig. 1) on an island called Daphne Major.
Do you have a dog?
Dogs are a result of centuries of selection by breeders through the process of artificial selection,
our next topic in this module.
We will then look at how variation occurs in populations by leaning about three mechanisms of
variation:
1. Mutations
2. Genetic Drift
3. Gene Flow
On the left is a figure of natural variation in plant species, Aquilegia formosa(red and yellow in
low elevations) and Aquilegia pubescens (white to yellow in mid elevations) flowers. Flowers at
mid elevation, where the two species meet and reproduce, are spectacular in floral variation (Fig.
2). For natural selection to occur there has to be variation between individual's traits.
Finally we will learn about how fitness is shaped by the environment, and that favorable traits
are those ensuring an organisms survival and reproduction relative to the environment it is living
in.
Darwin (Fig. 3) proposed the process of natural selection as a mechanism for evolution.
His proposal has four components:
1. Variation We all know that organisms within populations exhibit individual variation in
appearance and behavior. We see differences in body size, hair color, facial markings, voice
properties, or number of offspring. However, some traits show little to no variation among
individuals. A good example is number of eyes in vertebrates.
2. Inheritance The variation in some traits is heritable or is consistently passed on from parent
to offspring. Other traits are strongly influenced by environmental conditions and show weak
heritability.
3. High rate of population growth Most populations have more offspring each year than local
resources can support. That results in a struggle for resources. Therefore each generation may
experience substantial mortality. In other words, every generation produces more offspring than
can survive.
4. Differential survival and reproduction Individuals possessing traits well suited for the
struggle for local resources or environment will contribute more offspring to the next generation.

Today we understand the process of natural selection much better due to advances in molecular
genetics. Figure 4 is a schematic diagram of how variation that occurs due to a mutation or
change in the genetic make up of an organism. If favorable, this mutation would be passed on
and result in changing the characteristics of the population.
Variation between individuals in traits is displayed in all life forms at the genetic level.
A prerequisite for evolution through natural selection is the availability of variation in traits
within individuals in a population. Variation is reflected in both the organisms genotype (the set
of genes that it carries) and phenotype (all its observable characteristics).
It is at the level of genetic variation that selective forces act upon to bring change in gene
frequency within a population (a collection of inter-breeding organisms of a particular species)
over time.
The key is that genotype is heritable and passed on to the next generation. Yet, since an
individuals genotype often influences its phenotype, the phenotypes within a population are also
subjected to change.
How does natural selection work in the real word?
Do you remember the Galapagos finches (Fig. 5)? They are best known as Darwins finches,
which were named after Darwin several decades after he collected them during his voyage on the
Beagle. He was not really interested in them, but he sent the British Museum some skins that
were first collected specimens of these birds. The Galapagos islands are a chain of volcanic
islands west of Peru. There are only a few species of birds in these islands which look similar to
each other, but they vary in bill size. They look all relatively the same otherwise, with brown and
black feathers and similar body size.
Recently, a famous husband and wife team, Peter and Rosemary Grant (Fig. 6) who worked out
of Princeton, picked one little tiny island among the Galapagos called Daphne Major. (Fig. 7)
This island is small enough so that they could catch and mark every single bird on the island.
The research is very well known and one of the more accessible ways of learning about what
they did is to read Beak of the Finch (Fig. 8) by a popular, terrific, scientific writer, J. Weiner.
What did they show?
They showed that every part of natural selection is operating on this island. They demonstrated
that variation exists in Geospiza fortis finches. Among the population there were 751 birds and
these birds varied in how big their bill was (Fig. 9).
What kind of curve or distribution is this?
This would be a roughly normal distribution. We would get the same distribution if we graphed
human height within a population.

So, the first component in natural selection is met, which is:

1.Variation between individuals in traits
The second component of the natural selection process requires variation to be heritable.
So, what did Peter and Rosemary do?
They marked every bird using bird rings of different colors and and they found the nests of the
birds and marked the hatchlings so that they knew the parents of the baby birds. When they
looked at the bill size of the parents and the bill size of the adult baby birds they found that if the
parent birds have big bills the baby birds are going to have big bills.
So what is this called?
This is called heritability. In other words they showed that the variation is heritable (Fig. 10).
Next, they showed that in every generation there are more offspring produced than that can
survive. They also showed that the abundance of finches were closely correlated with the
abundance of resources (Fig. 11) which is, in this case, seeds that the birds eat. This is the third
component of natural selection that Darwin presented. Darwin said that there is a struggle for
resources and that, as a result, each generation may experiences substantial mortality.
But then something very interesting happened on the island
In 1977, a severe drought occurred on Daphne Major. Plants withered and seeds of all kinds
were scarce. Small soft seeds were quickly eaten by the finches, leaving mainly large, tough
seeds that finches normally ignore.
The drought ended when a small amount of rain fell on the island in January 1978. Over the
drought period the proportion of seeds that were big in the island became higher and the birds
with bigger beaks that could eat them survived and reproduced.
Over generations this resulted in selecting birds with a larger body size that also had a bigger
tougher beak.
Before the drought, the average beak size of theGeospiza fortis species was 10.68 mm long and
9.42 mm deep (Fig. 12). After the drought, it was 11.07 mm long and 9.96 mm deep (Fig. 13).
Variations too small to see with the naked eye made the difference between life and death (Fig.
14).
What is happening?
Why did the bigger birds survive?

A beak is like a nutcracker. The wider and bigger the beak, the more force it can generate. So, the
birds that could open the seed and feed on the larger seeds during the time of drought survived,
reproduced, and carried the larger beak trait to the next generation. In other words, the large beak
trait was naturally selected (and when selection happened due to mating preferences we call this
sexual selection) driven by the process of elimination of the smaller beak trait.
This example shows that individuals with traits that fit the environment will survive and will
become a greater proportion of the next generation. So, with the Geospiza fortis finches in
Daphne Major the Grants proved that the four steps of natural selection occur in nature.
Overall, what does natural selection do to the trait value of the population?
There are three things that can happen that can be explained using the bell shaped curve of
distribution of the trait (Fig. 15).
1. Stabilizing selection: average trait value is going to stay the same.
2. Directional selection: one side or the other of your bell curve is selected for.
3. Disruptive selection: the two sides of the bell curve is favored but the middle is not.
A good example of the importance of stabilizing selection can be drawn from the birth weight of
human babies (Fig. 16). Selection works towards stabilizing this trait.
When the birth weight is too low babies often have higher risk of infection and high birth
weights result in complications at birth.
So, in this case, selection works towards stabilizing the average value for the trait birth weight.
Until the beginning of the last century this has been true.
Today, since we have more C-section delivery averages, this trait value may have changed.
In our example of the finches we saw how the average size of the beak changed and resulted in
larger beaks in which the trait value moved towards on side of the bell curve and resulted in
directional selection.
What would have happened if there were two types of seeds (very large and very small) that
survived during the drought?
Remember how the flowers of the two species Aquilegia formosa (red and yellow in low
elevations) and Aquilegia pubescens were different at the ends of the elevational ranges (Fig.
17). This is an example of speciation that is still not completed as the individuals in the middle of
the mountain range are still interbreeding. When the trait values become so different that this is
no longer possible, selection may result in two species that have two types of flowers. So, when
the two populations can not interbreed naturally to give rise to viable offspring they become
species.

This is called speciation.

In the Origin of Species, Darwin began presenting his idea on natural selection using pigeons as
an example. At the time, breeding pigeons was a favorite hobby of the people in England. Puffers
and Tumblers are good examples of artificial selection in pigeons (Fig. 18). If you were Darwin
today, what would you start off with? Take a look at Figure 19!
What are the basic steps in the process of artificial selection?
1. Variation between individuals in traits
2. The variation in some traits heritable
3. Breeders select animals with traits that the breeders like
4. Next generation has more of these traits
We have used artificial selection for a long time to domesticate animals and plants for food.
Chicken that you and I eat is a result of taking the heaviest chickens and breeding among them
(Fig. 20).
An experiment that was started in 1957 tracked the weight of the chicken as they were artificially
selected and found that as time went by, the heavy chickens got heavier and the light chickens
got lighter. The result was a 600 percent difference between the weights of the light chickens and
the heavy chickens (Fig. 21). Ever since humans changed lifestyles from being hunters and
gatherers to farmers and breeders, we have recognized the advantages of selecting which
organisms get to reproduce.
A prerequisite for evolution is the availability of variation the uniqueness of every
individual and a characteristic of every sexually reproducing species (a group of individuals that
interbreed in nature). Variation is reflected at both the organisms genotype (the set of genes that
it carries) and phenotype (all its observable characteristics) levels. It is at the level of genetic
variation that selective forces act upon to bring change in gene frequency within a population (a
collection of interbreeding organisms of a particular species) over time. The key is that genotype
is heritable and passed on to the next generation. Yet, since an individuals genotype often
influences its phenotype, the phenotypes within a population are also subjected to change. But
how does this variation occur?
There are three mechanisms that produce variation and promote evolutionary change:
1. Mutations that occurs in the organisms DNA
2. Gene flow
3. Genetic drift that occurs at the population level.

1. Mutations
As previously described, genes are long linear DNA segments organized in chromosomes that
carry genetic information to make RNA molecules and proteins. As the hereditary unit of life,
DNA dictates all aspects of an individuals life and is subjected to changes called mutations
(Figure 22). Whether these changes in DNA are beneficial, neutral or harmful to the individual,
mutations are random and they occur in the bodys cells. Mutations can be heritable only if they
happen in reproductive cells and are known as germ-line mutations. Germ-line mutations can
have a range of effects on the individuals phenotype from non-detectable to lethal. Mutations
can happen due to intrinsic failures of DNA replication and repair, or extrinsic factors such as
chemicals, ultraviolet light and radiation. The bottom-line is that mutations increase the genetic
variance within a population.
2. Gene Flow
Gene flow, also known as migration, describes the process of movement of genes in and out of a
population. Gene flow occurs when organisms from one population migrate to another, and its
rate varies among different organisms. As you can expect, the gene flow rate for a population of
mosquitoes might be drastically higher compared to that of a tree. Genetically modified
organisms have the potential to transfer the new genes to their wild relatives, such technologies
are controversial (Fig. 23). The overall effect of gene flow on evolution is that it increases the
genetic variation in a population.
3. Genetic Drift
Genetic drift is a stochastic process based on chance. Basically, genetic drift is the loss of alleles
(alternate forms of a gene) in a population.
There are two types of effects that genetic drift cause:
The bottleneck effect occurs when a significant portion of a population is removed by some
random event such as natural disaster (e.g. earthquake), disease (e. g. yellow fever) or selective
predation (Fig. 24). This would be a dramatic effect if this loss of alleles happens in a small
population compared to a big one.
The second, founder effect, happens when a small fraction of a population splits off and goes
to become a pioneer of a new population at a different location (Fig. 25). A small population will
have a greater founder effect because the allele distribution in the new population may not be
representative of the original one. Overall, genetic drift will decrease the genetic variation of the
original population.
Amish people in eastern Pennsylvania originated from a small number of German immigrants -about 200 individuals. They carry unusual concentrations of gene mutations that cause conditions
such as Ellis-van Creveld syndrome (Fig. 25) resulting in short stature and polydactyly (extra
fingers or toes). The syndrome is common in the Amish because of the "founder effect."
Fitness
No, I am not talking about that kind of fitness (Fig. 26)! Biologists use the term fitness when
describing the ability of an organism to pass on survival-favoring attributes to their offspring. So,
in evolutionary terms what are favorable or unfavorable traits when discussing natural selection?
Fitness is NOT a property of an organism. There is not such a thing as only the strong survives

(Fig. 27). To be fit is not an issue of who is the strongest, fastest, or biggest. If you think in
these terms then dinosaurs would still be running around on Earth instead of humans! Rather,
fitness is a relative affair.
The fitness of an organism pretty much depends on its environment. For instance, if the Earths
temperature were to be reduced dramatically to the levels of the previous ice ages (the most
recent one peaked around 11,000 years ago), it is highly probable that an organisms fittest traits
today will cease to be favorable during extremely cold temperatures conditions. Also, the
exuberant tail of the peacock is thought to be the result of sexual selection by females. The
peacock in figure 28 is an albino; selection against albinos in nature is intense because they are
easily spotted by predators or are unsuccessful in competition for mates. Peacocks with the multi
colored tail are sexually selected or are preferred for mating. Therefore, we can conclude that
fitness is shaped by the environment.
Favorable traits are those ensuring an organisms survival and reproduction relative to the
environment it is living in.
It is important to understand that although natural selection acts on individuals, the effects of
chance mean that fitness can only really be defined "on average" for the individuals within a
population. When considering a particular genotype, its fitness corresponds to the average effect
on all individuals with that genotype. As in the example of many human genetic disorders such
as cystic fibrosis, very low-fitness genotypes cause their bearers to have few or no offspring on
average.
Adaptation
Adaptation is a process in which over many generations, a population becomes more suited to its
habitat. Adaptation also refers to the trait that provides enhanced fitness, and therefore, is a
product of natural selection.
Most commonly when the habitat or climate changes, the populations can move to a more
suitable habitat. This is called habitat tracking. However, through natural selection of organisms,
favorable characteristics for the new environment from the original population can result in the
population genetically adapting to the new environment. Such genetic changes can result in
adaptations that occur at the structural, physiological, behavioral, cellular or molecular level over
many generations and long time periods. However, if the habitat or environmental change is
rapid, species may be less adapted to the environment and may become extinct over time.
Mimicry
A perfect example of adaptation is mimicry. Mimicry is a common perceived characteristic
shared by different groups of organisms that protect one or both groups. A chameleon (Fig. 29) is
a reptile that has the ability to change the color of their skin. Although this change in color is in
response to communicate (e.g. mood and mating), or to exposure to light or temperature,
chameleons are naturally colored for their surrounding as a camouflage to avoid predators. Other

animals can have the ability to blend in to their natural surrounding although they cannot change
their skin as chameleons do (Fig. 30).
The criteria to define a trait as an adaptation must include factors like heritability and
functionality at the present moment. A vestigial structure, a trait that was an adaptation for an
organisms ancestor but it is no longer functional, cannot be considered an adaptation. For
instance, the coccyx (a tail bone) is a vestigial tail in humans with no apparent structural or
physiological function. Humans have over 100 vestigial structures (Fig. 31). Every species is
adapted to a selection of environmental properties such as climate and resources (e.g. food and
shelter), and they provide an organism with the required living conditions known as a niche.
Coevolution
Sometimes selective forces act upon two different species to reciprocally affect each others
evolution. This phenomenon is known as coevolution and it is mainly present in species that
have close ecological relationships with one another.
Here are some examples:
1. Hummingbirds and ornithophilous (bird-loving) flowers (Fig. 32) have evolved special
biological characteristics that support each other or form a mutualistic relationship.
Hummingbird flowers have nectar chemistry that support the birds diet and the flower's color,
shape, and size characteristics also coincide with the birds vision and morphology. Flowers
bloom during the hummingbirds' breeding seasons.
2. An example of antagonistic coevolution is the Old World Swallowtail (Papilio machaon)
caterpillar which lives on a plant called Fringed Rue (Ruta chalepensis; Fig. 33). Rue plant
produces etheric oils which repel plant-eating insects, but the caterpillar has developed
resistance to these poisonous substances, thus reducing competition of other plant-eating
insects .
3. In host-parasite coevolution the reciprocal adaptive genetic change of two antagonists (e.g.
different species or genes) coevolve through reciprocal selective pressures. Diseases that you
may be familiar with such as malaria, AIDS and common influenza are caused by coevolving
parasites.
Figure 34 explains why we have to get the flu or influenza vaccine every year.
The flu vaccine that you get each year has three flu strains, two A strains and one B strain. The
strains change from year to year because the influenza virus genes are made of RNA and can
mutate much faster than genes made with DNA. Once you receive the vaccination, your body
produces infection-fighting antibodies against the three flu strains in the vaccine. If you are
around others who have the flu, the antibodies will latch onto the viruss Hemagglutinin (HA)
antigens that help them to attach to healthy cells. So the virus can no longer infect you. But if a
mutation in the viral RNA allows it to change and therefore change the shape of the HA antigens

they will no longer be blocked from the antibodies in the vaccine that you got. Because antigens
and antibodies have a key and lock mechanism that has to match each other to form a bond. This
will allow the newly mutated virus to infect your bodys cells. That is why every year we have to
get the flu vaccine that has the most common and recent antibodies.
This type of genetic mutation is called antigenic drift.
Microevolution
Microevolution represents change in gene frequency within a population of a small scale. This
change introduced the sickle-cell gene within a human population that resulted in a favorable or
unfavorable trait depending on a given environment. Yet, this change was not enough to create a
new humanoid species. Mutation, migration and genetic drift are mechanisms that create
microevolution.
Microevolution Example: House sparrows in the United States
Because of the short timescale of microevolutionary change, we can often directly observe it
happening. A good example is the size of the house sparrows in United States. The house
sparrows were introduced to North America in 1852. Since then, the northern house sparrow
populations are larger-bodied compared to those in the south. Natural selection has acted on the
original house sparrow population and resulted in larger-bodied birds that can survive lower
temperatures in the north and smaller-bodied birds in the south. Physiologically larger body size
is an advantage to survive the northern cold winters.
Speciation
With time, selective forces bring evolutionary change that produces two or more separate
species. This is called speciation, and it is represented as the branching points on the
phylogenetic tree. For speciation to occur, there needs to be a genetic difference between two
populations that prevents their mating and reproduction. A good example of such genetic changes
is the single amino acid difference in the chestnut belly flycatcher (Monarcha castaneiventris) in
the Solomon Islands that transformed it into a completely black subspecies (Fig. 37).
Macroevolution
If given enough time, small changes can produce character changes that result in major
evolutionary changes or macroevolution. Macroevolution is defined as descent with modification
of groups above the species level (at a large scale). For example, instead of looking at genetic
changes with the human species, macroevolution encompasses changes at the primate, mammal,
or vertebrate levels. It is an analysis of evolution in separated gene pools.
Macroevolution Example: Vegetables from wild mustard
Many of the artificially developed vegetables and domesticated animals are good examples of
macroevolution. For example, human farmers cultivated wild mustard to select for desired traits
such as larger leaves, buds, and flowers. The common vegetables in figure 38 are cultivated
forms of wild mustard.

Extinction
One of the most important modes of macroevolution is extinction. Extinction can be defined as
the cessation of life for a single species or entire taxa. Consider this: over 99.9 % of the species
that have ever lived on this planet have gone extinct! Perhaps the most popular mass extinction is
that of non-avian dinosaurs that occurred about 65.5 million years ago. Earth has undergone five
mass extinctions (Fig. 39). In the last two hundred years we changed our habitat drastically (Fig.
40).
Do you think we might see the sixth mass extinction during our lifetime?
The Tree of Life
Biologists estimate that there are about 5 to 100 million species of organisms living on Earth
today. Evidence from morphological, biochemical, and gene sequence data suggests that all
organisms on Earth are genetically related, and the genealogical relationships of living things can
be represented by a vast evolutionary tree, the tree of life (Fig. 41).
Biologists are interested in general patterns that recur across the tree of life.
There are several patterns of macroevolution in the tree of life:
1. Stasis
2. Character Change
3. Lineage Splitting
4. Extinction
Stasis means that the lineages do not change much for a long time (Fig. 42). Coelacanths (Fig.
43) is a good example of stasis. It is a fish lineage that branched off of the tree near the base of
the vertebrate clade. Until 1938, scientists thought that coelacanths went extinct 80 million years
ago. Then they discovered a living coelacanth from a population in the Indian Ocean that looked
very similar to its fossil ancestors. So, coelacanth lineage exhibits about 80 million years worth
of morphological statis. Ginkgo biloba (Fig. 44) is an example of a living fossil tree that is
similar to the fossils found from 170 million years ago.
Tree of life continued...
Lineages can change quickly or slowly by changing characteristics. This is called character
change. In figure 45, lineage A changes rapidly but in no particular direction. Lineage B shows
slower, directional change. Trilobites, animals in the same clade as modern insects and
crustaceans, lived over 300 million years ago. As shown below, their fossil record clearly
suggests that several lineages underwent similar increases in segment number over the course of
millions of years. Lineage-splitting (or speciation) can be identified by constructing and
examining a phylogeny. The phylogeny might reveal that a particular lineage has undergone

unusually frequent lineage-splitting (Clade A, Fig. 46) or low rate of lineage-splitting (Clade B,
Fig. 46) or it might reveal that several lineages experienced a burst of lineage-splitting at the
same time (Clade C, Fig. 46). We already talked about extinction (Fig. 47) and it is extremely
important in the history of life. It can be a frequent or rare event within a lineage, or it can occur
simultaneously across many lineages (mass extinction). Every lineage has some chance of
becoming extinct. The woolly mammoth that is similar to the modern elephant became extinct
4,500 years ago.
In our next module we will look closely at human evolution and how evolution is relevant to
in our daily lives...
Mutation

increases the genetic variance within a population.

Genetic Drift

a stochastic process based on chance; the loss of alleles in a population.

Gene Flow

the process of movement of genes in and out of a population.

Stabilizing Selection

Natural
Selection

average trait value is going to stay the same.

the survival in nature of those individual and their progeny best equipped to adapt to environm

Directional Selection

one side or the other of your bell curve is selected for.

Disruptive Selection

the two sides of the bell curve is favorable but the middle is not.

Sexual
Selection
Speciation

a natural selection in which certain traits on a male or female are favorable and attract a mate i
favorable trait is passed down.

when two populations can no longer interbreed naturally and give rise to viable offspring which
become species.

Artificial Selection

a process in the breeding of animals and in the cultivation of plants where

choose favorable trait and breed the species that posses the favorable trait
different breed.

Coevolution

selective forces act upon two different species to reciprocally affect each

Mutualistic Relationship

species have evolved special biological characteristics that support each o

relationship where they benefit each other.

Host-Parasite Coevolution

the reciprocal adaptive genetic change of two antagonists who have coevo
reciprocal selective pressures.

Adaptation

the process in which over many generations, a population becomes more

Microevolution

change in gene frequency within a population of a small scale.

Macroevolution

decent with modification of groups above the species level or at a large sc

Evolution And Us
Transcription and Translation play a major role in developing new life forms. All living systems
including humans continue to evolve. Homo Sapiens is just one example of the power of the
Central Dogma.

In our first module we learned that Evolution isdescent with modification. We also learned
thatCharles Darwin wrote On the Origin of Species (Fig. 1). We then learned that there are
four significant lines of evidence that supports Darwins theory of evolution:
(A). The fossil record
(B). Common structures and behavior
(C). Biogeography
(D). Molecular evidence
Our final learning concept for the evolution module was that, the blending of Mendelian heredity
and natural selection resulted in neo-Darwinism. The second module described how evolution
works and gives rise to the living world around us through the process of natural
selection, which changes the trait values of a population (Fig. 2). A prerequisite for evolution
is the availability of variation. Mutations produce variation in the organisms DNA,
and gene flow and genetic drift produce variation in populations. Finally, we learned
that fitness is shaped by the environment, and that favorable traits are those ensuring an
organisms survival and reproduction relative to the environment it is living in.
We begin this module by exploring the ancient question that has persisted throughout the history
of humanity:
Where do we come from?

Humans have changed the environment they live in dramatically over the last couple of
centuries.
Where will we be going?
Have you wondered, how evolution affect the world's food supply or how knowledge of
evolutionary history can help us make conservation decisions or why evolution matters when it
comes to fighting pathogens?
The second part of this module will explore the relevance of evolution in three major areas of our
daily life:
(1) Medicine
(2) Agriculture
(3) Conservation
Every human society shares a fascination with our history and ancestry. Paleoanthropology is
the study of human origins and evolution from our ape-like ancestors. Studying our origin from
the deep past, over millions of years, allows us to understand the universal and defining traits
that make our species what it is.
What does it mean to be human?
Let us begin by looking at the evolution of our small branch in the Tree of Life
called hominid family (Fig. 3 and see Fig. 5 for species names). Hominids are members of the
family of humans or human like species. The hominid branch has a history of about 8 million
years, the time when the earliest ancestors of humans diverged from the apes. This branch has at
leasta dozen hominids that have lived on earth (Fig. 4 and Fig. 5).
Why do we say 'at least'?
Although there are about fifteen species categorized, this categorization is not definite because
fossils are not easy to neatly separate into species. In addition, like all creatures while no two
hominids were alike, it is not clear when a new species began and ended. Further, this list is
incomplete because as scientists find new fossil hominids, the hominid family tree grows new
branches. There is, however, one thing that is clear: over the millions of years species existed
hominids changed and evolved and adapted to new environmental conditions. Some species
diverged or separated into new species.
Do you think we are still evolving?
As discussed in the first e-module, there are multiple lines of evidence supporting the evolution
of all living beings, from simple bacteria (approximately 2.7 billion years ago) to the rise of
complex multicellular organisms such as humans.

Evolution tells us that humans and other life forms are all distant cousins. In 2005 Chimpanzee
Sequencing and Analysis Consortium reported that our closest living relatives shared perfect
identity with 96% of our DNA sequence. This is irrefutable evidence that our relationship to
apes goes beyond just simple resemblance.
Paleontologists and paleoanthropologists agree that our lineages separated about 5 to 10 million
years ago, when chimpanzees and hominids started evolving independently (Fig. 6). Therefore,
it is clear that despite the genetic similarity, we have not directly evolved from chimpanzees as
most people and the media tend to think.
In 1974 a team of scientists led by Donald Johanson uncovered the fossil remains of a creature
who fell to her death 3.2 million years ago (Fig. 6 middle skeleton and Fig. 7). They celebrated
the finding by listening to the song by the Beatles called Lucy in the Sky with Diamonds and
named her after the song. Lucy was a 25 year old female Australopithecus afarensiswho was
about 36 tall and weighing 62 lbs. Lucy was discovered in Hadar, Ethiopia.
Information gathered from Lucy and other A. afarensis specimens showed that the pelvic and leg
bones are arranged for bipedal locomotion similar to modern humans. The ratio between arms
and legs of Lucy is 84.6 (whereas that of men is about 71.8 and of chimpanzees 100). They were
also more human-like in that their canine teeth were smaller than those of apes, their brain size
expected to be 375 to 550cc, and the jaw angles intermediate between the rectangular shape of
chimpanzees and the parabolic of humans.
This evidence suggests that A. afarensis is the most ancient common ancestor from which all
other hominids sprang and A. afarensis are the intermediate species between apes and humans
(Fig. 6).
The confirmation of bipedalism in A. afarensis came with one of the most significant discoveries
in human evolution, the footprints of what now is thought to be twoA. afarensis walking side-byside in Laetoli, Tanzania (Fig. 8). The computer simulation from the gait of these hominids from
the 3.6 million years ago footprints (the ancient walk,) suggests that indeed Lucy walked
upright similarly to modern men (Fig. 8).
A. afarensis defined the Tree Savanna Stage, of hominid evolution, a full transition from
the Rain Forest Stagecharacteristic of chimpanzees.
Mary Leaky, who discovered the Laetoli footprints wrote, One cannot overemphasize the role
of bipedalism in hominid development. It stands as perhaps the salient point that differentiates
the forebears of man from other primates. This unique ability freed the hands for myriad
possibilities -- carrying, tool-making, intricate manipulations. From this single development, in
fact, stems all modern technology. ("Footprints in the Ashes of Time." National Geographic,
April 1979).
Mary and her husband Louise Leakey (Fig. 9) have a story to tell about human evolution as well
as the process of science. If you like reading scientific biographies an interesting book to read is,
Ancestral Passions: The Leakey family and the quest for humankinds beginnings by
Virginia Morell (Fig. 10).

Two other fossil findings of A. afarensis, the first family and Hadar skull (Fig. 11), added to our
understanding of how early humans moved. They had broad heels that could withstand the
upright gait and spongy shock absorbing bones rather than the more solid bones in the heels of
apes. Although their toe bones are longer compared to modern humans they do not curve towards
the heel as they do in modern tree climbing apes. Lucys broad fan shaped hip bones are similar
to a modern human womans hip bones and can support internal organs and the entire upper body
that is needed in an upright position.
In modern humans, there are several adaptations for upright bipedal movement:
1. Thigh bone slopes inward from the hip to knee, placing feet under the center of gravity.
2. Gluteal abductor muscles are well-developed on the side of the hips to contract and prevent
bodies toppling to one side when all the weight is on one foot in mid-stride.
3. The foot is specialized with an arch that acts as a shock absorber and weight bearing platform.
4. The spine has a characteristic double curve, which brings the head and torso into a vertical line
above feet.
5. The surfaces of the joints in legs and between vertebrae are enlarged, which is an advantage
for bearing weight.
6. The hole through which the spinal cord enters the skull, called the foramen magnum, is near
the center of the cranium, allowing the head to balance easily atop the spine rather than toward
the back of the cranium as in chimps.
But we are by no means perfectly adapted to bipedal locomotion. Our spines are a heritage from
distant ancestors who carried themselves horizontally. As in modern quadrupeds, the spine
functioned more like a flexible suspension bridge, supporting the body's organs. The human
spine has been transformed from this, into a weight bearing column, putting it under
unprecedented stress and dooming us to the likelihood of back injuries and pain.
Video link on bipedalism:
http://www.pbs.org/wgbh/evolution/library/07/1/l_071_02.html
As scientists have learned to reconstruct ancient climate from cores drilled in the ice of
Greenland and sediments on the seafloor, one of the favorite explanations for the transition
to bipedality has centered on drastic environmental changes that swept Africa more than five
million years ago. By that time, the global climate had become significantly cooler and drier.
This resulted in advancing grasslands in sub-Sahara Africa while the rain forests contracted,
shrinking the habitat where tree-dwelling primates lived and foraged.

In addition to bipedalism, a second major adaptive advantage that appeared later in human
evolution was bigger brains. This is the third concept in this module.
One of the structural parameters that scientists use to determine how close hominid fossils are to
modern humans is brain size. Brain size can be predicted by the skull-size of fossils of hominids.
However, brain size gives only limited information about the internal structure and capabilities
of the brain.
The oldest hominid fossil ever found was an almost complete skull nicknamed Toumai,
discovered in Chad, Central Africa (speciesSahelanthropus tchadensis) (Fig. 12).
Toumai proved to have a small brain size (about 350 cubic centimeters - cc), and its spinal cord
and skull connected at a posterior region (rather than central), features that are typical of apes.
However, its brow ridges and small canine teeth place it closer to later hominids. These
characteristics and its age (6-7 million years old) suggest it is the closest link to the common
ancestor of humans and chimpanzees, but its exact position in the tree of man is still uncertain.
Fossil evidence allows us to trace the development of the brain as it increased threefold over the
past 3 million years.
Early hominids such as the Australopithecines (Fig. 13;Australopithecus africanus 457 cm3) had
brains the size of modern apes (400 to 500 cm3).
Homo habilis (Fig. 13) with a brain of about 650 cm3, was probably the first hominid discovered
to make and use stone tools (Fig. 14).
As brain size increased, new capabilities evolved as well, such as using fire, giving these early
humans abilities to adapt to and modify their environments. Tools became more sophisticated
and eventually humans developed culturally as well as biologically.
Another earlier hominid, Homo erectus (Fig. 13), with a brain size ranging from 1200 to 1600
cm3 was the first to develop human-like culture (Fig. 15). Homo erectus used tools, such as hand
axes, made fires, and were the first hominid species believed to have spread from Africa into
Asia.
Modern humans, Homo sapiens sapiens (Fig. 13. with brains ranging from 1200 to 1600 cm3),
have even more sophisticated capabilities, probably due to neurological developments within the
brain rather than size alone.
One later hominid species, Homo neanderthalensis, had a brain size of over 1300 cm3 (Fig. 13)
but is considered to have been much less sophisticated than, and possibly even driven to
extinction by, modern humans.
Neanderthal and Man or Neanderthal Man?

Neanderthal man or H. neandertalensis (Fig. 16) was somewhat shorter but much more robust
than contemporary Homo sapiens. Distinctive cranial features of Neanderthals included
prominent brow ridges, low, sloping foreheads, a chinless and heavy, forward-jutting jaw, and
extremely large front teeth.
However, the Neanderthal braincase measured on average about 1600 cm3, larger than
contemporary H. sapiens. With their thick, squat build, they are the first hominid to spend
extensive times in cold environments in which they lived during the last glacial period. Large
front teeth may have reflected a practice common among Eskimo populations of softening
animal skins by chewing. Forceful chewing is also suggested by the heavy jaw and brow ridge,
both of which serve to buttress powerful muscles.
Neanderthals are known for having stone tools, being proficient hunters and having aesthetic
behaviors and religious beliefs (evidence from burial sites) but they were a highly mobile
species.
Some scientists argue that they became extinct and were replaced by modern H. sapiens and
others argue that their anatomical distinctions were diluted through gene flow with other H.
sapiens. In 2006, scientists at the Max Planck Institute for Evolutionary Anthropology in
Leipzig, Germany began working on mapping the Neanderthal genome.
The initial thought that Neanderthals were a subspecies of Homo sapienshas been dismissed by
analysis and comparison of mitochondrial DNA (mtDNA) from both species and calculates that
the closest ancestor common to both H. sapiens sapiens and H. neanderthalensis dates back to
about 450,000 years ago. However later analysis showed that Neanderthals had exactly the same
version of the FoxP2 gene associated with the use of language, as modern humans a similarity
that would be difficult to explain if the two groups evolved separately.
This would mean that Neanderthals not only were our long-ago relatives, but contributed an
important part of what it means to be human. In 2009, the newly completed sequence using DNA
from bone (Fig. 17) showed that humans and Neanderthals genomes are 99.5 % similar.
The Cro-Magnon Man
The first fossils of early modern humans, Homo sapiens, to be identified were found in 1868 in a
23,000-27,000 year old Cro-Magnon rock shelter in the Dordogne Valley rock site near the
village of Les Eyzies in southwestern France. They were subsequently named the Cro-Magnon
people (Fig. 18). They were very similar in appearance to modern Europeans. Males were 5 feet
4 inches to 6 feet tall (1.6-1.8 m.) That was 4-12 inches (10-31 cm.) taller than Neanderthals.
Their skeletons and musculature generally were less massive than the Neanderthals. The CroMagnon had broad, small faces with pointed chins and high foreheads.
There are several differences between the Neanderthal man and Cro-Magnon man. The
Neanderthal has a pronounced bun shape on the back of its skull, known as an occipital bun, and
the forehead and the top of the head are much lower and wider. Cro-Magnon do not have this
occipital bun and the forehead and top of the head are much higher and narrower. Their cranial
capacities were up to 1590 cm3, which is relatively large even for people today. Neanderthal had

a short robust body shape, while Cro-Magnon had a body shape much more like modern people
who are adapted to hot climates, tall with long arms and legs.
While Neanderthal showed many signs of "higher" culture such as burying their dead and caring
for their sick, and in the later stages of their existence maybe even created items such as
necklaces and jewelry. These characteristics are much clearer in Cro-Magnon. Cro-Magnon
culture was far more developed, probably not unlike that of modern hunter-gatherers. CroMagnon are also known to build communal shelters unlike the Neanderthal. Neanderthal had no
cave art (a characteristic for which Cro-Magnon is well known, see Fig. 19) or potable art such
as carvings. Although the two species may have coexisted towards the end of Neanderthals
existence, it is not clear whether they were existing in the same areas simultaneously.
The Modern Man
Modern Homo sapiens started existing about 195,000 years ago. Present day humans (Fig. 20)
evolved with further reduction in the size of molar teeth compared to the early H. sapiens. The
average size of the human brain reached 1350 cm3. We made the full transition from hunters and
gatherers to a sedentary lifestyle thanks to plant and animal domestication. We developed rich
and diverse cultures. After the industrial revolution, we took another step away from nature into
an urban lifestyle in the city. No other animal has ever achieved the dominance over nature like
human beings have.
Are we genetically different from our Homo sapien ancestors who lived 10-20,000 years ago?
The answer is almost certainly yes. In fact, it is very likely that the rate of evolution for our
species has continuously accelerated since the end of the last ice age, roughly 10,000 years ago.
This is mostly due to the fact that our human population has explosively grown (Fig. 21) and
moved into new kinds of environments, including cities, where we have been subject to new
natural selection pressures.
Have you wondered what it means to be human?
I have.
Is there a real answer?
To me being human is to be positively motivated and to be happy while not harming others.
Motivation is defined as the driving force of desire behind all deliberate actions of humans.
Motivation is based on emotion. We are motivated to gain satisfaction or positive emotional
experiences and avoid conflict. Positive or negative experiences are defined by the individual
brain state and are influenced by social norms and conditioning.
What is your motivation for coming to class or reading for your degree?
Motivation is important because it is involved in the performance of all learned responses. We
look for a reward when we learn something.

What does it mean to be happy?

Happiness is defined as the best condition that a human can have. A condition of mental and
physical health. It is also defined as freedom from want and distress, consciousness of the good
order of things, assurance of one's place in the universe or society.
What does it mean to be human to you?
Evolutionary Applications.
Now that you have a good understanding of what evolution is (Evolution Module) and how it
operates in biological systems (Natural Selection Module) including our own species lets
venture in to the topic of evolutionary applications. Figure 22 shows a map of global spread of
H1N1. H1N1 is becoming resistant to Tamiflu vaccine. How did this happen? The answers are
based on evolutionary principles.
How does evolutionary biology contribute to society?
The many sub-disciplines of evolutionary biology have made innumerable contributions to
meeting societal needs. Here we mention only a few examples. We focus especially on
contributions to human health, agriculture and conservation.
We will consider examples that illustrate both our ability to solve problems using evolutionary
biology concepts as well as problems we have generated by ignoring these principles.
A. Human Health and Medicine: Sickle-cell Anemia and Antibiotic Resistance
B. Agriculture and Natural Resources: Plant and Animal Breeding and Pest Resistance
C. Environment and Conservation: Bioremediation and Biodiversity Crisis.
This is going to be a brief discussion into a vast topic. If you are more interested Further
reading and online material at the end of this module and the Evolutionary Applications
journal (Fig. 23) are good places to venture into. But first, lets look at the importance of
evolutionary biology concepts in understanding biological mechanisms.
The concept of evolution is essential to understanding biological mechanisms.
Three great themes run through the biological sciences (Fig. 24):
1.Function
2.Unity
3.Diversity
Much of biology, from molecular biology to behavioral biology, from bacteriology to medicine,

is concerned with the mechanisms by which organisms function. Many of these mechanisms are
adaptations, features that enhance survival and reproduction. Some such features are found only
in certain groups of organisms, but others are shared by almost all living things, reflecting the
unity of life. At the same time, the diversity of characteristics among the earth's millions of
species is staggering. The unity, diversity, and adaptive characteristics of organisms are
consequences of evolutionary history, and can be understood fully only in this light. The science
of evolutionary biology is the study of the history of life and of the processes that lead to its
unity and diversity. Throughout the biological sciences, the evolutionary perspective provides a
useful, often indispensable framework for organizing and interpreting observations and for
making predictions.
The concept of evolution is essential to understanding biological mechanisms.
Example: Genetic disease - Sickle-cell Anemia.
Genetic diseases are caused by variant genes or chromosomes also known as alleles (one
inherited from the mother and another from the father) at one or more genetic loci, which range
in frequency from very rare to moderately common.
Allele frequencies are the subject of population genetics, which can be readily applied to two
tasks:
1. Determining the reasons for the frequency of a deleterious allele
2. Estimating the likelihood that a person will inherit the allele or develop the trait
Sickle-cell anemia is a disease where red blood cells take an irregular shape (Fig. 25) that makes
it difficult for them to travel the body and can lead to death. It is caused by a point mutation and
the full-blown disease requires both the gene alleles to be defective (homozygous condition).
Since homozygous individuals are highly susceptible to sickle cell anemia, they should be
selected against with time. But individuals with sickle-cell anemia are resistant to malaria,
highlighting the survival value in carrying the sickle-cell gene within the human population.
In the sickle-cell anemia example, there is a high frequency of individuals with sickle-cell
anemia genes in Western Africa (a range between 10 to 40 %, Fig. 26), compared to other parts
of the globe (less than 1 % in South Africa), an observation that intrigued doctors and
researchers. This signaled to population geneticists that some agent of natural selection probably
maintained these alleles in populations.
So why is it prevalent in Africa where as in the US about 8% of the African American population
are carriers?
The point mutation (Fig. 27) that occurs in the germ-line DNA hemoglobin beta gene (HBB) is
found on chromosome 11. This mutation results in the production of a structurally abnormal
hemoglobin (Hb), called HbS. Hb is an oxygen carrying protein that gives red blood cells (RBC)

their characteristic color.

Under certain conditions, like low oxygen levels or high hemoglobin concentrations, in
individuals who are homozygous for HbS the abnormal HbS clusters together, distorting the
RBCs into sickled shapes. These deformed and rigid RBCs become trapped within small blood
vessels and block them, producing pain and eventually damaging organs. In a malaria diseasefree environment, a human having defective red blood cells that cause an unfavorable anemic
condition should be at a great disadvantage to survive, find a mate and reproduce. However, the
presence ofPlasmodium parasites in sub-Saharan Africa changed the notion of fitness in this
environment. Plasmodium parasite infection thrived in individuals with healthy red blood cells,
causing disease and death, but the individuals who are carriers of the sickle-cell gene were more
resistant to malaria, and had enhanced survival and reproductive success. Yet, this advantage is
completely lost when a carrier of the sickle-cell gene moves into a malaria-free region, like the
United States, which is why the carrier population is much lower.
It can be important to couples to know the likelihood that their children will inherit genetic
diseases, especially if these have occurred in their family history. Genetic counseling has
provided such advice for many decades. Genetic counseling (Fig. 28) is applied population
genetics, for it relies on both pedigree analysis (standard genetics) and knowledge of the
frequency of a particular allele in the population at large to calculate the likelihood of inheriting
a genetic defect. Thus evolution has real applications in our lives.
The concept of evolution is essential to understanding biological mechanisms.
Example: Pathogenic diseases and evolution of drug resistance
The potential rapidity of evolution in natural populations of microorganisms, many of which
have short generation times and huge populations, has exceedingly important implications.
Pathogens may be expected to adapt to consistent, strong selection, such as that created by
widespread, intense use of therapeutic drugs (Fig. 29). Resistance to antimicrobial drugs (Fig.
30) has evolved in HIV, the tuberculosis bacterium, the malarial protozoan, and many other
disease-carrying organisms, rendering previously effective therapeutic controls ineffective. Many
of these organisms are resistant to drugs partly because antibiotic resistance genes are often
transferred between species of bacteria.
The current findings that the H1N1 virus also has gained resistance to Tamiflu required us to find
new drugs. The evolution of drug resistance has greatly increased the cost of therapy, increased
morbidity and mortality, and has raised fears that many infectious diseases will be entirely untreatable in the near future. Evolutionary theory suggests that such a grim future may be averted
by reducing selection for antibiotic resistance, and the World Health Organization has indeed
recommended more judicious, sparing use of antibiotics.
In addition, it is important to educate people that the full course of antibiotics have to be used in
order to prevent resistant varieties from having reproductive success and carrying on the resistant
genes to the next generation. Further studies of the population genetics of pathogens will be
important in future containment efforts. This is another area in which evolution has direct
applications in our lives.

Video Link:
http://www.pbs.org/wgbh/evolution/library/10/4/l_104_09.html
The concept of evolution is essential to understanding biological mechanisms.
Example: Domestication and Breeding versus Monocultures and Pesticides.
The relationships among agricultural scientists, geneticists, and evolutionary biologists have
been so long and intimate that their fields are sometimes hard to distinguish, especially in the
breeding of improved varieties of crops and domestic animals. Many geneticists have made
significant contributions to evolutionary genetics and to the basic genetics and
theories underlying effective selective breeding, giving us better and improved crops (Fig. 31).
However, the lack of planning in breeding and crop development with disregard for the
principles of evolution, impact our life today. Humans used to have small and diverse crops with
high genetic diversity that protected the crops from major plagues where the disease of one crop
did not compromise the others. The monocultures that are the norm today are a big incentive for
a few species of insects, which now have abundant food and a death sentence for others which
relied on different food sources. This was a man-made selection where reduced diversity and
providing unlimited food to one type of insect facilitated survival of insect pests but
compromised the crop resistance.
The same is true for pathogenic diseases and the potato crop failure and the Great Irish Famine,
which lost a million lives in Ireland and resulted in mass migration (Fig. 32). The answers to this
rely on understanding evolutionary principles and increasing the genetic diversity of our crops.
In developing pest and disease resistance for animals and plants, we only take another step in the
cycle of selection and resistance. Regardless of how good our breeding programs are,
maintaining diversity is an essential task for our survival.
The concept of evolution is essential to understanding biological mechanisms.
Example: Bioremediation and Biodiversity Crisis
Evolutionary studies have paved the way for new methods of environmental remediation and
restoration of degraded land. For example, some grasses and other plants have become adapted
to soils highly polluted with nickel and other toxic heavy metals. Extensive studies of the
systematics, genetics, and physiology of these plants have laid the foundation for techniques for
re-vegetating and stabilizing soils made barren by mining activities, and even for detoxifying
metal-contaminated soil and water.
It has been found that some bacteria have the capacity to metabolize mercury to a less toxic
form, and their genes for this capacity have been transferred into plants in laboratory
experiments. In other cases, plants that have evolved the capacity to hyperaccumulate heavy
metals (Fig. 33) and thus withstand toxic soils, are currently being used commercially as a
cleanup technology.
Likewise, studies of the evolutionary ecology of seed dispersal and germination are playing a
role in the reforestation of overgrazed land in tropical America, and in the revegetation of landfill

sites.
As a result of human activity, genetically unique species and populations are becoming extinct at
an alarming rate. Our activities threaten not only conspicuous species, such as large mammals
(E.g. Fig.34; Mexican Wolf) and sea turtles, but also innumerable plants, arthropods, and other
lesser-known organisms, which collectively are a potential source of natural products, pest
control agents, and other useful services.They also recycle chemical elements that enables the
entire ecosystem to operate.
Evolutionary biology is playing a major role in addressing this biodiversity crisis. An
important consideration is which species, ecological communities, or geographic regions merit
the most urgent conservation efforts, since there are economic, political, and informational limits
on the number of species we can save.
1. Using phylogenetic information to determine which regions contain the greatest variety of
biologically unique species.
2. Using the data and methods of evolutionary biogeography and the study of organisms'
distributions to identify hot spots - regions with high numbers of geographically localized
species (Fig. 35).
3. Using population genetic theory to determine the minimal population size needed to prevent
inbreeding depression and to design corridors between preserves to allow gene flow, both of
which maintain the ability of populations to adapt to diseases and other threats. For example with
Swedish Adders (snake), about 40 individuals were isolated from other members of their species
and forced to inbreed. The population became weaker with lower genetic variation and a higher
rate of genetic diseases that pushed it the edge of extinction, a process known as inbreeding
depression (Fig. 36). In an attempt to recover the adders population, researchers and
conservationists put into practice evolutionary principles. They continuously added outbred
males to the depressed population of adders. Over time, this procedure led to a steady increase in
the populations numbers and biodiversity, rescuing it from extinction. This case shows us that,
whenever possible, conservation efforts for recovering species should include principles in
evolution to maximize their chances of success.
4. Using genetic markers to control traffic in endangered species. These methods have been used
to spot illegal whaling, and are routinely used to distinguish illegally smuggled from legally
captive-bred parrots. In fact, these birds have such a high market value that insurance companies
are requiring DNA fingerprints of pet parrots.
We have discussed three major areas in which evolution plays an important role. In reality, there
are many more reasons that could be analyzed but it is beyond the scope of this course in general
biology.
In summary, the three lectures on evolution have presented a case underlying the importance of
understanding the fundamental principles of evolution as a natural process. The basic concept of
natural selection is closely associated in our lives. Evolutionary studies gives us a chance to see

the connection between all living beings and the level of similarity among them and help us learn
more about ourselves.
This knowledge, however, is not restricted to basic scientists and those of us who have a deep
interest in science. The benefits of this knowledge are shared among all of us. As we discussed in
the first e-module, molecular biology tells us that several genes present in humans are also found
in mice, rats, fish, and many diseases that we suffer from also affect them. For these reasons, the
use of animal models in biomedical research has led to incredible advances in the treatment of
diseases like asthma, arthritis, cancer, studies which would be impossible if working with only
human subjects. If done well and humanely, the knowledge generated through these controlled
studies can be extremely fruitful in advancing human well being.
But it is important to understand that mankind is in constant co-evolution with our planet.
Changes made to the environment will affect us directly and indirectly. We must be conscious
about making the right decisions in our lifestyles to reduce the impact on the environment. I end
with two more book suggestions, for those who want to learn more about evolution and ourselves
(Fig. 37 and 38).

The Central Nervous System coordinates all our sensory and motor systems. In addition, it plays
a major role in defining who we are.
Nervous System:
You run, you cry, you laugh, you sleep, you remember. These are all aspects of the controlling
function of the nervous system. All of these functions require the interaction of different systems.
When you are emotionally upset, you cry which involves the release of fluid from certain glands
in your eye, your heart rate and blood pressure may increase, you may feel the urge to urinate,
and you may feel sad. The nervous system integrates all these activities.
You can best see this interaction when you visit nursing homes and you see patients in whom
these functions are no longer coordinated or controlled. Persons have lost their memory but
maybe only their short term memory and still remember events that occurred 30 years ago. They
are not able to feed themselves or they may have inappropriate behavior. All of these functions
and many more are controlled by the nervous system and when one component is altered it
affects the patient.
Introduction to the Neuron
To understand the nervous system, keep in mind, it is similar to a set of interacting computers.
Instead of using the word computer, biologists use the word nuclei or ganglia which refer to
a group of neurons that work together.
In computers the key component is the chip whereas in the nervous system it is the neuron. In

some ways they function in a similar way. Different chips in the computer have different
functions such as adding and subtracting, etc and neurons also have different functions.
It is easier to study the neuron than the nuclei or ganglia because of the complex set of
interconnections between neurons. These connections called synapses are the communication
link between neurons. However to study the millions of neurons involved in you reading this
passage is a real challenge. Signals go from your eye to nerve pathways to nuclei to various parts
of the brain so that you can understand the words and at the same time savor your drink of coffee
while twirling your hair and listening to the music coming from your earbuds.
So, let's start with the neuron.
Neuron
The human brain has about 100 billion neurons with thousands of connections or synapses. They
receive information, process it, and transmit it to other cells by way of electrical signals.
Neurons vary in shapes and size, but they are like other cells since they have mitochondria that
produce ATP, nuclei that contain DNA, and endoplasmic reticula, which produce functional
proteins. What makes neurons unique are their extensions which can be very long. The neuron in
your motor cortex in your brain sends projection down to you leg.
There are two kinds of extensions, dendrites and axons. Extending from the neuronal cell body
are the dendrites, which are the receivers that gather signals from other neurons or from
sensory stimuli. At the other end of the neuron is a long extension known as the axon that
conducts action potentials to its terminal end which are called axon terminals.
The axon terminals interact with other neurons or cells such as muscle to transmit chemical or
electrical signals to those cells. The branches at the axon terminals allow one neuron to
simultaneously communicate with many other neurons, or with other cell types such as muscle
cells or gland cells.
The dendrites serve as a large receiving station since they receive information from many
(millions!) neurons and the axons serve as the command signal leaving the neuron to control
muscle, glands or other neurons.
Neurons are classified into three types: sensory neurons, interneurons,and motor neurons.

Sensory neurons transmit information from external stimuli such as sound, touch, smell, sight,
and taste by converting the signal from the physical stimuli into electrical and chemical signals.
They can also respond to internal stimuli such as blood pressure, the position of a joint, or the
orientation of the head. Interneurons exchange information between neurons and perform
complex computations that produce thought, complex motor movements and behavior. All
interneurons are stationed within the CNS. Motor neurons carry specific instructions to effector
cells such as skeletal muscles. For example, they cause muscles to contract or gland cells to
secrete various factors. The words, information and instructions refer to electrical and
chemical signals produced by these three kinds of neurons. You should be aware that there are
subsets to these classifications and I have only presented the general categories.
Glial Cells
There is another set of cells that interact with the neurons and these are called Glial cells which
outnumber neurons approximately 10 to 1. There are three types of glia: astrocytes, microglia,
and oligodendrocytes. Astrocytes help maintain a proper chemical environment for neurons and
help maintain the Blood Brain Barrier which protects the neurons from different chemicals.
The blood brain barrier is a mixed blessing. When new chemicals are developed to help patients
who suffer from different brain diseases, one of the challenges is to bypass the blood brain
barrier! Physicians therefore have to administer larger amounts of the drug to swamp the defense
mechanisms of the blood brain barrier.
The microglia function like immune cells and play a major role in terms of inflammation. They
also remove debris after an immune system response. Oligodendrocytes lay down myelin which
is a lipid structure that surrounds the axon of a neuron to insulate it and make the speed of
transmission of the electrical signal increase. Patients who have multiple sclerosis have areas in
their nervous system in which the myelin is not uniform resulting in a multitude of problems
depending on where the myelin is depleted.
Neuronal Communication
So how do neurons communicate electrically? There are two key terms you need to remember:
Action Potential and Resting Membrane Potential. The term potential is always confusing. It
has nothing to do with the ability to do anything, it refers to voltage. So instead of you having
120 volts coming into your house you would have 120 potential. Whenever you see the word
potential relative to neurons it refers to an electrical measurement. The RMP is approximately
-60 mv which means that the inside of the neuron is minus relative to outside. This negativity is
determined by the concentration of potassium ion inside the cell relative to the outside. The RMP
fluctuates if you sample the nerve cell body. It can become more negative or more positive
depending on the chemicals that are being released at that site. These chemicals are called
neurotransmitters of which some can be negative and others positive. However we cannot keep
this simple- negative neurotransmitters are called inhibitory and positive neurotransmitters are
called excitatory. But what are they inhibiting or exciting? The answer is the development of an

action potential. If there are more inhibitory neuro chemicals being released then it will be
difficult for the action potential to occur.
The action potential is a voltage that moves! Once the RMP reaches a certain electrical
threshold, an action potential is born. As the RMP has a minus electrical value, the AP has a
positive value. When an AP is generated it goes from the -60mv of the RMP to +60 mv and then
returns back to a value of -60mv. However, the change that occurs at the membrane to cause the
AP to be generated continues in the segments before and after the AP. Imagine an electrical
signal like a bolt of lightning being generated on a high power line and then it travels from that
initial site to other parts of the wire simultaneously. That is what an AP does. The voltage travels
from one part to another. I am sure that you might be asking- is that it? And the answer is no. The
end result of the AP is to release a chemical at the end of the axon. This chemical can be either an
inhibitory or excitatory neurotransmitter. The major scientific question has been to discover the
cause of the RMP and AP. The answer is that ions determine all the electrical events you see in
neurons. Depending on the ion and its concentration on either side of the neuronal membrane
will determine whether the inside is positive or negative. All cells in your body have an electrical
potential due to the difference of concentration of ions. Neurons are unique in that this difference
and be dramatically reversed by changes in the neuronal membrane which allow different ions to
move in and out of the cell causing different voltage levels at the membrane. Hence the name:
membrane potential which means membrane voltage.
The ions that are responsible for the RMP is primarily potassium which has a different
concentration across the membrane resulting in a negative voltage. Sodium ion is responsible for
the action potential in that the membrane permeability to sodium changes and as a result the
negative signal of the neuronal membrane becomes positive. Once the action potential reaches a
certain value, its permeability is altered and potassium ion will cause the signal to decrease back
to a negative value. This process repeats itself all the way down the axon. For you to move your
fingers requires that an action potential must travel from your brain down your spinal cord to
your finger muscles. It happens extremely fast due to the myelin on the axon.
The reflex
Let us take an example of how these various neurons work together in a neuronal circuit.
Reflexes are involuntary responses to stimuli. They are regulated by the simplest type of
neuronal circuit. They are handled by the spinal cord and do not require input from the brain.
The most commonly described of these is the knee-jerk reflex in which the doctor hits your knee
cap with a small hammer causing you leg to jerk forward in response. More specifically, tapping
on the knee stretches the tendon attached to the quadriceps muscle of the leg. A specialized
sensory neuron in the quadriceps detects the stretch. It sends its signal up to the spinal cord,
where the signal is passed on to another neuron. The second neuron, which is a motor neuron,
sends a signal back down the leg, where it results in the contraction of the quadriceps muscle,
causing the leg to jerk. This is the simplest neuronal circuit because it only comprises of two

neurons. At the same time, another circuit is signaling to affect the hamstring muscles during the
response. The sensory neuron also signals to an interneuron,which in this case inhibits motor
neurons attached to the hamstring muscle and prevents its contraction. The coordination between
quadriceps contraction and inhibition of hamstring contraction allows for a maximal response to
the stretching of the tendon.

The nervous system is a sophisticated system of cells called neurons and supporting cells that
coordinate all activity of the body. The endocrine system which is composed of chemicals that
influence cells throughout the body is the second major coordinating system in the body. Both
are connected from a functional point of view. This module will focus on the Nervous System
and for convenience sake it is divided into Central and Peripheral Nervous system. Please keep
in mind that this division is arbitrary and is used by scientists and clinicians as an organizational
method to organized the various parts of the complex system.
The central nervous system (CNS) is the part of the nervous system that integrates the sensory
information that it receives from receptors throughout the body and coordinates the motor
activity of all parts of the body. It not only coordinates, it thinks and plays a major role in terms
of your self identity. It contains the majority of the nervous system and consists of the brain and
the spinal cord but does not include the nerves and ganglia that are outside the brain or spinal
cord which is the peripheral nervous system (PNS). The PNS is divided into the somatic nervous
system and the autonomic nervous system. Though they are separate, in reality they work
together.
The brain can be divided into three main areas: cerebral cortex, brainstem, and cerebellum. The
average human brain weighs approximately 3 pounds and it has the consistency of jello. It rides
on a fluid called the cerebrospinal fluid (CSF) which is produced by cells in the brain called the

choroid villi. The brain is not a completely solid structure since it has a number of
interconnecting cavities called ventricles. The ventricles play a major role in the production and
transmission of the cerebrospinal fluid. Without cerebral spinal fluid, the weight of the brain
would collapse upon itself.
The cerebral cortex is the control center and it is made up of 4 different lobes: frontal, parietal,
occipital, and temporal. In humans, these lobes work together so that responses to the
environment are processed based on intelligence, previous experiences, memory, sensation, and
emotions. The cerebral cortex is also divided into two hemispheres: right and left, which further
compartmentalizes and specializes the behaviors coordinated by the brain. The two hemispheres
communicate with each other so that the function of one side of the body is coordinated with the
other. Your right hand knows what your left hand is doing. The connection between the
hemispheres is called the cerebral commissure and is much more developed in females than
males. Based on research papers, females can process data from both sides faster than males.
This might explain the commonly observed ability of females to listen and coordinate different
activities much faster than males. The various lobes of the cerebral cortex can be viewed as
specialized areas.
The frontal lobe is involved in what are called higher functions recognizing future
consequences resulting from current actions, to choose between good and bad actions (or better
and best), override and suppress unacceptable social responses, and determine similarities and
differences between things or events. Ever notice that when persons become intoxicated how
they do inappropriate behaviors such as dancing with a lampshade or doing very risky behavior?
Blame it on the alcohol that you drank that inhibits the frontal lobes. Normally, persons will not
do certain behavior, but drinking to excess inhibits the frontal lobes so you do risky behavior.
The parietal lobe plays important roles in integrating sensory information from various parts of
the body, knowledge of numbers and their relations, and in the manipulation of objects. Portions
of the parietal lobe are involved with visuospatial processing which involves visual
representation of images in space. It also includes tasks involving mental rotation of three
dimensional visualization. Is there a gender difference between males and females in the parietal
lobe? Using mental rotation tests, males are more adept at this task. From a parietal lobe
perspective, males have greater surface area than do females which might help them in their
mental rotation tests.
The occipital lobe is the primary visual cortex which means that the visual signals from your
retina are ultimately processed by the occipital lobe. The occipital data is transferred to the
parietal lobe which was already discussed. The occipital lobe has connections with motor centers
in the brain. Certain frequency of light flashes or images with multiple colors trigger seizures
suggesting connections between the image processed in the occipital and parietal lobe leading
ultimately to motor centers that produce the seizures.
The temporal lobe is involved in auditory perception. The tunes that you hear are processed by

the temporal lobe. Interestingly, the temporal lobe houses another group of neurons, called the
hippocampus which is involved in long term memory. As we age, what happens to the temporal
lobe? Males show a larger decrease in brain volume suggesting that they are losing more neurons
that their female counterparts. Possibly hormones play a role in producing this difference.
The brainstem, or lower brain, is the life support system of the CNS because it regulates
breathing, heart rate, and blood pressure. It is the lower extension of the brain and connects it to
the spinal cord. The brainstem is the pathway for nerves traveling to the highest parts of the
brain. It consists of the three parts: midbrain, pons, and medulla. The midbrain serves to initially
integrate sensory input and project it to regions within the cerebrum. It contains auditory and
visual reflex centers so when you get scared by a loud noise and respond it is the midbrain that
controls the response. The medulla helps control the body's autonomic functions (things you
don't need to think about to perform) like respiration, digestion and heart rate. Damage to this
site will cause the patient to have abnormal breathing patterns. Motor neurons in the medulla
also regulate swallowing, coughing, and vomiting. The medulla also acts as a relay station for
nerve signals going to/from the brain. The pons has roles in your level of arousal
or consciousness and sleep. The pons also relays sensory information to/from the brain and is
involved in controlling autonomic body functions. Axons from the medulla and pons signal to
areas of the cerebral cortex and cerebellum to cause changes in attention, alertness, appetite, and
motivation. Injury to the brainstem can result in death. It is extremely important since it houses
the cardiac center to control heart rate, vasomotor center to control blood pressure, and the
respiratory center in conjunction with the pons.
The cerebellum controls balance and the refinement of movements. It is also likely responsible
for learning and remembering motor responses. The cerebellum receives and integrates
information about the position of joints, length of muscles, visual and auditory stimuli to
coordinate fine motor movements. These include learning new dance steps, hand-eye
coordination, and playing the piano. Injury to the cerebellum will result in the loss of fine motor
control and tremors. The tremors or shakes of the hands that persons with cerebellar injuries is
interesting. It is call an intention tremor meaning that the patient does not show any signs of
tremor when he is completely rested. Once he moves his hand to get a glass of water for
example, the hand begins to demonstrate a large shaking of the hands.
Lastly, we have the spinal cord, a long stretch of axons and neurons that course from the brain
stem to the lumbar level of the vertebral column, the bone that encases and protects the spine.
The spinal cord has segments that innervate distinct areas of the body. These are the cervical,
thoracic, lumbar, and sacral spinal cord segments. Within the vertebral column, the spinal cord
actually only extends through the thoracic segment. The roots from the lumbar and sacral
segments thread downward into the base of the vertebral column. They make up the cauda
equina (or horse's tail). This area is the place where spinal taps are performed and epidural
injections are made, because no spinal cord neuronal cell bodies are here, only axons. Each
segment of the spinal cord contains 2 spinal nerves that flank the spinal cord. The picture beside
shows a cross-section of the spinal cord segment and that each individual spinal nerve,
containing sensory neurons, enters at a dorsal root ganglion (DRG) and thread into dorsal roots
before entering the spinal cord. The side on which afferents enter the cord is the dorsal side and
the opposite is called ventral. Many cell bodies in the ventral horn of the spinal cord send axons
through the ventral root to muscles to control movement. Some fibers make synapses with other
neurons in the dorsal horn (such as those in the reflex arc above), while others continue up to the
brain. Within the spinal cord, nerve cell bodies are located in the gray matter. Surrounding the

gray matter is white matter (lighter color shading) -this is where the axons of the spinal cord are
located.
For practical reasons, this concludes the description of the Central Nervous System. The
peripheral nervous system will be discussed in a separate module and is primarily presented as a
part of the nervous system involved in motor activity- be it activation of skeletal and smooth
muscle and responses to stresses. Keep in mind that this division is purely artificial since the
entire nervous system both Central and Peripheral work together. The central nervous system has
multiple functions which is beyond the scope of this course. However to kindle your curiosity,
lets consider memory. Who you are, what you memorize, where to go are all manifestations of
memory.
Memory refers to the storage, retention, and recall of information including past experiences,
knowledge, and thoughts. Most memories are reconstructions. Memories are not stored in our
brains like books on a shelf. Whenever we want to remember something, we have to reconstruct
it from elements scattered throughout various areas of our brains, like a computer stores and
accesses files before it is defragmented. This is one of the reasons that over time, our memories
can fade and change. Two people for example can watch the same movie, and a year, a month,
or even a day later remember or forget different parts of the same movie.Memory can be
categorized by both nature (e.g. the declarative memory which stores information that is
available to you consciously, such as language, songs, and images) and by the time over which it
is effective. Short-term and long-term memories are temporal or time-based classes of memory.
Short-term memory is the ability to store information for seconds to minutes after the present
moment has passed. Short-term memory, as the name suggests, is of limited capacity, usually 3-4
items. A common example of short-term memory is the ability to remember a phone number
until it is dialed, after which the number is forgotten. Interestingly, new information can "bump"
out other items from short-term memory.Short-term memory occurs in the part of the brain called
the hippocampus. Recent studies also suggest that short-term memory also requires a part of the
brain adjacent to the hippocampus called the subiculum. Both areas of the brain are required for
short-term memory, but work at different times. If a stroke damages these areas, the person
cannot remember current events even if they saw them minutes earlier. Working memory is a
special kind of short-term memory that refers to the ability to hold information in mind long
enough to carry out sequential actions. An example is searching for the lost cell phone! Working
memory allows the search to proceed efficiently, avoiding places already inspected. However
working memory is influenced by stress. If you are too anxious about the lost cell phone you will
not be able to focus and will not see the cell phone in the car where you last left it.
Long-term memory refers to information that is retained for months to years and includes
information such as facts, semantics (words, their symbols, and their meanings), and
autobiographical information. In general, long-term memory is organized so that it is easy to
reach a stored item by a number of routes. It is as if the brain is searching for the word cookie
and can access it by either thinking of chocolate chips, oatmeal, milk, sweet, forbidden (!) etc.
Retrieval of an item also facilitates other related items so that retrieving information about a
cookie can lead to retrieval of information about the taste of chocolate, the smell of cookies
baking, or watching the Cookie Monster on TV as a kid. Most types of long-term memory
appear to be stored in the the frontal cortex. Different areas of the cortex specialize in different
kinds of information. Visual information of a cookie, for example, may be stored in one location

(e.g., the inferior temporal cortex), while information about its associations to Santa Claus and
milk might be stored in another (e.g., the frontal cortex). Linkage between these two areas means
that seeing a picture of a cookie can retrieve a memory about receiving a special gift from Santa
at Christmas.
Short-term memories can be transferred to long-term memories (i.e. from the hippocampus to the
cortex) by retaining the new piece of information long enough either by repetition or association.
For example, if you are memorizing the fact that active transport of water requires ATP, you
could repeat it to yourself over and over again. However, you would retain the information much
better in your long-term memory if you associated the information with something you already
know, such as a water pump in a fish tank that requires electricity (an energy source). Because
you are associating the new information with old information (i.e. an existing network), it
strengthens the connections of the old network and provides another route for your brain to
access the information. Association is therefore a more efficient means of storing new
information in your long-term memory.
The molecular basis of creating of long-term memories is dependent on long-term potentiation
(LTP), a process which strengthens the connection between two neurons. LTP is the cellular
equivalent of a conditioned response. During LTP, signaling between the preand postsynaptic neurons are patterned (the signal is repeated). The response of
the postsynaptic neuron is subsequently stronger than the original signal (the response is
potentiated) and lasts for a longer period of time (long-term). The more you do something, the
greater are the connections. However, this chemical connection does not completely explain
memory. LTP explains that persons or animals can more quickly identify an object but does not
specifically state how it does it. Keep in mind that short and long term memory are not the sole
properties of humans since many vertebrates and invertebrates have short and long term memory.
During LTP, both neurons are activated at the same time resulting in more effective
communication. That is, if the presynaptic neuron releases a chemical message, the message will
be much better received by the postsynaptic neuron if that neuron is activated to receive the
message. It is an analogous feeling that you are much better friends with someone you have a
conversation with on a daily basis (someone you can have a dialogue with) vs. someone you only
write e-mails to (someone you have one-sided conversations with). LTP does not occur with
inactive neurons and is therefore specific to the activated neurons.
Memory can be impaired by various injuries and diseases. A common outcome of a brain injury
due to concussions as in observed in sports or a serious accident is amnesia. The brain is
physically damaged and as a result the person does not remember what occurred before, during,
or after the trauma. Amnesia is a severe disruption of memory without deficits in intelligence,
attention, perception, or judgment. It may occur following damage to any of several brain
structures that are critical for memory. There are three major classes of amnesia: anterograde
amnesia - an impairment in storing new memories-, retrograde amnesia - a loss of old
memories-, and psychogenic amnesia a temporary loss of identity. Anterograde and retrograde
amnesia usually result from brain injury or disease, while psychogenic amnesia is a
psychological condition that occurs in the absence of brain injury and usually involves both short
and long term memory loss.

Alzheimers disease is a common disease that causes memory loss. The disease is characterized
by the presence plaques and tangles in the brain (Fig. 19). Plaques build up between nerve cells,
containing deposits of a protein fragment called beta-amyloid. Tangles are twisted fibers of
another protein called tau. Researchers are not absolutely sure what role plaques and tangles play
in Alzheimers disease, but most people believe they block communication among nerve cells
and disrupt activities that cells need to survive. Interestingly, plaques and tangles appear in a
predictable pattern in the brains of Alzheimer patients. Early stages of Alzheimer's disease cause
memory impairments due to neuronal cell death in the hippocampus and the basal forebrain, the
area that produces acetylcholine, the neurotransmitter essential for learning. Damage to the
neurons in these areas result in a kind of anterograde amnesia, where new memories are not
formed while old memories are retained. As the disease progresses and more plaques and tangles
appear in other parts of the brain, other impairments in memory and motor function occur.
However, the presence of the tangles are by themselves not sufficient to cause Alzheimer's or to
explain Alzheimers memory loss.
A Stroke, while not a disease, is another common cause of memory loss. A Stroke is commonly
caused either by a sudden loss of blood flow to the brain (ischemic strokes, Fig. 20) or by a
bleeding inside the head. Large ischemic strokes are usually caused by narrowing of the large
arteries in the neck and brain or blockage of arteries by blood clots or pieces of atherosclerotic
plaque (buildup of cell debris on artery walls). People with uncontrolled high blood pressure and
diabetes often have small ischemic strokes that involve very small arteries in the brain. Strokes
can cause memory loss due to neuronal cell death when the blood supply is cut off. Remember,
the decrease in oxygen causes a decrease in ATP which leads to cell death. Consequently, there is
no specific medical treatment to help reverse the memory loss that occurs after a stroke. The
amount of recovery is dependent on the degree of injury that the patient suffers.
Another kind of impairment of memory can occur with alcohol use and is frequently referred to
as a blackout. Some of the factors involved in alcohol-induced blackouts are blood alcohol
level, the rate of consumption (the faster you drink, the more likely you will have a blackout),
your prior history with blackouts (some researchers believe that having a blackout damages your
brain which makes you more susceptible to having another blackout), and your gender (studies
suggest that females are more susceptible to blackouts than males). Females are more susceptible
than males since they do not have to drink as much as their male counterparts to overwhelm the
liver which detoxifies the ethanol drink. Research data suggests that alcohol disrupts electrical
and chemical activity in the hippocampus, thus impairing the brains ability to transfer
information from short-term memory to long-term memory, and resulting in a form of
anterograde amnesia. A person who is heavily intoxicated may remember an incident 2-3 minutes
after it has occurred, but not the next day. Alcohol also interferes with the establishment of LTP,
and this impairment can occur by consuming just one or two standard drinks (e.g., a 12oz beer,
1.5oz of liquor in a shot or mixed drink, or a 5oz glass of wine, Fig. 22). For chronic drinkers,
alcohol may also damage the frontal lobe (where the frontal cortex is involved in storage of longterm memories) by causing shrinkage in brain volume, changes in gene expression in brain cells
and changes in blood flow in the brain.
As you may know from your own experiences, sleep has a big effect on memory. If you are
feeling tired, or have not gotten enough sleep the night before, it is harder to in class to learn new
material. Conversely, you can perform certain tasks better after a good nights sleep. All
mammals require sleep, and spend much of their lives doing so (think of your pet cat or dog, who
spends most of their days sleeping!). Humans also require a lot of sleep, and researchers are still

not sure why. One of the reasons may be to help us learn new information and strengthen our
memories.
Some studies have shown that your brain actually undergoes remodeling when you sleep. Studies
in fruit flies show that the number of synapses increases during social interactions, while the
number of synapses decrease during sleep. This decline in synapses during sleep is thought to be
a consolidation of memories. This consolidation subsequently strengthens the connection of the
remaining synapses. A good example is when you are faced with several choices and need to
make a decision. If you sleep on it, your brain has time to process the information and you
may find that in the morning, you can more easily make a decision after your brain has
consolidated all of the information contained in those choices. In addition to information
consolidation, it also appears that your mind replays the newly learned tasks during sleep.This
replay is just like when you repeat something to yourself over and over to help transfer the
information from your short to your long-term memory. The same patterns of neuron activation
that occur while learning the activity while awake also occur during sleep. This reinforcement of
new information (and the reinforcement of the connection between the neurons) that happens
while we sleep may also help us in the learning process.
Just as sleep can help us learn new tasks and process information, the lack of sleep can also
affect our ability to learn or perform a newly learned task. Many studies have shown that sleep
deprivation for both animals and humans negatively affects both learning and performing a
newly learned task.
Many people know (including myself!) that if you are feeling tired, a cup of coffee or an energy
drink can give you a little mental boost. While studies have shown that some caffeine (e.g.
100mg, about the amount you find in an 8oz. cup of brewed coffee) can improve alertness and
even short-term memory functions, one study showed that a lot of coffee (e.g. 2-3 cups of coffee,
or one tall coffee from Starbucks, Fig. 25) has been shown to impair certain functions such as
motor tasks and recall tasks. Furthermore, the people who had caffeine performed these tasks
more poorly than people who had taken a nap instead. Researchers are not exactly sure of all of
the effects of caffeine from the brain, but one effect might be on the levels of acetylcholine (the
neurotransmitter involved in learning, discussed earlier). Levels of acetylcholine usually
decrease while you sleep, just like the number of synapses decrease. Caffeine boosts the levels of
acetylcholine in your basal forebrain, and may therefore negatively impact the learning process
by not allowing information consolidation to occur.
We spend about one-third of our lives sleeping. Why? Believe it or not, scientists dont know for
sure. But evidence is building that sleep may play a crucial role in strengthening memories and
facilitating learning, not just in humans but in most animals.
NOVA scienceNOW visits research labs at the University of Pennsylvania and MIT, where
scientists are peering into the brains of dozing flies and rats to understand the connection
between sleep and memory. At Harvard Medical School, host Neil deGrasse Tyson tests his
powers of learning on a virtual ski machine and a speed typing exercise, and then catches some
z's. He discovers that it's not practice that makes perfect, but practice plus a good night's sleep.

Central Nervous System (CNS)

refers to your brain and your spinal cord.

Memory

the storage, retention, and recall of information including past experienc

thoughts.

Short-term Memory

the ability to store information for seconds to minutes after the present m

Working Memory

special kind of short term memory that refers to the ability to hold inform
enough to carry out sequential actions.

Long-term Memory

information that is retained for months to years and includes information

and autobiographical information.

Frontal Cortex

area of the brain where most types of long-term memory appear to be sto

Neuron

also called nerve cell; an excitable cell in the nervous system that process
information by electrochemical signaling.

Axon

long projections that send signals from the neurons.

Dendrites

much shorter projections and receive signals from other neurons.

Synapses

Neurotransmitters

junctions between axons and dendrite, and where neurons communicate.

chemical messages which rely, amplify, and modulate signals between a neuron and ano

Pre-synaptic neuron

neuron sending the message before the synapse.

Post-synaptic neuron

the neuron receiving the message after the synapse.

Synaptic Vesicles

membrane-bound organelles that hold neurotransmitters.

Long-term Potentiation (LTP)

a process which strengthens the connection between two neurons. The c

conditioned response

Amnesia

a severe disruption of memory without deficits in intelligence, attention,

judgement.

Anterograde Amnesia

impairment in storing new memories.

Retrograde Amnesia

loss of old memories.

Psychogenic Amnesia

temporary loss of identity.

Peripheral Nervous System

" But I do not have any money!" The peripheral nervous system controls our muscles and all
involuntary responses. Both individuals have activated their peripheral nervous system which is
sending adrenalin coursing throughout their bodies.

Since the previous module covered the CNS, here we will focus on the PNS which by definition
is any part of the nervous system outside of the brain and spinal cord. As mentioned previously,
the PNS is responsible for collecting sensory input from external or internal stimuli and
conveying the information to the CNS via afferent, sensory neurons. It is also responsible for
conveying information using efferent motor neurons from the CNS back to the effector tissues
(glands and muscle). There are two sets of nerves which make up the PNS: cranial and spinal
nerves. Most of these nerves are bundles that contain both sensory and motor neurons. Cranial
nerves innervate organs in the head while spinal nerves innervate the rest of the body. We have
12 pairs of cranial nerves and 31 pairs of spinal nerves. Motor neurons in PNS can be divided
into two branches: the somatic nervous system, which regulates movements that can be under
voluntary control and mainly responds to external stimuli, and the autonomic nervous system,
which regulates movements that can be under involuntary control and responds primarily to
internal stimuli. Somatic motor neurons regulate skeletal muscle contraction while autonomic
neurons regulate smooth and cardiac muscle contraction as well as gland secretion.
Sensory neurons
We will begin by discussing how information is collected from both internal and external stimuli.

These neurons collect external stimuli and are involved in how we see, smell, taste, hear, touch,
etc. They also collect information on how our bodies are functioning (i.e. blood pressure,
temperature, etc.). Stimuli are typically detected by sensory receptors. These receptors change
the membrane potential of the sensory neuron, usually depolarizing it, which in turn causes the
neuron to send a signal.
Motor neurons - Somatic nervous system
The somatic nervous system carries motor information to skeletal muscle. The somatic nervous
system is considered voluntary because it can be subject to conscious control (i.e. signals from
the cortex of the brain); however, a lot of skeletal muscle movement is determined by reflexes
mediated by the spinal cord. An example of this would be the knee-jerk reflex that was covered
previously. Somatic motor neurons control fine and gross movements, body position, and
balance. This information comes from various areas of the CNS including: the spinal cord,
primary motor cortex, brainstem and cerebellum.
Motor neurons - Autonomic nervous system
The autonomic nervous system carries information to control the internal environment by
regulating the movement of glands, smooth, and cardiac muscle. It is extremely important for
maintaining homeostasis. Homeostasis is the physiologic setting of equilibrium or steady-state
function. It can control the organs of the gastrointestinal, cardiovascular, respiratory, excretory,
and endocrine systems. This is why it is impossible to consciously stop yourself from breathing
and why you don't have to think about contracting muscles to move food through your GI
system. There are two main divisions of the autonomic nervous system: the parasympathetic and
sympathetic nervous systems. In general, they have opposite effects on organ function which we
will now discuss in more detail.
Parasympathetic nervous system (ParaNS)
The ParaNS regulates day-to-day functions that are commonly associated with the phrase, rest
and digest. These functions help the body regain or maintain strength and energy. The rest and
digest analogy stems from ParaNS activity that increases salivary gland, gastric acid and
digestive enzyme secretion, regulates metabolism and waste removal, in addition to the resting
heart rate. If you notice in Figure 3, ParaNS neurons come from the cranial and sacral regions of
the CNS. In fact, nearly 75% of ParaNS fibers are in the vagus nerve (i.e., cranial nerve X)! This
nerve is critical for regulating heart rate and vagus nerve dysfunction can result in a resting heart
rate of 100 beats/minute, instead of the average ~70 beats/minute. The ParaNS has
long preganglionic nerves which synapse at ganglia near or on the innervated organ (Figure 1). A
ganglion is a collection of dendrites and provide an intermediate connection or relay point
between neuronal structure.

Sympathetic nervous system (SNS)

During stressful or strenuous events, autonomic nervous system activity predominates in the
sympathetic system. As such, stress and alarm have been used to characterize SNS activity.
Most of the SNS nerve fibers originate from the thoracic and lumbar regions of the spinal cord.
Their preganglionic nerves are short and synapse in paired ganglia adjacent to the spinal cord.
The SNS also signals to the adrenal medulla, an endocrine gland to release epinephrine and
norepinephrine into the bloodstream. Increased SNS activity allows an individual to cope with
events like rage.The neurotransmitters of the autonomic nervous system worry, pain, fear or a
fight. Increased epinephrine release in the SNS increases heart rate, airway opening, respiration,
and blood flow to muscles. The aforementioned events, in addition to increased sweating and
pupil dilation, are classic hallmarks of the fight or flight response.
How do these two different systems mediate cardiovascular function, especially if both cause
opposing biological effects? They do it through the activation of specific receptors by specific
neurotransmitters! Earlier, we learned that neurotransmitters are proteins that can bind receptors
in order to either inhibit or excite neuronal activity. Now let's discuss how this relates to the
autonomic nervous system. As mentioned previously, autonomic neurons synapse onto ganglia
prior to innervating their target organ. Therefore for an organ to receive a signal from either
branch of the autonomic nervous system, neurotransmitters must be released at two synapses (the
connection between two neurons), from the preganglionic neuron and the postganglionic neuron.
Each branch of the autonomic nervous system uses different neurotransmitters to exert its effects
on its target organs. Neurotransmitters released from the preganglionic neuron excite
the postganglionic neuron by causing an increased graded potential. This will lead to the
generation of action potentials that will transmit the signal down the axon. Once the action
potential reaches the axon terminal or synapse, this will cause the release of other
neurotransmitters which will exert various effects on target organs (for a review of this process
see The Nervous System e-module).
One important neurotransmitter released at both ParaNS and SNS ganglia is acetylcholine (Ach)
which binds and activates cholinergic receptors. In the ParaNS, acetylcholine is also released
onto at the target organ (e.g., heart). Thus, during resting or digesting, when the ParaNS is
activated, acetylcholine release and cholinergic receptor activation dominate. While Ach is also
released in the SNS ganglia, a different neurotransmitter called epinephrine (Epi) is released onto
the target organ. Epinephrine, which is also known as adrenaline, binds and activates adrenergic
receptors. Thus, during stress or the fight or flight response, epinephrine is released and
adrenergic receptor activation dominates.
Neurons originating from the medulla inhibitory center of the brainstem transmit to axons in the
vagus nerve. The nerve leaves the brainstem and makes a synapse in the peripheral ParaNS
ganglia next to the heart. Acetylcholine is released at this synapse. The continuing signal will
trigger acetylcholine release onto the heart and decrease cardiac muscle. This is a tonic, or ongoing, type of activity that keeps the heart rate nice and low, near 70 beats/minute! A different
neuron originating from the medulla acceleratory center leaves the brainstem and travels to the
SNS ganglia near the spinal cord. Acetylcholine release at this synapse will result in epinephrine

release, and adrenergic receptor activation in the heart. This increases heart muscle contraction
and rate, as well as the amount of blood pumped through the body (cardiac output). So, when the
blood pressure is too low, baroreceptor activity will be diminished and it will decrease activity at
the medulla inhibitory center. This will, in turn, permit increased activity at the medulla
acceleratory center.
So let's put all this knowledge into an applied setting. As you listen to your genre of music, you
feel happy. As you listen you activate the PNS, not only the autonomic but also the somatic
nervous system so that you are tapping with your foot to the music as well as to your heart rate
and blood pressure might increase. Sounds are disturbances of air molecules caused by vibrating
objects (such as strings on a guitar). The air disturbance in the form of waves emanate from the
vibrating object, like water rippling from a stone thrown in the water. Sounds are produced by
anything causing this air disturbance, such as a car engine, waves on the shore, book pages being
turned, etc. Music is a collection of sounds that are organized with a purpose, such as dancing,
storytelling and communication, expression, entertainment, or even to just sound appealing.
Music is one of the oldest and most basic forms of communication between humans. It is also
worthy to mention the difference between any sound and music. Noise is a sound consisting of
unorganized or unevenly spaced waves. Music however is mostly composed of tones (musical
notes) which are sounds made of regular, evenly spaced waves of air molecules.
There are several important features of sound waves that the human ear can distinguish. The
wavelength of a sound wave refers to the spacing of the waves, the distance between the high
points of two waves. How fast or how often peaks of waves go by a certain point can be
measured and is referred to as the frequency. Frequency, therefore, refers to 2 components of the
sound wave: 1) the wavelength and 2) the speed at which the wavelength is traveling. Waves
with a long wavelength, such as very low sounds, do not arrive at your ear as frequently as
shorter ones do. Frequency is measured in hertz, which is the amount of peaks of waves that pass
a point in one second. Humans have a hearing range of 20-17000 hertz. Tone, frequency, and lag
time (the time it takes for a wavelength to reach both of our ears) are all important properties of
sounds help us locate their source.
Sound waves are typically not perfectly shaped as described in the previous slide. Think about
how a piano and a guitar sound. Both can play the same note, but each instrument has its own
distinct sound so that you can tell the difference between them. This is because a musical
instrument produces a sound wave composed of a combination of different but related
frequencies (known as harmonics) which all mix together to create the distinctive sound of the
instrument. The lowest frequency within the harmonic is usually dominant, and you perceive this
one as the note (e.g. both the guitar and the piano can play the C note). The combination of the
other waves provides the distinctive shape of the waveform, giving rise to the distinctive tone of
the instrument. These subtle differences in sound waves are distinguished by the brain so that
you can tell the difference between a note from a piano and a note from a guitar.The other
measurable aspect of sound waves is the height of each wave, or the amplitude. Amplitude
determines the loudness or volume of the sound and is measured in decibels. Electric guitars can
barely be heard unless they are connected to an amplifier, which amplifies or multiplies the
amplitude of sound wavelengths.

How do vibrations in the air get translated to a recognizable sound or musical note?
Central to the process of physically converting sound into something our brains can interpret is
the system in our ears. First, the sound waves are received by the outer ear (or the pinna), which
acts as a funnel to channel sound to the auditory canal. Sound waves then travel to the eardrum,
or the tympanic membrane. As the name implies, the eardrum vibrates when hit by a sound wave
(think of the head of a drum which vibrates when a drumstick hits it). The eardrum acts to further
amplify the sound by transferring the vibrations to the ossicles, the three tiniest bones in your
body. The individual bones of the ossicles are referred to as the hammer, anvil, and stirrup based
on their shape. The ossicles are connected to the eardrum, and their movement moves the air in
your middle ear, thereby converting the vibrations to sound pressure. Sound pressure is the
difference in pressure between the atmospheric air and the pressure caused by the sound wave.
You can imagine sound pressure as different gusts of wind, from a soft breeze (e.g. from a low
frequency/low amplitude sound) to a hurricane force wind (e.g. from a high frequency/high
amplitude sound). The sound pressure information then gets passed to the inner ear into the area
called the cochlea. The cochlea is a fluid-filled snail-shaped organ that converts sound pressure
into electrical impulses, which are passed to the auditory nerve. Within the cochlea are hair cells,
which act as the sound receptors for the brain. Hair cells are not actually composed of hair, but
rather are a special kind of neuron named for the bundle of hair-like structures at one end of the
cell. Sound pressure causes the hair-like structures to physically move or be displaced. You can
think of it as the gust of wind (the sound pressure) moving the hair on your head around (moving
the hair cells). Hair cells convert the information carried by sound waves into information by
releasing neurotransmitters upon their movement, creating a form of electrical potential. Hair
cells can convert the displacement of the hair-like structures into an electrical potential in as little
as 10 microseconds! This speed is required to transduce high-frequency signals and enable the
accurate localization of the source of the sound. Because this process occurs so quickly, it also
requires neurotransmitters instead of RNA and protein synthesis (just like short-term memory
formation as you learned in the last module).
Finally, the auditory nerve receives the electrical signal from the hair cells and sends the signal to
the auditory cortex in your brain. The auditory cortex, located in the temporal lobe, is the portion
in your brain that processes the sound signals. The auditory complex can be mapped; that is, a
physical portion of the auditory complex corresponds to specific wavelengths. Studies in animals
show that the auditory complex is important for distinguishing spacing in sounds. In humans, it
is thought that the auditory complex serves the same function, and is important for distinguishing
sounds in speech (e.g. different syllables in words) as well as for complex sounds such as in
music.
Cochlear implants
Some people who are born with damaged or nonfunctional parts of the outer, middle, or inner ear
can get an implanted device to help them hear. These devices are known as cochlear implants and
consist of a spiral of electrodes threaded into the cochlea to stimulate the auditory nerve,
bypassing damaged parts of the ear. A microphone connects to a removable external processor
that converts sound to digital code. The code is transmitted to the implanted mechanism by way
of a magnet. When fed through the cochlea, the decoded digital information is perceived as

sound. Most implants use eight channels of frequency, while the capacity of a normal ear has the
equivalent of 3,500 channels. Eight channels is usually enough to understand speech, which does
not have much pitch variation. However, it is estimated that it takes at least 100 channels of
auditory information to make music pleasurable. Thus, while patients with cochlear implants can
hear speech, they most likely will not be able to fully hear and appreciate music.
Tone deafness
Some people have the ability to discriminate specific tones. This ability is commonly referred to
as perfect pitch or absolute pitch. These people can specifically name the pitch of a note or even
a sound without a reference note. That is, they can recognize and name sounds like most people
can recognize and name colors. Musicians can acquire relative pitch, the ability to recognize a
note or tone if they hear a reference tone first and then rapidly calculate the note from that
reference pitch. There is some evidence to suggest that there is a genetic basis for perfect pitch.
There is also some evidence that language is responsible for perfect pitch. One study for example
showed that 74% of people tested who speak tonal languages such as Mandarin had perfect pitch
versus 14% of English-speaking people. On the other hand, tone deafness is the inability to
distinguish between musical notes. When you watch all of the bad singers on American Idol, it
may seem like most of those people are tone deaf. Tone deafness is often used to describe poor
singers, but in fact, poor singers often can identify notes as well as good singers can. Rather, the
inability to sing might be related to a persons inability to control their vocal cords, imitate a
musical note, or remember the correct musical note to sing. Researchers have found that only 1
in about 20 people are truly tone deaf. Interestingly, tone deaf people have normal hearing and
speech. A very recent study suggests that people who are tone deaf possess fewer neurons
between the temporal (where the auditory complex is) and frontal regions of the brain compared
with people who are not tone deaf.
When you listen to a song you like, you may notice you feel pumped up (your heart races, your
breathing quickens), remember another time that the song was played, or tap your foot to the
beat. All of these responses to music correspond to different portions of your brain and different
parts of your nervous system at work.Music can elicit all kinds of emotions, from happiness to
sadness to anger. All of these emotions are tied to physiological changes. Your pulse, for
example, typically gets faster when you are happy or excited. This physiological change
associated with your emotional response is a function of your autonomic nervous system (ANS).
So how does listening to music trigger the physiological changes associated with emotional
responses? Listening to music you like triggers a neurotransmitter, called dopamine, to be
released in your brain which causes you to feel pleasure. Norepinephrine is made from dopamine
and affects your sympathetic system, which then controls heart rate, blood pressure, and other
physiological changes associated with happiness. This quick response by your sympathetic
nervous system then gives rise to your emotional response.We all know that music can convey
emotions such as happiness or sadness, but what is it specifically about the music that conveys
the emotions? Most happy music is written in major keys, and includes faster rhythms, short
phrases, and repetitive sections, while sad music typically features minor keys and slower
tempos. Do we learn to associate faster rhythms with happy music? One study found that babies
as young as 5 months can respond to happy music while babies as young as 9 months can
respond to sad music. Both of these musical distinguishing capabilities precede talking, and since
they are babies, they have no prior memory to associate these songs to emotions. One of the first

forms of communication for babies is emotion, and music seems to be one way we can talk to
our babies. These studies suggest that communicating with music is one example of something
that pre-exists in our wiring. That is, our brains have evolved to hear, understand, and react to
music. As we just discussed, listening to music you like triggers a pleasure response. Although
there are several areas of the brain that are involved in the feelings of pleasure, the area which
produces the most pleasure is a bundle of neurons called the reward circuit. The reward circuit
(along with the punishment circuit) provides the motivation for most of our conscious behavior.
The ventral tegmental area (VTA) and the nucleus accumbens are the two major centers in this
circuit. The VTA consists of neurons that release the neurotransmitters dopamine (which we
talked about earlier) and serotonin. Dopamine and serotonin are received by neurons in the
nucleus accumbens which signal to the brain that a reward has been received.Normally, neurons
in the VTA are inhibited by GABA interneurons. GABA interneurons use the inhibitory
neurotransmitter GABA, which prevents the neurons in the VTA from signaling. When a
pleasurable experience occurs, other neurotransmitters like endorphins prevent GABA from
being released. When GABA is no longer present, neurons in the VTA can then release dopamine
to signal reward.
Drugs
Drugs have many effects on the brain, but their heaviest impact is often their effects on the
reward circuit (Fig. 9). Some drugs, such as opiates, imitate natural neurotransmitters. For
example, our brains cannot tell the difference between heroin and endorphins. Other drugs such
as cocaine and ecstasy effectively increase the amount of dopamine and serotonin, which signal
reward. Still, other drugs such as alcohol and cannabis (marijuana) inhibit the release of the
inhibitory neurotransmitter GABA, allowing the reward circuit to be turned on. Since these drugs
positively affect the reward circuit, drug users are driven to repeat using drugs, often leading to
drug addiction (which will be further discussed in a later module).
With one listen, I was hooked. I was a 15-year-old suburban New Jersey nerd, racked with
teenage lust but too timid to ask for a date. When I came acrossBolro among the LPs in my
parents' record collection, I put it on the turntable. It hit me like a neural thunderstorm, titanic
and glorious, each cycle building to a climax and waiting but a beat before launching into the
next.
I had no idea back then of Bolro's reputation as one of the most famous orchestral recordings
in the world. When it was first performed at the Paris Opera in 1928, the 15-minute composition
stunned the audience. Of the French composer, Maurice Ravel, a woman in attendance reportedly
cried out, "He's mad he's mad!" One critic wrote that Bolro "departs from a thousand years
of tradition."
I sat in my living room alone, listening. Bolro starts simply enough, a single flute
accompanied by a snare drum: da-da-da-dum, da-da-da-dum, dum-dum, da-da-da-dum. The
same musical clause repeats 17 more times, each cycle adding instruments, growing louder and
more insistent, until the entire orchestra roars in an overpowering finale of rhythm and sound.
Musically, it was perfect for my ear. It had a structure that I could easily grasp and enough
variation to hold my interest.
It took a lot to hold my interest; I was nearly deaf at the time. In 1964, my mother contracted
rubella while pregnant with me. Hearing aids allowed me to understand speech well enough, but
most music was lost on me. Bolro was one of the few pieces I actually enjoyed. A few years

later, I bought the CD and played it so much it eventually grew pitted and scratched. It became
my touchstone. Every time I tried out a new hearing aid, I'd check to see if Bolro sounded OK.
If it didn't, the hearing aid went back.
And then, on July 7, 2001, at 10:30 am, I lost my ability to hear Bolro - and everything else.
While I was waiting to pick up a rental car in Reno, I suddenly thought the battery in my hearing
aid had died. I replaced it. No luck. I switched hearing aids. Nothing.
I got into my rental car and drove to the nearest emergency room. For reasons that are still
unknown, my only functioning ear had suffered "sudden-onset deafness." I was reeling, trying to
navigate in a world where the volume had been turned down to zero.
But there was a solution, a surgeon at Stanford Hospital told me a week later, speaking slowly so
I could read his lips. I could have a computer surgically installed in my skull. A cochlear implant,
as it is known, would trigger my auditory nerves with 16 electrodes that snaked inside my inner
ear. It seemed drastic, and the $50,000 price tag was a dozen times more expensive than a highend hearing aid. I went home and cried. Then I said yes.
For the next two months, while awaiting surgery, I was totally deaf except for a thin trickle of
sound from my right ear. I had long since become accustomed to not hearing my own voice when
I spoke. It happened whenever I removed my hearing aid. But that sensation was as temporary as
waking up without my glasses. Now, suddenly, the silence wasn't optional. At my job as a
technical writer in Silicon Valley, I struggled at meetings. Using the phone was out of the
question.
In early September, the surgeon drilled a tunnel through an inch and a half of bone behind my
left ear and inserted the 16 electrodes along the auditory nerve fibers in my cochlea. He hollowed
a well in my skull about the size of three stacked quarters and snapped in the implant.
When the device was turned on a month after surgery, the first sentence I heard sounded like
"Zzzzzz szz szvizzz ur brfzzzzzz?" My brain gradually learned how to interpret the alien signal.
Before long, "Zzzzzz szz szvizzz ur brfzzzzzz?" became "What did you have for breakfast?"
After months of practice, I could use the telephone again, even converse in loud bars and
cafeterias. In many ways, my hearing was better than it had ever been. Except when I listened to
music.
I could hear the drums of Bolro just fine. But the other instruments were flat and dull. The
flutes and soprano saxophones sounded as though someone had clapped pillows over them. The
oboes and violins had become groans. It was like walking color-blind through a Paul Klee
exhibit. I played Bolro again and again, hoping that practice would bring it, too, back to life. It
didn't.
The implant was embedded in my head; it wasn't some flawed hearing aid I could just send back.
But itwas a computer. Which meant that, at least in theory, its effectiveness was limited only by
the ingenuity of software engineers. As researchers learn more about how the ear works, they
continually revise cochlear implant software. Users await new releases with all the anticipation
of Apple zealots lining up for the latest Mac OS.
About a year after I received the implant, I asked one implant engineer how much of the device's
hardware capacity was being used. "Five percent, maybe." He shrugged. "Ten, tops."
I was determined to use that other 90 percent. I set out on a crusade to explore the edges of

auditory science. For two years tugging on the sleeves of scientists and engineers around the
country, offering myself as a guinea pig for their experiments. I wanted to hear Bolro again.
Helen Keller famously said that if she had to choose between being deaf and being blind, she'd
be blind, because while blindness cut her off from things, deafness cut her off from people. For
centuries, the best available hearing aid was a horn, or ear trumpet, which people held to their
ears to funnel in sound. In 1952, the first electronic hearing aid was developed. It worked by
blasting amplified sound into a damaged ear. However it (and the more advanced models that
followed) could help only if the user had some residual hearing ability, just as glasses can help
only those who still have some vision. Cochlear implants, on the other hand, bypass most of the
ear's natural hearing mechanisms. The device's electrodes directly stimulate nerve endings in the
ear, which transmit sound information to the brain. Since the surgery can eliminate any
remaining hearing, implants are approved for use only in people who can't be helped by hearing
aids. The first modern cochlear implants went on the market in Australia in 1982, and by 2004
approximately 82,500 people worldwide had been fitted with one.
When technicians activated my cochlear implant in October 2001, they gave me a pager-sized
processor that decoded sound and sent it to a headpiece that clung magnetically to the implant
underneath my skin (see "Reprogramming the Inner Ear," page 154). The headpiece contained a
radio transmitter, which sent the processor's data to the implant at roughly 1 megabit per second.
Sixteen electrodes curled up inside my cochlea strobed on and off to stimulate my auditory
nerves. The processor's software gave me eight channels of auditory resolution, each
representing a frequency range. The more channels the software delivers, the better the user can
distinguish between sounds of different pitches.
Eight channels isn't much compared with the capacity of a normal ear, which has the equivalent
of 3,500 channels. Still, eight works well enough for speech, which doesn't have much pitch
variation. Music is another story. The lowest of my eight channels captured everything from 250
hertz (about middle C on the piano) to 494 hertz (close to the B above middle C), making it
nearly impossible for me to distinguish among the 11 notes in that range. Every note that fell into
a particular channel sounded the same to me.
So in mid-2002, nine months after activation, I upgraded to a program called Hi-Res, which gave
me 16 channels - double the resolution! An audiologist plugged my processor into her laptop and
uploaded the new code. I suddenly had a better ear, without surgery. In theory, I would now be
able to distinguish among tones five notes apart instead of 11.
I eagerly plugged my Walkman into my processor and turned it on. Bolro did sound better. But
after a day or two, I realized that "better" still wasn't good enough. The improvement was small,
like being in that art gallery again and seeing only a gleam of pink here, a bit of blue there. I
wasn't hearing the Bolro I remembered.
At a cochlear implant conference in 2003, I heard Jay Rubinstein, a surgeon and researcher at the
University of Washington, say that it took at least 100 channels of auditory information to make
music pleasurable. My jaw dropped. No wonder. I wasn't even close.
A year later, I met Rubinstein at another conference, and he mentioned that there might be ways

to bring music back to me. He told me about something called stochastic resonance; studies
suggested that my music perception might be aided by deliberately adding noise to what I hear.
He took a moment to give me a lesson in neural physiology. After a neuron fires, it goes dormant
for a fraction of a second while it resets. During that phase, it misses any information that comes
along. When an electrode zaps thousands of neurons at once, it forces them all to go dormant,
making it impossible for them to receive pulses until they reset. That synchrony means I miss
bits and pieces of information.
Desynchronizing the neurons, Rubinstein explained, would guarantee that they're never all
dormant simultaneously. And the best way to get them out of sync is to beam random electrical
noise at them. A few months later, Rubinstein arranged a demonstration.
An audiologist at the University of Iowa working with Rubenstein handed me a processor loaded
with the stochastic-resonance software. The first thing I heard was a loud whoosh - the random
noise. It sounded like a cranked-up electric fan. But in about 30 seconds, the noise went away. I
was puzzled. "You've adapted to it," the technician told me. The nervous system can habituate to
any kind of everyday sound, but it adjusts especially quickly to noise with no variation.
Stochastic-resonance noise is so content-free that the brain tunes it out in seconds.
In theory, the noise would add just enough energy to incoming sound to make faint details
audible. In practice, everything I heard became rough and gritty. My own voice sounded vibrato,
mechanical, and husky - even a little querulous, as if I were perpetually whining.
We tried some quick tests to take my newly programmed ear out for a spin. It performed slightly
better in some ways, slightly worse in others - but there was no dramatic improvement. The
audiologist wasn't surprised. She told me that, in most cases, a test subject's brain will take weeks
or even months to make sense of the additional information. Furthermore, the settings she chose
were only an educated guess at what might work for my particular physiology. Everyone is
different. Finding the right setting is like fishing for one particular cod in the Atlantic.
The university loaned me the processor to test for a few months. As soon as I was back in the
hotel, I tried my preferred version of Bolro, a 1982 recording conducted by Charles Dutoit
with the Montral Symphony Orchestra. It sounded different, but not better. Sitting at my
keyboard, I sighed a little and tapped out an email thanking Rubinstein and encouraging him to
keep working on it.
Music depends on low frequencies for its richness and mellowness. The lowest-pitched string on
a guitar vibrates at 83 hertz, but my Hi-Res software, like the eight-channel model, bottoms out
at 250 hertz. I do hear something when I pluck a string, but it's not actually an 83-hertz sound.
Even though the string is vibrating at 83 times per second, portions of it are vibrating faster,
giving rise to higher-frequency notes called harmonics. The harmonics are what I hear.
The engineers haven't gone below 250 hertz because the world's low-pitched sounds - air
conditioners, engine rumbles - interfere with speech perception. Furthermore, increasing the total
frequency range means decreasing resolution, because each channel has to accommodate more
frequencies. Since speech perception has been the main goal during decades of research, the
engineers haven't given much thought to representing low frequencies. Until Philip Loizou came
along.
Loizou and his team of postdocs at the University of Texas at Dallas are trying to figure out ways

to give cochlear implant users access to more low frequencies. A week after my frustratingly
inconclusive encounter with stochastic resonance, I traveled to Dallas and asked Loizou why the
government would give him a grant to develop software that increases musical appreciation.
"Music lifts up people's spirits, helps them forget things," he told me in his mild Greek accent.
"The goal is to have the patient live a normal life, not to be deprived of anything."
Loizou is trying to negotiate a trade-off: narrowing low-frequency channels while widening
higher-frequency channels. But his theories only hinted at what specific configurations might
work best, so Loizou was systematically trying a range of settings to see which ones got the
better results.
The team's software ran only on a desktop computer, so on my visit to Dallas I had to be plugged
directly into the machine. After a round of testing, a postdoc assured me, they would
run Bolro through their software and pipe it into my processor via Windows Media Player.
I spent two and a half days hooked up to the computer, listening to endless sequences of tones none of it music - in a windowless cubicle. Which of two tones sounded lower? Which of two
versions of "Twinkle, Twinkle, Little Star" was more recognizable? Did this string of notes sound
like a march or a waltz? It was exacting, high-concentration work - like taking an eye exam that
lasted for two days. My responses produced reams of data that they would spend hours
analyzing.
Forty minutes before my cab back to the airport was due, we finished the last test and the
postdoc fired up the programs he needed to play Bolro. Some of the lower pitches I'd heard in
the previous two days had sounded rich and mellow, and I began thinking wistfully about those
bassoons and oboes. I felt a rising sense of anticipation and hope.
I waited while the postdoc tinkered with the computer. And waited. Then I noticed the frustrated
look of a man trying to get Windows to behave. "I do this all the time," he said, half to himself.
Windows Media Player wouldn't play the file.
I suggested rebooting and sampling Bolro through a microphone. But the postdoc told me he
couldn't do that in time for my plane. A later flight wasn't an option; I had to be back in the Bay
Area. I was crushed. I walked out of the building with my shoulders slumped. Scientifically, the
visit was a great success. But for me, it was a failure. On the flight home, I plugged myself into
my laptop and listened sadly to Bolrowith Hi-Res. It was like eating cardboard.
It's June 2005, a few weeks after my visit to Dallas, and I'm ready to try again. A team of
engineers at Advanced Bionics, one of three companies in the world that makes bionic ears, is
working on a new software algorithm for so-called virtual channels. I hop on a flight to their Los
Angeles headquarters, my CD player in hand.
My implant has 16 electrodes, but the virtual-channels software will make my hardware act like
there are actually 121. Manipulating the flow of electricity to target neurons between each
electrode creates the illusion of seven new electrodes between each actual pair, similar to the way
an audio engineer can make a sound appear to emanate from between two speakers. Jay
Rubinstein had told me two years ago that it would take at least 100 channels to create good
music perception. I'm about to find out if he's right.

I'm sitting across a desk from Gulam Emadi, an Advanced Bionics researcher. He and an
audiologist are about to fit me with the new software. Leo Litvak, who has spent three years
developing the program, comes in to say hello. He's one of those people of whom others often
say, "If Leo can't do it, it probably can't be done." And yet it would be hard to find a more modest
person. Were it not for his clothes, which mark him as an Orthodox Jew, he would simply
disappear in a roomful of people. Litvak tilts his head and smiles hello, shyly glances at Emadi's
laptop, and sidles out.
At this point, I'm rationing my emotions like Spock. Hi-Res was a disappointment. Stochastic
resonance remains a big if. The low-frequency experiment in Dallas was a bust. Emadi dinks
with his computer and hands me my processor with the new software in it. I plug it into myself,
plug my CD player into it, and press Play.
Bolro starts off softly and slowly, meandering like a breeze through the trees. Da-da-da-dum,
da-da-da-dum, dum-dum, da-da-da-dum. I close my eyes to focus, switching between Hi-Res
and the new software every 20 or 30 seconds by thumbing a blue dial on my processor.
My God, the oboes d'amore do sound richer and warmer. I let out a long, slow breath, coasting
down a river of sound, waiting for the soprano saxophones and the piccolos. They'll come in
around six minutes into the piece - and it's only then that I'll know if I've truly got it back.
As it turns out, I couldn't have chosen a better piece of music for testing new implant software.
Some biographers have suggested that Bolro's obsessive repetition is rooted in the
neurological problems Ravel had started to exhibit in 1927, a year before he composed the piece.
It's still up for debate whether he had early-onset Alzheimer's, a left-hemisphere brain lesion, or
something else.
But Bolro's obsessiveness, whatever its cause, is just right for my deafness. Over and over the
theme repeats, allowing me to listen for specific details in each cycle.
At 5:59, the soprano saxophones leap out bright and clear, arcing above the snare drum. I hold
my breath.
At 6:39, I hear the piccolos. For me, the stretch between 6:39 and 7:22 is the most Bolro of
Bolro, the part I wait for each time. I concentrate. It sounds right.
Hold on. Don't jump to conclusions. I backtrack to 5:59 and switch to Hi-Res. That heartstopping leap has become an asthmatic whine. I backtrack again and switch to the new software.
And there it is again, that exultant ascent. I can hear Bolro's force, its intensity and passion.
My chin starts to tremble.
I open my eyes, blinking back tears. "Congratulations," I say to Emadi. "You have done it." And
I reach across the desk with absurd formality and shake his hand.
There's more technical work to do, more progress to be made, but I'm completely shattered. I
keep zoning out and asking Emadi to repeat things. He passes me a box of tissues. I'm overtaken
by a vast sensation of surprise. I did it. For years I pestered researchers and asked questions.
Now I'm running 121 channels and I can hear music again.
That evening, in the airport, sitting numbly at the gate, I listen to Bolroagain. I'd never made it
through more than three or four minutes of the piece on Hi-Res before getting bored and turning

it off. Now, I listen to the end, following the narrative, hearing again its holy madness.
I pull out the Advanced Bionics T-shirt that the team gave me and dab at my eyes.
During the next few days I walk around in a haze of disbelief, listening to Bolro over and over
to prove to myself that I really am hearing it again. But Bolro is just one piece of music.
Jonathan Berger, head of Stanford's music department, tells me in an email, "There's not much of
interest in terms of structure - it's a continuous crescendo, no surprises, no subtle interplay
between development and contrast."
"In fact," he continues, "Ravel was not particularly happy that this study in orchestration became
his big hit. It pales in comparison to any of his other music in terms of sophistication, innovation,
grace, and depth."
So now it's time to try out music with sophistication, innovation, grace, and depth. But I don't
know where to begin. I need an expert with first-rate equipment, a huge music collection, and the
ability to pick just the right pieces for my newly reprogrammed ear. I put the question to
craigslist - "Looking for a music geek." Within hours, I hear from Tom Rettig, a San Francisco
music producer.
In his studio, Rettig plays me Ravel's String Quartet in F Major and Philip Glass' String Quartet
no. 5. I listen carefully, switching between the old software and the new. Both compositions
sound enormously better on 121 channels. But when Rettig plays music with vocals, I discover
that having 121 channels hasn't solved all my problems. While the crescendos in Dulce
Pontes' Cano do Mar sound louder and clearer, I hear only white noise when her voice
comes in. Rettig figures that relatively simple instrumentals are my best bet - pieces where the
instruments don't overlap too much - and that flutes and clarinets work well for me. Cavalcades
of brass tend to overwhelm me and confuse my ear.
And some music just leaves me cold: I can't even get through Kraftwerk's Tour de France. I
wave impatiently to Rettig to move on. (Later, a friend tells me it's not the software - Kraftwerk
is just dull. It makes me think that for the first time in my life I might be developing a taste in
music.)
Listening to Bolro more carefully in Rettig's studio reveals other bugs. The drums sound
squeaky - how can drums squeak? - and in the frenetic second half of the piece, I still have
trouble separating the instruments.
After I get over the initial awe of hearing music again, I discover that it's harder for me to
understand ordinary speech than it was before I went to virtual channels. I report this to
Advanced Bionics, and my complaint is met by a rueful shaking of heads. I'm not the first person
to say that, they tell me. The idea of virtual channels is a breakthrough, but the technology is still
in the early stages of development.
But I no longer doubt that incredible things can be done with that unused 90 percent of my
implant's hardware capacity. Tests conducted a month after my visit to Advanced Bionics show
that my ability to discriminate among notes has improved considerably. With Hi-Res, I was able
to identify notes only when they were at least 70 hertz apart. Now, I can hear notes that are only
30 hertz apart. It's like going from being able to tell the difference between red and blue to being
able to distinguish between aquamarine and cobalt.
My hearing is no longer limited by the physical circumstances of my body. While my friends'

ears will inevitably decline with age, mine will only get better.
Sound

disturbances of air molecules caused by vibrating objects.

Wavelength

Frequency

Hertz

the space or distance between the high points of two waves.

measurement of how fast or how often peaks of a wave go by a certain point.

the amount of peaks of waves that pass a point in one second.

Amplitude

the height of each wave and determines the loudness or volume of the sound and is measured in

Cochlea

a fluid-filled, snail-shaped organ that converts sound pressure into electrical impulses, which are p
nerve.

Sound
Pressure

the difference in pressure between the atmospheric air and the pressure caused by the sound wave

Ossicles

three tiny little bones, the hammer, anvil and stirrup, in the ear where vibrations from sound are tra

Hair

sound receptors for the brain and are a special kind of neuron named for the bundle of hair-like structu

Cells

cell.

Auditory
Nerve

receives the electrical signal from the hair cells and send the signal to the auditory cortex in your b

Auditory
Cortex

located on the temporal lobe and is the portion in your brain that processes the sound signals.

Tone Deafness
Autonomic
Nervous System
(ANS)

the inability to distinguish between musical notes.

part of the peripheral nervous system and is the reason why physiological change assoc
emotional response happens.

Peripheral
Nervous System

Sympathetic
System

connects your central nervous system to your limbs and organs.

also know as the "fight or flights" system and is dominant when you need immediate energy, s
emergency or stress. Controls heart rate, blood pressure, adrenaline, and blood flow to skeletal

Parasympathetic
System

Somatic
System

dominant when energy can be conserved and thus controls digestion, storage of nutrients,
rate, and decreasing respiration.

the part of the peripheral nervous system that controls voluntary responses.

Mechanosensory
Receptors

Nociceptors

monitor touch, vibration, pressure and tension of the skin.

specialized nerves which detect actual or potential tissue damage.

Smooth and Skeletal System

What makes us move? What moves our food?. Muscle! Mankind is ingenious in developing
their skeletal muscles for different functions. Occasionally, drugs are used to enhance skeletal
muscle which might adversely affect smooth muscle.

For you to be reading this page- requires skeletal muscle contraction. Your head must be pointed
towards the monitor, for some of you, your eyeballs will be moving to read the page, your back
muscles are contracting to maintain your posture, etc. There are a number of steps involved in
these complex activities. So let's start with where the signal originates. For you to get up and
leave this module, your brain initially decides on the action and directs various other parts of the
brain to coordinate this activity. The brain is like the foreman in that he send the command to
other sites. Ultimately, the signals will leave the brain and go to the spinal cord and from the
spinal cord to the muscle. This module will address the signal going from the spinal cord to the
muscle. Keep in mind that the term signal refers to an electrical event called an action potential
that travels from one neuron to another and ultimately ends up at the neuromuscular junction.
There is a major point that I want to emphasize. For muscle to contract it requires an electrical
signal to activate the chemical processes involved in contraction. Contraction ultimately involves
the movement of two proteins, actin, and myosin. This movement requires an energy source
which is ATP. From an overall perspective think of contraction as the following: Electrical
Signal that causes the release of a chemical that causes the actin and myosin to interact with each
to generate force. There are a number of steps involved in this process and scientists have spent
their life understanding and discovering the various chemicals involved. For you, keep in mind
the big picture and the following will make more sense.

Skeletal Muscle Anatomy

Movement is caused by protein interaction of actin and myosin. This sentence might
seemfunnyor hard for you to comprehend, but any kind of movement requires contractile
protein. To understand how we run, walk, laugh, we need to understand the anatomy and
physiology of skeletal muscle. As you study the information, keep in mind that what you are
learning are the names of different proteins that interact with each other to produce movement.
So how is the movement produced? In humans, the muscles attach to the bone or tissue and
attach to another site which could be a bone or tissue across a joint. Movement occurs when the
joint is moved. When the muscle contracts, it cause joint movement. We will not go into depth
about this point, but keep in mind that all that you learn in this module is really designed to move
a joint.
So what is the anatomy of the muscle?
Figure 4 shows you a muscle and how it is broken down into muscle fibers to a single muscle
fiber to a myofibril to a single sarcomere which is composed of different protein components of
which the two most important are myosin and actin. A sarcomere is defined as the segment
between two neighboring Z-lines. I-band is the zone of thin filaments that is not superimposed by
thick filaments. An A-band contains the entire length of a single thick filament. H-band is the
zone of the thick filaments that is not superimposed by the thin filaments. Finally, inside the Hzone is a thin m-line formed of cross-connecting elements of the cytoskeleton. So where does
actin and myosin fit into this picture? Actin filaments are the major component of the I-band and
extend into the A-band and they are crosslinked in the center by the M-band. Myosin filaments
are bipolar -meaning that have two heads (!) and extend throughout the A-band. They are cross
linked at the center by the M-band.The sliding filament theory is considered to be the best
explanation of muscle contraction. Simply stated- myosin connects to actin and moves by way of
attaching and detaching itself from actin. The collective bending of numerous myosin heads on
either side of the M line (all in the same direction), combine to move the actin filament relative
to the myosin filament. This results in muscle contraction and ultimately force. Imagine the
myosin fibers moving along the actin protein. These results are that the actin filaments are drawn
together. Thus, the end of the sarcomere are drawn together and you have a muscle contraction.
ATP is key to this entire process. Once myosin attaches to actin, what will cause its release so
that myosin can attach again to actin? ATP! ATP allows myosin to detach from actin and then
ATP is chemically broken into ADP and phosphate to re-energize the myosin head so that it can
re-attach to actin.
For skeletal muscles to contract, they require a signal from neurons in the spinal cord. Figure 5
demonstrates a key aspect of control of your muscles. The motor neuron activates a certain group
of muscle fibers. This is called a motor unit. Study Figure 5 and see that the neuron connects to
the skeletal muscle by way of unique junctions called neuromuscular junctions. These
neuromuscular junctions are the bridge between the neural control system and the skeletal
muscle. If the motor neuron does not generate an electrical signal to cause the muscle to contract,
the fibers will wither. In patients with no signals coming from the motor neuron, the muscles will
be very skinny. What is key towards understanding skeletal muscle contraction is that it is
controlled by neural signals. An electrical signal travels from the spinal cord to the skeletal

muscle and to its smaller component parts to make them contract. The name of the neuron in the
spinal cord that sends the action potential to the muscle is called the alpha motor neuron. This
neuron determines whether or not the motor unit that it innervates will contract. The neuron
communicates with the motor unit by way of the neuromuscular junction. The name makes great
sense. The action potential from the alpha motoneuron travels to the neuromuscular junction.
When the action potential reaches the junction, it causes the calcium ion to flow inward through
specific openings called calcium channels. These channels are activated by the action potential
which is nothing more than a traveling voltage signal. Hence these channels are called voltage
gated calcium channels which means that a voltage must open the channels for calcium to enter.
The calcium influx will causes vesicles located at the end of the alpha motor neuron to release
acetylcholine. In other words, the vesicles are like water balloons containing acetylcholine. The
calcium will cause the vesicle to bind to the alpha motor neuron causing a release of
acetylcholine. The water balloons burst and release their contents. This chemical is now between
the alpha motor neuron and the neuromuscular junction in a region called the cleft. Imagine that
you interlaced your fingers. The right hand fingers are the extensions of the alpha motor neuron
and the fingers from the left hand is the neuromuscular junction. The space between the fingers is
the space that acetylcholine is dumped from one neuron to another. Once acetylcholine is
released it will diffuse across the space to combine with a protein that is called the acetylcholine
receptor that is on the surface of the neuromuscular membrane. Once the acetylcholine attaches
to the acetylcholine receptor it causes a change in the membrane so that it causes sodium ion to
rush in triggering an action potential. Thus, we have had two action potentials. One coming from
the alpha motor neuron and the other on the neuromuscular junction. The action potential at the
neuromuscular junction now traverses the muscle fiber causing the T-Tubules to be depolarized.
Depolarization means that the positive and negative signals have reversed at the membrane. The
depolarization opens up another set of calcium channels which happen to be in close proximity
to the sarcoplasmic reticulum which have their own set of calcium release channels. Once the
voltage dependent calcium channels interact with the calcium release channels on the
sarcoplasmic reticulum, it releases calcium. The calcium from the sarcoplasmic reticulum binds
to a protein on the actin called troponin C which is on the thin filaments of the myofibrils.
Troponin is like a can opener. It now interacts with tropomyosin which normally does not allow
myosin to connect with actin and causes tropomyosin to move unlocking the blocking
sites.Subsequently myosin binds to actin and then it releases ADP and inorganic phosphate which
is associated with the power stroke of myosin. Myosin pulls itself along actin by way of the
power strokes. Finally, a new molecule of ATP unbinds the myosin from the actin so that
myosin can do another powerstroke.
Muscle generates force and to do that it contracts. Hence, the ultimate result of the muscle
function is to generate force. In an isotonic contraction, tension remains unchanged and the
muscle's length changes. Lifting an object at a constant speed is an example of isotonic
contractions. Weight lifting is a great example of isotonic contraction. There are two types of
isotonic contraction (1) concentric and (2) eccentric. In a concentric contraction, the muscle
tension increases to meet the resistance or load, then remains the same as the muscle shortens;
whereas in eccentric, the muscle lengthens due to the resistance being greater than the force the
muscle is producing. A biceps curl is an example of a concentric isotonic contraction, whereas
running downhill is an example of eccentric contraction of the leg muscles since the muscles are
being stretched while they are being contracted. When does this occur when you are running
downhill? When you are trying to stop from falling, the muscle is stretched while it is

contracting. This is the main explanation of the extreme muscle soreness experienced after
running downhill. A good way to remember what eccentric contraction is to imagine it being
used as a way to slow down the motion. Muscle injury, shakes, also called tremors, and soreness
are selectively associated with eccentric contraction. Muscle strengthening may be greatest
doing exercises that involve eccentric contractions. Isometric exercise or contraction involves a
static contraction of a muscle without any visible movement in the angle of the joint. A good
example of this kind of exercise would be arm wrestling in which the two opponents are
contracting their arm muscles but neither one is generating any movement. Image needed to
show force production.
Energy for Muscle contraction
This figure demonstrates the various ways that the muscle gets its energy. Notice that ATP is
what is being produced for muscle contraction that was discussed previously. The first source of
energy is creatine phosphate which donates a phosphate to reconstitute ADP to become ATP. The
second source is glycogen from your liver that is released and converted into glucose where it is
used in glycolysis to either produce energy directly or to be shunted to the oxidative
phosphorylation pathway. The third source of energy is Oxidative Phosphorylation in which
oxygen is needed to produce the most ATP. This is a critical step. Notice how proteins and fatty
acids can be converted into metabolites that feed into the oxidative phosphorylation pathway. A
couple of major points: for sprinters or those who generate a great amount of muscle force
quickly- glycolysis is the best way for them to generate energy. For marathon runners, oxidative
phosphorylation is the preferred method. When the muscle is no longer able to generate the
amount of force required- it is fatigued. This fatigue state is due to either a lack of glycogen or
glucose for sprinters or lack of oxygen for marathon runners. Notice in the diagram that Lactic
acid is produced by way of glycolysis and is considered by some to be the chemical cause of
fatigue. The data on lactic acid being the culprit that causes fatigue is not considered to be the
only cause of fatigue. Fortunes have been made on companies that have sold creatine to enhance
strength, oxygen delivery systems to be given to athletes to help minimize fatigue, and hot or
cold paths to minimize fatigue. None of these products have much scientific data to support their
claims. My favorite is oxygenated drinks. As you drink these solutions, the amount of oxygen in
your system is increased- according to the claim. Nothing could be further from the truth.
Humans do not get their oxygen from their stomach or gut. It is a great marketing gimmick to
sell oxygenated drinks but it is scientifically not possible to get oxygen from a drink into your
lungs or blood stream.
Smooth muscle in contrast to striated muscle is not striated, meaning that you do not see nice
lines in the cellular structure and it is not under voluntary control. A unique feature about smooth
muscle is that it is able to contract without any external electrical signal. It is by nature
twitchy. However, for the smooth muscle to work in a coordinated fashion it has neural
innervations. Thus, the spontaneous nature of the smooth muscle to contract is controlled by
neural innervation. Interestingly, this neural innervation is not voluntary. The nervous system that
controls smooth muscle is called the Autonomic Nervous System. Although much attention is
paid to the skeletal muscle, smooth muscle is in many ways just as important than striated
muscle. Smooth muscle is found:

1. Within the walls of blood vessels of large and small arteries and veins and is called vascular
smooth muscle. Smooth muscle controls the diameter or these vessels.
2. Lymphatic vessels which contract
3. In the urinary bladder where it plays a major role in contracting the bladder
4. In the uterus in which it contracts to expel the fetus
5. In male and female reproductive tracts in which it causes erection and ejaculation
6. In the gastrointestinal system in which is it the main explanation for peristalsis
7. In the respiratory tract in which it cause the bronchii to constrict
8. Arrector pili of skin in which it causesgoose bumpsand hair to stand up
9. In the pupil of the eye in which it causes the pupil to open or close
Stop for a minute.
Look at this list again. Smooth muscle is involved in digestion, reproduction, directing blood
flow throughout your body so when you exercise, the blood flows to your muscles and not to
your intestinal tract, etc. It is very important and usually never acknowledged much. Smooth
muscle is more difficult to study than skeletal muscle since the latter has a joint that moves and it
is therefore easier to study function. Smooth muscle does not move any joints and it can generate
force at different parts of the structure. Most smooth muscle is of the single-unit variety so that
the whole sheet of smooth muscle contracts or relaxes, but there is multiunit smooth muscle in
the trachea, the large elastic arteries, and the iris of the eye. Single unit smooth muscle, however,
is most common and lines blood vessels, the urinary tract, and the digestive tract.
There are two major divisions of smooth muscles: the single-unit (unitary) and multiunit smooth
muscle. Within single-unit smooth muscle tissues, the nervous system innervates a single cell
within a sheet or bundle and the action potential is propagated to neighboring cells such that the
whole bundle contracts as a single unit which is called a syncytium. Multiunit smooth muscle
tissues innervate individual cells, as such, they allow for fine control and gradual responses,
much like motor unit recruitment in skeletal muscle. As a reminder, the part of the nervous
system that controls smooth muscle is the Autonomic Nervous System.
Cardiac muscle is the last of the major muscle groups. We have discussed striated and smooth
and have saved the most important for last. The heart must continuously beat to propel blood into
the aorta to supply the entire body with oxygenated blood. The cell involved in this continuous
contraction is the cardiac muscle cell. It is an involuntary striated muscle cell found in the walls
of the heart, specifically the myocardium. Cardiac muscle is spontaneous active similar to
smooth muscle but it is also under the control of nervous systems. The Autonomic Nervous
System controls the heart rate and the strength of contraction of the cardiac muscle. The entire
muscle group acts together. If the cardiac muscle does not act together the consequences are
deadly since the heart cannot expel the blood to the rest of the body. This condition is called
fibrillation which means that the cardiac cells are acting individually rather than as a whole team.
Cardiac muscle exhibits cross striations formed by alternating segments of thick and thin protein
filaments composed of proteins, myosin, and actin respectively. The actin filaments are thin
causing the lighter appearance of the I bands in striated muscle, while the myosin filament is
thicker lending a darker appearance to the alternating A bands. Cardiac muscle cells may be
branched instead of linear and longitudinal as is seen in striated muscle. Another difference is

that there are fewer t-tubules in comparison with skeletal muscle. Probably the most important
anatomical development for cardiac muscle is that it contracts simultaneously. This function is
due to the intercalated discs which connect cardiac cells and allow for the rapid transmission of
electrical signals from one cell to another. The contraction of cardiac muscle has some aspects
similar to skeletal muscle in that calcium and ATP are involved in the joining of actin and myosin
and the generation of force. However the specifics are different since the cardiac cell must
contract continuously for your entire life.
One of the major concerns of the cardiac muscles is that there be sufficient amount of oxygen.
Without oxygen, the mitochondria in the cardiac cells cannot generate enough ATP to cause
contraction-hence the heart stops beating. Without oxygen, the cardiac cells stop contracting and
the person will be dead in 3-5 minutes depending on which part of the heart is affected. If there is
any blockade of oxygenated blood to the heart, that segment will have cell death. Cardiac tissue
receives its oxygen from the coronary arteries and the majority of ATP produced is by way of
oxidative phosphorylation. What is a tremendous backupsystem for cardiac cells is the
presence of special proteins called myoglobins which are oxygen-binding proteins. Myoglobins
are similar to the hemoglobin molecule and it releases oxygen when the concentration of oxygen
decreases.
As you study this section, you might wonder what are some of the differences between skeletal
and cardiac tissue. A major one deals with the duration of the contraction. Cardiac cells generate
force for a much longer period of time than do skeletal muscle.
This concludes this short presentation of different kinds of muscle. The one that you will spend
the most time with will be your skeletal muscle. Smooth muscle is the forgotten child of the
muscle groups unless you get sick and have stomach problems such as vomiting or diarrhea.
Most medications which are either solidly based on science or those that deal with scams are
associated with the gastrointestinal system. Both smooth muscle and skeletal muscle work
together. Do not think one works without the other. Finally, healthy cardiac muscle is key for
your survival. In most cases, the cardiac muscle is damaged due to alterations with its blood
supply and not with the muscle per se. Keep cardiac muscle happy by exercising daily. With the
advances in genetic medicine, many of the diseases of the muscle cell per se are being studied.
Stem cells, which we will be discussing later may also be a new medicine for addressing
various structural and molecular problems of muscle.
Rods and Cones

neurons that receive light waves in the eye. Rods perceive the intensity or th
of the light wave while cones perceive the frequency.

Primary Visual Cortex

responsible for processing information about static and moving objects and p
recognition.

Motor Cortex

the part of your brain that controls movement.

Premotor Cortex

responsible for planning and selecting the appropriate movements.

Primary Motor Cortex

responsible for the control and execution of voluntary movements.

Skeletal Muscle System

the system that connects your muscles that are under voluntary control to yo

nervous system.
Myofibrils

bundles of contractile unites that contain the machinery to contract the muscle

Sarcomeres

one contractile unit of the myofibrill that consists of thick and thin filaments.

Actin

a protein that composes the thin filaments of the sarcomere.

Myosin

a protein that compose the thick filaments of the sarcomere.

Myosin II

the protein responsible for movement of the skeletal muscles.

Mirror Neurons

signal equally when you watch someone do a particular task as they do when
actually perform the task yourself.

Amygdala

a structure in your temporal lobe that helps translate signals from sensory inputs to responses in y
autonomic nervous

The skeletal muscle cell is composed of myofibrils (1). Each myofibril is made up of many
repeating units of sarcomeres (2). Each sarcomere is made up of actin (thin) and myosin (thick)
filaments (3). One myosin unit is composed of 2 myosin proteins that form a "tail" and a "head"
(4). The head of the myosin unit contains the motor that drives the movement of the muscle.

Cardiovascular System
Exercise! It is good for you! The cardiovascular system is supposed to be the main focus of
exercise. However, good looks e.g. a thinner you- plays a close second.

Emergency Room
The patient is wheeled into the emergency room - a victim of an automobile accident. The
emergency room staff immediately slaps electrodes on his chest to measure his
electrocardiogram (ECG), check his pulse on his wrist and neck, and measure his blood pressure.
He is conscious and afraid. The staff tells him that he is okay - just a little shaken up and he has
some minor bruises. However, one of the nurses notices that his heart rate is very fast and the
ECG does not look normal. Are these signs just due to stress of the accident and pose no
immediate threat to the patient or are they predictors of a biological failure of the heart? Within
minutes of his reassurance, the patient feels a deep pressure on his chest and his ECG records no
electrical waves. His heart rate is not able to be detected. The emergency team scrambles to take
care of this heart failure.
The cardiovascular system is without doubt the major biological system in multicellular animals
since it is responsible for transferring oxygen to the mitochondria in all cells as well as the
nutrients needed by the cells to generate ATP. The blood also transfers the metabolic end
products such as carbon dioxide from the millions of cells and releases them into
the environment by way of kidneys or lungs in the case of humans.
Textbooks usually state that the major function of the cardiovascular system is to pump blood to
all cells. While that is correct, it is not its primary function. The primary function of the
cardiovascular system is to transfer oxygen to the cells by way of the blood. The various reflexes

that maintain the functionality of the cardiovascular system sense blood oxygen and carbon
dioxide levels as well as blood pressure and keep them at certain levels necessary for supporting
life. Overall, the circulatory system is a pressure generating system that controls the transfer of
oxygenated blood to all cells in your body. Blood flow follows the change in pressures produced
by the cardiovascular system. Blood flows from a higher pressure to a lower pressure.
Circulation Pattern: The Freeway - Designed to be in Parallel
The cardiovascular system has a circulation pattern that is a masterpiece of engineering. It is
designed to ensure that all cells receive the mitochondria supporting oxygen. The circulation
pattern is arranged in parallel so that in the event that there is a decrease in blood to certain
organs, there can be an instantaneous redirection of blood to the major organs. For example,
freeways are also designed with parallel systems. If there is a major accident on the freeway and
all roads were in series, one leading to another, there would be no way for you to leave the traffic
blocked freeway. However, if there is a side road that runs parallel to the freeway, you can use it
if the major freeway is blocked. In the same way, the circulation system is designed. The arteries
supply all organs in a parallel fashion. Thus the blood supply to the brain does not depend on the
blood coming from the legs first. Even if blood supply to the legs is compromised blood will
continue to flow into the brain (Figure 1).
Blood Vessels: More than Collapsing and Expanding Pipes Chemical Factories
Blood vessels are presented as pipe-like structures that carry blood to and from the heart or
organs. They are much more than that. The blood vessels are composed of three major types:
arteries, capillaries, and veins. The capillaries are the main component of the cardiovascular
system that join the arterial and venous sides. In addition, the capillaries have the largest surface
area of the cardiovascular system relative to arteries and veins. The function of the capillaries
will be discussed in greater detail in another module, but even in this first discussion of the
cardiovascular system, this essential component needs to be emphasized. The capillaries are
responsible for the transfer of oxygen and nutrients to the cells and the transfer of metabolic
wastes.
The cells produce metabolic waste products, but these should not be considered to be poisons as
is frequently mentioned in advertisements for pseudo-medications to get rid of "metabolic
poisons." If we did produce metabolic poisons, we would not be living.
The anatomy of the blood vessels has to be understood in the context of their function. The
arteries receive the major pressure from the heart as it pumps the blood for all cells in the body.
The heart is a pressure generator and the arteries are superbly designed to handle the jolt of the
pressure wave of the blood as it surges out from the heart. Thus, the arteries tend to be thick
walls composed of smooth muscle which is innervated by nerves from the autonomic nervous
system. These nerves control the diameter of the arteries so as to expand or constrict depending
on the situation as well as to direct the blood flow.
The arteries become progressively smaller as they reach the cells going from arteries, arterioles,
and finally to metarterioles. At the metarterioles, there is a precapillary sphincter that controls the

blood flow into the capillary bed. The precapillary sphincter acts like a gate. When closed, the
blood is directed elsewhere. The sphincter is made up of smooth muscle and is controlled by the
autonomic nervous system. Figure 2 shows the different types of blood vessels.
The capillaries are single-celled tubes that have no smooth muscle. There are different types of
capillaries that are mentioned in a different module, but they have pores that allow nutrients to
leave and metabolic end products to enter. They are just passive tubes, but still can effect blood
flow. The capillaries are lined with a cell called an endothelial cell. They can release chemicals to
influence blood flow.
The veins are usually considered the stepchild of the cardiovascular system. No one pays too
much attention to them. However, they have most of the blood volume of the body (Figure 3).
The arterial system is usually characterized as carrying oxygenated blood and the venous system
as carrying deoxygenated blood. The idea that the venous blood is completely deoxygenated is
not correct. Not all of the oxygen is used when the capillary blood enters the venous system. The
blood is only partially deoxygenated - allowing for a safety factor. Think about this, if all the
arterial blood was deoxygenated during one cycle of blood flow, there would be no way to
support cells if something interfered with the transfer of oxygen into the lungs, or a hemorrhage
etc. Thus, even if all oxygen entering your lungs is shut off, you still have 3-5 minutes of
oxygenated blood before you have to get oxygen. Why? The blood is not completely
deoxygenated while it travels from the heart, supplies organs with oxygen, and then returns to the
heart.
The Heart: Heart Mechanics - The Pressure Generating Pump
The heart is a pressure generator. When the cardiac cells contract, e.g. systole, they generate a
specific sequence of pressures that move the blood from one chamber of the heart to another,
from one organ to another, and back to itself. The generation of the pressure is precisely
controlled by inherent properties of the cardiac muscle, nervous innervation, and hormones.
Most students believe that the heart is a pump but do not realize that this pump, like all pumps,
generates a pressure. Hence the clinical reason for recording blood pressure is so important. It
gives an overall idea of the health of the heart as well as the blood vessels.
Pressure Generation in the Heart: Cardiac Cells
Although the cardiac muscle cells that make up each chamber of the heart can contract
independently, in real life, they are controlled by various factors so that they contract together.
When the cardiac cells contract independently, they no longer generate pressure and circulation
fails. The cells must work like a person making and relaxing her fist around a water filled
balloon. As you make a fist, you generate pressure inside the balloon. You make enough pressure
and eventually, the balloon will explode. Consider each finger is a cardiac cell. When one finger
is no longer able to contract and relax, the fist cannot generate enough pressure. Transferring this
analogy to your heart, each finger is thousands of cardiac muscle cells. They contract and
generate a pressure inside their chamber which when it gets high enough, will send the blood
into the next chamber, the lungs or into the body.
Keep in mind that the blood flow will follow the pressure difference. Blood will flow from high

pressure to low pressure. Thus for blood to go from chamber A to chamber B, the pressure must
be greater in chamber A. If chamber B has a higher pressure for whatever reason, fluid will not
flow into B. The cardiovascular system follows this fundamental law of physics.
Pressure Generation in Heart Chambers
The heart is usually presented from a chamber point of view. (Figure 4) It has four chambers that
sequentially generate pressure. However for this pressure to be generated in chambers, each
chamber must be closed off temporarily from the others. Consider the water balloon. If you put
water into a balloon and squeezed it without closing off its opening, you would never get
pressure in the balloon.
Blood Flow: Path in the Heart, Lungs, Body - Due to Pressure (Fig. 5)
1. Right Atrium to the Right Ventricle
The right atrium receives venous blood from the entire body. When I state the entire body, I
mean the entire body. The blood from your toes, intestines, brain all return to the right atrium.
The blood vessels that return venous blood to the right side of the heart are the superior and
inferior vena cava. In addition, the venous blood from the heart returns to the right atrium as well
by way of the coronary sinus. The blood vessels return blood to the right atrium which generates
a force to propel it into the right ventricle. The pressure must be high enough to open the valve
between the right atrium and ventricle. Once this pressure is exceeded, the tricuspid valve (also
known as the right atrioventricular valve) opens and the blood rushes into the right ventricle.
2. Right Ventricle to the Lungs by way of the Pulmonary Artery
The right ventricle receives the blood from the right atrium and generates enough pressure to
send it to the lungs by way of the pulmonary arteries. The critical function for the right ventricles
is to send enough blood into the lungs so that it can be oxygenated. If the pressure increases in
the lungs for any reason, the partially deoxygenated blood will not flow into the lungs. The
partially deoxygenated blood in the lungs must be oxygenated to return to the rest of the body.
Thus the blood must leave the right ventricle through the pulmonary artery into the vast expanse
of the pulmonary circulation to get oxygenated. The pulmonary capillary bed is essential for reoxygenating the venous blood simultaneously by being an avenue for the escape of carbon
dioxide.
3 . Pulmonary Veins to the Left Atrium
Four pulmonary veins, two from the right lung and two for the left lung, send oxygenated blood
into the left atrium.
4. Left Atrium to the Left Ventricle
The oxygenated blood from the lungs is now in the left atrium from where it now flows into the
left ventricle which is the largest and strongest of the cardiac chambers. The valve between the
left atrium and the left ventricle is the bicuspid or mitral valve which opens during left atrial
systole.
5. Left Ventricle to Aorta
The real workhorse of the heart is the left ventricle since it generates enough pressure in
conjunction with the arteries to send blood to all parts of your body. To accomplish this goal, the

left ventricle must be large enough and strong enough to generate these pressures. Although each
chamber of the heart generates pressure to drive the blood, the left ventricle is most important. If
it fails to generate enough pressure, all organ systems will fail due to lack of oxygen reaching
them. The aortic valve must open for the blood to leave the left ventricle and enter the aorta.
6. Aorta to the Heart and then to Rest of the Body
The aorta is a special artery. All oxygenated blood that supplies all organs passes through it. No
exceptions. Another point that is often overlooked is that at the base of the aorta are the first two
arteries. They go immediately back to the oxygen demanding cardiac muscles. These are the
coronary arteries. Many students think that the first arteries that project off the aorta go to the
brain. Nothing could be further from the truth. The heart must receive the oxygenated blood first
to feed the mitochondria in the cardiac cells. If the heart does not contract, there is no pressure
generation and no oxygen rich blood to supply all your organs. The right coronary artery supplies
the right atrium, right ventricle, and parts of the left ventricle whereas the left coronary supplies
most of the left ventricle.
Note: As the pressure generating cycles were presented, it seems as if the pressure goes in
sequence from the right atrium to right ventricle, right ventricle to lungs, etc. In the real world
this is not the case. The two atria are contracting simultaneously, so blood is going into the two
ventricles at the same time. The two ventricles are also contracting at the same time: one sending
the blood into the vast expanse of the lung and the other sending blood throughout your heart and
the rest of your body. It only makes sense that this is how the heart has to work. If the heart
worked in sequence, literally going from the right atrium to right ventricle etc.. there would be
no way to get blood in a fast efficient manner to all parts of the body.
AV Valves
There are two sets of valves that control the flow of blood from one set of chambers to the other.
The atrioventricular valves (AV) separate the atrium from the ventricles. The right AV valve is
called the tricuspid valve and the left AV valve is called the bicuspid or mitral valve.
Semilunar valves
The semilunar valves connect the right atrium with the pulmonary circulation and is
appropriately called the pulmonary valve. The valve that connects the left ventricle with the aorta
is called the aortic valve. Thus as blood is propelled out of the left ventricle, it is not propelled
back in! It is on its way through the aorta.
Murmur - "What did You Say?"
The valves play a major role in directing the flow of blood from one set of chambers to another.
The AV valves are anchored in the ventricles by small strands of tissue called chordae tendinaea.
They look like strings, but they are attached to muscle at their base called papillary muscle.
When the papillary muscle contracts, it causes the valves to move into the ventricles.
However, these papillary muscles only contract during systole (cardiac muscle contraction) when
the greatest pressure is being generated. Thus, the papillary muscle contraction stops the blood in

the ventricle to flow back into the atrium. If for any reason, the valves are not working properly
when the ventricles contract, some of the blood returns into the atrium causing a sound similar to
a murmur. The semilunar valves are designed to withstand a greater amount of pressure and are
shorter and thicker than the AV valves. They also do not have chordae tendinaea.
Control of Pressure Generation
Control of cardiac cell pressure generation has three levels of control: cellular level, intrinsic
nerve level, and extrinsic nerve level. The cardiac cells can contract individually. However, for
pressure to be generated, a group of cells must contract together. To coordinate this activity the
pacemaker (or intrinsic) system of the heart sets a rhythm for cell contraction. This system is
composed of cardiac cells that are specialized to cause a group of cells to fire. In addition to the
pacemaker cells of the heart, there is an external neural control. When you get excited and heart
rate increases, a part of the peripheral nervous system which is called the autonomic nervous
system will direct the firing of the pacemakers.
Pacemaker Cells of the Heart- Pressure Generation
The contraction of all cardiac cells is controlled by the inherent electrical system of the heart.
The pathway is critical so that the atria contract first followed by the ventricles. To accomplish
this act of coordination various specialized muscle cells called pacemakers have to excite certain
heart cells. For cardiac cells to contract, there is a change in its electrical signal. The term
"depolarization" refers to the change in the polarity of the electrical signal. The signal changes
from a negative to a plus value. The heart is composed of pacemaker cells called nodes and
cardiac cells. The nodes are similar to a coach and the cells a player. The nodes send an electrical
signal to the cells which then contract. The nodes fire electricity first and send the signal to the
cardiac cells. The cardiac cells will depolarize and then contract in unison (i.e. altogether). The
Sinoatrial (SA) node is depolarized first and it then sends a signal to the atrioventricular node
which transmits the signal to the Purkinje fiber that innervate the ventricles number. After each
depolarization, the cardiac muscle contracts. Thus, after the SA node fires, both atria contract
followed by an electrical firing of the AV node to the bundle of His leading to firing of the
Purkinje bundle resulting in the ventricles contracting (Figure 6).
After the atria and ventricles contract, they produce characteristic electrical waveforms that
travel throughout the body called the electrocardiogram (ECG). It is important to emphasize that
the ECG comes after the specific cardiac muscle group contraction and not before. The various
phases of the ECG represent the sequence of contraction of the various chambers of the heart.
These electrical signals travel throughout the body and are recorded by a group of electrodes
placed on the body. The electrodes, called leads, carry the signal to a recording system which is
then read by nurses, physicians, and even relatives (Figure 7).
In theory, the electrocardiogram can be detected anywhere on the body. By convention, certain
body sites and lead configurations are used to analyze the electrical signals produced by the heart
(Figure 8).
Recall the pathways that the blood flows in the heart. The chambers must contract first and then
generate the pressure. However, it is clinically very difficult to measure the pressures in the
chambers of the heart. Consequently, the ECG is used as an indirect measure of the pressure

generation in the heart. If the ECG is not normal, this would indicate that the chambers are not
contracting and as a consequence pressure generation in various chambers is not being generated.
The result will be that blood flow will be halted. If there is not sufficient blood flow, the primary
organ affected will be the heart.

Timing of the ECG

1) The P wave represent the wave of atrial depolarization that spreads from the SinoAtrial node
and it is usually 80-100 ms in duration. 2) After the P wave, there is a very brief baseline signal
followed by the QRS complex which represents ventricular depolarization. The time from the
onset of the P wave to the beginning of the QRS complex is called the PR interval and its time
ranges from .12 to .20 seconds. This time represents the depolarization of the atria to the time for
ventricular depolarization. If the PR interval is greater than 0.2 sec, there is a block in the atria to
ventricular systems. It is termed the AV conduction block (Figure 9).
The QRS complex represents ventricular depolarization which is usually 0.06 to 0.1 sec in
duration suggesting that this depolarization occurs very fast. If the QRS complex is longer than
0.1 second, it indicates that there is a problem with the conduction in the ventricles.
The ST segment represents the time in which the entire ventricle is depolarized.
The T wave represents ventricular repolarization and is longer in duration than ventricular
depolarization.
Remember the Coronary Arteries? Life and Death
Arterial supply to the cardiac muscles is by way of the coronary arteries that are the first set of
arteries that leave the aorta. The coronary arteries are essential for the functioning of the cardiac
muscle as well as the pacemakers of the heart. The coronary arteries are compressed during
systole or muscle contraction while during diastole or cardiac muscle relaxation, blood flows
through the cardiac muscle capillaries. Thus, it is when the heart is relaxing that it receives the
blood. The right coronary artery supplies a major part of the SA and AV nodes, part of the bundle
of His and left bundle branch whereas the left coronary artery supplies the right bundle branch as
well and the left bundle branch.
The Cardiac Muscle of the Heart
Cardiac muscle fibers are long branching cells that combine at a specialized cell junction called
the intercalated disks. The intercalated disks act as electrical connections allowing all muscle
cells to contract simultaneously. This feature allows atrial or ventricular cells to contract
simultaneously. The anatomical and physiological union of cardiac cells is called a syncytium.
Consider it like a team that works together. The heart has two syncitia: the atrial and ventricular
teams. Each syncytium has the right and left atrial syncitia and the right and left ventricular
syncitia. It is the control of these syncitia by the pacemaker cells that controls their activity.
The cardiac muscle cells have a large number of mitochondria which produce the ATP needed for
contraction. A decrease in oxygen associated with blockage to one of the coronary arteries will

result in a decrease in ATP which leads to a decrease in cardiac cell contraction and pressure
generation. A decrease in pressure leads to a change in the pressure profile so that blood does not
flow into the chambers, the lungs, etc., resulting in loss of ATP throughout the body. The nodes
that control the contraction of the atria and ventricles also depend on ATP. A decrease in blood
flow or oxygen to the nodes will cause them to not fire.

Back to the ER Room - CPR - Once You Start, Do not Stop

The patient demonstrated a clinical change in his ECG (Figure 10). This ECG signal is called
ventricular fibrillation. The cardiac muscle cells are no longer contracting in unison, but they are
individually contracting resulting in a significant decrease in pressure generation in the ventricle.
This is extremely life threatening.
Cardiopulmonary resuscitation (CPR) refers to the actions, the team must take to preserve the
heart and the patient (Figure 11). Pushing on the chest is similar to the ventricles generating
pressure to propel the blood to the lungs. Breathing into the patient is a replacement for normal
breathing. Hence the rescue team is generating the pressure in the heart and oxygenating the
partially deoxygenated blood. Time is of the essence. Although any chamber of the heart can
have a decrease in blood flow, the major chamber that must continue to work is the left ventricle.
Due to damage to the pacemaker system or to the cardiac muscle itself, the ventricular cells will
contract independently of each other. This leads to a condition called ventricular fibrillation. In
addition to CPR, the team will be injecting various drugs to stimulate the heart to contract. There
is a misconception that a person should initiate CPR if the patient is not breathing. This
misconception is wrong, you must initiate CPR if the patient's heart has stopped and is no longer
beating.
In the worst of conditions, when CPR does not work, electrically shocking the cardiac muscle
sometimes is able to reverse the electrical chaos that is sweeping the cardiac muscle and it is
reset. The ECG is the major indicator of ventricular fibrillation. The heart rate is extremely fast
(300-600 bts/sec) all forms of a normal ECG are absent and there is a wave-like signal that is
recorded. Unlike most of representations in television, in which the ECG is a straight line, a
more common lethal ECG is ventricular fibrillation. This condition must be reversed within
minutes otherwise there is irreversible damage to the cardiac muscle.
One Final Point
Always call 911 first before you start to do any CPR and once the rescue team initiates CPR, it
cannot stop until the ECG signals return to normal. If CPR is started and stopped, it will cause
massive damage to the cells leading to almost certain irreparable damage especially to the
oxygen demanding organs, such as the heart, brain, kidneys, and intestinal tract.
Cardiovascular System
(AKA Circulatory System)

The bodily system consisting of the heart, blood vessels, and blood that circu
blood throughout the body, delivers nutrients and other essential materials to
and removes waste products.

Capillaries

The main component of the cardiovascular system that bind the arterial and v
sides. It is responsible for the transfer of oxygen and nutrients to the cells and
transfer of metabolic wastes.

Metarterioles

Any of the small peripheral blood vessels that are structurally and anatomical
intermediate between the arterioles and the true capillaries and that contain sc
groups of smooth muscle fibers in their walls.

Sphincter

A circular band of voluntary or involuntary muscle that encircles an orifice of

body or one of its hollow organs.

Veins

Any of the blood vessels that carry blood toward the heart from the body's ce
tissues, and organs. Veins are thin-walled and contain valves that prevent the
backflow of blood. All veins except the pulmonary vein carry blood with low
of oxygen.

Arterial System

Canals that carry oxygenated blood.

Atrioventricular Valves (AV)

Two valves that ensure blood flows from the atria to the ventricles, and not th
way.

Tricuspid Valve

The right AV valve; receives venous blood from the entire body.

Bicuspid Valve
(AKA Mitral Valve)

The left AV valve; regulates blood flow between the left atrium and left ventr

Semilunar Valves

Either of two valves, one in the aorta and one in the pulmonary artery, consist
set of three crescent shaped flaps of tissue and serving to prevent blood from
back into the heart after contraction.

Pulmonary Valve

A semilunar valve between the pulmonary artery and the right ventricle of the
that prevents the blood from flowing back into the right ventricle.

Aortic Valve

A semilunar valve between the aorta and the left ventricle of the heart that pre
the blood from flowing back into the left ventricle.

Chordae Tendinaea

Any of the tendons extending from the papillary muscles to the atrioventricul
valves and preventing the valves from moving into the atria during ventricula
contraction.

Papillary Muscle

One of the small bundles of muscles attached to the ventricle walls and to the
chordae tendinaea that tighten these tendons during ventricular contraction.

Systole

The normal rhythmical contraction of the heart, during which the blood in the
chambers is forced onward.

Inferior Vena Cava

Conveys blood from all parts below the diaphragm.

Superior Vena Cava

Either of two large veins discharging blood into the right atrium of the heart;
blood from the head, chest, and upper extremities.

Coronary Sinus

A large venous channel in the heart wall that receives blood via the coronary
and empties into the right atrium.

Aorta

The main trunk of the arterial system, conveying blood from the left ventricle
heart to all of the body except the lungs.

Coronary Arteries

The two arteries that supply blood to the heart tissue.

Electrocardiogram (ECG)

A graphic recording of the electrical activity of the heart, used to evaluate car
function and to diagnose arrhythmias and other disorders.

Ventricular Depolarization

When the ventricle contracts (systole), pushing blood into the aorta, and the a
repolarized. Finally, the ventricles repolarize, during which time the atrium re
and refills.

AV Conduction Block

If the PR interval is greater than 0.2 sec, there is a block in the atria to ventric
systems.

QRS Complex

Represents ventricular depolarization which is usually 0.06 to 0.1 sec in durat

suggesting that this depolarization occurs very fast.

ST Segment

Represents the time in which the entire ventricle is depolarized.

T wave

Represents ventricular repolarization and is longer in duration than ventricula

depolarization.

Syncytium

The anatomical and physiological union of cardiac cells. Consider it like a tea
works together. The heart has two syncitia: the atrial and ventricular teams.

Ventricular Fibrillation

An often fatal form of arrhythmia characterized by rapid, irregular fibrillar tw

of the ventricles of the heart in place of normal contractions, resulting in a los
pulse.

Cardiopulmonary
Resuscitation (CPR)

Emergency procedure for reviving heart and lung function, involving special
physical techniques and often the use of electrical and mechanical equipment

Blood Pressure Control

Rage! Fear! Suprise! All these emotions share a common feature- Autonomic Nervous System
activation causes the blood vessels to vasoconstrict resulting in an increase in blood pressure. If
the pressure becomes too high, it will cause blood vessels to rupture. So- be Cool !

Systolic and Diastolic Pressures

We have discussed the basic design of the cardiovascular system and that its major function is to
generate pressures. This module will discuss the pressure generating characteristics of the
cardiovascular system.
Before the left ventricle ejects blood into the coronary arteries and the aorta, the pressure rises.
The pressure generated before the actual ejection is called the systolic pressure. After systole, the
pressure in the chamber decreases as the left ventricle relaxes. The lowest pressure in the left

ventricle before the ventricle begins to contract is called the diastolic pressure (Figure 1).
In clinical practice, the patient is evaluated based on both the systolic and diastolic pressures.
The values are presented as Systolic/Diastolic in terms of mm of Hg (millimeter of Mercury)
pressure. Normal systolic pressure is 120 whereas diastolic is 80. Thus the designation would be
120/80 mm/Hg. Most importantly, it is the difference between systolic and diastolic pressure that
determines blood flow. This value is called the pulse pressure referring to the net pressure
generated with each pulse or cardiac contraction that propels the blood throughout the body.
However, pulse pressure is determined by two other factors. 1. As the blood is ejected from the
left ventricle it pushes against the aorta. Subsequently, the aorta expands followed by a
compression. This compression is due to the elastic fibers in the aorta. Thus the aorta balloons
out and then returns to its normal circumference. The expansion of the aorta is called
compliance. Imagine a water hose that has very elastic walls. As the water enters the hose, the
elastic material of the hose will expand and then contract. This hose would have high
compliance.
If, on the other hand, the hose had hardly any elastic material, when water enters the hose, the
hose would not stretch. This kind of hose has low compliance. The aorta has the highest
compliance because it has the greatest amount of elastic tissue fibers. The consequence of aortic
compliance is that it minimizes a large pressure difference being transmitted throughout the
body. As the aorta compresses the blood volume, it neutralizes the systolic and diastolic pressure
differences. 2. The other factor that influences pulse pressure is the amount of blood ejected per
heart contraction. This is called stroke volume. Pulse pressure is directly related to stroke volume
and indirectly to compliance (Figure 2).
The characteristic that is most important to meet the energy demands of the cell is the amount of
blood that leaves the heart to supply the metabolic demands of the body. This value is called the
cardiac output and is determined by the heart rate and the stroke volume.
CO=SV x HR
The heart rate is determined by neural and endocrine factors. The sympathetic nervous system
causes an increase in heart rate (tachycardia) but no change in coronary artery diameter. The
coronary arteries must not constrict as heart rate increases, otherwise, the amount of blood will
decrease resulting in less oxygen getting to the cardiac cells. Although the coronary arteries do
not constrict, other arterial beds constrict with increased sympathetic activity. The blood vessels
that supply the skin and intestinal tract will constrict (e.g. their diameter will decrease) thereby
directing more blood to the skeletal muscle. The parasympathetic nervous system causes a
decrease in heart rate and has no effect on any vascular system. Hormones such as
catecholamines and vasopressin, alter cardiac function and pressure profiles. Heart rate values
ranges from 80-100 beats per minute.
Stroke volume is determined by three factors: preload, afterload, and contractility in the
ventricle. Preload refers to the volume of blood in the ventricle before contraction, afterload
refers to the pressure against which the ventricle muscle must contract. Contractility refers to the
strength of contraction of the cardiac muscle.

Preload refers to the fact that the more the cardiac muscle is stretched, the greater its contraction.
Thus, if there is a large amount of blood in the ventricle, the muscle will stretch more and
contraction will be stronger. Conversely, if you lose a large amount of blood, the amount of
blood available for ejection is less in the heart resulting in less strong contractions.
As you exercise, and more venous blood is returning to your heart, this increased volume will
increase the strength of contraction. In real life situations, when people lose blood, one of the
main reasons for putting fluid into the patient is to increase the strength of cardiac contraction.
Preload is determined by the amount of blood that enters the right atrium (Figure 3).
Afterload is related to the pressure that ventricle blood faces before ejection. This occurs at two
sites. The right ventricle must generate enough pressure to overcome the pressure in the
pulmonary circulation which is called the pulmonary artery pressure. The left ventricle must over
come the pressure in the aorta which is called aortic pressure. For instance: if the pressure in the
lungs increases, then the blood in the right ventricle cannot enter the lungs and will not be
oxygenated. In the same manner, if the pressure in the aorta is higher than that in the left
ventricle, no oxygenated blood will leave the left ventricle resulting in a loss of oxygenated
blood to the body.
Contractility is the force that muscles generate at a given muscle length. Another name for
contractility is inotropism. A drug that increases the contractility of the cardiac muscle is called a
positive inotrope.
Control of Blood Pressure - Pressure Reflexes: Carotid and Aortic Baroreceptors
Control of blood pressure is regulated by various positive and negative feedback loops controlled
by the nervous system. The blood pressure to the brain must be tightly controlled and as such
there are pressure receptors called baroreceptors in the carotid arteries that supply the brain. If
the pressure in the carotid arteries becomes too great, the blood vessels expand, the receptors
sense the expansion, and send signals to the Parasympathetic Nervous system to decrease blood
pressure by way of decreasing heart rate and vasodilating blood vessels. Conversely if the
pressure in the carotids is too low, the receptors will decrease their firing which will influence
the Sympathetic Nervous system to increase blood pressure again by way of heart and blood
vessels. There are also receptors in the Aorta, specifically the Aorta branch that also function
similar to the carotid sinus receptors. However, the carotid sinus receptors are more sensitive.
Both sets of receptors can have their sensitivity changed depending on the history of the blood
pressure profile. For example, hypertension can decrease the sensitivity of the carotid and aortic
receptors.
Baroreceptors are remarkable in that they sense a change in blood pressure not just the final
value. This sensitivity allows the receptors to respond very fast to subtle changes in blood
pressure. The changes that are produced by these receptors is mediated by a special group of
neurons in the medulla of the brain. This part of the brain stem controls the cardiovascular
responses to signals from the carotid and aortic baroreceptors. For example, as the pressure
decreases in the patient in the ER room, the pressure reflexes relay this decrease to the Medulla
which causes an inhibition of the parasympathetic nervous system and an excitation of the
sympathetic nervous system. The sympathetic nervous system will cause a vasoconstriction so

that there will be a greater systolic pressure, an increased in heart rate, and stronger cardiac
muscle contraction.
Blood pressure = Cardiac output x peripheral resistance (BP=CO x PR)
Why is Hypertension So Dangerous? Why Do Obese People have High Blood Pressure?
Hypertension (HTN) is defined as an elevated diastolic pressure and/or systolic pressure. HTN
can kill two different ways: 1. if there is not a great difference between systolic and diastolic
pressure, there is no flow or 2. the high pressure causes damage to blood vessels leading to
hemorrhage. The diastolic pressure is considered to be the most important since the higher its
value, the less mean arterial pressure. In the majority of patients (95%) the cause of HTN is
unknown and is therefore called essential HTN. If the HTN is due to renal or endocrine
disorders, it is called secondary HTN since it is the result of a disease. This kind of HTN
accounts for only 5-10% of all cases.
The treatment of primary (or essential HTN) is to decrease the amount of pressure generated by
the heart. Since cardiac contractility is associated with preload, to decrease the venous volume
has some merit. The more fluid entering the heart will cause the heart to beat stronger. Thus
drugs that cause patients to lose fluids such as diuretics are very effective in treating the HTN.
Instead of focusing on the heart, the other approach is to decrease the resistance of the systemic
circulation by way of vasodilator drugs. As the blood vessels vasodilate, they will not generate as
much pressure. Vasodilation medication has to be carefully monitored since too much can cause
the patient to faint easily. In summary, to decrease HTN from a cardiac output point of view,
reduce blood volume, reduce heart rate, and reduce stroke volume, or reduce systemic vascular
resistance by dilating the blood vessels.
HTN is the major cause of 50% of the cases of stroke, dementia, heart attacks, and heart failure.
It is defined as a systolic value of 140- 159 or a diastolic ranging from 90-99. A more dangerous
stage of HTN is with systolic being 160mm or higher and diastolic as 100 mm or more. 25% of
the population suffers from HTN. The lethality of HTN is that the extreme pressures will
eventually wear away the arterial response to this constant bombardment of pressure leading to
blood vessels springing a leak or in the case of the heart, presenting a huge afterload that
weakens cardiac muscle over time leading to heart failure.
Hypotension
As important as hypertension is, it is not usually acutely life threatening as is hypotension. In the
case of hypotension, there is not enough of a pressure differential between systolic and diastolic
pressures consequently leading to low blood flow. Hypotension is referred to a systolic pressure
of 90 mmHg and a diastolic of 60 mm Hg (Figure 4). There are some individuals who basically
have a low systolic and diastolic, but in clinical cases of hypotension, it is clear that the persons
are sick. The causes of hypotension are:
1. A decrease in blood volume due to blood loss or dehydration. The result of the decrease in
blood volume is a decrease in blood returning to the right side of the heart resulting in a low
cardiac output. In other words, preload is decreased.

2. The cardiac output is decreased due to an inability of heart muscles to generate enough
pressure. The pathology can be due to either acute or chronic heart failure or arrhythmias. If the
condition is due to failure of the cardiac cells it is called cardiogenic shock. If for some reason,
the AV node does not fire, it is called AV nodal block. This block maybe due to coronary artery
occlusion since the coronary arteries supply the pacemaker system of the heart.
3. A massive vasodilation that reduces the amount of blood that returns to the right side of the
heart. Either drugs or some form of bacterial infection can lead to this vasodilation. Again, there
is a decrease in blood flow returning to the right side of the heart, cardiac output decreases
resulting in an overall decrease in blood delivery to the cells.
4 . A change in blood volume such as due to a rapid change in posture. You are lying in a supine
position and you are scared and get up very fast. The cardiovascular system does not respond fast
enough to generate the pressure to send blood to the brain. In short, the cardiac output is
decreased and the person passes out. This condition is called orthostatic hypotension.
Hypotension Treatment
How do we take care of persons in a hypotensive crisis? From a drug point of view, drugs that
have the same effect as the autonomic nervous system, sympathetic division will stimulate the
heart and vasoconstrict blood vessels.
Agents that increase blood pressure are called pressor drugs. In the case of the person who is in
the emergency room and is suffering from ventricular fibrillation, the emergency team injects
pressor drugs to increase his blood pressure. The increase in heart rate (tachycardia) and stronger
muscle contraction (increase inotropy) will increase cardiac output. With an increase in cardiac
output and increase in vasoconstriction, the arterial pressure will rise. As the pressure rises, the
flow increases and the patient lives. However, if there is damage to the brain stem due to an
accident, none of these magnificent reflexes will work.

Systolic Pressure

Blood pressure within the arteries when the heart muscle is contracting in the
ventricle.

Diastolic Pressure

The blood pressure after the contraction of the heart while the chambers of th
refill with blood.

Inotropism

The force that muscles generate at a given muscle length.

Positive Inotrope

A drug that increases the contractility of the cardiac muscle.

Hypertension

An elevated diastolic pressure and/or systolic pressure.

Essential (or Primary)

Hypertension

Hypertension with an unknown cause.

Secondary Hypertension

The hypertension is due to renal or endocrine disorders.

Beta Blockers

Any of various substances that interfere with the action of the beta receptors
primarily to reduce the heart rate or force in the prevention, management, or
of angina, hypertension, or arrhythmias.

Vasodilator Drugs

A drug or chemical that relaxes the smooth muscle in blood vessels, which c
to dilate. Dilation of arterial blood vessels (mainly arterioles) leads to a decr
blood pressure.

Hypotension

Abnormally low blood pressure.

Orthostatic Hypotension

A fall in blood pressure associated with an upright position, usually occurrin

result of standing still for a long time or rising from a prolonged stay in bed

causing faintness, dizziness, and vision disturbances.

Tachycardia

Abnormally rapid heartbeat (over 100 beats per minute).

Inotropy

Stronger muscle contraction that increases cardiac output.

Capillaries:
Capillaries- where transfer occurs in the body. The food you eat, the drugs you take will
eventually go to cells requiring a transfer at the capillary level. A drug deal involves the transfer
of funds for illegal drugs. In the capillaries, oxygen leave the capillaries and enters the cell and
carbon dioxide leaves the cell and enters the capillary.

The capillaries are the link between the arterial and venous circulations. They are the only
anatomical avenue by which oxygen and nutrients reach the cells. They are considered to be like
the freeways to your cells or another way of looking at them, they are like specialized river ways
that go to all your cells. Yes, they supply, nourish, and remove metabolic products from cells. To
keep us alive, all 100 trillion cells in our bodies must be no less than 3-4 cell lengths from a
capillary.
There are three types of blood vessels: arteries, veins, and capillaries (Figure 1). Throughout the
body, arteries and veins run parallel with a web-like network of capillaries that is embedded in
tissue and that connects them. From a chemical point of view, the arteries pass their oxygen and
nutrient-rich blood to the capillaries and allow exchange of oxygen for carbon dioxide and
wastes. The capillaries then pass their waste-rich blood to the veins. From a physical point of
view, the arteries carry blood away from the heart at high blood pressure. Most of this pressure is
lost in the capillaries and the veins then carry blood back to the heart at lower pressures and use
one-way valves to prevent backflow. The pressure loss through the large capillary networks of
the lungs and the combined capillary networks of the remaining organs is also why the blood
circulation requires the heart to have a separate pumping component for each.

Arteries have three layers: an outer layer of tissue, a muscular middle, and an inner layer of
epithelial cells. The muscle in the middle is elastic and very strong. The inner layer is very
smooth so that the blood can flow easily with no obstacles in its path. The arteries are innervated
by nerves from the autonomic nervous system which involuntarily controls their diameters.
Like arteries, veins have three layers: an outer layer of tissue, muscle in the middle, and a smooth
inner layer of epithelial cells. However, the layers are thinner and not as strong, containing less
tissue as the arteries. Veins also have one-way valves to prevent backflow. In addition, they also
have nerves from the autonomic nervous system which involuntarily controls their diameters.
Capillaries control which substances actually enter and leave the blood and bathe cells. No
exchange of materials takes place in the arteries and veins, whose walls are too thick and
impermeable. Unlike the arteries and veins, capillaries are very thin and fragile. The capillaries
are actually only one epithelial cell thick. They are not innervated by any nerves.
There are three major types of capillaries which vary in the degree of permeability to solutes.
Capillaries are 3-10 m in diameter and red blood cells 2-8 m, so red blood cells have to
squeeze through the capillaries. Red blood cells do not leave the capillaries unless the capillaries
are damaged. Capillaries are made of a single layer of endothelial cells and basement collagen
membrane. The exchange of materials (like oxygen, carbon dioxide, nutrients, and wastes) takes
place through the thin capillary wall.
Continuous Capillaries have tight junctions between endothelial cells restricting movement of
solutes through the capillaries. The following tissues have continuous capillaries: muscle,
neuronal (brain), connective tissue (skin), and exocrine glands (salivary glands, sweat glands).
The capillaries that support the neurons have a very specialized group of cells to tightly control
movement of solutes into the brain. This physical/chemical barrier is called the Blood Brain
barrier.
Fenestrated Capillaries have large gaps or pores through endothelial cells called fenestrae. The
following tissues need to have a more leaky type of capillary so that the most amount of solutes
can pass through: intestines, renal glomerulus (kidney), and endocrine glands (hormone glands).
Sinusoidal Capillaries have the largest gaps between and within endothelial cells. The following
tissues need to have large solutes to come in close contact with their cells: liver and bone
marrow.
Capillary Biology
Capillary beds are about 1 mm in length. There is not enough blood to fill all the body's
capillaries, and at any given time up to 20% of the capillary beds are closed. Blood flow
regulation occurs at the capillary beds. Blood flow through individual organs and tissues is
controlled by the chemical local environment. This phenomenon is called autoregulation, which
means that blood flow to vessels remains constant independent of perfusion pressure. For
example, if perfusion pressure decreases, the blood flow will initially fall and then return to
normal in minutes. This response is independent of neuronal and hormonal influences.

Autoregulation works between a range of perfusion pressures. Various organs have degrees of
autoregulation ranging from: the cerebral, coronary, and renal circulation as being the most
autoregulated; skeletal and intestinal vasculature being secondary; and skin show no
autoregulation. The biological rationale for this range of autoregulation deals possibly with the
high oxygen demand of the brain, heart, and kidneys and with the skin requiring much less.
There are anatomical, chemical, physical, and temperature determinants of autoregulation. From
an anatomical point of view:
An AV shunt is a short vessel that directly connects the feeder arteriole and the drainage venule
at the opposite end of the bed. It bypasses the capillary bed. Thus if you want to bypass some
non-essential tissue such as skin, the blood is directed to the AV shunt.
Precapillary sphincters (Figure 3) are found on arterioles (blood supply vessels) and control
flow through a capillary bed. They are controlled by the sympathetic nervous system. When they
contract, they stop blood from entering the capillary bed. When a person is emotionally excited,
the sympathetic nervous system causes the precapillary sphincters of the capillary beds to the
skin of the face to contract. As a result, there is no blood flowing through the capillary bed and in
fair complected persons, the facial skin turns chalk white.
Pericytes are vascular smooth muscle cells that are on the outside of the precapillary and post
capillary structures that help guide flow within the capillary bed to further optimize metabolite
exchange. In the brain, they contract and direct blood flow to various capillaries. They are
similar to precapillary sphincters but are located along brain capillaries.
Oxygen Delivery
Oxygen delivery to cells occurs in the capillary bed. For example, heart capillaries are always
open since the heart muscle requires a large amount of oxygen to make ATP. In contrast,
capillaries in skeletal muscles in your legs can have only 20% flow while you are reading this
message but can increase to 100% if you have to run out of the building.
There are a number of major chemicals that influence the capillary blood flow in various organs.
If local oxygen levels are decreased, the capillary beds will have increased blood flow and with
high levels of oxygen the oxygen beds will have less blood flow. (Remember this depends on the
organ. The brain can survive for no more than 3-5 minutes without oxygen, whereas the skeletal
muscle can survive for 20 minutes without oxygen.) Carbon dioxide is the end result of the
metabolism of cells so it needs to be expelled. If the carbon dioxide increases locally, this
suggests that blood flow is decreased and oxygen concentrations are low. Thus high levels of
carbon dioxide will cause the precapillary sphincters to open to increase the blood entering the
capillary bed.
Associated with the levels of carbon dioxide in the blood is its effect on the pH level. The higher
the carbon dioxide level, the lower the pH. The pH must be maintained in a small range of 7.4. If
too much carbon dioxide is produced, it will cause the pH to drop and become more acidic
leading to protein denaturation and death. As the pH drops, the blood flow will increase in the
capillary beds.

Certain nutrients are required by the cells. For example, brain cells will only metabolize glucose.
If there is a decrease in glucose (hypoglycemia) in the capillary bed, the blood flow will increase
to that capillary bed.
Physical
So far, we have concentrated on chemical concentrations of oxygen, carbon dioxide, glucose, and
pH that will affect the blood flow into the capillary bed. In addition there are physical forces. If
the blood pressure is decreased in the capillary bed, this will cause the capillary sphincters to
open. The decrease in blood pressure also causes a decrease in oxygen and an increase in carbon
dioxide. In summary, there are both chemical and physical forces that influence blood flow
through the capillary.
Temperature
In addition to chemical and physical forces, temperature will also affect capillary blood flow.
During exercise, as the temperature increases, the blood flow in the capillaries of the skin
increase but decrease in the intestine. Conversely, when the skin is cold, the blood flow through
the skin capillaries will decrease so that there is more blood flowing to the intestines. Keep in
mind, that with exercise, although the blood flow to the skin and muscles increase in the
capillary bed, it does not decrease in the brain. When it does, the person faints.
Interactions at the Capillary Bed Level
Once the blood enters the capillary bed, what determines the movement of chemicals across the
various capillary beds into the interstitial space? Oxygen enters the capillary bed attached to the
hemoglobin molecule in the red blood cells. The oxygen molecule will separate from
hemoglobin if the concentration of oxygen is low in the capillary bed and will diffuse into the
interstitial space and then into the cell to reach the mitochondria. The chemical force driving this
important movement of oxygen is diffusion. The same process works for carbon dioxide but in
the opposite direction. Cells are producing large amounts of carbon dioxide and there is little in
the capillaries. Due to the forces of diffusion, the carbon dioxide will diffuse into the capillary to
eventually reach the lungs.
How about the movement of fluids in the capillary bed? The exchange of fluids at the capillary
level is dependant on the type of capillary bed, and two major physical/chemical forces called:
hydrostatic and colloidal osmotic forces.
Hydrostatic Osmotic Forces
Imagine that as the arterial blood enters the capillary bed, there is its associated high pressure
entering the arterial side of the capillary bed. This pressure is called the hydrostatic pressure. As
the fluid enters at the arteriolar side, the hydrostatic pressure is high relative to the pressure at the
venous side. Hence hydrostatic pressure decreases from the arteriole to the venous side. This
difference is essential for the blood to move from the arterial side of the capillary bed to the
venous side. What happens across the capillary membrane? If the hydrostatic pressure is high
inside the capillary then the pressure on the outside of the membrane will be low. This difference
of pressure will push the fluids out of the capillary depending on the physical and chemical

properties of the capillary. On the venous side of the capillary, the hydrostatic pressure is low
relative to the outside of the capillary. Thus fluids on the venous side of the capillary will flow
into the capillary (Figure 4).
Colloidal Osmotic Forces
The other physical force that influences the movement of fluid into the capillary is osmotic
pressure. It is also called colloidal osmotic pressure since it is the particles in solution that will
play a major role in determining the osmotic pressure. Osmotic pressure refers to the force
exerted by the particles in solution. If there are more particles inside the capillary and less on the
outside, the osmotic pressure will be greater on the inside of the capillary. Thus the water from
outside the capillary will enter the capillary to equilibrate the osmotic pressures on both sides of
the capillary. This condition exists on the venous side.
On the other hand, on the arterial side of the capillary bed, there is more fluid and hence a lower
concentration of solutes. Relative to the outside of the capillary bed, the inside of the capillary
has less solutes. Thus fluid will leave the capillary and enter the interstitial space (Figure 5).
So far we have discussed what is occurring inside the capillary. What is occurring on the outside
of the capillary? This is the interstitial space that is close to the cells. Cells are very close to the
capillaries which is essential for the exchange of gases, fluids, and solutes.
Interstitial Hydrostatic and Osmotic (or Oncotic) Pressures
Hydrostatic pressure differences between the capillary and the interstitial space determine the
movement of fluid (Figure 6). If the interstitial hydrostatic pressure is higher than the hydrostatic
pressure inside the capillaries, fluid will flow into the capillaries. Usually, this pressure is
negative meaning that the capillary hydrostatic pressure is positive forcing fluid into the
interstitial space. This force acts as a pump to push fluids out of the capillaries into the interstitial
space.
The interstitial oncotic pressures are determined by the amount of solute in solution. The more
concentrated the solution, the more fluid will be drawn from the capillary. When fluid leaves the
capillary, it is considered to be filtered and when fluid is attracted back into the capillary it is
considered to be reabsorbed.
How Is Osmotic Pressure Determined and What Brings the Osmotically Active Molecules
into the Cells?
There are three main mechanisms by which molecules are transported across the capillary wall
into the tissues. These mechanisms play a major role in determining the osmotic or oncotic
pressure of the capillaries. Although all function to some degree in all capillary beds, the kidney
especially uses these processes to promote filtration of blood. The mechanisms for transport are:
1.Passive Transport (follows concentration gradient)
In this case, oxygen enters the cells based on a diffusion gradient. There is more oxygen in the
capillary at the arteriole end vs. the amount in the interstitial space and thus by the laws of

diffusion, it will diffuse from the capillary into the interstitial space of the cell and ultimately to
the mitochondria. Diffusion can either be the movement of solutes based on pure concentration
differences or can be the diffusion of molecules across the membrane with the assistance of
transport proteins.
2. Active Transport (against concentration gradient)
Involves the movement of molecular substances across the membrane - against a concentration
gradient- using cellular energy. This condition is similar to salmon migrating against the force of
a waterfall. If the fish used only diffusion, it would never climb over the waterfall. It needs
energy (ATP) to overcome the force of the waterfall. There are various kinds of active transport,
those that require ATP and those that require an electrochemical difference across the membrane
(Figure 7).
3. Transcytosis
In this case, materials are carried across the capillary wall by vesicles. Proteins and large
molecules are primarily the major chemicals that are carried by this process.
The Lymph at the Capillary Bed
Fluid and nutrient exchange at the capillary bed allows for 99% of the fluid to be absorbed.
Where does the 1% that is left over go? This leftover fluid at the capillary bed is picked up by the
lymph vessels that are at the capillary bed. The fluid is transferred to the right atrium where it is
returned to the circulation.
Edema and Capillaries
Edema refers to an increase in interstitial water. You can see this easily in yourself if you are
standing all day. Your feet swell. Actually there is more fluid in your interstitial space. How does
this occur? As you stand all day, the hydrostatic pressure increases in your veins causing the
hydrostatic pressure in the capillaries to increase. As it increases, it pushes fluid into your
interstitial space causing the edema or puffiness in your feet. This form of edema is found only in
your legs and not your arms since it is easier to decrease the hydrostatic pressure in your arms by
muscle contraction. For your legs to minimize edema, it is important that you walk or find some
way to contract the skeletal muscles to minimize the production of hydrostatic pressure in your
legs.
Inflammation and Edema
Any kind of inflammation will also cause an increase in interstitial fluid. For example, an
infection will usually cause an increase in interstitial fluid due to the death of cells which causes
the arterioles, capillaries, and venules to become leaky. White blood cells move through the
capillaries to reach the infectious site (Figure 8).
Brain Edema
Edema can occur anywhere there are capillaries. In the case of the brain, if there is an obstruction
to the venous flow, then the hydrostatic pressure will increase in the capillaries since the blood

has nowhere else to go. As the fluid leaves the brain capillaries, it enters the interstitial space
consequently leading to more fluid in between the neurons. This is a very critical condition since
the edema exerts its pressure on the capillaries thereby clamping them shut and resulting in
neuronal death. Cerebral edema is life threatening since the increased interstitial fluid cannot be
dissipated as in your leg since the skull will not allow any expansion. Cerebral edema can be
caused by direct damage to the skull such as in boxing or a car accident. which causes damage to
the arterioles, capillaries, and venules. Or, inflammation of brain tissue can also cause the blood
vessels to become leaky also causing edema (Figure 9).
Cerebral edema can be caused by damage to the brain blood vessels allowing fluids to enter the
interstitial space which compresses the blood vessels. As a result, oxygen cannot be transferred
to the neurons, resulting in coma and death.
Capillaries

Any of the tiny blood vessels that connect the smallest arteries (arterioles) to the smallest veins (
Capillaries form a network throughout the body for the exchange of oxygen, metabolic waste pr
carbon dioxide between blood and tissue cells.

Arteries

A blood vessel that conveys blood from the heart to any part of the body.

Veins

Any of the membranous tubes that form a branching system and carry blood
heart.

Fenestrated Capillary

Sinusoidal
Capillaries
(AKA Discontinuous
Capillaries)

Autoregulation
AV
Shunt

A blood capillary found in renal glomeruli, intestinal villi, and some glands,
ultramicroscopic pores of variable size occur.

Special forms of fenestrated capillaries that have larger openings in the epithelium allo
blood cells and serum proteins to enter.

Processes that maintain a generally constant physiological state in a cell or o

A short vessel that directly connects the feeder arteriole and the drainage venule at the opposite en
bed. It bypasses the capillary bed.

Precapillary Sphincters

A sphincter of smooth muscle tissue located at the arterial end of a capillary a

serving to control the flow of blood to the tissues.

Pericytes

Vascular smooth muscle cells that are on the outside of the precapillary and post capillary structur
help guide flow within the capillary bed to further optimize metabolite exchange. Their function is
that well known.

Oxygen

Responsible for cellular respiration.

Carbon Dioxide

Waste product of cellular respiration.

Nutrients

Provides nourishment for cellular metabolism.

pH

A measure of the acidity or alkalinity of a solution.

Osmotic Pressure
(AKA Colloidal Osmotic
Pressure
or Oncotic Pressures)

The force that a dissolved substance exerts on a semipermeable membrane, th

which it cannot penetrate, when separated by it from pure solvent.

Hydrostatic Pressure

The pressure exerted by a fluid at equilibrium at a given point within the fluid
the force of gravity. Hydrostatic pressure increases in proportion to depth mea
from the surface because of the increasing weight of fluid exerting downward
from above.

Passive
Transport

The movement of a chemical substance across a cell membrane without expenditure of energy by
cell, as in diffusion; follows gradient.

Active
Transport

The movement of a chemical substance through a gradient of concentration or electrical potential

direction opposite to normal diffusion, requiring the expenditure of energy; against gradient.

Transcytosis
(AKA
Vesicular
Transport)

A mechanism for transcellular transport in which a cell encloses extracellular material in an

invagination of the cell membrane to form a vesicle, then moves the vesicle across the cell to
the material through the opposite cell membrane by the reverse process.

Edema

An accumulation of an excessive amount of watery fluid in cells, tissues, or body cavities.

Brain
Edema

Swelling of the brain due to the uptake of water in the neuropile and white matter.

Respiration/Ventilation
The human ventilatory system is a biological pump that generates positive and negative pressure
to draw air in and out of alveoli. In this case, this person is trying to blow up a balloon which
means he is expiring or developing a positive pressure.

The ventilatory system is responsible for bringing air into the lungs and expelling the residual air

and metabolic gases from the body (Figure 1). Overall, the system works as a pump. We have
already seen how the heart works like a pump and so does the ventilatory system. The heart
pumps blood while the ventilatory system pumps air in and out of the body. While the lung is
superbly designed for gas exchange, it also has other functions unrelated to gas exchange owing
to its large blood volume that passes through the lung each minute and the immense capillary
surface area available for gas exchange. Functions of the lung not directly related to gas
exchange are referred to as non-respiratory functions. Some non-respiratory functions of the lung
vasculature include its role as a blood filterer, blood reservoir, and a metabolizer of circulating
substances.
The anatomy of the ventilatory system is designed to generate intrathoracic negative and positive
pressures for oxygen and carbon dioxide exchange. The major components of the ventilatory
system are designed to ultimately transfer the air into the alveoli or the small cavities that are
surrounded by pulmonary capillaries carrying partially deoxygenated blood. For air to reach the
alveoli, it travels through a number of interesting anatomical routes.
The route for the air is (Figure 2):
0. Atmosphere
1. Nose and mouth
2. Pharynx
3. Larynx - also known as the voice box
4. Trachea
5. Bronchi
6. Bronchioles
7. Alveoli
8. Pulmonary capillaries
The route for carbon dioxide is in the opposite direction going from 8 to 0.
A key area in which the ventilatory system and the intestinal system meet is at the
pharynx/larynx region. The pharynx is a muscle lined space that connects the nose and mouth to
the larynx and esophagus. When you swallow food, it must go from the mouth to pharynx and
into the esophagus - not into the larynx since it would block air going into the lungs. When you
swallow food, the larynx is reflexively cut off so that the food goes into the esophagus. This
reaction is automatically controlled by the medulla - the part that also controls ventilation. When
you swallow, the reflex temporarily stops breathing. It happens so fast, you are not even aware of
it. Remember when you are chewing food-- your mother's warning, "Don't talk with your mouth
full!"
The ventilatory system, by way of the trachea, is in front of the throat whereas the digestive
system, by way of the esophagus, is behind the trachea (Figure 3). This anatomical arrangement
requires the inspired/expired air to cross paths with the digestive system in the pharynx. Thus, as
food is being swallowed, ventilation is temporarily stopped so that the food does not go down the
wrong pipe. Serious occlusions to the larynx can lead to suffocation and death. The control of
the larynx which controls access to the vocal cords that are situated on top of the trachea are

controlled by multiple reflexes. Two different sets of cartilage in the larynx protect the vocal
cords and trachea during swallowing: the epiglottis and the arytenoid cartilage. They functionally
act as a trap door not allowing food to enter the trachea.
Once the inspired air enters the trachea, it is then funneled into the bronchi, bronchioles, and
alveoli. The trachea branches into two main tubes: the right and the left bronchi (plural form of
bronchus). These structures branch into succeeding smaller and smaller tubes called secondary
bronchi, tertiary bronchi, bronchioles, and terminal bronchioles.
At the end of the terminal bronchioles are the alveoli. The structure of bronchi has less and less
supporting tissue. The first seven major divisions of the bronchi, as they get smaller, have a wall
of cartilage and smooth muscle, a layer of cells that have cilia and mucous secreting goblet cells,
and some endocrine cells as well. As the structures get smaller and smaller, there is no more
cartilage, only a smaller muscular layer, cells with cilia, and some goblet cells. The smooth
muscle that lines the various divisions of the bronchi are key players in determining their
diameter. When they contract, the diameter of the bronchial tree that they envelope gets smaller
resulting in less air getting into the alveoli.
The terminal bronchioles branch into alveolar sacs which are composed of alveoli (Figure 4).
Each lung has approximately 300 million alveoli! The alveoli is surrounded by two kinds of
cells. Imagine an air filled balloon surrounded by two types of cells and that will give you a good
mental image of the alveoli. The cells are called pneumocytes, meaning cells of the pulmonary
system. Pneumocytes 1 provide a thin layer for exchange of the air gases with those from the
blood. Pneumocytes 1 are connected to pneumocytes II that produce a chemical called surfactant
that keeps the alveoli in a round shape. For the alveoli to exchange gases (air and blood) it has to
maintain its shape. So to make sure that there are 300 million little balloons already expanded
waiting for the air - surfactant is required. Without surfactant, the alveoli would collapse
resulting in no gas exchange between the air and the blood.
The blood supply to the lungs has two circulations:
1. to bring the partially deoxygenated blood from the right ventricle to the alveoli so that it
becomes oxygenated.
2. Supply oxygen to the cells that compose the pulmonary alveoli system. The system that brings
the partially deoxygenated blood to the alveoli is called the pulmonary circulation whereas the
circulatory system that brings oxygen and nutrients to the cells of the pulmonary system is called
the bronchial circulation.
What Drives the Blood into the Pulmonary Vasculature? Pressure!
The blood from the right ventricle enters the lungs driven by a hydrostatic pressure difference
between the two. The pressure is low in the pulmonary arteries and they do not have much
smooth muscle (Figure 5). The arteries progress to arterioles and capillaries. These capillaries are
the pulmonary capillaries and they surround the alveoli at which junction gas exchange occurs.
The pulmonary capillaries eventually get bigger leading to venules, veins, and finally the
pulmonary veins which dumps the blood into the left atrium.
The gas exchange in the pulmonary capillary is one in which oxygen diffuses from the air to the
alveolus to the blood. Simultaneously, carbon dioxide diffuses from the blood, to the alveolus to

the air. The driving force for this gas exchange is diffusion. If there is more CO2 in the blood then
in the air, the CO2 will diffuse out. In a similar manner, if there is more oxygen in the atmosphere
than in the blood, it will diffuse into the blood.
The Ventilation System As A Pump: Where is the Force? The Diaphragm and Intercostal
Muscles!
The atmospheric air must enter the lungs for gas exchange to occur. This simple fact means that
the air has to be drawn into the lungs all the way to the alveoli. Thus, the lungs must suck in the
air from the atmosphere. To accomplish this, it must generate a negative air pressure relative to
the atmosphere to drawn the air into the lungs. On the other hand, to expel air, the pulmonary
system must then generate positive pressure relative to the atmosphere.
The major anatomical components of the ventilation system make the thoracic cavity air tight.
No air can enter except through the mouth and nose. Except for pathological conditions, air
enters or leaves the ventilation system based on the pressure generated by the diaphragm and rib
cage muscles. The major muscle that generates the rhythmic intrathoracic positive and negative
pressures is the diaphragm. As the diaphragm contracts, it goes lower into the abdominal cavity
and in the process generates a negative pressure. As the diaphragm contracts, it causes the lungs
to expand due to the attachment of the diaphragm to the rib cage. Conversely, when the
diaphragm relaxes, it pushes into the thoracic cavity causing a positive intrathoracic pressure.
The diaphragm (Figure 6) has three major structures passing through it:
1) The esophageal opening allows the esophagus to pass from the thorax to the abdomen where it
joins the stomach. There are a special group of muscles that surround the esophagus that relax
during swallowing. They are independent of the other diaphragmatic muscles and are thought to
work in conjunction with the smooth muscle in the esophagus.
2) The caval opening is the passage of the inferior vena cava. This important blood vessel brings
blood from the entire lower part of the body. During inspiration, the caval opening is stretched
allowing more blood to enter the right atrium (Figures 7 and 8).
3) The final opening in the diaphragm is the aortic hiatus which is the passage way for the most
important artery in the body, the aorta, which carries the oxygenated hemoglobin to all organs in
the body.
The diaphragm is controlled by nerves that originate from the brain stem. These nerves are
collectively called the phrenic nerve. When the phrenic nerve fires, the diaphragm contracts and
a negative pressure is generated in the thorax. When the phrenic nerve does not fire, the
diaphragm relaxes and a positive pressure is generated in the thorax. This rhythmic contraction
and relaxation of the diaphragm draws air in and out of the thorax and as a consequence, the
chest moves up and down. This movement is considered to be one of the primary signs of life.

Ventilation and Perfusion Differences in the Lung. Look to the Bottom - Not the Top!
The critical biological junction in the ventilatory system is the pulmonary capillary and the
alveoli. By this route, carbon dioxide leaves and the oxygen enters the capillaries. From the
alveoli perspective, the oxygen leaves and the carbon dioxide enters. The amount of air that
enters the alveoli relative to blood flow in the region is called the ventilation/perfusion. There are
ventilation/perfusion differences in the lungs. The upright human lung measures about 30
centimeters from the apex to the base and the pulmonary artery enters the lung midway between
the apex and base of the lung. The adult lung has about 300 million alveoli. Each alveolus is
surrounded by a capillary mesh.
Gas exchange is optimal in alveoli where ventilation is closely matched to blood flow or
perfusion. Due to gravitational forces, intravascular pressures and blood flow are significantly
less at the apex than at the base of the lung. Concerning air, more air volume goes to alveoli at
the base than apex because alveoli at the base are on a more compliant portion of the lung
compliance curve. As a result, they expand more for a given change in transmural pressure. On
the average, alveoli at the lung base receive about twice as much ventilation per unit lung
volume as those at the apex and four times more blood flow. When a person assumes a supine
position, the pressure differences between the apex and base are less. This results in a more
uniform distribution of blood flow and smaller vascular pressure differences (Figure 9).
The End Result: Pulmonary Volumes
The cardiovascular system is evaluated based on the rate of cardiac contractions, heart rate, and
the pressure it generates that is, blood pressure. The ventilatory system is evaluated in a similar
manner. The rate of ventilation and the volume of air inspired and exhaled are overall
measurements of the system's ability to function. If the ventilation rate is too high, the person has
tachypnea and if it is too low it is called bradypnea.
Due to the forces generated by the diaphragm and intercostal muscles under the control of the
central nervous system, certain volumes of air enter the lungs. What should be emphasized is that
the ventilatory system has a reserve of air so that we are not completely dependent on the air that
enters and leaves with each ventilatory cycle.
The ventilatory system is evaluated by the volume of air that you can either inhale or exhale. The
following are some examples:
Tidal Volume (TV) = 500 mL measured: The amount of air breathed in or out during normal
respiration. The volume of air an individual is normally breathing in and out (Figure 10).
Functional Residual Volume: The amount of air left in the lungs after a tidal breath out. The
amount of air that stays in the lungs during normal breathing.
Residual Volume (RV) = 1.2 L measured: The amount of air left in the lungs after a maximal
exhalation. The amount of air that is always in the lungs and can never be expired (i.e. the

amount of air that stays in the lungs after maximal expiration).

Edema in the Lungs: "Water in the Lungs"
The pulmonary capillary bed and the alveoli form a very important anatomical and physiological
border. This critical site must have minimal physical barriers otherwise oxygen and carbon
dioxide transfer cannot occur. Disturbances in lung fluid balance are a common clinical
occurrence. An accumulation of fluid between the alveoli and pulmonary capillary blood or
within alveoli themselves increases diffusion distance and impedes gas exchange.
Left Heart Failure and Pulmonary Edema
Refresh your memory about the route of deoxygenated blood from the left atrium to the left
ventricle. The blood entering the left atrium has returned from the pulmonary circulation loaded
with oxygenated blood. However, if the left ventricle is failing it will not generate enough
pressure to completely expel the blood in the ventricle. The blood backs up into the left atrium
and into the pulmonary capillaries. The patient is not able to get enough oxygen to all parts of his
body due to the left heart failure. As the blood backs up, it pushes the fluid in the capillaries into
the capillary alveolar space creating an edema that makes it difficult for oxygen to diffuse into
the blood. Since this edema is caused by left heart failure, it is termed cardiogenic edema. Left
heart failure leads to shortness of breath, "fluid in lungs", and an inability to do any physical
work (i.e. walking).
Permeability Edema
The pulmonary capillary permeability is increased in this kind of edema. The cells that determine
the permeability of the capillary are affected by various causes which allows the capillaries to be
leaky allowing more fluid to leave the capillary and separate the distance between the alveoli and
the capillary. Adult respiratory distress syndrome (ARDS) is considered to be the major cause of
pulmonary edema. It can be caused by a loss of blood anywhere in the body resulting in a
condition of hypotension and extensive changes to the permeability of capillaries. Thus, there
can be edema in the lungs caused either by heart failure or high membrane permeability. The
challenge for the physician is to ascertain the cause of the edema to execute the appropriate care.
Asthma
Asthma occurs when the bronchial tubes become inflamed and constricted. The smooth muscle
of the bronchial walls constrict and mucous cells are activated. The end result is shortness of
breath, difficulty breathing, and if not treated--death. The current thoughts on the development of
this disease is that it is an immunological disease.
The Lungs Many Functions
The Lung as a Filter
Since the pulmonary circulation contains more capillaries than are normally required for gas
exchange, lung capillaries trap particles without affecting gas exchange. For example, small
blood clots called emboli are trapped by pulmonary vessels that are removed by macrophage

ingestion, or absorption into the lymphatic system. In this manner, the lung microvessels
prevents entry of potentially harmful large size blood clots that could block systemic vessels.
Lung as a Reservoir of Blood
The blood vessels of the pulmonary circulation are very distensible and thus typically have about
500 ml of blood in an adult male. This large lung blood volume serves a reservoir for the left
ventricle, particularly during periods when left ventricular output exceeds venous return. Thus,
cardiac output can be increased rapidly by drawing upon pulmonary blood volume without
depending on an instantaneous increase in venous return. Due to this reserve capability, the lungs
are sometimes called the second heart.
Lung as a Metabolic Processor
Since all the blood of the body is processed in the lungs, it is not unusual to consider the fact that
endothelial cells that line the vessel lumen, are involved in the uptake or metabolic conversion of
several vasoactive substances in the circulation. Epinephrine and other biogenic amines along
with histamine, serotonin and nitric oxide are metabolized by the lung.
Ventilatory System

Alveoli

Pharynx

Responsible for bringing air into the lungs and expelling the residual air
the body.

Any of the tiny air-filled sacs arranged in clusters in the lungs, in which the exchange of oxygen and
place.

The tube or cavity, with its surrounding membrane and muscles, that con

nasal passages with the esophagus.

Medulla

The inner part of an organ or structure in plant or animal; also controls v

Diaphragm

The major muscle that generates the rhythmic intrathoracic positive and

Phrenic Nerve

One of a pair of nerves that arises from cervical spinal roots and passes d
innervate the diaphragm and control breathing.

Pnea

The rate of ventilation.

Bradypnea

Abnormal slowness of respiration.

Cardiogenic Edema

An excessive accumulation of serous fluid in the heart.

Asthma

A paroxysmal, often allergic disorder of respiration, characterized by bronchospasm, wheezing, and

often accompanied by coughing and a feeling of constriction in the chest.

Cellular Communication
A fender bender is the result of the lack of communication! Hormones play a major role in
coordinating responses between cells and organs. Besides the nervous system, the hormones
reign supreme in coordinating responses by way of chemical communication systems. ( I hope
he had insurance!)

Ligands Bind to Receptors

How do cells communicate? Cells communicate by sending and receiving signals. These
extracellular signals begin as molecules (often referred to as ligands) that can be secreted from
the signaling cell into the extracellular space where it acts on a target cell that has a receptor for
the ligand. Ligands can also be attached to the surface of a signaling cell whereby the signal is
propagated to the cells that are juxtaposed to the signaling cell via cell-cell contact. How does
the binding of a ligand to a receptor result in a signaling event? This occurs via a conformational
change in the receptor that results in the propagation of a signal in the target cell. Let us take a
look at a classic example of this.
In the absence of a ligand, a cell surface receptor is in the off position meaning that this receptor
is not able to propagate a signal (Figure 1). When the ligand binds to its receptor, the receptor
undergoes a conformational change that turns on the receptor and initiates a signaling cascade
in the target cell. These receptors can also be ion channels whereby the binding of a ligand to the
channel either opens or closes the channel, which can result in changes in the membrane

potential of the target cell and the initiation of a signaling event.

Signaling Is Propagated by Extracellular and Intracellular Molecules
Signaling molecules can be chemicals, proteins, lipids, nucleic acids, and even dissolved gases
such as nitric oxide. Most receptors are located on the surface of a cell, (cell surface receptors)
but some are located inside the cell (intracellular receptors). Signal molecules can only interact
with their specific receptors. Think of a lock and key mechanism with the receptor being the lock
and the signal being the key. This is important because cells are exposed to hundreds of different
signals in their environment and they have to be able to distinguish between them. In other
words, if the cell does not express the specific receptor for a signal molecule, it will not respond
to that signal molecule (Figure 2). Remember, although all normal cells will have the gene for
every kind of receptor, it will only be expressed in some of them as proteins. Cell specialization
that occurs during development will determine which receptor genes are expressed and which are
not.
Sometimes these signal molecules travel over long distances to their target cells. This type of
signaling is called endocrine signaling and requires a circulatory system. We will learn more
about that in the next section of this e-module and when we talk about menstruation. If a signal
travels over a shorter distance it is referred to as paracrine signaling. This is a localized signaling
event whereby the signaling molecules are released into the extracellular space and diffuse to
neighboring target cells. A good example of paracrine signaling is blood clotting. An open
wound, which is essentially a localized area with broken cells, releases intracellular molecules
which signal your blood platelets to aggregate and begin the wound healing process. Two other
types of localized signaling events are referred to as contact dependent and autocrine signaling.
Autocrine signaling often occurs at the same time as paracrine signaling if the signaling cell
expresses a receptor for the signaling molecule that it releases. Contact dependent signaling
occurs when a signaling molecule is membrane bound to the signaling cell and the target cell has
a receptor for the membrane bound signaling molecule and is in direct physical contact with the
signaling cell. Neuronal signaling is a specialized type of signaling that occurs in the nervous
system and is initiated by a specialized type of cell called a neuron that releases a hormone
(referred to as a neurotransmitter) into a localized area referred to as a synapse. We will learn
more about neuronal signaling in the depression section (different types are illustrated in Figure
3).
Signaling Pathways Control Cellular Functions
If every function a cell needed to perform were transmitted by a different extracellular signal, we
would need millions of different signaling molecules instead of hundreds.
To generate more diversity, cells often respond to combinations of extracellular signal molecules.
Cell survival is usually dependent on a combination of signals. Without them, a cell may activate
a built-in suicide program to kill itself. This is one way a cell is prevented from taking up
residence in a part of the body it should not be. For example, if a breast cell needs to receive
signals A, B, and C to survive and if it somehow migrates inappropriately to another part of the
body where signals A, B, and C are not produced, the breast cell will die (see Figure 4).

Can you see why this type of mechanism would be important? What would happen if you had a
breast cell that no longer responded to signal A, B, and C and somehow migrated to another part
of your body, like your lungs or brain, where it began to uncontrollably divide? This is one of the
things that can happen in cancer. Cancerous cells lose their ability to respond to the signals that
properly regulate them. This allows the cancerous cells to continue to survive and replicate long
after they should have stopped. Besides these survival signals, additional signals may tell a cell
to perform specific functions, like divide, differentiate, contract, or express proteins X, Y, and Z.
These different combinations of extracellular signal molecules eliciting different cellular
responses enables an organism to control its cells in highly specific ways using a limited number
of signal molecules (Figure 5).
Let's talk a little more about how signals are transmitted. Extracellular signal molecules send an
external signal to the cell where it is received by a specific receptor. Since most receptors are
located on the outside of the cell, intracellular signals within the cell must transmit the
information to generate a cellular response. These intracellular signals form pathways (called
intracellular signaling pathways) that convey the information contained in the external signal to
the part of the cell that needs to respond. There are many different kinds of intracellular signaling
pathways, but many of these pathways are mediated by a series of proteins that pass the
information from one to another. Signaling pathways control cellular functions. Every cellular
function is controlled at some level by a signaling pathway. A general example of a signaling
pathway is illustrated in Figure 5. In this example, the extracellular signal molecule binds the
receptor protein.
This allows the receptor protein to interact with the first intracellular protein in the pathway. The
first intracellular protein conveys the message to the second protein in the pathway, and the
second protein to the third protein. A very common way of conveying the message is via
phosphorylation where one molecule adds a phosphate (PO4) to specific amino acids (i.e. serine,
threonine, tyrosine) on the target protein. This phosphorylation changes the conformation of the
target protein by either activating or inhibiting its functions. The target protein might modulate
gene expression and stimulate or repress the production of new proteins. It might also stimulate
the cell to divide and proliferate. The target protein could also be involved in controlling the
shape or movement of a cell, for example, it might be responsible for a muscle cell contracting. It
could also be an important enzyme involved in speeding up or slowing down a chemical reaction
involved in the metabolism in the cell. Lastly, the target protein might also be responsible for the
secretion of substances from a cell.
All of the signaling classifications we spoke about in Figure 3 and signaling pathways discussed
in figures 4 and 5 make up the endocrine system. The endocrine system is responsible for
coordinating an organisms development and the day to day functions of the different tissues and
organs in the body (Figure 6).
Endocrine System Regulates Organ Physiology
Although endocrine glands are found all over the body, one of the major glands in the endocrine
system is the pituitary. The importance of the pituitary gland became clear in 1909 when the
surgical removal of the pituitary cured a man of a disorder called Acromegaly. This disorder is
characterized by uncontrolled secretion of growth hormone from the pituitary and symptoms
include gigantism (extreme height), enlarged hands and feet and exaggerated facial features. The

tallest human being ever recorded had acromegaly. Robert Wadlow was born in 1928 and grew to
8 feet 11 inches tall before dying at the age of 22. He was still growing the year he died. Other
famous patients include Andre the Giant and WWE wrestler Paul Wight "The Big Show" (Figure
7). Since then, the pituitary has been found to secrete 8 different hormones! The pituitary is
located at the base of the brain below a region of the brain called the hypothalamus. The
hypothalamus regulates the secretion of the pituitary hormones. These hormonal regulators
control a variety of physiological processes by acting on many different organs of the body.
This includes growth (bones and muscles), reproduction (ovary and testes), water retention
(kidney), lactation (mammary gland), labor (uterus), metabolic rate (thyroid), and the stress
response (adrenal glands). Let's look at a few examples of these: Anti-diuretic hormone or ADH
for short (also known as vasopressin) is a hormone secreted from the posterior part of the
pituitary. It acts on the kidneys to increase water retention and it is a key hormone in maintaining
water homeostasis in the body. Cells in the hypothalamus can detect blood pressure. If it is too
high, ADH secretion decreases, water is not retained in the kidneys and leaves the body in urine
and blood pressure decreases. If blood pressure is too low, ADH secretion increases, water is
retained and blood pressure increases. ADH was first discovered in the 1950s when a man who
had been shot in the head began to urinate every 30 minutes (and you thought having a bullet in
your head would be bad enough!). It turned out that the bullet had lodged in the pituitary gland
and destroyed ADH production. The disease diabetes insipidus is due to the inability to make
ADH or the inability of the kidney cells to respond to ADH because they lack the receptor for
ADH. Symptoms include frequent urination (because the kidneys do not reabsorb water) and
excessive thirst (because of frequent urination). Have you ever noticed an increased need to
urinate after consuming beverages containing either alcohol or caffeine? This is because ADH
secretion is inhibited by both substances.
Reproduction is another process controlled by hormones secreted from the hypothalamus and
pituitary. The hormone GnRH is secreted from the hypothalamus and acts on cells within the
pituitary. In response to GnRH, these cells secrete two additional hormones called FSH and LH.
Both FSH and LH act on the gonads, either the ovaries in females or testes in males. FSH and
LH regulate egg and sperm production in females and males respectively. They also regulate the
production of the steroid hormones estrogen and progesterone in females and testosterone in
males. LH is also responsible for ovulation in females.
Not all hormones are regulated from the hypothalamus and pituitary. Insulin is produced in
specialized cells called the islets of Langerhans that are found in the pancreas. When you eat,
your food is broken down into simpler molecules, including glucose (a type of sugar). The
increased levels of glucose in your blood signal the islets of Langerhans to secrete insulin into
the blood stream.
Insulin allows the cells in your body to take up the glucose present in your bloodstream after a
meal and use it for energy. If there is excess glucose, your body stores it in the liver or converts it
into fat and stores it in fat cells. Later, once cells have used all this energy and need more, a
second hormone called glucagon is secreted from other cells in the islets of Langerhans.
Glucagon tells your liver cells to release the stored glucose and tells fat cells to convert the fat
back into glucose (Figure 8).

Ligands

Ligands are molecules secreted by cells that bind to receptors on other cells.

Receptor

Receptors are found on the surface of cells and are bound to by

ligands or other signaling molecules.

Intracellular Receptors

Intracellular Receptors are receptors that are found within a cell.

Endocrine Signaling

This type of signaling relies on the secreting of hormones into a

circulatory system.

Paracrine
Signaling

Paracrine Signaling is localized signaling done by the release of locally acting signaling
molecules into the extracellular space which then diffuse to neighboring cells.

Contactdependent
Signaling

This is a type of localized signaling in which the two communicating cells must be in
physical contact.

Autocrine
Signaling

Autocrine signaling occurs when a cell secretes a hormone that binds to one of its own
external receptors.

Neuronal
Signaling

Neuronal Signaling occurs within the cells of the nervous system and involves the release of
hormones into localized areas of the nervous system called synapses.

Neurotransmitter

Neurotransmitter is the name given to signaling hormones released by the nervous system

Intracellular
Signals

These are signals within a cell that transmit information from the receptors on the
outside of the cell to generate a response from the cell.

Intracellular
Signaling
Pathways

These pathways are formed by intracellular signals to convey the information from
external signals to the part of the cell that needs to respond.

Conformational Change

A shape-change within a molecule.

Hormones and Menstruation

Hormones control many aspects of the body's function.

Hormones are Potent Signaling Molecules

The endocrine system is composed of specialized cells that form glands and secrete extracellular
signal molecules called hormones. Hormones enable cells all over the body to communicate.
They also work to control and coordinate all the various actions of the body. Endocrinology is
the study of how hormones carry out these duties. Hormones can act in an autocrine, paracrine,
or endocrine manner. Hormones can be grouped as either steroid hormones or peptide hormones.
Steroid hormones, such as estrogen and testosterone, are synthesized from cholesterol by a series
of chemical reactions. Since cholesterol is a type of lipid and the cell membrane is composed of a
phospholipid bilayer, steroid hormones are able to diffuse across the cell membrane and bind to
intracellular receptors in the cytoplasm of a cell. Once the steroid hormones bind their receptor,
the complex can travel to the nucleus to regulate gene expression. A peptide hormone is a small
protein and they can be as short as 10 amino acids.
This triggers intracellular signaling pathways which transmit the information to the part of the
cell that needs to respond. Thus, these two hormones together keep glucose levels in the blood
within narrow limits.
Drugs Can Mimic Hormone Action
Understanding how hormones are used by the body has allowed us to manipulate this regulatory
system. Hormonal manipulation can be very beneficial and has allowed many patients suffering

from endocrine disorders to be effectively and safely treated.

One of the best examples of this is the treatment of type I diabetes mellitus by insulin. Type I
diabetes occurs when insulin secretion is abnormally low. Even though glucose levels in the
blood are high, because no insulin is released, glucose can not enter into the cells that need it.
Instead, excess glucose is excreted in urine. In fact, mellitus means sweet. Want to take a guess
how they figured out that the urine was sweet? Before 1922, the diagnosis of type I diabetes
mellitus was a death sentence. Although cells were surrounded by food, they could not utilize the
food efficiently and the body would literally starve to death. With the discovery and purification
of insulin, diabetes has become a chronic but treatable condition. By monitoring their glucose
levels and injecting insulin after meals, diabetics are able to manually control their blood glucose
levels. However, even though methods for monitoring blood glucose levels and injecting insulin
have vastly improved over the last 80 years, there is no way to match the efficiency with which
the body itself can regulate this process.
Hormonal manipulation can also be used irresponsibly. Anabolic steroids are steroid hormones
that promote muscle growth. Testosterone is the most potent anabolic steroid. Testosterone is
normally produced in the gonads. It is found in males and females, although at much higher
levels in males. Medically, anabolic steroids are used to treat males with testosterone
insufficiency or patients with chronic wasting illnesses such as AIDS.
However, many normally healthy adults, especially athletes, seek to use these steroids. Normal
adults and athletes seek the use of anabolic steroids because it results in increased protein
synthesis, increased muscle mass and strength, increased appetite, and increased production of
red blood cells all of which are seen as desirable for enhancing athletic performance. But as we
have pointed out earlier, the human body is precisely regulated. A decision to increase the
amount of a particular hormone when there is no natural deficiency can cause many problems in
the body's ability to regulate itself.
Undesirable side effects of anabolic steroid use include elevated blood pressure, increases in bad
(LDL) cholesterol levels and decreases in good (HDL) cholesterol, acne, reduced sexual
function, increased aggression, heart enlargement, liver damage, and increased risk of gingivitis.
Male specific side effects include breast development and testicular atrophy. Female specific side
effects include increase in body hair, deepening of the voice, and irregular menstrual cycles. So
besides the fact that the use of these hormones is illegal and dangerous to long term health, they
also have some extremely unpleasant side effects.
Feedback Loops Maintain Homeostasis
Hormones levels are regulated by feedback loops. This means that the hormone at the end of the
chain regulates the hormone at the beginning forming a loop. The hormones involved in
reproduction are an example of a negative feedback loop. GnRH stimulates the secretion of FSH
and LH which stimulate the secretion of progesterone and estrogen (females) or testosterone
(males). Progesterone, estrogen, and testosterone then feedback to the hypothalamus and inhibit
GnRH secretion.

Some hormones operate in positive feedback loops, although this is not as common. An example
of this is the regulation of oxytocin. Oxytocin is secreted from the pituitary and causes the uterus
to contract during labor. The signal for the secretion of oxytocin is the stretching of the uterus
and cervix caused by the baby's head. Oxytocin causes the uterus to contract forcing the baby's
head down further causing more stretching thereby positively regulating more oxytocin to be
secreted. This positive loop continues until the baby is delivered.
Menstruation Is Controlled by Hormone Release
Females produce eggs (gametes) in a monthly cycle called the menstrual cycle. It is named the
menstrual cycle because the cycle is marked by a 3-7 day period of menses. We will talk more
about this shortly. The average length of the menstrual cycle is 28 days. However this is just an
average, menstrual cycles lasting between 24-35 days are considered normal. The goal of the
menstrual cycle is to produce an egg. The egg is the largest cell in the body. Figure 3 gives you
an idea of how large an egg is as compared to a sperm.
The menstrual cycle consists of two phases or cycles: the ovarian cycle and the uterine cycle.
The cycle is divided in this manner in order to describe the production of the egg in the ovaries
and the physiological changes in the uterus that occur during the menstrual cycle. These cycles
are controlled by a combination of two classes of hormones, the gonadotrophic hormones
released from the anterior pituitary gland and the ovarian hormones. The gonadotrophic
hormones are luteinizing hormone and follicle stimulating hormone, and the ovarian hormones
are estrogen and progesterone. The first day of the menstrual cycle is designated by the first day
of menstruation. Menses describes a phase of the uterine cycle. The follicular phase is the phase
of the ovarian cycle that corresponds to menses in the uterine cycle. Let's start by taking a look at
the ovarian cycle and then the uterine cycle. We will then follow with a discussion on the
cessation of the cycle (menopause) and on how we can control the cycle. Figure 4 is a diagram of
the menstrual cycle. It shows the ovarian and uterine cycle. In addition, the diagram shows the
cycle of pituitary and ovarian hormones that occurs during the menstrual cycle. It will be helpful
to follow along with the diagram as we discuss the different cycles.
Both the ovarian and uterine cycles are under the control of various hormones. These hormones
include two that are released from the anterior pituitary gland: luteinizing hormone (LH) and
follicle stimulating hormone (FSH). The ovaries produce the sex hormones (also called
androgens) estrogen and progesterone. The hormonal control of the menstrual cycle is complex.
We will discuss the role each of these hormones plays in the cycle in turn as we go through the
different cycles.
You can follow the cycle the hormones go though on Figure 4. The ovarian cycle is responsible
for the production of a mature egg for fertilization and has three phases: 1) Follicular Phase 2)
Ovulation 3) Luteal Phase.
The follicular phase marks the start of the ovarian cycle. The entire phase lasts an average of 12
days. Each egg called a primary oocyte is surrounded by a layer of cells that form a structure
called a follicle. FSH is primarily responsible for the growth of the egg in the ovaries. There are
two types of cells in the follicle: granulosa and thecal cells. Granulosa cells produce estrogen
under the influence of FSH and thecal cells produce both estrogen and progesterone under the

influence of LH. Right before the beginning of the follicular phase, secretion of FSH increases.
This stimulates the growth of the follicle and the release of estrogen from the granulosa cells. LH
levels increase during this time and stimulate the thecal cells to produce estrogen as well.
As you can see from the diagram, estrogen levels rise continuously during the follicular phase.
Estrogen levels have two consequences. First, low levels of estrogen give a negative feedback to
the anterior pituitary to stop the secretion of FSH and LH. This occurs so that no more follicles
are stimulated to mature. Second, when the estrogen levels reach higher concentrations as the
follicular phase progresses, estrogen switches to give a positive feedback to the cells of the
follicle so that estrogen can still be produced in the absence of FSH and LH, which stimulated
production of estrogen from the follicular cells in the first place. During the early stages of the
follicular phase, some follicles will undergo a process called atresia. Atresia is regulated cell
death. This occurs until only one follicle survives the follicular cycle to proceed to ovulation, the
next phase of the ovarian cycle.
About 24 hours after the LH surge, ovulation begins. Simply put, the follicle ruptures and
releases the egg. Here is how it happens: The follicle secretes an enzyme called collagenase that
causes the breakdown of connective tissue that holds the follicular cells together. The egg is
released. The granulosa and thecal cells are transformed into luteal cells. They will form another
important structure called the corpus luteum. This process is called luteinization and is under the
control of LH. The luteal cells begin to secrete progesterone and estrogen production drops off.
Progesterone is important in the uterine cycle, so we will hold off on discussing the role of
progesterone until we discuss the uterine cycle. Ovulation occurs around the 14 day of the
menstrual cycle and lasts around 2 days before the ovarian cycle moves into the final phase, the
luteal phase. This time period represents the time in which you are most likely to become
pregnant.
The luteal phase is the last phase of the ovarian cycle. Progesterone, secreted by the corpus
luteum, is the dominant hormone of the luteal phase. The luteal phase has two outcomes, either
pregnancy or luteolysis (the degradation of the corpus luteum if no fertilization occurs). The
corpus luteum has a life span of around 12 days. If the egg is not fertilized after this time, it
undergoes apoptosis (programmed cell death). When the corpus luteum disintegrates, the level of
estrogen and progesterone decrease. If the egg is fertilized, the corpus luteum will continue to
secrete progesterone. This is important because progesterone is responsible for maintaining the
thick lining of the uterus, which provides an area rich in blood vessels that deliver nutrients to
the developing zygote.
The uterine cycle consists of the physiological changes that the endometrium of the uterus goes
through during the menstrual cycle. As you can see from Figure 5, the endometrium is the inner
lining of the uterus. The uterine cycle proceeds in a cyclic manner and has three phases that work
in conjunction with the phases of the ovarian cycle to promote pregnancy. The phases of the
uterine and ovarian cycles do not last the same length of time, so the phases do not match up
exactly.
The phases of the uterine cycle are:
1) Menses
2) Proliferative Phase

3) Secretory Phase.
Refer to Table 1 and 2 while reading about the uterine cycle phases.
The first day of menses corresponds to the late stage of the luteal phase and the start of the
follicular phase in the ovarian cycle. Menses is marked by a 3-7 day period of bleeding from the
uterus. The first day of the menstrual cycle is the first day of menses. This was arbitrarily chosen
as Day 1 of the cycle because it is easily recognized. Menses is the shedding of the endometrium
of the uterus. Remember that towards the end of the luteal phase of the ovarian cycle, the corpus
luteum secretes progesterone which maintains a thick blood vessel rich endometrium. When the
corpus luteum disintegrates, it no longer produces progesterone. Without the progesterone, the
thick lining of the endometrium degrades and begins to sloth off. The discharge of the lining
represents menses. Menses ends in the early part of the follicular phase. This phase represents the
growth of the endometrium in the uterus. The proliferative phase begins after menses and
corresponds to the early to middle stage of the follicular phase. Remember that during the
follicular phase estrogen levels are constantly increasing. The endometrium lining begins to
increase in thickness under the influence of estrogen.
The cells of the endometrium increase in number (proliferate). Angiogenesis also occurs.
Angiogenesis is the growth of new blood vessels from pre-existing vessels. This increases the
blood supply to the endometrium in order to bring in more nutrients and oxygen needed for
further growth of the endometrium and nourishment of the zygote if pregnancy occurs. By the
end of the follicular phase the endometrium reaches its thickest point and the uterus is ready for
ovulation.
Ovulation is followed by the luteal phase. Remember that in the luteal phase the corpus luteum
secretes progesterone. Progesterone has an influence on the endometrium. Progesterone
stimulates additional blood vessel growth. It also stimulates endometrial cells to deposit lipids
and glycogen in their cytoplasm that will nourish the embryo until the placenta is developed. The
endometrium is now called the secretory endometrium (this is the secretory phase). Progesterone
must be present to maintain the secretory endometrium. If fertilization does not occur, the corpus
luteum disintegrates and the production of progesterone ceases, blood vessels that were formed
begin to contract. Without the blood supply, the endometrium cells begin to die and sloth off.
This leads to menstruation and we are now back to the beginning of the cycle.
Birth Control
From implants to injections to the pill, there is a dizzying array of birth control methods
available on the market today. There is also a wide variety of non-hormonal forms of birth
control such as condoms or intrauterine devices (IUD). Since there are so many variations, we
will limit our discussion of birth control to hormonal methods of birth control such as the pill
(Figure 6).

The primary mechanism of action of oral contraceptives is to prevent ovulation. In addition, oral
contraceptives alter the endometrium of the uterus in such a way as to prevent implantation of
the egg in the uterus if ovulation does occur.
How do oral contraceptives prevent ovulation? Oral contraceptives inhibit the pituitary hormones
LH and FSH. That is great, but you may be asking yourself how are oral contraceptives are able
to do this? Remember that the key event to ovulation is the LH surge. LH is responsible for the
release of the egg from the ovaries. Without the LH surge, ovulation does not occur. Also
remember that low levels of estrogen give a negative feedback to the pituitary gland to inhibit the
release of LH and FSH.
Oral contraceptives provide just enough estrogen and progesterone to provide a constant negative
feedback to the pituitary to prevent the release of LH and FSH thereby preventing the LH surge
responsible for ovulation. This is why it is important to take the pill at the same time everyday,
24 hours apart. If a constant low level of estrogen is not maintained, it is possible depending on
where a woman is in her cycle that if she misses a pill, LH and FSH production will start leading
to the cascade of events that cause ovulation.
Hormones

A chemical substance secreted by an endocrine gland or group of endocrine

cells that acts to control or regulate specific physiological processes, including
growth, metabolism, and reproduction.

Endocrinology

The study of the glands and hormones of the body and their related disorders.

Autocrine

Of, relating to, promoted by, or being a substance secreted by a cell and acting

on surface receptors of the same cell.

Paracrine

Of, relating to, promoted by, or being a substance secreted by a cell and acting
on adjacent cells.

Endocrine

Hormones that secrete internally.

Steroid hormones

Steroids that act like hormones (i.e estrogen and testosterone)

Peptide hormones

A class of peptides that are secreted into the blood stream and have endocrine
functions in living animals.

Estrogen

Any of several steroid hormones produced chiefly by the ovaries and

responsible for promoting estrus and the development and maintenance of
female secondary sex characteristics.

Testosterone

A steroid hormone that is the most potent naturally occurring androgen and
that regulates the development of the male reproductive system and male
secondary sex characteristics.

Intracellular signaling
pathways

Transmit the information to the part of the cell that needs to respond.

Anabolic Steroids

Steroid hormones that promote muscle growth.

LDL Cholesterol

The cholesterol in low-density lipoproteins; the 'bad' cholesterol.

HDL Cholesterol

The cholesterol in high-density lipoproteins; the 'good' cholesterol.

Feedback loops

Regulate hormone levels; the hormone at the end of the chain regulates the
hormone at the beginning of the chain.

Negative feedback loop

When the output of a pathway inhibits inputs to the pathway.

Gonadotropin (GnRH)

A hormone produced by the hypothalamus that signals the anterior pituitary

gland to begin secreting luteinizing hormone (LH) and follicle-stimulating
hormone (FSH).

Progesterone

A steroid hormone secreted by the corpus luteum of the ovary and by the
placenta, that acts to prepare the uterus for implantation of the fertilized
ovum, to maintain pregnancy, and to promote development of the mammary
glands.

Hypothalamus

The part of the brain that lies below the thalamus, forming the major portion
of the ventral region of the diencephalon and functioning to regulate bodily
temperature, certain metabolic processes, and other autonomic activities.

Oxytocin

A short polypeptide hormone released from the posterior lobe of the pituitary
gland, that stimulates the contraction of smooth muscle of the uterus during
labor and facilitates ejection of milk from the breast during nursing.

Gamete

A reproductive cell having the haploid number of chromosomes, especially a

mature sperm or egg capable of fusing with a gamete of the opposite sex to
produce the fertilized egg.

Menstrual cycle

The periodic series of changes in the female reproductive system associated

with the preparation of the uterus for pregnancy; the cycle is repeated roughly
every 28 days. During the menstrual cycle, an ovum is released from one of
the ovaries (the release is called ovulation), and the uterus develops an inner
lining enriched with blood to prepare it for the possible implantation of a
zygote. If fertilization and implantation do not take place, the lining of the
uterus is discharged during menstruation.

Depression
Depression is not new. The economic downturn in the "Great Depression" of the 1930s caused a
significant amount of psychological depression. War is also a cause of depression.

Life Events Trigger Neurotransmitter Imbalances and Depression

Depression presents itself in many forms. Each individual responds differently to depression and

that is why it can be so difficult to diagnose and treat. The symptoms of depression fall into four
categories: mood, cognitive, behavioral, and physical. In other words, depression affects how
individuals feel, think, and behave as well as how their bodies work. People with depression may
experience symptoms in any combination of the above categories. Perhaps the most common
symptom of depression is the feeling of sadness combined with the loss of interest in activities
previously enjoyed. Other symptoms of depression include too much sleep or the inability to
sleep, agitation, emptiness, hopelessness, and profound apathy.
Depression can last weeks, months and even years. Most depression is treatable. Clinical
depression should be distinguished from the day to day blues. Many people can develop the
blues which can last for up to a week or two, however if the blues persist, a person could become
clinically depressed and may need treatment.
As the illness worsens the cognitive ability of the brain is affected leading to slowed thinking and
concentration, and decision making problems.
Depression can often be accompanied with other psychiatric disorders like psychosis and
anxiety, and it is a major cause of suicide. In the general population, major depression has been
documented in certain populations with a prevalence as high as 1 in 5 people (Figure 1). That
statistic came from a study in Beirut, Lebanon. In the United States, major depression is reported
in 1 in 20 people and in Taiwan 1 in 100. Why are these numbers so different? One could
imagine that the current social and economic conditions in a region contribute greatly to
depression, such that for example in times of extreme poverty, war, or natural disaster, incidence
of depression increases. We also know that genetics can predispose people to severe depression.
These are the types of factors that need to be taken into consideration when looking at the
statistics of depression.
What causes depression? The truth is that we have been striving since the earliest of times to
understand the nature of depression and its causes, but we still do not know for sure the exact
mechanism by which depression is triggered. There are a myriad of theories out there --- some
originating in the earliest of cultures including the ancient Greeks, Egyptians, and Hindus. There
are psychosocial theories, which include psychoanalytic, behavioral, and environmental among
several others. The psychoanalytic theories were pioneered by the prestigious Sigmund Freud
who developed the concept of looking at the mind for the cause of depression and other mental
illnesses. He postulated that illnesses of the mind are caused by unconscious conflicts between
human instincts. Behaviorists believe that humans come into the world with a blank slate that is
slowly filled with life experiences. They think that when the social environment no longer
supports individuals and no longer reinforces their behavior, depression sets in. Environmental
theories tie the depressive state to catastrophic life events like death, destruction, and loss of
love. Modern studies seem to support that the likelihood of depression increases five to six times
in the six months following a stressful life event.
Since many of the physiological causes and the underlying biology of depression are not fully
understood, let's focus on the drugs and their biological targets in the treatment of the depression.
We do know that physical changes occur in the brain of people and animals with depression.
Advances in brain imaging techniques have shown a reduction in activity in the left prefrontal
cortical and limbic areas (Figure 2) in individuals with recurrent or chronic depressive disorders.
This is not very surprising since the limbic system has been referred to as the seat of human

emotion since the late 1930s. The idea that depression is caused by genetic, neurotransmitter, or
neurohormonal factors are referred to as neurobiological theories.
Many of the most effective drugs to treat depression on the market today target the
neurotransmitters that are used by the brain's limbic system to communicate with the rest of the
brain and body. The most effective strategy for treatment of depression to date has been targeting
the neurotransmitter levels in neuronal synapses. A synapse is the area between two neurons
(brain cells) where neurotransmitters are released (Figure 3). This is called neuronal signaling.
Neuronal signaling occurs when a neurotransmitter is released from the presynaptic neuron into
the synapse.
What triggers this release? The release of a neurotransmitter occurs when a presynaptic neuron is
depolarized. This depolarization travels down the axon (cell body of a neuron) and causes the
opening of Ca2+channels at the presynaptic nerve terminal. This influx of Ca2+ into the
presynaptic neuron induces an intracellular signaling cascade that ultimately results in the release
of a neurotransmitter where it diffuses across the synapse and binds to receptors on the
postsynaptic cell. The resultant effect is neuronal cell signaling. The signal travels from the
presynaptic to the postsynaptic neuron. Now, depending on the type of neurotransmitter that is
released and the receptors that are expressed on the postsynaptic neuron, the binding of the
neurotransmitter to its receptor can either activate or repress the postsynaptic nerve. The
type of neurotransmitter that is released depends on the region of the brain that you are in, among
several other factors. Furthermore, multiple neurotransmitters can be released at the same time.
Medications Target Neurotransmitters
For reasons that are not clear, depression occurs when the brain functions as if it had insufficient
amounts of certain neurotransmitters in the synaptic clefts. The first effective medications to treat
depression worked by inhibiting the enzyme monoamine oxidase. These drugs are referred to
as monoamine oxidase inhibitors (MAOIs). MAOIs block the breakdown of certain
neurotransmitters (most biology terms that end in -ase have something to do with breaking
down).
Blocking these is like taking your foot off the brakes, the end result is an increased level of
certain neurotransmitters in the synaptic cleft. Examples of monoamine neurotransmitters are
dopamine (the target of cocaine), norepinephrine (also known as adrenaline), and serotonin.
These early treatments had severe side effects when taken with other medications or foods that
increased the levels of the targets of Monoamine oxidase. What happens when you step on the
gas and let off on the break? What happens if you have too much adrenaline? Aside from raising
your heart rate, adrenaline (epinephrine) increases your blood pressure by constricting your
blood vessels. People taking MAOIs that also took over the counter cough medicines,
decongestants, or diet pills were at high risk for severe elevations in blood pressure, strokes, and
even death.
Beginning in the late 1980s, a new armory of antidepressants became available in the fight
against depression. These are known as the selective serotonin reuptake inhibitors (SSRI)s.
SSRIs work by inhibiting the pumps (channels) that pump serotonin back into the presynaptic

nerve terminal. The end result is that there is more serotonin present in the synaptic clefts. When
a neurotransmitter is released into the postsynaptic cleft it needs to be removed so that the
signal can be turned off. This is yet another example of a feedback mechanism that is so
prevalent in biology. The only way to turn off a transmitter that is released is to either break it
down (like the MAO enzymes) or to pump it back to where it came from. The first SSRI was the
now-legendary Prozac, which was touted as a miracle drug by some clinicians and patients
because of its effectiveness and relatively low rate of side effects, as well as its much lower
lethal potential in overdose (Figure 4). Several other flavors of these drugs have come on the
market since Prozac. These drugs are also effective in a growing number of related psychiatric
conditions such as panic disorder and obsessive-compulsive disorder.
Medications Target Neurotransmitters
For reasons that are not clear, depression occurs when the brain functions as if it had insufficient
amounts of certain neurotransmitters in the synaptic clefts. The first effective medications to treat
depression worked by inhibiting the enzyme monoamine oxidase. These drugs are referred to
as monoamine oxidase inhibitors (MAOIs). MAOIs block the breakdown of certain
neurotransmitters (most biology terms that end in -ase have something to do with breaking
down).
Blocking these is like taking your foot off the brakes, the end result is an increased level of
certain neurotransmitters in the synaptic cleft. Examples of monoamine neurotransmitters are
dopamine (the target of cocaine), norepinephrine (also known as adrenaline), and serotonin.
These early treatments had severe side effects when taken with other medications or foods that
increased the levels of the targets of Monoamine oxidase. What happens when you step on the
gas and let off on the break? What happens if you have too much adrenaline? Aside from raising
your heart rate, adrenaline (epinephrine) increases your blood pressure by constricting your
blood vessels. People taking MAOIs that also took over the counter cough medicines,
decongestants, or diet pills were at high risk for severe elevations in blood pressure, strokes, and
even death.
Beginning in the late 1980s, a new armory of antidepressants became available in the fight
against depression. These are known as the selective serotonin reuptake inhibitors (SSRI)s.
SSRIs work by inhibiting the pumps (channels) that pump serotonin back into the presynaptic
nerve terminal. The end result is that there is more serotonin present in the synaptic clefts. When
a neurotransmitter is released into the postsynaptic cleft it needs to be removed so that the
signal can be turned off. This is yet another example of a feedback mechanism that is so
prevalent in biology. The only way to turn off a transmitter that is released is to either break it
down (like the MAO enzymes) or to pump it back to where it came from. The first SSRI was the
now-legendary Prozac, which was touted as a miracle drug by some clinicians and patients
because of its effectiveness and relatively low rate of side effects, as well as its much lower
lethal potential in overdose (Figure 4). Several other flavors of these drugs have come on the
market since Prozac. These drugs are also effective in a growing number of related psychiatric
conditions such as panic disorder and obsessive-compulsive disorder.
Genetics Predispose to Depression
Behavioral genetics is the study of the role of genes in behavior with the goal of identifying the

genes that predispose individuals to mood disorders. Because of the differences in the various
forms of depression, it seems unlikely that any single gene or gene combination will be found to
be responsible for all forms of depression. Studies of identical twins (that have the virtually
identical chromosomal pairs) have been effective for researching the role of genetic factors in the
cause of depression.
Furthermore studies that use twins who have been separated from birth or early age and reared in
different environments can test the role of genetic versus environmental factors in the causes of
depression. These studies have confirmed a genetic predisposition in most forms of depression.
For example, if one parent has a major depressive disorder, the risk of a child having depression
has been found to be 25-30%; with both parents affected, the percentage is doubled.
The detection of genes coding for mood disorders has turned out to be substantially more
difficult than previously anticipated. Depression, like so many other psychiatric disorders, does
not have defined cut and dry characteristics (Figure 5). There are many variables in a depressive
disorder, as we have talked about, there are social, genetic, and environmental triggers for
depression. If you mix these with other factors including severity of depression, age of onset, and
recurrence of the disease, it quickly becomes evident that there are no simple answers in this
complex disease.
Depression

A condition of general emotional dejection and withdrawal greater and m

that warranted by any objective reason.

Turn flashcard

Synapse

Turn flashcard

A synapse is a specialized region in the nervous system through which ne

Neuronal Signaling

Neuronal Signaling occurs within the cells of the nervous system and inv
hormones into localized areas of the nervous system called synapses.

Turn flashcard

Depolarization

A chemical process by which a neural cell changes its electrical potential,

positive through ion exchange with the help of channels of chloride and s
is part of the synaptic transmission.

Turn flashcard

Ca2 / Ca2+

Turn flashcard

Ca2+ = Calcium ions. Calcium ions are important for synaptic signal tran

Monoamine Oxidase Inhibitors

(MAOIs)

MAOIs are a type of powerful antidepressant drugs that function by block

monoamine neurotransmitters.

Turn flashcard

Selective Serotonin Reuptake

Inhibitors (SSRIs)

SSRIs are a type of antidepressant drug that extend the effect of serotonin
reabsorption of serotonin by neurons.

Exam 3 Test review

30. The central nervous system
The brain consists of the brain, brainstem and cerebellum
The spinal cord has cervical, thoracic, lumbar and sacral divisions
Memory may be differentiated into short-term and long term
Memory may be altered disease, drugs, and sleep abnormalities
Neuronal Biology
To understand this system, you have to realize that its output is similar to a large group of
interacting computers which are composed of select group of neurons that are responsible
for certain functions. The word ganglia or nucleus refers to a group of neurons that
have a specific function such as processing auditory signals. (The word nucleus can mean
an organelle or a group of neurons that have a specific function)
Connections between neurons are called synapses and are characterized by having pre and
post synaptic sites. Chemicals from the presynaptic site cross the synaptic cleft to reach the
postsynaptic site. The human brain has 100 billion neurons with thousands of synapses.
The neurons receive information, process it and transmit it to other cells by way of
electrical signals which cause the release of chemicals at the synapses.
Neurons have two types of extensions:
Dendrites: Neuronal extensions that receive electrical signals and transmit them to the
neuron.
Axons: Neuronal extensions that transmit electrical signals to otherneurons or muscle
cells. At the synapse, the electrical signal causes a release of neurochemicals.
There are three general categories of neurons:
Sensory neurons: transmit external information such as sound, touch, smell, etc..
Interneurons: exchanging information between neurons
Motor neurons: send signals to the effector cells and skeletal muscle. For example:
muscle contraction or gland secretion.
Neuronal communication is dependent on various electrical signals. The major ones are
Resting Potential, Action Potential, Inhibitory, and Excitatory potentials.
Memory
The brain
Is divided into 3 three main areas:
Brain: formed by lobes: frontal, parietal, occipital and temporal. These work together to
process intelligence, previous experiences, memory, feeling and emotions.
Brainstem: is the system of life support, regulates breathing, heart rate, and blood
pressure. It is the part of the brain that connects the brain to the spinal cord. Cerebellum is the
best friend of a skater, surfer and skier and that controls balance and
movement. It is also responsible for learning and remembering motor responses. For
example: learning to play the piano, dance,

Memory
Short-term memory: the ability to store information in seconds or minutes after passing.
For example, memorizing a phone number is dialed and then forgets it.
Long-term memory: information that is retained for months or years as words, symbols.
This is stored in the frontal cortex.
The information in the short-term memory can be transferred to the long term (the
hippocampus to the cortex) through practice, it is important to associate it with things
because it facilitates this process.
How alcohol affects your memory?
Research has shown that alcohol consumption disrupts the electrical and chemical activity
in the hippocampus making more difficult the transfer of information from short term
memory to the long term.
How sleep helps your memory?
When we sleep our brain enters a stage of restoration which helps us learn things, clear
your mind and be able to continue with our daily lives. So you know make sure you do your
homework early so you can get enough sleep.
31. Peripheral Nervous System
Neurons control smooth, skeletal and cardiac muscles
Autonomic neurons regulate secretion of smooth muscle, cardiac muscle and
glands
Sound waves activate the cochlea which sends electrical signals to the auditory
areas of the brain.
Music activates skeletal, cardiac, and smooth muscle
The peripheral nervous system resides outside the brain and spinal cord and is
responsible for collecting sensory information from external or internal stimuli and
transmitting this information to the CNS (central nervous system) through afferent sensory
neurons. It is also responsible for sending commands using different CNS neural circuits to
the glands and muscles. The nerves of this system are the twelve cranial nerves which
originate in the brain stem and 31 spinal nerves that originate in the spinal cord.
Motor neurons in the PNS are divided into two: the somatic nervous system that
regulates the movements that are under our control and respond to external stimuli and
autonomic nervous system which regulates smooth muscle and cardiac muscle which are
not directly under our control.
The autonomic nervous system controls the internal environment of the body. It
consists of a sympathetic and a parasympathetic component.
Parasympathetic nervous system regulates functions known as "rest and digest" and
the sympathetic nervous system dominates in stressful situations and emotional events
such as flight and fright and frolic (sexual function).
The autonomic nervous system has the neurotransmitters, acetylcholine and
adrenaline.
Sound waves are picked up by the auditory system that transfers sound wave
signals to electrical signals. The electrical signals are a reflection of the amplitude and
frequency of the sound waves.
Once sound waves are converted to electrical signals, they are transferred to different
areas of the brain which will trigger the somatic and autonomic nervous system
32. Skeletal, Smooth, and Cardiac Muscle

 Skeletal muscle contracts using actin, myosin, and intercalated discs

Smooth muscle is found in all involuntary systems, requires actin and myosin
Cardiac muscle has actin, myosin, and intercalated discs
Decrease in ATP causes skeletal, smooth, cardiac muscles to not function
To produce movement of the limbs, the brain sends signals to the spinal cord and
from there to the skeletal muscles (striated), when they contract. The movement is caused
by the molecular interaction of actin and myosin and ATP for both contraction and
relaxation.(Know the specific neural and molecular steps involved in skeletal muscle
contraction)
Smooth muscle is different from skeletal and cardiac muscle in that it is not under
voluntary control. Smooth muscle is found in the intestinal tract and blood vessels.
It controls blood vessels by altering their diameter and is under the control of the
autonomic nervous system.
Cardiac muscle is only located in the heart walls specifically in the myocardium.
Cardiac tissue receives its oxygen from coronary arteries which is used to produce ATP by
way of oxidative phosphorylation. There is a backup system. Normally oxygen is carried by
hemoglobin in the red blood cell to the cardiac tissue. However, there is another protein
called myoglobin found in the cardiac cells which binds oxygen and similarly to hemoglobin
releases oxygen when the oxygen concentration decreases.
The autonomic nervous system controls smooth and cardiac muscle. The somatic
nervous system controls skeletal muscle. 33. The Cardiovascular System
The Cardiovascular system has both systemic and pulmonary circulations
Blood flows from the heart (left side) into the arteries, capillaries and veins, and
returns to the heart (right side)
Differences in pressure are required for blood to flow from the heart's left side to
the right side with the left side having the greater pressure
An electrocardiogram, ECG, measures the electrical activity associated with cardiac
muscle contraction
The cardiovascular system is the most important biological system since it transfers
oxygen to the mitochondria in every cell, by way of the red blood cells, as well as the
nutrients required by the cells to form ATP and other important chemical structures.
Blood flows from the high pressure chamber (left ventricle) to the low pressure
chamber.
The cardiovascular system has a circulation designed in parallel so if there is a
decrease of blood there can be an instant redirection of blood to major organs. It's like a
highway. If an accident happens you can change lanes and continue on your way.
The cardiovascular system is characterized by systemic arteries that carry
oxygenated blood while the systemic venous system carries deoxygenated blood. The idea
that the blood in the venous system is completely deoxygenated is incorrect, since in case
something interferes with the transport of oxygen into the lungs the hemoglobin in the red
blood cells attaches 4 oxygen molecules which allows for 3-5 minutes reserve of
oxygenated blood.
The AV valves separate the atrial from the ventricles whereas the semilunar valves
control the output from ventricles.
The electrocardiogram records the electric signals generated and transmitted by the
contracting cardiac muscle of the atria and ventricles.

Coronary Arteries- these are the first branches of the aorta and are essential for
supplying oxygen to the cardiac muscle during diastole so that blood flows through the
capillaries of the heart muscle. (Know the difference between systole and diastole)
34. Blood Pressure Control
Systolic / diastolic pressures dictate blood flow
The cardiac output is determined by multiplying the stroke volume by the heart rate
Baroreceptors are sensors that monitor and control blood pressure
Hypertension / hypotension are serious clinical conditions
Emotions such as joy, fear and excitement as well as genetic factors activate the
autonomic nervous system, which regulates blood pressure and if it is too high for a period
of time will cause structural damage and weakness to the vasculature leading to hemorrhage and
death. Hypotension is a decrease in blood pressure resulting in a decrease
in blood flow that may lead to cell death.
Before the left ventricle ejects blood into the coronary arteries and the aorta, the
pressure must rise to propel the blood throughout the body. This pressure generated
before the expulsion is called systolic pressure. Subsequently, the pressure in the chamber
decreases and the left ventricle relaxes. The lower pressure in the left ventricle before the
ventricle begins to contract is the diastolic pressure. Normal blood pressure is usually
referred to as systolic/diastolic pressures in terms of mm of Hg (millimeters of mercury)
pressure of 120/80
The difference between systolic and diastolic pressure is the pulse pressure, referred
to the net pressure generated by each heartbeat or cardiac contraction pumps blood to the
body.
Pulse pressure is directly related to the amount of blood pumped by each contraction
of the heart. This is called a stroke volume which is determined by three factors:
Preload: refers to the fact that the more cardiac muscle is stretched is the more
powerful the contraction. When we exercise, there is increased venous blood returning to
the heart which increases its force of contraction. Preload is determined by the amount of
blood entering the right ventricle.
After load: pressure is related pressure that the ventricles must overcome to eject
the blood. It occurs in two places: where the right ventricle has to produce enough pressure
to overcome the pressure of the pulmonary circulation and the left ventricle has to
overcome the pressure of the aorta which is called aortic pressure.
Contractility is the force that muscles generate.
The pressure control is regulated by feedback loops controlled by the autonomic
nervous system. For example, if the pressure in the carotid arteries rises sharply, the blood
vessels expand and the baroreceptor senses this change and sends signals to the
parasympathetic nervous system to decrease heart rate.
Risk of hypertension and hypotension:
Hypertension: can cause death in two different ways: if there is no signicant
difference between systolic and diastolic pressure, there will be decrease flow. In addition
high blood pressure can cause damage and weakening of the blood vessels resulting in
strokes or damage to capillary beds. .
Hypotension: is defined as systolic and diastolic blood pressures of 90 mm Hg/ 60
mm Hg. Its causes include: dehydration, blood loss, and inability of the heart muscles to
generate enough pressure. When there is not enough difference between systolic and

diastolic pressure this leads to low blood flow, decrease in oxygen delivery to the
mitochondria, decrease in ATP and subsequent cessation of chemical activity in the cells,
tissues and organs.35. Capillaries
These are some of the functions performed by the capillary:
Self-regulation redistributes blood flow
Transport molecular exchange of substances.
Oncotic pressure influences blood pressure
Movement of water (osmosis) hydrating tissues
There are three types of blood vessels: arteries, veins and capillaries. Pies arteries and
veins are parallel between them. The arteries away from the heart and branch into smaller
and smaller vessels to form capillaries, they are continuous with the veins are vessels that
carry blood back to the heart. We can say that there is a "spider web" of capillaries
connecting the terminal branches of the arteries and veins.
Perhaps some of us are familiar with the veins and arteries, but not so much with the
capillaries. Capillaries play a role in the circulatory system, as they are as a web connecting
the arterial and venous circulation and allow oxygen and nutrients to the cells. We can
imagine them as rivers reach our cells nutrients and carry them collect the resulting
products of cellular metabolism.
Control capillaries which substances into and out of the blood and the cells bathed unlike
capillary arteries and veins are very thin and fragile. There are three major types of
capillaries varying permeability grade solutes. The capillaries are formed by a layer of
endothelial cells and a collagen membrane. This module teaches the characteristics of three
kinds of major capillaries: capillary continuous sinusoidal fenestrated and autoregulation
like plays an important role in the body to maintain the constant pressure and at a normal
level. Also learn how oxygen is released in the body in the capillary network. For example,
the capillaries of the heart are always open because the heart muscle requires a large
amount of oxygen to make ATP. In contrast, capillaries in the legs change their flow as
needed, only have a 20% flow as you read, but may increase to 100% if you had to run.
36. Respiration and Ventilation
(Respiration refers to the metabolic systems that require oxygen to make ATP whereas
Ventilation refers to the contraction of the diaphragm and chest muscles to move air in and
out of the lungs. Many times respiration is used in place of ventilation)
Brainstem neurons controls the diaphragm and other muscles involved in ventilation Pressure
differences between the thorax and the atmosphere move air in and out of the
lungs
Depth and rate of ventilation influence the blood pH (7.4) which affects all metabolic
systems
Lung Diseases cause a decrease in oxygen and an increase in carbon dioxide in the blood
The respiratory system is responsible for bringing air which has oxygen into the lungs and
expelling carbon dioxide from the body. The anatomy of this system is designed to generate
positive and negative intrathoracic pressure to allow the exchange of oxygen and carbon
dioxide between the air and the blood.
The path of air containing oxygen is 1 to 8 and for carbon dioxide 8 to 1
1. Nose and Mouth
2. Pharynx
3. Larynx

4. Trachea
5. Bronchi
6. Bronchioles
7. Alveoli
8. Capillaries surrounding the alveoli
Notice: The gas exchange occurs between the alveoli and the pulmonary capillaries
The pharynx is the area where the respiratory and digestive system is connected. When we
swallow, the food goes from the mouth to the pharynx and the esophagus but, not the
larynx as this will block the air going into the lungs. (This occurs when you eat and talk).
The larynx is the opening to the pulmonary system.
At the end of the terminal bronchioles are the alveoli and pulmonary capillaries which is
the site for the exchange of oxygen and carbon dioxide . The contraction and relaxation of
the diaphragm allows for the entry and exit of air by producing positive and negative
pressure in the lungs.
The diagram has three different openings called hiatus through which the aorta, esophagus
and inferior vena cava pass.
Asthma occurs when the bronchial tubes become inflamed and constricted. Smooth muscle
contracts the bronchial walls and mucus cells are activated resulting in a decrease in air
reaching the alveoli. 37. Cellular Communication
Ligand (chemical messenger) binds to receptors on or in cells
Signaling involves both extracellular and intracellular molecules attaching to receptors
Signaling pathways control cell functions by releasing molecules either close by or into the
blood
The endocrine system is an example of a system that uses signaling to control function
Cells communicate by sending and receiving signals. Signals are molecules which act on a
target cell that have an internal or external receptor for that ligand. Signaling molecules may be
chemicals, proteins, lipids, nucleic acids, and dissolved gases such as nitric oxide. Most receptors
are located on the cell surface, but some are located within the cell (intracellular receptors). The
molecular signals can only interact with their specific receptors.
The endocrine glands are found throughout the body. A major endocrine gland is the
pituitary gland (or pituitary) located at the base of the brain below the hypothalamus. The
hypothalamus regulates the secretion of pituitary hormones. These hormonal regulators control a
variety of physiological processes, acting in many different organs of the body. These include
growth, reproduction, water retention, breast development, metabolic rate, and the stress
response.
38. Hormones and menstruation
Hormones are potent signaling molecules
Drugs can mimic and block hormonal action
Endocrine (Hormonal) Feedback maintains homeostasis
Menstruation is controlled by the sequential increase and decrease of various hormones.
The endocrine (hormonal) system is composed of specialized cells that form glands which
secrete hormones that may be called extracellular signals. Hormones allow communication
between cells throughout the body. They work to control and coordinate the various
actions of the body. Endocrinology is the study of how hormones perform these tasks.
Besides the nervous system, the hormonal system is the other great coordinator of bodily
functions.

Certain types of medications can mimic hormonal reactions. Understanding how hormones
are used by the body allows for the manipulation of these regulatory systems. Hormonal
manipulation can be very beneficial and allows many patients suffering from endocrine
disorders to be treated. One of the best examples is the treatment for of type 1 diabetes
with insulin which is a hormone which is secreted from the pancreas and controls blood
glucose levels.Endocrine circuits maintain homeostasis and are regulated by feedback circuits.
This
means that the hormone at the extreme end of the endocrine chain regulates the release of
hormones at the beginning of the endocrine chain forming a molecular "loop." A hormone
involved in reproduction is an example of a negative feedback loop.
For example, Gonatotrophin Releasing Hormone (GnRH) stimulates the secretion of Follicle
Stimulating Hormone (FSH) and Luetinizing Hormone (LH ) which stimulates the secretion
of progesterone and estrogen or testosterone. Hormonal levels of progesterone, estrogen
and testosterone in the blood are detected by the hypothalamus which inhibits the further
secretion of GnRH.
Other examples are the hormones that regulate the menstrual cycle. The menstrual cycle
consists of two phases: the ovarian cycle and uterine cycle:
- The ovarian cycle: egg production in the ovaries
- Uterine cycle: physiological changes in the uterus that occur during the menstrual cycle.
These cycles are controlled by two types of hormones, ovarian hormones and gonadotropin
hormones:
- Gonadotropin hormones: released by the anterior pituitary gland (adenohypophysis)
- Ovarian hormones: are estrogen and progesterone
In short, it is just a connection of several feedback loops that lead to the formation of
hormones that regulate the menstrual cycle of women.
39. Depression
Neurotransmitters (chemicals) released at the synaptic region in certain areas of the
brain play a role in determining mood
Medications influence the release or inhibition of neurotransmitters that influence
mood.
Life events generate altered levels of the neurotransmitters which may trigger mood
changes.
Genotype influences the release of neurotransmitters that determine mood.
Some life events like the death of a loved one, a "broken heart", or low self-esteem leads to
feelings of sadness which may lead to a clinical state of depression which is explained by a
chemical imbalance in the brain. Certain neurotransmitters have abnormal levels in areas
of the brain such as the limbic system that determine mood.
Depressive symptoms are grouped into four categories: mood, cognitive, behavioral, and
physical. In other words, depression affects how people feel, think and behave and how
your body works. Depression may last for weeks, months or even years. Clinical depression must
be distinguished from everyday blues. The blues are feelings we have when sad
events happen in our lives such as the loss of a loved one, but if they last a longer time than
normal people, the clinical diagnosis of depression is used.
Many of the most effective drugs for the treatment of depression in the market today affect
neurotransmitters that are located in the limbic system of the brain. The most effective
strategy for the treatment of depression so far has been the regulation of neurotransmitter

levels in synapses .The first effective drugs used for the treatment of depression are those
that act by inhibiting the enzyme monoamine oxidase. These drugs are known as
monoamine oxidase inhibitors (MAOIs) which block decomposition of certain
neurotransmitters such as norepinephrine, dopamine and serotonin so that they persist
longer in the synaptic region. Selective serotonin reuptake inhibitors (SSRI) are used more
frequently and work by inhibiting the uptake of only serotonin at the synapse. All these
medications have side effects. Genetics also plays a role in depression since certain
transcription and translation control mechanisms for the release of monoamines is altered
in persons who have inherited a propensity to be depressed.

Innate Immune System

Can you imagine being unable to touch your mother or to play with a friend or to walk outside
your house? That was the story of David Vetter who was the boy in the bubble. He had no
immune system (also known as SCID). He died at the age of 12 and never left his bubble until
his death. This module will reveal the secret weapons your body uses to defend itself from the
outside

In order to understand immunology and infectious diseases, we have to remember that we are
completely surrounded by microbes. Our bodies not only have to nourish us, but they also have
to shelter us from extreme environments using an active defense system. This defense system
uses a regulatory and recognition mechanism that allow us to distinguish self and nonself. The
origins of these mechanisms go far back in evolutionary history and many, in fact, originated as
markers for allowing cells to recognize and interact with each other to set up symbiotic
households, and to keep away undesired neighbors. For instance, genetically related sponge
colonies that are placed close to each other will tend to grow toward each other and fuse into one
large colony, however, unrelated colonies will react in a different way, destroying cells that come
in contact and leave a zone of rejection between the colonies.

The immune system is composed of two branches: innate immunity and adaptive immunity
(concept 1). This module will focus on characteristics of the innate immune system while the
adaptive immune system will primarily be covered in the next e-module. Cells of the immune
system are derived from white blood cells. White blood cells, along with red blood cells
(circulatory system, Fig.1), are formed from the cells in the bone marrow called hematopoietic
stem cells. An average adult human has about 1-2% white blood cells in his/her total blood
volume. These cells communicate and coordinate their actions through the release of chemical
signals called cytokines. White blood cells of the innate immune system are phagocytes and
natural killer cells. White blood cells of the adaptive immune system are T and B cells.
The innate immune system is also called constitutive immunity because it is always active and
will respond to any invading microbe without prior exposure to it. The innate immune system is
often the initial line of defense against a pathogen. We have three lines of defense (Fig. 2). The
first and second lines of defenses are associated with innate immunity and the third one with
adaptive immunity. The first line of defense consists of nonspecific surface defenses, which are
physical barriers (structural/mechanical) along with a broad array of chemicals/proteins
(biochemical) that prevent pathogens from entering deeper tissue. The second line of defense
occurs in the interior of the tissue and refers to inflammation, which leads to phagocytosis.
These two lines of defenses are considered nonspecific because they act in the same way against
all microbes. In evolutionary terms, the innate immune system is old and can be found in nearly
all forms of life including plants, fungi, and insects. The third line of immune defenses (Fig. 2)
is adaptive immunity, which is activated when innate immunity is not successful at combating
the infection. All three lines of defense are essential parts our response to microbial infection.
Areas of your body that are directly exposed to the outside world such as the surface of our skin,
the respiratory tract and the digestive tract are carefully guarded by an extra level of defense and
common protection methods are mucus and other body secretions. In addition, your normal flora
also provides a natural barrier to infection. Under optimal conditions, a persons internal tissues
(brain, muscle, etc.) are free of microorganisms; however, his/her surface tissues (skin, mucous
membranes, etc) are in contact with environmental organisms and become readily colonized by
various microbial species. The mixture of organisms regularly found at any anatomical site is
referred to as the normal flora. The normal flora of humans consists of a few eukaryotic fungi
and protists, but bacteria are the most numerous microbial components. Normal flora has formed
a symbiotic relationship with your body and provides another protective barrier to illness causing
bacteria by producing secondary metabolites that inhibit adhesion, and growth of the attacking
microbes. Staphylococcus epidermidis (S. epidermidis) and Staphylococcus aureus (S. aureus)
are normal flora of the skin (Fig. 3). S. aureus tends to be found in moist environments such as
the nostrils and armpits, whereas S. epidermidis is usually found in drier areas of the skin. S.
epidermidis is rarely pathogenic, whereas S. aureus is widely known as a troublesome
opportunistic pathogen.
It was not until recently that the scientific community has become aware of the importance of
bacteria living in you. The NIH (National Institute of Health) will fund the genome sequencing
of these bacteria to investigate their properties and elucidate how they aid the immune system.
Although, this genome sequencing endeavor will be difficult due to very diverse bacteria, it will
reveal information about its origins. For instance, there is current speculation that some type of
bacteria can help you maintain a healthy weight, and this type of information will be useful if
you are trying to lose weight.

Skin is the largest organ in vertebrates, in an adult human 15% of the total weight is skin, and it
is an absolutely essential organ. We all have different types of skin (Fig. 4) but they all serve the
same purpose: to keep water in, and keep microbes out. This is very important when you
consider the fact that one square inch of skin contains around 50 million bacteria that no amount
of cleaning can completely remove. Skin keeps these microbes on the surface by providing a
nearly impenetrable physical barrier that is supplemented with chemical weapons. For example,
oil and sweat glands within the skin lower the pH to a level that inhibits microbial growth. Sweat
and oily secretions produce hydrolytic enzymes such as lysozyme (Fig. 5) that digest the cells
walls of many bacteria.
Lastly, dead skin is constantly sloughing off taking the adherent microbes along with it.
Hopefully, you maintain a basic level of hygiene to assist your innate immune system because
dead skin cells mixed with dirt and oil provide an extra food source for bacteria. These cellular
defenses create an almost impassable barrier that is mainly breached when skin is damaged
through cuts, burns, and abrasions (Fig. 6).
An additional port of entry is through inhalation into the respiratory tract. Cells lining our upper
respiratory tract secrete sticky mucus that traps microbes before they can reach the warm, moist
areas deep in our lungs that make such ideal breeding grounds (Fig. 7). Cilia on the cells lining
sweeps the mucus and any microbe upwards where it can be removed through coughing,
sneezing, or swallowing (where the acidic medium of the stomach will eliminate them).
Another, important protecting factor of the immune system is lysozyme. The lysozyme is
abundant in a number of secretions such as tears, saliva, and mucus. It is responsible for breaking
down the polysaccharide walls of many kinds of bacteria and thus it provides some protection
against infection. Bacteria found in the foods we eat, are typically removed by the lysozyme
produced in saliva, stomach acid, and/or digestive enzymes in the small intestine. However, our
body has an efficient method of getting rid of microbes in the event that your hydrolytic enzymes
do not kill the ingested bacteria, you would vomit or develop diarrhea (Fig. 8). These processes
are necessary pathogen removal mechanisms employed by our bodies. Although unpleasant, it
can be beneficial to allow the body to purge these microbes rather than to try to stop it through
the use of anti-vomiting/anti-diarrhea medication. However, prolonged diarrhea or vomiting
(more than 3 days) can also be a symptom of serious illnesses and you need to seek medical
assistance because the loss of bodily fluids can lead to dehydration, and in severe cases,
permanent damage or death.
Physical barriers are not always sufficient to stop smart pathogenic microbes, and a second line
of defense is necessary. These are immune cells that protect the bloodstream and tissues from
invading microbes as well as host cells that have been infected by microbes. Immune system
cells are not located in one particular tissue as in other body systems, nor are the immune system
controlled by a central organ. Rather, the immune system is composed of a host of individual
cells that rush to the site of infection upon request. The various components of the immune
system are combined in an exquisitely complex communications network that functions as an
effective defense against foreign microorganisms and against body cells that have become
abnormal.
Inflammation response

One of the first responses to infection is the generation of an inflammatory response by the
innate immune system. The symptoms of inflammation include redness, a sense of heat,
swelling (edema), and throbbing pain (see Fig. 9). Although the inflamed tissue may feel
uncomfortable, these reactions are a critical step in controlling an infection. Inflammation at the
site of infection speeds up the killing of invading microbes by the front-line microphages and
causes changes in the walls of local blood vessels that enable additional molecules and
macrophages to enter the infected tissue from the blood. Local expansion of capillaries increases
the flow of blood to the site of infection/injury. Without inflammation, wounds and infections
would not heal. The increased blood flow results in the characteristic redness and increased heat
at the site of inflammation. Since the capillaries are leakier, an increase in fluid, along with
phagocytes, will leak into the tissue. This causes swelling of the area. Pain is caused by
compression of nerves due to the swelling.
Sometimes, pus is often seen within an infected area, and pus is comprised of dying phagocytes,
broken down tissue cells and dead microbes. Inflammation also induces local blood clotting,
making a physical barrier to the spread of infection through the bloodstream. The inflammatory
response has to be carefully controlled because if it malfunctions it can damage healthy tissue
and cause diseases such as arthritis. Fever is one of the most common manifestations of infection
and inflammation. Fever is caused by many bacterial products. Fever contributes to your bodys
defenses by creating a temperature that is less favorable to microbial growth. Fever also
stimulates phagocytosis and causes the body to reduce blood levels of iron, which bacteria need
to grow. Fever is caused by chemical signals called pyrogens that are released by macrophages
that have encountered invading microbes. Pyrogens travel to the hypothalamus, and signal for an
increase in body temperature. The hypothalamus acts as the bodys thermostat. However,
this system has to be carefully monitored since very high temperatures can damage your healthy
cells. As a rule of thumb, temperatures greater than 103 F are considered dangerous, and you
might need medical assistance, temperatures greater than 105 F can be fatal.
Cells of the immune system
The distribution of lymphoid tissues in the body is shown in Figure 10 and the lymphatic organs
are those in which lymphocyte maturation, differentiation, and proliferation take place. These
organs are divided into primary lymphoid organs -thymus and bone marrow, and secondary
lymphoid organs - spleen and lymph nodes. We will discuss these organs in more detail in the
next e-module. Cells of the innate immune system are phagocytes and natural killer cells.
Phagocytes are a type of cell that kills microbes by ingesting them through a process called
phagocytosis (see Fig. 11). During phagocytosis, flowing cytoplasmic extensions engulf the
microbe. Then, the phagocyte uses lysozyme and other chemicals to destroy the microbe. There
are different types of phagocytic cells that your body uses to fight infection, but one of the most
important phagocytic cells is called a macrophage. Macrophages will engulf anything that is not
normal including cell debris, dust particles, invading microbes, and cells infected by microbes.
Macrophages are motile and can move through your blood and tissues searching out and
destroying invading microbes (see Fig. 12).
Dendritic cells are long-lived phagocytic cells and reside in an immature state in most tissues,
where they recognize and phagocytize pathogens and other antigens. They are important in both

innate immunity and the initiation of adaptive immune responses. Natural killer cells differ from
phagocytes in that they do not kill invading microbes, but rather the host cells that are infected
with them. In viral infections, this prevents the infected host cell from producing more viral
progeny and infecting neighboring cells.
Natural killer cells also recognize altered features of the membranes of abnormal cells such
cancer cells and get rid of them. Natural killer cells kill by the release of various cytotoxic
molecules. Some of these molecules cause the formation of pores in the membrane of the target
cell, leading to cell destruction (Fig. 13).
Innate defenses are considered non-specific because they target all microbes in the same general
manner. These innate defenses cannot recognize or distinguish one microbe from another and
they do not remember specific microbes or the most effective way to get rid of infection.
Your immune cells can also recognize your own cells and distinguish them, even from other
human cells. If your immune system loses the ability to recognize itself, your immune system
can attack your own healthy cells resulting in an autoimmune disease such as allergies.
Cells in your body contain a surface protein marker that identifies them as self. Each person
has a different version of this marker, although all cells within an individual contain the same
one. The cells of the immune system ignore any cells having self marker, but will attack cells
that lack the self marker or, as is the case with tumor cells, have an altered self marker (Fig.
14).
Although, we have an incredible immune system, microbes have evolved mechanisms to evade
our killing mechanism. A classic example is how microbes make proteins that help them adhere
to host cells. They also will make proteins that can degrade the chemical weapons of the innate
immune system or they secrete toxins that poison the immune system. Because of this reason,
the innate immune system is not sufficient in controlling infection and another line of immunity
is essential. Innate immunity protects our bodies from small infections or stalls the progress of
infection until our adaptive immune system is activated with the help of innate immunity. The
two branches of the immune system form a synergistic relationship in their fight against infection
and by working together they are more efficient at controlling infection (Fig. 15). As we will
learn in the next e-module interrelationships between innate and adaptive immunity build a
strong defense system.

Adaptive Immune System

And you thought your mom was kidding when she told you that you needed to get your shots or
you would get chicken pox even on your butt. Mom was right. Chickenpox is caused by
the varicella-zoster virus (VZV). Kids can be protected from VZV by getting the chickenpox
(varicella) vaccine, usually between the ages of 12 to 15 months.

Adaptive immunity is more specialized than innate immunity and it supplements the protection
provided by innate immunity. Adaptive immunity came into play relatively late, in evolutionary
terms, and is present only in vertebrates. A major difference between the innate and adaptive
immune system is the ability to recognize specific pathogens. In other words, while the innate
immune system may recognize bacteria in general, the adaptive immune system will recognize a
specific bacterium (Fig 1.). The adaptive immune system can respond rapidly after coming in
contact with a microbe because it can remember prior encounters. This is the reason why you
might develop an infection the first you come across a specific microbe such as the chickenpox
virus, but you will not get sick the second time you contact it.
All systems of the body depend on one other for its survival; however, the immune system is
particularly tied to the circulatory system. Remember, the cells of the immune system do not
reside in any one place, but rather circulate throughout the entire body via the circulatory
system. This continuous movement through the body ensures that the T and B cells will be
exposed to foreign antigens. Capillaries are particularly important because these are the smallest
of the blood vessels where the interchange between oxygen and carbon dioxide between blood
and tissue cells occurs. This means that capillaries have access to all tissues of the body and can
aid in monitoring those tissues for signs of infection. Endothelial cells that make up the capillary

walls will capture immune cells such as phagocytes as they pass by a site of tissue infection. The
peripheral blood contains 2050% of circulating lymphocytes; the rest move in the lymph
system. Roughly 80% of them are T cells, 15% B cells and remainder are undifferentiated cells.
Lymphocytes constitute 2040% of the body's White Blood Cells. Their total mass is about the
same as that of the brain or liver.
Key elements of a successful immune response
The main characteristics of the adaptive immune system response are its ability to recognize,
activate, and quickly respond to foreign entities (Fig. 2). These characteristics are founded on
specificity, which is the ability to discriminate among different molecular entities, and to respond
to only those uniquely required (non-self).
Adaptiveness is the ability to respond to previously unseen molecules that may in fact never have
naturally existed before.
Memory is a property shared with the nervous system, is the ability to recall previous contact
with a foreign molecule and respond to it in a learned manner.
Organs of the immune system
Lymphatic organs are those organs in which lymphocyte maturation, differentiation, and
proliferation take place. They are divided into two categories. The primary lymphoid organs
(bone marrow and thymus) are those in which the maturation of T and B lymphocytes into
antigen-recognizing takes place. Antigen-shifting is the term used for the one of the direct
weapon used by microbes against the immune system. Mature B and T lymphocytes migrate
from the primary lymphoid organs through the bloodstream to the secondary lymphoid organs
(lymph nodes, the spleen, and gut-associated lymphoid tissues such as the tonsils). The
secondary (peripheral) lymphoid organs are those organs in which antigen-committed
lymphocytes are stimulated by antigens to undergo further division and differentiation. The
adaptive immune response occurs mainly in the secondary lymphoid organs. Pathogens and
their secreted antigens are trapped in these secondary lymphoid tissues, and presented to the
native lymphocytes that constantly pass through. Microorganisms that enter the body through
the skin or the lungs drain to the regional lymph nodes where they stimulate an immune
response. Microorganisms and food antigens that enter the gastrointestinal tract are collected in
the gut-associated lymphoid tissue.
Microbes that enter the bloodstream stimulate an immune response in the spleen. In addition to
being a lymphoid organ, the spleen filters the blood to remove aged or abnormal red cells and
invading microorganisms.
All the cells of the immune system are initially derived from the bone marrow. They form
through a process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells
differentiate into either mature cells of the immune system or into precursors of cells that migrate
out of the bone marrow to continue their maturation elsewhere. The bone marrow produces B
cells, natural killer cells, granulocytes, and immature thymocytes in addition to red blood cells
and platelets. The function of the thymus is to produce mature T cells (thymus cells). Immature
thymocytes leave the bone marrow and migrate into the thymus. Through an interesting

maturation process in which the first positive selection process weeds out only those T cells with
the correct set of receptors that can recognize the MHC (Major Histocompatibility Complex)
molecules responsible for self-recognition. Then a negative selection process begins whereby T
cells that can recognize MHC molecules complexed with foreign peptides are allowed to pass out
of the thymus. The mature T cells are then released into the bloodstream.
The role of the Major Histocompatibility Complex (MHC)
MHC molecules play a crucial role in the response of T cells to antigens that penetrate or live
inside cells of the body. MHC molecules bind to amino acids derived from proteins and present
them to T cells with the appropriate receptor. Thus, T cells responses are said to be MHC
restricted. The MHC codes for two major categories of cell surface transmembrane molecules,
MHC class I and class II molecules.
MHC class I are expressed on all nucleated cells, but MHC class II are only found on B cells and
macrophage or dendritic cells (both of these are known as APCs-antigen presenting cells).
Each individual expresses a distinct array of MHC class I and class II molecules from other
individuals. This diversity comes about because different individuals within a species have a
range of slightly different forms of MHC class I, and class II genes. However, an individual
expresses the same MHC class I and II molecules in all his/her cells, and expresses them at the
cell surface. An immune response to foreign antigen requires the presence of an antigenpresenting cell. When an APC presents an antigen on its cell surface to a B cell, the B cell is
signalled to proliferate and produce antibodies that specifically bind to that antigen. If the
antibodies bind to antigens on the surface of the bacteria/pathogen, it acts as a signal for
macrophages to kill them.
The spleen is an immunologic filter of the blood. It is made up of B cells, T cells, macrophages,
dendritic cells, natural killer cells, and red blood cells. In addition to capturing foreign materials
(antigens) from the blood that passes through the spleen, migratory macrophages and dendritic
cells bring antigens to the spleen via the bloodstream. An immune response is initiated when the
macrophage or dendritic cells present the antigen to the appropriate B or T cells. You can picture
this organ as an immunological conference room where important people meet to make sure the
body is safely guarded. In the spleen, B cells become activated and produce large amounts of
antibody. Also, old red blood cells are destroyed in the spleen. This brings us to the lymph nodes
which function as an immunologic filter for the bodily fluid known as lymph. Lymph nodes are
found throughout the body (see diagram). Composed mostly of T cells, B cells, dendritic cells
and macrophages, the nodes drain fluid from most of our tissues. Antigens are filtered out of the
lymph in the lymph node before returning the lymph to the circulation.
There are two fundamental adaptive mechanisms
Parts of the immune system are changeable and can adapt to better attack the invading antigen.
There are two fundamental adaptive mechanisms: cell-mediated immunity and humoral
immunity. To completely understand these concepts we will learn in detail how T and B cell
function.
Cell-mediated immunity- refers to macrophages engulfing antigens, processing them internally,
and then displaying parts of them on their surface. This sensitizes the T cells to recognize these

antigens.
Humoral immunitytypically refers to an immature B-lymphocyte is stimulated to maturity
when an antigen binds to its surface receptors and an observant T helper cell releases a cytokine.
This reaction signals to the B cell to undergo clonal selection-asexual reproduction by mitosis.
Most of the family of clones become plasma cells. These cells, after an initial lag, produce highly
specific antibodies at a rate of as many as 2000 molecules per second for four to five days. The
other B cells become long-lived memory cells.
B and T cells are the white blood cells that comprise the adaptive immune system. These cells
can remember the microbes they encounter by recognizing very specific cell surface markers on
those microbes. B and T cells can bind to antigens through specific receptors located on the
surface of the B and T cells. Each B or T cell expresses only one kind of receptor and therefore
can bind only one type of antigen (see figure 2). While T-cell receptors are only found bound to
the surface of the T-cell, B cell receptors can be bound to the surface of the B-cell or secreted
into the bloodstream. B-cell receptors are also known as antibodies.
B cells
A diagram of a B-cell receptor or antibody is shown in figure 6. (The T-cell receptor has similar
features). This Y-shaped molecule is composed of two identical light chains (shorter, outer
structure) and two identical heavy chains (longer structure and therefore heavier). The antigen
binding sites are located at the end of each arm of the Y and are formed by the pocket between
the heavy and light chains. The antigen binding sites at the tip of the receptor are highly variable
with each receptor having a slightly different antigen binding site. Each of these receptor
variants will therefore bind a different antigen. We need millions of different receptor variants to
anticipate all possible antigens. However, considering the entire human genome consists of
around 30,000 genes, we cannot encode each T and B cell receptor variant as an individual gene.
Instead, the variable antigen binding site of the heavy and light chains is composed of a random
combination of DNA segments that are stitched together to form this region of the receptor.
Since there are different versions of these DNA segments, the many possible combinations
literally generate millions of different antigen binding sites.
Recognition of antigens by T and B cell receptors is very specific; even one amino acid change
can alter antigen recognition. This high degree of specificity is a necessary property of the
immune system because otherwise the distinction between foreign molecules and self-molecules
would not be possible. This specificity is also what makes antigen recognition different from the
more general recognition systems employed by phagocytes and natural killer cells. The
distinction between the foreign antigen and the organisms own molecules is so subtle that only
the highly specific receptors on the T and B cells can make the distinction.
Clonal Selection Theory
If you are infected with a virus for the first time and you innate immune system cannot contain
the infection, your adaptive immune system will be activated. Since each B or T cell can only
recognize one microbial antigen, and the receptors to these antigens are randomly generated, it
can take awhile for those T and B cells to find their antigen. Once they do, those T and B cells
will begin to divide and make more copies of themselves. This is called clonal expansion (Fig.

8). Clonal selection theory has become a widely accepted model for how the immune system
responds to infection and how certain types of B and T lymphocytes are selected for destruction
of specific antigens invading the body. About 52 years ago, Australian immunologist Frank
Macfarlane Burnet developed this theory. Burnet explained this theory as the cloning of two
types of lymphocyte. One clone acts immediately to combat infection while the other is longer
lasting, remaining in the immune system for a long time, which results in immunity to that
antigen.
For instance, B-cells will undergo about 8 cell divisions which will take approximately 5 days
and will lead to a large population of identical B-cells. Many of these B-cells will stop dividing
and will become plasma cells. Plasma cells are B-cells dedicated to producing copies of the B
cell receptor, which are secreted into the bloodstream as antibodies. During its short lifespan, one
plasma cell will typically secrete around 2,000 antibodies per second. Antibodies constitute
about 20% of total protein in blood plasma. Antibodies do not destroy a microbe directly, but
bind to a specific antigen on the microbe and signal its presence to the innate immune system.
Effectors of the innate immune system (phagocytes and natural killer cells) react to this signal by
targeting the specific microbe or infected cell. This cooperation between the adaptive and innate
immune systems leads to efficient elimination of the infection (Fig. 9).
Antibodies are also called immunoglobulins or Igs and constitute part of the blood proteins.
These are the ways antibodies work or inactivate antigens:
(a) complement fixation--proteins attach to antigen surface (causing cell lysis)
(b) neutralization-- bind to specific sites to prevent antigen attachment
(c) agglutinationthey just clump with each other (blocking antigen)
(d) precipitation: force insolubility and settled out of solution along with antigens
T cells
Without T cells, human life would not be sustained. In the absence of B cells, life is possible as
long as infusions of immunoglobulin IgG are maintained. When children are born without T
cells, they appear normal for the first few weeks. Then, they begin to acquired opportunistic
infections and die in infancy. This ailment is called severe combined immunodeficiency (SCID)
such as the case of David Vetter in emodule 33. It is called severe because it is fatal and called
combined because, in humans, B cells cannot function without help from T cells, so that even if
the B cells are not directly affected by the defect, both humoral and cell-mediated immunity are
lost (Fig. 10).
Two important types of T-cells are cytotoxic T-cells and helper T-cells (Fig.11). Cytotoxic T-cells
bind and kill infected host cells that are displaying the specific antigen by punching holes in their
cell membranes. This is essential for the destruction of host cells that have been infected with
viruses or intracellular bacteria or host cells that have become abnormal such as cancer. Foreign
antigens do not necessarily have to come from a harmful source such as a microbe. Tissues that
are taken from one individual and placed in another (organ transplant) will also be recognized as
foreign. Cytotoxic T cells will attack these foreign cells leading to transplant rejection or graft
rejections. If a piece of skin from a mouse of one strain B is grafted onto the flank of a mouse of
a second strain A, the graft does well at first. Blood vessels from the host grow into it and it
functions normally. After some 1014 days, however, the blood supply to the graft breaks down

and the graft degenerates. Finally it is sloughed off like an old scab (Fig. 12). What happens in
humans can be more complicated. Since the 1960s, we have had a greater success with organ
transplants, but once a patient has an organ transplant, he/she will have to take
immunosuppressant drugs for the rest of his/her life.
Another example of our immune system protection to foreign agents is blood transfusion (Fig.
13). In the ABO blood typing system, when an A antigen is present (in a person of blood type
A), the body produces an anti-B antibody, and similarly for a B antigen. The blood of someone
of type AB, has both antigens, hence has neither antibody. Thus that person can be transfused
with any type of blood, since there is no antibody to attack foreign blood antigens. An individual
of blood type O has neither antigen but both antibodies, and cannot receive AB, A, or B type
blood, but they can donate blood for use by anybody. If someone with blood type A received
blood of type B, the body's anti-B antibodies would attack the new blood cells and death would
be imminent.
Suppressor T cells inhibit the production of cytotoxic T cells once they are unneeded, lest they
cause more damage than necessary.
Helper T-cells do not have cytotoxic or phagocytic activity. Instead, they are helpers to the
immune response by directing other cells to perform these tasks. This management is absolutely
critical. Without helper T cells, an individual cannot mount an adaptive immune response. As
with B-cells and cytotoxic T-cells, helper T-cells become activated once they find and bind their
matching antigen. However, helper T-cells usually find their antigen through the assistance of
macrophages. Once macrophages have eliminated a microbe or a cell infected with a microbe,
they display the microbial antigens on their surface. This is called antigen presentation and
macrophages are known as antigen presenting cells. Helper T cells bind their matching antigen
presented on the macrophage and secrete cytokines.
Immune Response
Cytokines are signaling molecules (a type of hormone) that coordinate the other immune system
cells response, without this coordination, the immune system would not be able to function
correctly (Fig. 14).
In response to infection, the adaptive immune system activates killing mechanisms directly by
cytotoxic T cells and indirectly by antibodies, but this immediate response is relatively shortlived. One of the greatest strengths of the adaptive immune system is the ability to remember a
specific antigen and therefore microbe. The first time a microbe invades your body; there are
only a few B cells that, by chance, have the receptor to recognize it (Fig. 15).
The immune response that this first encounter sets off is called the primary immune response. It
will take several days for these cells to form a clone of cells that will secrete antibodies, and it is
likely that by the time the immune system can mount an effective response, the infection will
progress to the point where you will become sick. However, not all B and T cells become
plasma cells or cytotoxic T cells. Rather, some activated B and T cells become memory cells
that will survive for decades. If the body encounters this microbe again, then the memory cells
recognize the antigens on the intruder and immediately initiate an immune response. This is
called the secondary immune response, and because of the pre-existing population of memory

cells, it is much quicker and stronger than the first one. In most cases, the microbe will be
eliminated before it can cause disease. This is why we rarely contract diseases such
as chickenpox or the mumps more than once. These microbes have a surface that rarely changes
from year to year so the same antibody will recognize these microbes even decades later. The
ability of the adaptive immune system to remember a microbe is also why vaccination works.
Vaccination
Ancient records show that the Chinese practiced a form of vaccination in which people were
exposed to skin scabs from survivors of smallpox infection. Although this practice had about a
1% fatality rate, it did protect those who had been treated. In the 1790s, Edward Jenner, "the
father of immunology", noticed that milkmaids caught a mild form of cowpox but they rarely
contracted a related viral infection, smallpox. He deliberately infected people with the relatively
harmless cowpox virus and found they were protected against smallpox. Vaccines work by
exposing the immune system to microbial antigens to generate a primary immune response.
The antigens use in preparations of vaccines have been altered so as not to cause disease
(typically they are only a small part/or an inactive form of the pathogen so that it should not
cause infection). However, if the person later comes in contact with the fully pathogenic
microbe, the body will already have memory cells that recognize the antigen. The secondary
immune response will be strong and quick enough to destroy the microbe before it can cause
disease. Immunological memory provides the basis for the use of vaccines. You know that we
are vaccinated against many infectious diseases that used to be fatal. Measles, mumps, rubella,
whooping cough, typhoid, hepatitis A and B, polio, tetanus, and diphtheria (Fig. 16) commonly
resulted in death or great disability prior to vaccine development.
Perhaps the most noteworthy triumph of vaccination is the eradication of smallpox (Fig.17).
Throughout history, smallpox was fatal in 30% of cases and resulted in blindness in as high as
90% of infected individuals. In some cultures, smallpox killed so many infants that it was
customary not to name the baby until it had caught the disease and proved it could survive. Even
as recently as the 1950s, 50 million cases of smallpox occurred throughout the world. Many
diseases are much less common than they were even one hundred years ago because of
vaccinations.
As long as most people are vaccinated, it is much more difficult for an outbreak of a disease to
spread. This effect is called herd immunity, and it provides protection to unvaccinated
individuals. In other words, if most people are immune to a disease, it is very difficult, although
not impossible, for a susceptible person to even come in contact with the disease because no one
has it.
Autoimmune disorders
Autoimmune disorders arise when the immune system attacks its own body. While the
embryonic immune system will respond to both self and nonself molecules, as the individual
matures, the immune system learns to recognize the difference between self
and nonself markers.

During development, T and B cell clones that would respond to self-antigens are eliminated or
suppressed. This is called natural immunological tolerance. Thus, the only clones that circulate
are those that are directed at non-self antigens. Sometimes natural tolerance breaks down
spontaneously, allowing B and/or T cells to attack unnecessarily. Examples of autoimmune
diseases include: type I diabetes mellitus, rheumatoid arthritis, multiple sclerosis, lupus, and
myasthenia gravis. Exactly what triggers an autoimmune disease is not known, but women are
more often affected than men.
Our immune system can also mount a major defense against a harmless antigen such as plant
pollen. These are called allergies, which usually result in sneezing, runny nose, and fever. More
dangerous is when allergic reactions are so strong that they can be life threatening. This is called
anaphylactic shock and symptoms include respiratory distress, swelling and decreased blood
pressure.
Finally, microbes have also developed techniques to evade the immune system. For example,
most people have gotten the flu more than once. This is due to a technique employed by the
influenza virus called antigen shifting. Every few years a major new strain of flu is generated
with a rearranged surface antigen that human antibodies no longer recognize. While immunity to
this new version builds up, people may get sick and the whole process will repeat within a few
years. Although we normally think of the flu as more of an annoyance, it can fatal to the elderly
and immunocompromised individuals. However, the greatest fear is that a truly deadly strain
will emerge. This is what happened during the Spanish flu epidemic of 1918-1919, in which 20
million people died. The Spanish flu is believed to have come from a bird flu that jumped from
infecting only birds to also infecting humans. This is why we were worried about the pandemic
of the H1N1 flu in third world countries.
Adaptive Immune System

The second component of the immune system capable of recognizing an

microbes in order to eliminate them from the body in future attacks.

Antigens

Molecules (proteins, sugars or lipids) located on a microbes surface tha

receptors leading to activation of the immune system

Antigen presenting cells (APC)

Cells such as macrophages that present a fragment of microbial antigen

order to activate B and T cells.

Antibody

Secreted B-cell receptors that will bind a specific antigen on the surface
marking the microbe for more efficient destruction by effectors of the in

Autoimmune disorders

Failure of an organism to distinguish between self and non-self so that th

its own body.

Allergies

An exaggerated immune response to a harmless antigen such as pollen o

triggers.

Cell Mediated Immunity

Refers to an immune response that does not involve antibodies, but rather
activation of macrophages, natural killer cells (NK), antigen-specific cyto
and the release of various cytokines in response to an antigen

Clonal selection theory

Burnet explained this theory as the cloning of two types of lymphocyte. O

immediately to combat infection whilst the other is longer lasting, remain
system for a long time, which results in immunity to that antigen. Clonal
reproduction by mitosis

B cells

Are cells of the adaptive immune system. The abbreviation "B" comes fro
Fabricius, where they mature in birds. In mammals, immature B cells are
marrow. They include plasma cells that produce antibodies and memory
specific antigens.

T cells

Are cells of the adaptive immune system. The abbreviation T stands for
mature. They include helper T-cells that help manage the immune respon

that kill infected host cells, and memory cells that remember specific anti

Receptors

Proteins often found on the surface of a cell that can bind a specific mole
communication.

Immunosuppressant

Any substance that performs immunosuppression of the immune system s

immunosuppressive drugs taken daily.

Primary immune response

Adaptive immune response generated upon the first encounter with a mi

longer for the adaptive immune system to mount a response and the mic
before it can be eliminated.

Secondary immune response

Adaptive immune response generated upon subsequent encounters with

memory cells result in a fast and strong response that usually eliminates
cause a disease.

Herd immunity

Occurs when vaccination of the majority of a population protects the un

because there are so few individuals who can actually spread the disease

Humoral Immunity

Is the type of immunity that is mediated by secreted antibodies produced

Natural immunological tolerance

A process when the body does not mount an immune response to self an

Innate Immune System

Can you imagine being unable to touch your mother or to play with a friend or to walk outside
your house? That was the story of David Vetter who was the boy in the bubble. He had no
immune system (also known as SCID). He died at the age of 12 and never left his bubble until
his death. This module will reveal the secret weapons your body uses to defend itself from the
outside

In order to understand immunology and infectious diseases, we have to remember that we are
completely surrounded by microbes. Our bodies not only have to nourish us, but they also have
to shelter us from extreme environments using an active defense system. This defense system
uses a regulatory and recognition mechanism that allow us to distinguish self and nonself. The
origins of these mechanisms go far back in evolutionary history and many, in fact, originated as
markers for allowing cells to recognize and interact with each other to set up symbiotic
households, and to keep away undesired neighbors. For instance, genetically related sponge
colonies that are placed close to each other will tend to grow toward each other and fuse into one
large colony, however, unrelated colonies will react in a different way, destroying cells that come

in contact and leave a zone of rejection between the colonies.

The immune system is composed of two branches: innate immunity and adaptive immunity
(concept 1). This module will focus on characteristics of the innate immune system while the
adaptive immune system will primarily be covered in the next e-module. Cells of the immune
system are derived from white blood cells. White blood cells, along with red blood cells
(circulatory system, Fig.1), are formed from the cells in the bone marrow called hematopoietic
stem cells. An average adult human has about 1-2% white blood cells in his/her total blood
volume. These cells communicate and coordinate their actions through the release of chemical
signals called cytokines. White blood cells of the innate immune system are phagocytes and
natural killer cells. White blood cells of the adaptive immune system are T and B cells.
The innate immune system is also called constitutive immunity because it is always active and
will respond to any invading microbe without prior exposure to it. The innate immune system is
often the initial line of defense against a pathogen. We have three lines of defense (Fig. 2). The
first and second lines of defenses are associated with innate immunity and the third one with
adaptive immunity. The first line of defense consists of nonspecific surface defenses, which are
physical barriers (structural/mechanical) along with a broad array of chemicals/proteins
(biochemical) that prevent pathogens from entering deeper tissue. The second line of defense
occurs in the interior of the tissue and refers to inflammation, which leads to phagocytosis.
These two lines of defenses are considered nonspecific because they act in the same way against
all microbes. In evolutionary terms, the innate immune system is old and can be found in nearly
all forms of life including plants, fungi, and insects. The third line of immune defenses (Fig. 2)
is adaptive immunity, which is activated when innate immunity is not successful at combating
the infection. All three lines of defense are essential parts our response to microbial infection.
Areas of your body that are directly exposed to the outside world such as the surface of our skin,
the respiratory tract and the digestive tract are carefully guarded by an extra level of defense and
common protection methods are mucus and other body secretions. In addition, your normal flora
also provides a natural barrier to infection. Under optimal conditions, a persons internal tissues
(brain, muscle, etc.) are free of microorganisms; however, his/her surface tissues (skin, mucous
membranes, etc) are in contact with environmental organisms and become readily colonized by
various microbial species. The mixture of organisms regularly found at any anatomical site is
referred to as the normal flora. The normal flora of humans consists of a few eukaryotic fungi
and protists, but bacteria are the most numerous microbial components. Normal flora has formed
a symbiotic relationship with your body and provides another protective barrier to illness causing
bacteria by producing secondary metabolites that inhibit adhesion, and growth of the attacking
microbes. Staphylococcus epidermidis (S. epidermidis) and Staphylococcus aureus (S. aureus)
are normal flora of the skin (Fig. 3). S. aureus tends to be found in moist environments such as
the nostrils and armpits, whereas S. epidermidis is usually found in drier areas of the skin. S.
epidermidis is rarely pathogenic, whereas S. aureus is widely known as a troublesome
opportunistic pathogen.
It was not until recently that the scientific community has become aware of the importance of
bacteria living in you. The NIH (National Institute of Health) will fund the genome sequencing
of these bacteria to investigate their properties and elucidate how they aid the immune system.
Although, this genome sequencing endeavor will be difficult due to very diverse bacteria, it will

reveal information about its origins. For instance, there is current speculation that some type of
bacteria can help you maintain a healthy weight, and this type of information will be useful if
you are trying to lose weight.
Skin is the largest organ in vertebrates, in an adult human 15% of the total weight is skin, and it
is an absolutely essential organ. We all have different types of skin (Fig. 4) but they all serve the
same purpose: to keep water in, and keep microbes out. This is very important when you
consider the fact that one square inch of skin contains around 50 million bacteria that no amount
of cleaning can completely remove. Skin keeps these microbes on the surface by providing a
nearly impenetrable physical barrier that is supplemented with chemical weapons. For example,
oil and sweat glands within the skin lower the pH to a level that inhibits microbial growth. Sweat
and oily secretions produce hydrolytic enzymes such as lysozyme (Fig. 5) that digest the cells
walls of many bacteria.
Lastly, dead skin is constantly sloughing off taking the adherent microbes along with it.
Hopefully, you maintain a basic level of hygiene to assist your innate immune system because
dead skin cells mixed with dirt and oil provide an extra food source for bacteria. These cellular
defenses create an almost impassable barrier that is mainly breached when skin is damaged
through cuts, burns, and abrasions (Fig. 6).
An additional port of entry is through inhalation into the respiratory tract. Cells lining our upper
respiratory tract secrete sticky mucus that traps microbes before they can reach the warm, moist
areas deep in our lungs that make such ideal breeding grounds (Fig. 7). Cilia on the cells lining
sweeps the mucus and any microbe upwards where it can be removed through coughing,
sneezing, or swallowing (where the acidic medium of the stomach will eliminate them).
Another, important protecting factor of the immune system is lysozyme. The lysozyme is
abundant in a number of secretions such as tears, saliva, and mucus. It is responsible for breaking
down the polysaccharide walls of many kinds of bacteria and thus it provides some protection
against infection. Bacteria found in the foods we eat, are typically removed by the lysozyme
produced in saliva, stomach acid, and/or digestive enzymes in the small intestine. However, our
body has an efficient method of getting rid of microbes in the event that your hydrolytic enzymes
do not kill the ingested bacteria, you would vomit or develop diarrhea (Fig. 8). These processes
are necessary pathogen removal mechanisms employed by our bodies. Although unpleasant, it
can be beneficial to allow the body to purge these microbes rather than to try to stop it through
the use of anti-vomiting/anti-diarrhea medication. However, prolonged diarrhea or vomiting
(more than 3 days) can also be a symptom of serious illnesses and you need to seek medical
assistance because the loss of bodily fluids can lead to dehydration, and in severe cases,
permanent damage or death.
Physical barriers are not always sufficient to stop smart pathogenic microbes, and a second line
of defense is necessary. These are immune cells that protect the bloodstream and tissues from
invading microbes as well as host cells that have been infected by microbes. Immune system
cells are not located in one particular tissue as in other body systems, nor are the immune system
controlled by a central organ. Rather, the immune system is composed of a host of individual
cells that rush to the site of infection upon request. The various components of the immune
system are combined in an exquisitely complex communications network that functions as an
effective defense against foreign microorganisms and against body cells that have become

abnormal.
Inflammation response
One of the first responses to infection is the generation of an inflammatory response by the
innate immune system. The symptoms of inflammation include redness, a sense of heat,
swelling (edema), and throbbing pain (see Fig. 9). Although the inflamed tissue may feel
uncomfortable, these reactions are a critical step in controlling an infection. Inflammation at the
site of infection speeds up the killing of invading microbes by the front-line microphages and
causes changes in the walls of local blood vessels that enable additional molecules and
macrophages to enter the infected tissue from the blood. Local expansion of capillaries increases
the flow of blood to the site of infection/injury. Without inflammation, wounds and infections
would not heal. The increased blood flow results in the characteristic redness and increased heat
at the site of inflammation. Since the capillaries are leakier, an increase in fluid, along with
phagocytes, will leak into the tissue. This causes swelling of the area. Pain is caused by
compression of nerves due to the swelling.
Sometimes, pus is often seen within an infected area, and pus is comprised of dying phagocytes,
broken down tissue cells and dead microbes. Inflammation also induces local blood clotting,
making a physical barrier to the spread of infection through the bloodstream. The inflammatory
response has to be carefully controlled because if it malfunctions it can damage healthy tissue
and cause diseases such as arthritis. Fever is one of the most common manifestations of infection
and inflammation. Fever is caused by many bacterial products. Fever contributes to your bodys
defenses by creating a temperature that is less favorable to microbial growth. Fever also
stimulates phagocytosis and causes the body to reduce blood levels of iron, which bacteria need
to grow. Fever is caused by chemical signals called pyrogens that are released by macrophages
that have encountered invading microbes. Pyrogens travel to the hypothalamus, and signal for an
increase in body temperature. The hypothalamus acts as the bodys thermostat. However,
this system has to be carefully monitored since very high temperatures can damage your healthy
cells. As a rule of thumb, temperatures greater than 103 F are considered dangerous, and you
might need medical assistance, temperatures greater than 105 F can be fatal.
Cells of the immune system
The distribution of lymphoid tissues in the body is shown in Figure 10 and the lymphatic organs
are those in which lymphocyte maturation, differentiation, and proliferation take place. These
organs are divided into primary lymphoid organs -thymus and bone marrow, and secondary
lymphoid organs - spleen and lymph nodes. We will discuss these organs in more detail in the
next e-module. Cells of the innate immune system are phagocytes and natural killer cells
Phagocytes are a type of cell that kills microbes by ingesting them through a process called
phagocytosis (see Fig. 11). During phagocytosis, flowing cytoplasmic extensions engulf the
microbe. Then, the phagocyte uses lysozyme and other chemicals to destroy the microbe. There
are different types of phagocytic cells that your body uses to fight infection, but one of the most
important phagocytic cells is called a macrophage. Macrophages will engulf anything that is not
normal including cell debris, dust particles, invading microbes, and cells infected by microbes.
Macrophages are motile and can move through your blood and tissues searching out and
destroying invading microbes (see Fig. 12).

Dendritic cells are long-lived phagocytic cells and reside in an immature state in most tissues,
where they recognize and phagocytize pathogens and other antigens. They are important in both
innate immunity and the initiation of adaptive immune responses. Natural killer cells differ from
phagocytes in that they do not kill invading microbes, but rather the host cells that are infected
with them. In viral infections, this prevents the infected host cell from producing more viral
progeny and infecting neighboring cells.
Natural killer cells also recognize altered features of the membranes of abnormal cells such
cancer cells and get rid of them. Natural killer cells kill by the release of various cytotoxic
molecules. Some of these molecules cause the formation of pores in the membrane of the target
cell, leading to cell destruction (Fig. 13).
Innate defenses are considered non-specific because they target all microbes in the same general
manner. These innate defenses cannot recognize or distinguish one microbe from another and
they do not remember specific microbes or the most effective way to get rid of infection.
Your immune cells can also recognize your own cells and distinguish them, even from other
human cells. If your immune system loses the ability to recognize itself, your immune system
can attack your own healthy cells resulting in an autoimmune disease such as allergies.
Cells in your body contain a surface protein marker that identifies them as self. Each person
has a different version of this marker, although all cells within an individual contain the same
one. The cells of the immune system ignore any cells having self marker, but will attack cells
that lack the self marker or, as is the case with tumor cells, have an altered self marker (Fig.
14).
Although, we have an incredible immune system, microbes have evolved mechanisms to evade
our killing mechanism. A classic example is how microbes make proteins that help them adhere
to host cells. They also will make proteins that can degrade the chemical weapons of the innate
immune system or they secrete toxins that poison the immune system. Because of this reason,
the innate immune system is not sufficient in controlling infection and another line of immunity
is essential. Innate immunity protects our bodies from small infections or stalls the progress of
infection until our adaptive immune system is activated with the help of innate immunity. The
two branches of the immune system form a synergistic relationship in their fight against infection
and by working together they are more efficient at controlling infection (Fig. 15). As we will
learn in the next e-module interrelationships between innate and adaptive immunity build a
strong defense system.

And you thought your mom was kidding when she told you that you needed to get your shots or
you would get chicken pox even on your butt. Mom was right. Chickenpox is caused by
the varicella-zoster virus (VZV). Kids can be protected from VZV by getting the chickenpox
(varicella) vaccine, usually between the ages of 12 to 15 months.

Adaptive immunity is more specialized than innate immunity and it supplements the protection
provided by innate immunity. Adaptive immunity came into play relatively late, in evolutionary
terms, and is present only in vertebrates. A major difference between the innate and adaptive
immune system is the ability to recognize specific pathogens. In other words, while the innate
immune system may recognize bacteria in general, the adaptive immune system will recognize a
specific bacterium (Fig 1.). The adaptive immune system can respond rapidly after coming in
contact with a microbe because it can remember prior encounters. This is the reason why you
might develop an infection the first you come across a specific microbe such as the chickenpox
virus, but you will not get sick the second time you contact it.
All systems of the body depend on one other for its survival; however, the immune system is
particularly tied to the circulatory system. Remember, the cells of the immune system do not
reside in any one place, but rather circulate throughout the entire body via the circulatory
system. This continuous movement through the body ensures that the T and B cells will be
exposed to foreign antigens. Capillaries are particularly important because these are the smallest
of the blood vessels where the interchange between oxygen and carbon dioxide between blood
and tissue cells occurs. This means that capillaries have access to all tissues of the body and can
aid in monitoring those tissues for signs of infection. Endothelial cells that make up the capillary
walls will capture immune cells such as phagocytes as they pass by a site of tissue infection. The
peripheral blood contains 2050% of circulating lymphocytes; the rest move in the lymph
system. Roughly 80% of them are T cells, 15% B cells and remainder are undifferentiated cells.
Lymphocytes constitute 2040% of the body's White Blood Cells. Their total mass is about the
same as that of the brain or liver.
Key elements of a successful immune response

The main characteristics of the adaptive immune system response are its ability to recognize,
activate, and quickly respond to foreign entities (Fig. 2). These characteristics are founded on
specificity, which is the ability to discriminate among different molecular entities, and to respond
to only those uniquely required (non-self).
Adaptiveness is the ability to respond to previously unseen molecules that may in fact never have
naturally existed before.
Memory is a property shared with the nervous system, is the ability to recall previous contact
with a foreign molecule and respond to it in a learned manner.
Organs of the immune system
Lymphatic organs are those organs in which lymphocyte maturation, differentiation, and
proliferation take place. They are divided into two categories. The primary lymphoid organs
(bone marrow and thymus) are those in which the maturation of T and B lymphocytes into
antigen-recognizing takes place. Antigen-shifting is the term used for the one of the direct
weapon used by microbes against the immune system. Mature B and T lymphocytes migrate
from the primary lymphoid organs through the bloodstream to the secondary lymphoid organs
(lymph nodes, the spleen, and gut-associated lymphoid tissues such as the tonsils). The
secondary (peripheral) lymphoid organs are those organs in which antigen-committed
lymphocytes are stimulated by antigens to undergo further division and differentiation. The
adaptive immune response occurs mainly in the secondary lymphoid organs. Pathogens and
their secreted antigens are trapped in these secondary lymphoid tissues, and presented to the
native lymphocytes that constantly pass through. Microorganisms that enter the body through
the skin or the lungs drain to the regional lymph nodes where they stimulate an immune
response. Microorganisms and food antigens that enter the gastrointestinal tract are collected in
the gut-associated lymphoid tissue.
Microbes that enter the bloodstream stimulate an immune response in the spleen. In addition to
being a lymphoid organ, the spleen filters the blood to remove aged or abnormal red cells and
invading microorganisms.
All the cells of the immune system are initially derived from the bone marrow. They form
through a process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells
differentiate into either mature cells of the immune system or into precursors of cells that migrate
out of the bone marrow to continue their maturation elsewhere. The bone marrow produces B
cells, natural killer cells, granulocytes, and immature thymocytes in addition to red blood cells
and platelets. The function of the thymus is to produce mature T cells (thymus cells). Immature
thymocytes leave the bone marrow and migrate into the thymus. Through an interesting
maturation process in which the first positive selection process weeds out only those T cells with
the correct set of receptors that can recognize the MHC (Major Histocompatibility Complex)
molecules responsible for self-recognition. Then a negative selection process begins whereby T
cells that can recognize MHC molecules complexed with foreign peptides are allowed to pass out
of the thymus. The mature T cells are then released into the bloodstream.
The role of the Major Histocompatibility Complex (MHC)

MHC molecules play a crucial role in the response of T cells to antigens that penetrate or live
inside cells of the body. MHC molecules bind to amino acids derived from proteins and present
them to T cells with the appropriate receptor. Thus, T cells responses are said to be MHC
restricted. The MHC codes for two major categories of cell surface transmembrane molecules,
MHC class I and class II molecules.
MHC class I are expressed on all nucleated cells, but MHC class II are only found on B cells and
macrophage or dendritic cells (both of these are known as APCs-antigen presenting cells).
Each individual expresses a distinct array of MHC class I and class II molecules from other
individuals. This diversity comes about because different individuals within a species have a
range of slightly different forms of MHC class I, and class II genes. However, an individual
expresses the same MHC class I and II molecules in all his/her cells, and expresses them at the
cell surface. An immune response to foreign antigen requires the presence of an antigenpresenting cell. When an APC presents an antigen on its cell surface to a B cell, the B cell is
signalled to proliferate and produce antibodies that specifically bind to that antigen. If the
antibodies bind to antigens on the surface of the bacteria/pathogen, it acts as a signal for
macrophages to kill them.
The spleen is an immunologic filter of the blood. It is made up of B cells, T cells, macrophages,
dendritic cells, natural killer cells, and red blood cells. In addition to capturing foreign materials
(antigens) from the blood that passes through the spleen, migratory macrophages and dendritic
cells bring antigens to the spleen via the bloodstream. An immune response is initiated when the
macrophage or dendritic cells present the antigen to the appropriate B or T cells. You can picture
this organ as an immunological conference room where important people meet to make sure the
body is safely guarded. In the spleen, B cells become activated and produce large amounts of
antibody. Also, old red blood cells are destroyed in the spleen. This brings us to the lymph nodes
which function as an immunologic filter for the bodily fluid known as lymph. Lymph nodes are
found throughout the body (see diagram). Composed mostly of T cells, B cells, dendritic cells
and macrophages, the nodes drain fluid from most of our tissues. Antigens are filtered out of the
lymph in the lymph node before returning the lymph to the circulation.
There are two fundamental adaptive mechanisms
Parts of the immune system are changeable and can adapt to better attack the invading antigen.
There are two fundamental adaptive mechanisms: cell-mediated immunity and humoral
immunity. To completely understand these concepts we will learn in detail how T and B cell
function.
Cell-mediated immunity- refers to macrophages engulfing antigens, processing them internally,
and then displaying parts of them on their surface. This sensitizes the T cells to recognize these
antigens.
Humoral immunitytypically refers to an immature B-lymphocyte is stimulated to maturity
when an antigen binds to its surface receptors and an observant T helper cell releases a cytokine.
This reaction signals to the B cell to undergo clonal selection-asexual reproduction by mitosis.
Most of the family of clones become plasma cells. These cells, after an initial lag, produce highly
specific antibodies at a rate of as many as 2000 molecules per second for four to five days. The

other B cells become long-lived memory cells.

B and T cells are the white blood cells that comprise the adaptive immune system. These cells
can remember the microbes they encounter by recognizing very specific cell surface markers on
those microbes. B and T cells can bind to antigens through specific receptors located on the
surface of the B and T cells. Each B or T cell expresses only one kind of receptor and therefore
can bind only one type of antigen (see figure 2). While T-cell receptors are only found bound to
the surface of the T-cell, B cell receptors can be bound to the surface of the B-cell or secreted
into the bloodstream. B-cell receptors are also known as antibodies.
B cells
A diagram of a B-cell receptor or antibody is shown in figure 6. (The T-cell receptor has similar
features). This Y-shaped molecule is composed of two identical light chains (shorter, outer
structure) and two identical heavy chains (longer structure and therefore heavier). The antigen
binding sites are located at the end of each arm of the Y and are formed by the pocket between
the heavy and light chains. The antigen binding sites at the tip of the receptor are highly variable
with each receptor having a slightly different antigen binding site. Each of these receptor
variants will therefore bind a different antigen. We need millions of different receptor variants to
anticipate all possible antigens. However, considering the entire human genome consists of
around 30,000 genes, we cannot encode each T and B cell receptor variant as an individual gene.
Instead, the variable antigen binding site of the heavy and light chains is composed of a random
combination of DNA segments that are stitched together to form this region of the receptor.
Since there are different versions of these DNA segments, the many possible combinations
literally generate millions of different antigen binding sites.
Recognition of antigens by T and B cell receptors is very specific; even one amino acid change
can alter antigen recognition. This high degree of specificity is a necessary property of the
immune system because otherwise the distinction between foreign molecules and self-molecules
would not be possible. This specificity is also what makes antigen recognition different from the
more general recognition systems employed by phagocytes and natural killer cells. The
distinction between the foreign antigen and the organisms own molecules is so subtle that only
the highly specific receptors on the T and B cells can make the distinction.
Clonal Selection Theory
If you are infected with a virus for the first time and you innate immune system cannot contain
the infection, your adaptive immune system will be activated. Since each B or T cell can only
recognize one microbial antigen, and the receptors to these antigens are randomly generated, it
can take awhile for those T and B cells to find their antigen. Once they do, those T and B cells
will begin to divide and make more copies of themselves. This is called clonal expansion (Fig.
8). Clonal selection theory has become a widely accepted model for how the immune system
responds to infection and how certain types of B and T lymphocytes are selected for destruction
of specific antigens invading the body. About 52 years ago, Australian immunologist Frank
Macfarlane Burnet developed this theory. Burnet explained this theory as the cloning of two
types of lymphocyte. One clone acts immediately to combat infection while the other is longer
lasting, remaining in the immune system for a long time, which results in immunity to that
antigen.

For instance, B-cells will undergo about 8 cell divisions which will take approximately 5 days
and will lead to a large population of identical B-cells. Many of these B-cells will stop dividing
and will become plasma cells. Plasma cells are B-cells dedicated to producing copies of the B
cell receptor, which are secreted into the bloodstream as antibodies. During its short lifespan, one
plasma cell will typically secrete around 2,000 antibodies per second. Antibodies constitute
about 20% of total protein in blood plasma. Antibodies do not destroy a microbe directly, but
bind to a specific antigen on the microbe and signal its presence to the innate immune system.
Effectors of the innate immune system (phagocytes and natural killer cells) react to this signal by
targeting the specific microbe or infected cell. This cooperation between the adaptive and innate
immune systems leads to efficient elimination of the infection (Fig. 9).
Antibodies are also called immunoglobulins or Igs and constitute part of the blood proteins.
These are the ways antibodies work or inactivate antigens:
(a) complement fixation--proteins attach to antigen surface (causing cell lysis)
(b) neutralization-- bind to specific sites to prevent antigen attachment
(c) agglutinationthey just clump with each other (blocking antigen)
(d) precipitation: force insolubility and settled out of solution along with antigens
T cells
Without T cells, human life would not be sustained. In the absence of B cells, life is possible as
long as infusions of immunoglobulin IgG are maintained. When children are born without T
cells, they appear normal for the first few weeks. Then, they begin to acquired opportunistic
infections and die in infancy. This ailment is called severe combined immunodeficiency (SCID)
such as the case of David Vetter in emodule 33. It is called severe because it is fatal and called
combined because, in humans, B cells cannot function without help from T cells, so that even if
the B cells are not directly affected by the defect, both humoral and cell-mediated immunity are
lost (Fig. 10).
Two important types of T-cells are cytotoxic T-cells and helper T-cells (Fig.11). Cytotoxic T-cells
bind and kill infected host cells that are displaying the specific antigen by punching holes in their
cell membranes. This is essential for the destruction of host cells that have been infected with
viruses or intracellular bacteria or host cells that have become abnormal such as cancer. Foreign
antigens do not necessarily have to come from a harmful source such as a microbe. Tissues that
are taken from one individual and placed in another (organ transplant) will also be recognized as
foreign. Cytotoxic T cells will attack these foreign cells leading to transplant rejection or graft
rejections. If a piece of skin from a mouse of one strain B is grafted onto the flank of a mouse of
a second strain A, the graft does well at first. Blood vessels from the host grow into it and it
functions normally. After some 1014 days, however, the blood supply to the graft breaks down
and the graft degenerates. Finally it is sloughed off like an old scab (Fig. 12). What happens in
humans can be more complicated. Since the 1960s, we have had a greater success with organ
transplants, but once a patient has an organ transplant, he/she will have to take
immunosuppressant drugs for the rest of his/her life.
Another example of our immune system protection to foreign agents is blood transfusion (Fig.
13). In the ABO blood typing system, when an A antigen is present (in a person of blood type

A), the body produces an anti-B antibody, and similarly for a B antigen. The blood of someone
of type AB, has both antigens, hence has neither antibody. Thus that person can be transfused
with any type of blood, since there is no antibody to attack foreign blood antigens. An individual
of blood type O has neither antigen but both antibodies, and cannot receive AB, A, or B type
blood, but they can donate blood for use by anybody. If someone with blood type A received
blood of type B, the body's anti-B antibodies would attack the new blood cells and death would
be imminent.
Suppressor T cells inhibit the production of cytotoxic T cells once they are unneeded, lest they
cause more damage than necessary.
Helper T-cells do not have cytotoxic or phagocytic activity. Instead, they are helpers to the
immune response by directing other cells to perform these tasks. This management is absolutely
critical. Without helper T cells, an individual cannot mount an adaptive immune response. As
with B-cells and cytotoxic T-cells, helper T-cells become activated once they find and bind their
matching antigen. However, helper T-cells usually find their antigen through the assistance of
macrophages. Once macrophages have eliminated a microbe or a cell infected with a microbe,
they display the microbial antigens on their surface. This is called antigen presentation and
macrophages are known as antigen presenting cells. Helper T cells bind their matching antigen
presented on the macrophage and secrete cytokines.
Cytokines are signaling molecules (a type of hormone) that coordinate the other immune system
cells response, without this coordination, the immune system would not be able to function
correctly (Fig. 14).
In response to infection, the adaptive immune system activates killing mechanisms directly by
cytotoxic T cells and indirectly by antibodies, but this immediate response is relatively shortlived. One of the greatest strengths of the adaptive immune system is the ability to remember a
specific antigen and therefore microbe. The first time a microbe invades your body; there are
only a few B cells that, by chance, have the receptor to recognize it (Fig. 15).
The immune response that this first encounter sets off is called the primary immune response. It
will take several days for these cells to form a clone of cells that will secrete antibodies, and it is
likely that by the time the immune system can mount an effective response, the infection will
progress to the point where you will become sick. However, not all B and T cells become
plasma cells or cytotoxic T cells. Rather, some activated B and T cells become memory cells
that will survive for decades. If the body encounters this microbe again, then the memory cells
recognize the antigens on the intruder and immediately initiate an immune response. This is
called the secondary immune response, and because of the pre-existing population of memory
cells, it is much quicker and stronger than the first one. In most cases, the microbe will be
eliminated before it can cause disease. This is why we rarely contract diseases such
as chickenpox or the mumps more than once. These microbes have a surface that rarely changes
from year to year so the same antibody will recognize these microbes even decades later. The
ability of the adaptive immune system to remember a microbe is also why vaccination works.
Vaccination
Ancient records show that the Chinese practiced a form of vaccination in which people were

exposed to skin scabs from survivors of smallpox infection. Although this practice had about a
1% fatality rate, it did protect those who had been treated. In the 1790s, Edward Jenner, "the
father of immunology", noticed that milkmaids caught a mild form of cowpox but they rarely
contracted a related viral infection, smallpox. He deliberately infected people with the relatively
harmless cowpox virus and found they were protected against smallpox. Vaccines work by
exposing the immune system to microbial antigens to generate a primary immune response.
The antigens use in preparations of vaccines have been altered so as not to cause disease
(typically they are only a small part/or an inactive form of the pathogen so that it should not
cause infection). However, if the person later comes in contact with the fully pathogenic
microbe, the body will already have memory cells that recognize the antigen. The secondary
immune response will be strong and quick enough to destroy the microbe before it can cause
disease. Immunological memory provides the basis for the use of vaccines. You know that we
are vaccinated against many infectious diseases that used to be fatal. Measles, mumps, rubella,
whooping cough, typhoid, hepatitis A and B, polio, tetanus, and diphtheria (Fig. 16) commonly
resulted in death or great disability prior to vaccine development.
Perhaps the most noteworthy triumph of vaccination is the eradication of smallpox (Fig.17).
Throughout history, smallpox was fatal in 30% of cases and resulted in blindness in as high as
90% of infected individuals. In some cultures, smallpox killed so many infants that it was
customary not to name the baby until it had caught the disease and proved it could survive. Even
as recently as the 1950s, 50 million cases of smallpox occurred throughout the world. Many
diseases are much less common than they were even one hundred years ago because of
vaccinations.
As long as most people are vaccinated, it is much more difficult for an outbreak of a disease to
spread. This effect is called herd immunity, and it provides protection to unvaccinated
individuals. In other words, if most people are immune to a disease, it is very difficult, although
not impossible, for a susceptible person to even come in contact with the disease because no one
has it.
Autoimmune disorders
Autoimmune disorders arise when the immune system attacks its own body. While the
embryonic immune system will respond to both self and nonself molecules, as the individual
matures, the immune system learns to recognize the difference between self
and nonself markers.
During development, T and B cell clones that would respond to self-antigens are eliminated or
suppressed. This is called natural immunological tolerance. Thus, the only clones that circulate
are those that are directed at non-self antigens. Sometimes natural tolerance breaks down
spontaneously, allowing B and/or T cells to attack unnecessarily. Examples of autoimmune
diseases include: type I diabetes mellitus, rheumatoid arthritis, multiple sclerosis, lupus, and
myasthenia gravis. Exactly what triggers an autoimmune disease is not known, but women are
more often affected than men.

Our immune system can also mount a major defense against a harmless antigen such as plant
pollen. These are called allergies, which usually result in sneezing, runny nose, and fever. More
dangerous is when allergic reactions are so strong that they can be life threatening. This is called
anaphylactic shock and symptoms include respiratory distress, swelling and decreased blood
pressure.
Finally, microbes have also developed techniques to evade the immune system. For example,
most people have gotten the flu more than once. This is due to a technique employed by the
influenza virus called antigen shifting. Every few years a major new strain of flu is generated
with a rearranged surface antigen that human antibodies no longer recognize. While immunity to
this new version builds up, people may get sick and the whole process will repeat within a few
years. Although we normally think of the flu as more of an annoyance, it can fatal to the elderly
and immunocompromised individuals. However, the greatest fear is that a truly deadly strain
will emerge. This is what happened during the Spanish flu epidemic of 1918-1919, in which 20
million people died. The Spanish flu is believed to have come from a bird flu that jumped from
infecting only birds to also infecting humans. This is why we were worried about the pandemic
of the H1N1 flu in third world countries.
Adaptive Immune System

The second component of the immune system capable of recognizing an

microbes in order to eliminate them from the body in future attacks.

Antigens

Molecules (proteins, sugars or lipids) located on a microbes surface tha

receptors leading to activation of the immune system

Antigen presenting cells (APC)

Cells such as macrophages that present a fragment of microbial antigen

order to activate B and T cells.

Antibody

Secreted B-cell receptors that will bind a specific antigen on the surface
marking the microbe for more efficient destruction by effectors of the in

Autoimmune disorders

Failure of an organism to distinguish between self and non-self so that th

its own body.

Allergies

An exaggerated immune response to a harmless antigen such as pollen o

triggers.

Cell Mediated Immunity

Refers to an immune response that does not involve antibodies, but rather
activation of macrophages, natural killer cells (NK), antigen-specific cyto
and the release of various cytokines in response to an antigen

Clonal selection theory

Burnet explained this theory as the cloning of two types of lymphocyte. O

immediately to combat infection whilst the other is longer lasting, remain
system for a long time, which results in immunity to that antigen. Clonal
reproduction by mitosis

B cells

Are cells of the adaptive immune system. The abbreviation "B" comes fro
Fabricius, where they mature in birds. In mammals, immature B cells are
marrow. They include plasma cells that produce antibodies and memory
specific antigens.

T cells

Are cells of the adaptive immune system. The abbreviation T stands for
mature. They include helper T-cells that help manage the immune respon
that kill infected host cells, and memory cells that remember specific anti

Receptors

Proteins often found on the surface of a cell that can bind a specific mole
communication.

Immunosuppressant

Any substance that performs immunosuppression of the immune system s

immunosuppressive drugs taken daily.

Primary immune response

Adaptive immune response generated upon the first encounter with a mi

longer for the adaptive immune system to mount a response and the mic
before it can be eliminated.

Secondary immune response

Adaptive immune response generated upon subsequent encounters with

memory cells result in a fast and strong response that usually eliminates
cause a disease.

Herd immunity

Occurs when vaccination of the majority of a population protects the un

because there are so few individuals who can actually spread the disease

Humoral Immunity

Is the type of immunity that is mediated by secreted antibodies produced

Natural immunological tolerance

A process when the body does not mount an immune response to self an

Infectious Disease

Infectious diseases can be described as human illnesses caused by the presence of pathogenic
microbial agents such as bacteria, fungi, protozoa, viruses, multicellular parasites, and proteins
known as prions. Not all microorganisms are pathogens; only a small fraction can cause disease.
The pathogens that cause disease in animals and/or plants are not closely related to each other.
The only single property that links them is their small size (Fig. 1). A primary distinction
between these entities is cell structure. Lets review their properties. Bacteria are prokaryotes
(meaning before a nucleus)and their cells lack internal membrane-bound structures. In contrast,
fungi and protozoa are eukaryotes (meaning true nucleus) and their cells contain a membranebound nucleus as well as other membrane bound structures called organelles. Viruses are
acellular (meaning not containing any cells), it is only nucleic acid wrapped in a coat (typically a
protein). Finally, multicellular parasites are multicellular organisms that benefits from a host and
typically, the parasite is smaller than the host.
Infectious pathogens are usually qualified as contagious agents because they can be transmitted
from one person or species to another. Once the agent comes in contact with a host, the pathogen
can enter and multiply using the hosts resources, or it can die if the host has a good vigilant
immune system. Although, there are almost an infinite number of microorganisms, relatively
few cause disease in healthy individuals. Infectious disease results from the interaction between
those few pathogens and the immune system of the hosts they infect. Infectious microorganisms
can be classified as either primary pathogens or as opportunistic pathogens according to the
status of host defenses. Primary pathogens cause disease as a result of their presence or activity
within a healthy host because of the severity of the disease they cause. Many common primary
pathogens of humans only infect humans and they do not cross species. However, many serious
diseases are caused by organisms that jumped to our species from non-human hosts.

Opportunistic pathogens are organisms that cause an infectious disease to an

immunocompromised host (newborn, sick person, etc.). Opportunistic disease is typically
caused by microbes that are in contact with the host for example bacteria found in the
gastrointestinal tract that would be controlled by a good immune system. However, there are
some instances when these pathogens can be acquired from other hosts (a flu-virus carrier kisses
a newborn) or introduction during surgery via nonsterile needless. It may also occur as a result
of genetic defects, or exposure to antimicrobial drugs/immunosuppressive drugs.
Transmission
An infectious disease has to be transmitted from some source. Understanding the infectious
agent and its ability to move from one host to another is important. Transmission of an
infectious agent can occur through various mediums such as liquids, food, body fluids,
contaminated objects, and airborne inhalation. The following examples are representations of
these transmission mechanisms (Fig. 2). Respiratory diseases are commonly acquired by contact
with aerosolized droplets spread by sneezing, coughing, talking, or kissing. Gastrointestinal
diseases are often acquired by ingesting contaminated foods. Sexually transmitted diseases are
acquired from sexual activity through body fluids. Some infectious agents may be spread as a
result of contact with a contaminated fomites (inanimate objects) such as a dollar bill passed
from one person to another. In addition, transmission of infectious diseases may also involve a
vector (a carrier). There are two types of vectors: mechanical and biological. A mechanical
vector picks up an infectious agent on the outside of its body and transmits it in a passive
manner. An example of a mechanical vector is a mosquito/fly (Fig. 3) that touches a
contaminated surface and the insect touches your food prior to consumption. The pathogen never
enters the insects body, only the human body.
A biological vector harbors pathogens within its body and delivers them to new hosts in an active
manner. Some examples of biological vectors are arthropods (mosquitoes, ticks, lice, etc.),
which are responsible for many blood-borne diseases such as malaria, viral encephalitis, Lyme
disease, and African sleeping sickness. An effective strategy used to control vector transmitted
infectious diseases is to kill the vector since the vector is required in the life cycle of the
pathogen (Fig. 4). The relationship between virulence and transmission has important
consequences for the long term evolution of a pathogen. It takes many generations for a microbe
and a new host species to co-evolve, that is why an emerging pathogen may hit its earliest
victims hard. However, if a disease is rapidly fatal, the host may die before the microbe can get
passed along to another host, killing the pathogen as well.
The human strains of the Ebola (Fig. 5) virus kill their victims extremely quickly and as a result,
the victims of this disease do not have the opportunity to travel very far from the initial infection
zone. Additionally, this virus spreads through skin lesions or permeable membranes so the initial
stage of Ebola is not very contagious since its victims experience only internal hemorrhaging.
Usually the spread of Ebola stays within a relatively confined geographical area. On the other
hand, Human Immunodeficiency Virus (HIV) kills its victims slow by attacking their immune
system. This mechanism allows a lot of its victims to transmit the virus to many others before
even realizing that they are carrying the disease. This relatively low virulence allows its victims
to travel long distances, increasing the likelihood of an epidemic.
Virulence factors

Virulence factors are molecules expressed and secreted by pathogens that enable them to adhere
to a host, evade the host's immune response, and feed from a host. These factors are often
responsible for causing disease in the host because they have the ability to inhibit certain hosts
functions.
Pathogens possess a wide range of virulence factors. One important group of virulence factors is
bacterial toxins (algae, fungi, and protozoa also produce them). These toxins are divided into two
groups: endotoxins and exotoxins. The endotoxin (refers to bacterial toxin) is the
lipopolysaccharide (LPS, Fig. 6) which is part of Gram-negative bacteria release upon bacterial
lysis. LPS is a very potent antigen and stimulates an intense host immune response. If purified
LPS is administered to laboratory animals, it results in imminent death. However, in humans, it
is responsible for septic shock which, in severe cases, can lead to death as well. Exotoxins
(meaning inside the cell) are actively secreted by some bacteria and have a wide range
of effects including inhibition of certain biochemical pathways in the host. The most potent
exotoxins known are the tetanus toxin (tetanospasmin, Fig. 7) and the botulinum toxin (Fig. 8).
Tetanus is a highly fatal disease in humans. Recorded mortality rates vary from 40% to 78%.
The disease develops when the potent neurotoxin spores germinate after gaining access to
wounds.
The organism multiplies locally, but symptoms appear remote from the infection site. The use of
the tetanus toxoid for immunization (as part of the DPT vaccine) allows for fewer than 100 cases
annually in the U.S., but the disease is a significant problem worldwide.
Botulinum toxin is a lethal naturally occurring substance, but since 2007 has become known to
women as botox injections that will render the muscle unable to contract for 3-4 months (keeping
you looking younger).
Another group of virulence factors possessed by bacteria are immunoglobulin (Ig) proteases.
Proteases are enzymes that break down specific proteins (Fig. 9). Remember that
Immunoglobulins are antibodies expressed and secreted by hosts in response to an infection.
Bacteria such as Streptococcus pyogenes (scarlet fever) are able to break down the host's
antibodies by using proteases. These virulence factors allow the bacteria to successfully succumb
the hosts immunity.
A Successful Bacterial Infection
It is estimated that half of the world's population is infected with H. pylori (Fig. 10).
Helicobacter pylori (H. pylori) is the bacteria responsible for most ulcers and many cases of
stomach inflammation (chronic gastritis). The bacterium only grows in the stomach and is
usually contracted during childhood through food or water. The bacteria can weaken the
protective coating of the stomach, allowing digestive juices to irritate the sensitive stomach
lining. If you are a carrier of H. pylori, you may have no symptoms, but some of the symptoms
are abdominal pain, belching, bloating and fullness, feeling very hungry 1 to 3 hours after
eating. Patients who have H. pylori are treated with a 10-14 day antibiotic regimen. Those
living in developing countries or crowded, unsanitary conditions are most likely to contract the
bacterium, which is passed from person to person. Simple blood, breath, and stool tests can
determine if you are infected with H. pylori. A clean and germ-free environment may help

decrease your risk of H. pylori infection.

Sexually Transmitted Diseases or Sexually Transmitted Infection (STDs or STI)
We would not be able to learn about infectious diseases without talking about some of the
sneakiest and most triumphant pathogenic agents. STDs incidence rates remain high worldwide
despite diagnostic and therapeutic advances. STDs are transmitted from one person to another by
certain sexual activities rather than being actually caused by those sexual activities. STDs are
transmitted through the mucous membranes of the penis, vulva, rectum, urinary tract, and
mouth. Mucous membranes differ from skin in that they allow certain pathogens into the body.
Pathogens are also able to pass through breaks or abrasions of the skin during sex, for example
the shaft of the penis is particularly susceptible due to the friction caused during penetrative sex.
Depending on the STD, a person may still be able to spread the infection even if no signs of the
disease are present. A person can spread HIV infection at any time, even if he/she has not
developed symptoms of AIDS. All sexual behaviors that involve contact with body fluids of
another person should be considered to be a risk of pathogen transmittance. Sexual norms and
condom use can prevent the spread of these pathogens.
The following list containing some of the most common STDs pathogenic causes:
Bacterial: Chancroid (Haemophillius ducreyi); Chlamydia infection (Chlamydia trachomatis);
Donovanosis (Granuloma inguinale); Gonorrhea (Neisseria gonorrhoeae); Lymphogranuloma
venereum (Clamydia trachomatis); Syphilis (Treponema pallidum, Fig. 11).
Viral: Cytomegalovirus; Hepatitis B; Herpes (Herpes simplex virus); Human Immunodeficiency
Virus (HIV); Human Papilloma Virus (HPV); Molluscum (MC).
Parasites: Pubic Lice or crabs (Phthirius pubis); Scabies (Sarcoptes scabiei).
Fungal: Candidiasis (Candida albicans).
Protozoal: Trichomoniasis (Trichomonas vaginalis)
A Common Deadly Virus: HPV
The most deadly STD is HIV, but many other viruses can also cause death. Genital
human papillomavirus (HPV) is the most common sexually transmitted infection. The virus
infects the skin and mucous membranes. There are more than 40 HPV types that can infect the
genital areas of men and women, including the skin of the penis, vulva (area outside the vagina),
and the linings of the vagina, cervix, and rectum. HPV is not visible to the naked eye and a lot of
infected individual do not even know they have it. Most people with HPV do not develop
symptoms, but certain types of HPV can cause genital warts in men and women, cervical cancer
and other less common cancers, such as cancers of the vagina and penis. HPV types are divided

into two groups: low-risk (wart-causing) and high-risk (cancer-causing). Most of the time, the
bodys immune system clears the HPV infection naturally within two years.
Genital warts usually appear as small bumps or groups of bumps, usually in the genital area in
men and women (Fig. 13). Warts may appear within weeks or months after sexual contact with
an infected person. If left untreated, genital warts may go away, remain unchanged, or increase
in size/number. They will not turn into cancer. About 1% of sexually active adults in the U.S.
have genital warts. Cervical cancer does not have symptoms until it is quite advanced. For this
reason, it is important for women to get screened regularly for cervical cancer. Genital HPV is
passed on through genital contact, most often during vaginal and anal sex. Approximately 20
million Americans are currently infected with HPV and it is estimated that 6.2 million people
become newly infected each year. At least 50% of sexually active men and women acquire
genital HPV infection at some point in their lives. The American Cancer Society estimates that
in 2008, 11,070 women were diagnosed with cervical cancer in the U.S. A vaccine can now
protect females from the four types of HPV that cause most cervical cancers and genital warts.
The vaccine is recommended for females age 13-26. Condoms may lower the risk of contracting
HPV.
Predicting disease clusters is performed by monitoring the pathogen in given communities.
Epidemiologists attempt to determine what factors are associated with diseases (risk factors), and
what factors may protect people or animals against disease (protective factors). The science of
epidemiology was first developed to discover and understand possible causes of contagious
diseases like smallpox, typhoid and polio. Diagnosis of an infectious disease involves
identifying the infectious agent either directly or indirectly. For practical reasons, minor
infectious diseases such as warts, cutaneous abscesses, respiratory system infections, and
diarrheal diseases are diagnosed by their clinical symptoms and treated on the clinical
assessment. Conclusions about the cause of the disease are based upon the likelihood that a
patient came in contact with a particular agent, the presence of a microbe in a community, and
other epidemiological considerations. Detailed identification techniques involve the culture of
infectious agents isolated from a patient.
Microbiological culture is a principal tool used to diagnose infectious diseases. A sample taken
from potentially diseased tissue or fluid is then tested for the presence of an infectious agent able
to grow within that medium. Most pathogenic bacteria are easily grown on nutrient agar, a form
of nutrients that allows a bacterium to grow into a visible mound on the surface of the plate
called a colony. The size, color, shape, and form of a colony is characteristic of the bacterial
species, its specific genetic makeup (its strain), and the environment which supports its growth.
Culture techniques rely on microscopic examination for definitive identification of the infectious
agent. Microscopy may be carried out with the compound light microscope. Microscopy is
often also used in conjunction with biochemical staining techniques. Biochemical tests used in
the identification of infectious agents include the detection of metabolic or enzymatic products
characteristic of a particular infectious agent. The isolation of enzymes from infected tissue can
also provide the basis of a biochemical diagnosis of an infectious disease. For example, humans
do reverse transcriptase so the presence of this enzyme is characteristic of specific viral
infection.

Infectious Diseases Treatment and Prevention: Vaccination and Antibiotics

Smallpox killed an estimated 60 million Europeans during the 18th century. The Influenza
Pandemic of 1918 (or the Spanish Flu) killed 25-50 million people. Today Influenza kills about
250,000 to 500,000 worldwide each year. What are we doing differently? We are using
vaccination and antibiotics for the general control of infectious diseases. The goal of all
vaccines is promote a primary immune reaction so that when the organism is again exposed to
the antigen, a much stronger secondary immune response will be elicited.
There are three efficient methods of vaccination:
1.Active artificial (immunization): develops slowly, lasts for several years, and is specific to the
antigen for which the immunization was given.
2.Passive natural (mother to child): develops immediately, is temporary, and affects all antigens
to which the mother has immunity.
3.Passive artificial (injection of gamma globulin): develops immediately, is temporary, and
affects all antigens to which the donor has immunity.
Some individuals develop natural serum antibodies to the surface of some pathogenic agents
although they have had little or no contact with the agents, these natural antibodies confer
specific protection to adults and are passively transmitted to newborns.
Antibiotics
For the past 60 years, antibiotics have been critical in the fight against infectious disease caused
by bacteria and other microbes. Antimicrobial chemotherapy has been a leading cause for the
dramatic rise of the average life expectancy. However, many pathogens have become resistant to
antibiotic drug therapies. The first antibiotic was discovered in 1929 by Sir Alexander Fleming,
who observed inhibition of staphylococci on an agar plate contaminated by a Penicillium mold
(Fig.15). Fleming called it penicillin. He noticed that a patch of the mold Penicillium notatum
had grown on a plate containing the bacterium Staphylococcus and that around the mold there
was a zone where no Staphylococcus could grow. After more research, he was able to show that
culture broth of the mold prevented growth of the Staphylococcus even when diluted up to 800
times.
Since then wound infections, gonorrhea, tuberculosis, pneumonia, septicemia, and childhood ear
infections have been treated with antibiotics, but in response these pathogens have become
resistant to a lot of antibiotics and are becoming more difficult to treat. One part of the problem
is that bacteria and other microbes that cause infections are remarkably resilient and have
developed several ways to resist antibiotics and other antimicrobial drugs. Another part of the
problem is due to increasing use for unnecessary health problems and misuse in veterinary
medicine and in agriculture. Unless antibiotic resistance problems are detected as they emerge,
and rapidly contain, we will face the same fate our ancestors face when they had not develop
antibiotics.

The World Health Organization (WHO) collects information on global deaths by category and
the worldwide mortality due to infectious diseases per year is 3-1.5 million. The top 3 disease
killers are HIV, Tuberculosis (TB), and malaria. Although, the overall number of deaths due to
nearly every disease has decreased, deaths due to HIV/AIDS (Fig. 16) have increased fourfold.
HIV is considered a pandemic.
Figure 18

Click here to view full-size Image

Spread of Swine Flu as of July 2009
In 2009, the world was tracking the novel H1N1 influenza virus. The 2009 H1N1 virus was not
the everyday flu, which does not mean it would make you feel sicker, it was just different (Fig.
17). Most reported cases were mild, and treated within a week. However, it was alarming that it
caused young people to get sick and even die, compared with seasonal flu. The H1N1 virus
accounted for about 60% of flu viruses that were circulating worldwide during that time. Flu
viruses subtypes are designated by their surface proteins, one of 16 possible hemagglutinins
(H1-H16) and one ofnine neuraminidases(N1-N9). Despite the large number of possible
permutations, human flu is usually caused by H1, H2, and H3 subtypes in combination with N1
or N2. H1N1 subtypes are quite common among influenza viruses, but the H1N1 virus was a
very unique alteration of reassorted genetic elements from avian, human, and swine sources. Its
mixed heritage initially made it unidentifiable when it cropped up during routine tests, and it was
eventually identified by the CDC after sequencing the strains.
In June 2009, the WHO declared that a new virus, not previously circulating in humans, was
being rapidly transmitted (Fig. 18). Worldwide, this virus killed over 17,000 people since the
begging of 2010. Zanamivir and tamiflu were the only two known antivirals effective for treating
the H1N1 virus. In August 2010, the WHO claimed that the worldwide epidemic H1N1 virus was
over and that the world had returned to its normal seasonal flu patterns. H1N1 is still around in
some countries, but is not as prevalent as it was back in 2009/2010. Vaccinations are still
available in those countries where the H1N1 virus is still present.
Concluding Remarks
In most cases, microorganisms live in harmony with their hosts. Such is the case for many
tropical viruses and the insects or other animals in which they have co evolved for thousands of
years. However, when a microbe jumps from a long-time animal host to a human being, it may
cease to be a harmless parasite and become pathogenic. Several human activities have led to the
emergence and spread of new diseases such as:
1. Construction of new villages and housing developments in rural areas forces animals to live in
dense populations, thus, creating opportunities for microbes to mutate and emerge (antigenic

shift).
2. Changes in agriculture such as new crops in certain terrains attract new pests and bring new
microbes to farmers.
3. Modern transportation systems harbor unintended passengers that can spread diseases to
faraway destinations.
What can you do to prevent the spread of infectious diseases?
These measurements should prevent the spread of infectious diseases:
Wash your hands before eating or touching your face
Cook meats thoroughly
Do not have unprotected sex
Make sure you have been properly vaccinated
If you work in a public place get a flu shot that includes the swine flu vaccine
When taking antibiotics, make sure to finish your prescribed medication (Fig. 19)

Alexander
Fleming

discovered the world's first antibiotic Penicillin in 1928

and discovered the lysozyme in 1923.

Microbial
culture

a growth medium is provided for a specific agent.

Pathogen

Epidemiology

Botulinum
toxin

infectious agent or germ, a biological agent that causes

disease to its host.

is the study of diseases in populations of humans or

other animals, specifically how, when and where
they occur.

is a lethal naturally occurring substance, when carefully

isolated and purified, it can be used as an effective and
powerful medication.

Endemic

disease usually found in a particular people or country.

Epidemic

affecting a disproportionately large number of

individuals within a population.

Endotoxin

Louis
Pasteur

a toxic heat-stable lipopolysaccharide substance present

in the outer membrane of gram-negative bacteria that is
released during lysis of bacteria.

proved beyond doubt that certain diseases are caused by

infectious agents and developed a vaccine for rabies.

Virulence

the relative capacity of a pathogen to overcome body

defense.

Pandemic
(or global
epidemic)

is a disease that affects people over an extensive

geographical area.

Antigenic
Shift

refers to the genetic strain that enables a flu strain to

jump from one animal species to another, including
humans.

Exotoxin

is a toxin excreted by a microorganism (bacteria, fungi,

algae, and protozoa. An exotoxin can cause damage to
the host by destroying cells or disrupting normal cellular
metabolism.

Endotoxin

CDC

WHO

Vaccines

are toxins associated with certain bacteria. Typically

and endotoxin is not secreted by live bacteria, but is a
structural component of the bacteria, which is released
mainly when bacteria are lysed.

Centers for Disease Control and Prevention

(http://www.cdc.gov/).

World Health Organization (http://www.who.int/en/).

typically contains a small amount of an agent that

resembles a microorganism. The agent stimulates the
body's immune system to recognize the agent as foreign,
destroy it, and "remember" it, so that the immune system
can more easily recognize and destroy these
microorganisms if encounters them later.

HIV/Aids

HIV/AIDS has become a pandemic because it has spread all over the world. 25 to 30 million
people have died from AIDS to date. In fact, 5000 people die from AIDS every day, and
currently, 1 out of 7 of those deaths are children. This means that 30 children die of AIDS every
30 minutes.
The HIV virus causes a collapse of the immune system (or immune deficiency) and the final
stage of this condition is known as AIDS (Acquired Immune Deficiency Syndrome). HIV/AIDS
is known as the quiet epidemic because it affects primarily people in sub-Sahara Africa where
the support for prevention and medical care of these millions of afflicted men, women, and
children is not available. Figure 1 compares the number of AIDS cases of the world, to the
number that occur within Africa, and as it shows, African cases makes up over half of the
worldwide AIDS cases.
To understand HIV or Human Immunodeficiency Virus that infects millions of people, we need
to first understand how viruses work. So what are viruses? Viruses are microscopic parasites that
can reproduce only inside a host cell. Some consider viruses amazing cellular terrorists since
they infect and kill the cell by taking over the DNA molecular systems in the infected cells. They
can infect all types of organisms: animals, plants, and bacteria.
Viruses consist of two basic components: the genome, a core of genetic material (DNA or
RNA), and the capsid, a surrounding protein coat that protects the genome (refer to Figure 2).
HIV is a Retrovirus, which means that it is a virus with an RNA genome that uses Reverse
Transcriptase to make a DNA copy of its RNA genome (This is the opposite of the first step of
the Central Dogma). This DNA copy of the genome is then integrated into the host's cells DNA.

More specifically, HIV (figure 3) is a Lentivirus (a specific type of Retrovirus). Lentiviruses

have biological properties that are responsible for long-duration illnesses with a long incubation
period. This means that symptoms of the disease may not become evident for years after the
initial infection. This is why a patient may be HIV+ for many years before developing full blown
AIDS.
There are three important features of the HIV virus. The first two are the glycoproteins gp120
and gp41. These two proteins allow the HIV virus to attach to and penetrate into the host cell.
The third important feature of the HIV virus is the enzyme, Reverse Transcriptase. The function
of Reverse Transcriptase is to synthesize DNA, using HIV's RNA genome as a template after cell
infection has occurred.
The HIV replication cycle can be described in 7 essential steps necessary for successful viral
infection. The primary target cell of HIV are cells that express the CD4 (complementary
determinant 4) protein on their cell surface, mainly cells of the immune system such as 'Helper' T
cells (also known as CD4 T cells) and some brain cells. CD4 interacts with the gp120 protein on
the virus to create a firm attachment of the virus to the host cell.
Steps in the HIV Replication Cycle (Figure 4)
1. Fusion of the HIV cell to the host cell surface.
2. HIV RNA, Reverse Transcriptase, Integrase, and other viral proteins enter the host cell.
3. Viral DNA is formed by reverse transcription.
4. Viral DNA is transported across the nucleus and integrates into the host DNA with the help of
the viral Integrase protein.
5. This viral DNA is then used as a template to make new viral RNA and to make viral proteins.
6. New viral RNA and proteins move to the cell surface and a new, immature, HIV virus forms.
7. The virus matures by protease releasing individual HIV proteins.
The HIV virus infects and kills 'Helper' T cells (CD4 T cells), an important part of the immune
system. This leaves the host (HIV+ patient) with an immune system that becomes ineffective.
This ineffective immune system allows for the invasion of bacteria, mold, and fungus into the
body.
HIV infects 'Helper' CD4 T cells leading to death of these cells. Because the immune system is
compromised patients are more susceptible to infections than a normal healthy person would be
able to easily fight off.
In a normal immune system, after T-cells have been activated and proliferate in an immune

response to a particular antigen, most die by apoptosis as the response to that antigen wanes.
However, some of the cells do not die, instead they remain for a long time in the body so that
they can respond promptly to a second exposure to the same antigen. This is called
immunological memory and is why the response to the second encounter with an antigen is more
rapid than the primary response. The T cells that remain after the antigen are called memory T
cells. Memory T cells can survive for decades.
A strong immune defense reduces the number of viral particles in the blood stream, marking the
start of the HIV infection's clinical latency stage. Clinical latency can vary between two weeks
and over 20 years. During this early phase of infection, HIV is still active within lymphoid
organs. If an activated T cell happens to be infected by HIV, it also is more likely to die by
apoptosis but a few of these cells become memory cells. In their resting state, these memory cells
do not replicate the virus, but still harbor it as a DNA copy integrated into the chromosomes, the
provirus (Figures 5 and 6). Latency is broken when the virus starts to proliferate and this occurs
when the T cells are stimulated during an antigenic response.
Transition from HIV to AIDS
Because HIV infection results in progressive loss of immune function marked by depletion of
CD4+ T cells, people with advanced HIV infection are vulnerable to infections and malignancies
that are called opportunistic infections" (listed in Table 1) because these infections take
advantage of the opportunity offered by a weakened immune system. This is a key characteristic
of AIDS.
Different conditions typically occur at different stages of HIV infection. In early HIV disease
people can develop tuberculosis, malaria, bacterial pneumonia, herpes zoster (Figure 7),
staphylococcal skin infections, septicemia, and Kaposis sarcoma (Figure 8). Classic Kaposis
sarcoma is typically limited to elderly men from the Mediterranean region, or of Eastern Europe
descent. However, in 1981 an unusual cluster of Kaposi Sarcoma in young homosexual men was
observed and this event brought AIDS to clinical attention. These are diseases that people with a
normal immune system can also get, but with HIV they occur at a much higher rate. It also takes
longer for a person with HIV to recover than it takes for someone with a healthy immune system.
When the immune system is very weak due to advanced HIV disease or AIDS, opportunistic
diseases such as Pneumocystis carinii pneumonia (PCP), toxoplasmosis and cryptococcosis
meningitis develop. PCP is a common opportunistic disease, which causes an infection in the
lungs of people with a weak immune system. Once the infection develops, there will be pus in
the lungs, just as when a skin wound is infected, which makes it difficult to breathe since oxygen
cannot be drawn from the air into the bloodstream. Some infections can spread to a number of
different organs, which is known as disseminated or systemic disease. Many of the
opportunistic diseases that occur at this late stage are life threatening.
Stages of HIV Infection
HIV infection can generally be broken down into four distinct stages: primary infection,
clinically asymptomatic stage, symptomatic HIV infection, and progression from HIV to AIDS.

Stage 1: Primary HIV infection-lasts for a few weeks

This stage of infection is sometimes accompanied by a short flu-like illness. During this stage,
there is a large amount of HIV in the peripheral blood and the immune system begins to respond
to the virus by producing HIV antibodies and cytotoxic lymphocytes. This process is known as
seroconversion. If an HIV antibody test is done before seroconversion is complete then it may
not be positive.
Stage 2: Clinically asymptomatic stage-lasts for an average of ten years
This stage is free from major symptoms. The level of HIV in the peripheral blood drops to very
low levels but people remain infectious and HIV antibodies are detectable in the blood, so
antibody tests will show a positive result.
Stage 3: Symptomatic HIV infection
This stage is mainly caused by the emergence of opportunistic diseases and cancers that the
immune system would normally prevent. Treatment for the specific infection or cancer is often
carried out, but the underlying cause is the action of HIV erodes the immune system. Unless HIV
itself can be slowed down, the symptoms of immune suppression will continue to worsen.
Stage 4: Clinical AIDS
This occurs when the opportunistic diseases become fatal to the patient as the immune system
and all treatments fail. The CDC defines AIDS as having a CD4 cell count of 200 cells per
microliter of blood and the patient develops one or more of a specific number of severe
opportunistic infections or cancers. A normal healthy individual has a CD4 cell count of about
1,000 cells per microliter.
HIV Testing
Diagnosis has substantial importance because infected individuals can be identified and they can
take measures to prevent the spread of HIV as well as delay the development of AIDS by
medical treatment. The following are common HIV tests:
1.The HIV antibody test shows whether a person has been infected with HIV. These tests are
based on the assumption that the bodys immune system has produced antibodies in response to
the exposure of HIV. Positive results after 6-10 weeks of initial infection.
2. The HIV P24 antigen test are sometimes used to screen donated blood, but they can also be
used for testing for HIV in individuals, as they can detect HIV earlier than standard antibody
tests. P24 is the HIV antigen that most commonly provokes an antibody response. Early in the
infection, P24 is produced in excess and can be detected in the blood serum by a commercial
test.
3.The PCR test detects the genetic material of HIV itself, and can identify HIV in the blood
within two to three weeks of infection.
4.CD4 tests measures the number of helper CD4 T-cells in your blood. Because HIV causes

many helper CD4 T cells to be damaged or destroyed, there are fewer cells in the blood of HIV
patients compared to normal healthy individuals.
5.The Viral Load test can provide important information about the likely course of HIV
infection. Viral load refers to the amount of HIV in your blood. The results of these test tell you
whether your viral load is low, medium, or high.
HIV Treatment
The main type of treatment for HIV or AIDS is called HIV antiretroviral drug treatment. While,
it is not a cure, it can minimize the progression of the disease for many years. The treatment
consists of drugs that have to be taken everyday for the rest of a persons life. The aim of
antiretroviral treatment is to keep the amount of HIV in the body at a low level. This reduces or
stops any weakening of the immune system and allows it to recover from any damage that HIV
might have caused already.
In order for antiretroviral treatments to be effective for a long time, many HIV/AIDS patients
take more than one antiretroviral drug at a time called combination therapy. The term Highly
Active Antiretroviral Therapy (HAART) is used to describe a combination of three or more antiHIV drugs.
Why do people need to take more than one drug at a time?
The HIV virus escapes the immune response through rapid mutation because of error-prone
reverse transcription plus a very high replication rate. In other words, HIV is constantly
mutating, so if only one drug was taken, HIV would quickly mutate and become resistant to it
and the drug would stop working. Taking two or more antiretrovirals at the same time vastly
reduces the rate at which resistance would develop, making treatment more effective in the long
term.
Treatment with HAART therapy has been shown to drastically lower viral set point (the amount
of virus during the first stage of HIV) that appears to predict the subsequent rate and survival of
HIV patients. Importantly survival for HIV+ individuals improved dramatically when treatment
with HAART therapy started (Figure 9). The five groups of anti-HIV drugs are listed in table 2.
Prevention of HIV
Stopping the spread of the virus requires knowledge and changes in social customs and cultural
practices. Here are a few methods to avoid the transmittance of HIV:
1. Use condoms-They reduce the risk of infection for both wearer and the sexual partner.
2. Use safer sex practices-Avoid having sex with anyone who has multiple and/or anonymous
sexual partners or anyone who is a member of a high risk group for AIDS.
3. Do not share needles if you are a drug user.

4. Healthcare workers- Safety should be considered at all times during invasive procedures and
during dental and medical laboratory procedures that involve blood.
5. Exercise caution regarding procedures, such as acupuncture, tattooing, ear piercing, etc, in
which needles or other non-sterile instruments may be used repeatedly to pierce the skin and/or
mucous membranes.
Remember, You cannot get HIV/AIDS from touching someone or sharing items, mosquito bites,
or through coughing and sneezing. Additionally, HIV is not spread through routine contact in
restaurants, the workplace or school. The CDC does caution against french kissing someone who
is HIV positive because open sores in the mouth can lead to HIV exchange.
Who Should Get Tested For HIV
Anyone who has engaged in the following behaviors which increase the chances of getting HIV.
Anyone who has injected drugs or steroids or shared equipment (such as needles, syringes,
works) with others.
Anyone who has unprotected vaginal, anal, or oral sex with men who have sex with men,
multiple partners, or anonymous partners.
Anyone who has exchanged sex for drugs or money.
Anyone who has been diagnosed with or treated for hepatitis, tuberculosis (TB), or a sexually
transmitted disease (STD), like syphilis.
Anyone who has had unprotected sex with anyone described above.
If you have had sex with someone whose history of sex partners and/or drug use is unknown to
you or if you or your partner has had many sex partners, then you have more of a chance of
being infected with HIV. Both you and your new partner should get tested for HIV, and learn the
results, before having sex for the first time.
For women who plan to become pregnant, testing is even more important. If a woman is infected
with HIV, medical care and certain drugs given during pregnancy can lower the chance of
passing HIV to her baby. All women who are pregnant should be tested during each pregnancy

HIV

Human immunodeficiency virus, the virus that causes acquired

immune deficiency syndrome (AIDS); it replicates in and kills helper
T-cell

Viruses

Microscopic parasites that can only reproduce inside a host cell

AIDS

Acquired immune deficiency syndrome, an incurable viral disease that l

failure in otherwise healthy people

Antibody

A protein made by a B-cell that specifically binds a particular antigen

Antigen

A moleulce that leads to a specific immune system response

Combination Therapies

A drug cocktail-or-combination of antiviral drugs given to HIV infected

more effective than when given individually

CD4 protein

A surface protein that is known to be the receptor for HIV. It is characteri

They are also found on macrophages and dendritic cells.

Co-receptors for HIV

Molecules that are on the surface along with CD4 protein, and are necess
HIV to the host cell.

ELISA

The most used test for HIV antibodies since it is inexpensive. If the tested
exposed to HIV, he/she would carry specific antibodies to HIV that would
However, the test can not be accurate if the person has not carried the viru
weeks.

Immune System

The system that circulates through the blood to provide protection agains

Incubation Period

The time between infection by a microorganism and the appearance of sy

Lentiviruses

A subclass of retroviruses in which HIV is a member

Opportunistic Diseases

As the immune system becomes increasingly compromised by HIV, it be

opportunistic infections-which would usually be fought off easily by a h
but a low helper T-cell count means opportunistic infections can be fatal

T-lymphocytes (T-cells)

Lymphocytes that recognize and bind foreign antigens. The main lymph

and helper T-cells.

Vaccines

A preparation used for stimulating and immune response in the body.

Viral Load

The amount of virus in the tissues of an infected person.

Provirus

The DNA form of a retrovirus incorporated into a hosts cell in the nucle

Drug Addiction
as a general rule, we reserve the term drug abuse to apply to the illegal, nonmedical use of a
limited number of substances, most of them drugs, which have properties of altering the mental
state in ways that are considered by social norms and defined by statute to be inappropriate,
undesirable, harmful, threatening, or, at minimum, culture-alien. -Glasscote et al. American
Psychiatric Association 1932

There have been numerous celebrities, Heath Ledger, Anna Nicole Smith, Elvis Presley, Jimi
Hendrix, Marilyn Monroe, and OlDirty Bastard to name a few, who had all died of drug
overdoses. Some of them died as a result of abusing illegal street drugs, such as cocaine, heroin,
etc, while others have died as a result of abusing prescription medications. Either illegal street
drugs or prescription medication can lead to drug abuse, which has very negative consequences.
This module will take you through the classification of drugs, what leads to drug abuse, the
consequences of drug abuse, and treatment and prevention strategies.
What is a drug?
A drug, broadly speaking, is any substance (natural products or synthetic compounds) that, when
absorbed into the body of a living organism, alters normal bodily function. Drugs have been used
for centuries for medical purposes. People abuse and become addicted to both pharmacological
drugs (i.e. prescriptions and over the counters), and recreational drugs (i.e. cocaine, heroin, etc).
All drugs when abused can be toxic to the body.
The Food and Drug Administration (FDA) is the government agency responsible for regulating
the legal drug market. They impose policy in response to the health treatment of the public.
Classification of drugs
A drug is often classified according to their chemical structures. Although this is useful for
medicinal chemists, it does not provide a meaningful classification scheme for categorizing drug
effects. Some compounds with similar chemical structures produce very similar biological
effects, but others which belong to the same chemical class can produce different effects.

Although, it seems like a lot of classes, they can be easily compressed into four categories that
you should recognize. You might have heard the terms uppers and downers referring to
stimulants and depressants accordingly. Lets go over these terms in detail.
Depressants- slows down the CNS and produces a feeling of relaxation. Examples: barbituates
and alcohol (figure 2).
Narcotics- slows down the CNS and blocks pain. Examples: morphine and heroin (figure 3).
Stimulants- speeds up the CNS, increasing alertness; producing a sense of euphoria. Examples:
caffeine and cocaine.
Hallucinogens- slows down and speeds up the CNS randomly, and alters perception. Examples:
LSD and marijuana (figure 4).
Drug Abuse versus Drug Addiction
Drug abuse is using a drug excessively, or for purposes for which it was not medically intended.
It is considered a timeless affliction because users are found everywhere in all occupations,
income, social class levels, and age groups. Although drug use can lead to potential abuse, the
benefits of licit drugs for the sick are countless. Indeed, advancements in drug development are
considered one of the highest achievements in our society because they have helped us live
healthier and longer. Drug addiction is compulsively using a substance, despite its negative and
sometimes dangerous effects. Drug addiction is a pathological condition. The disorder of
addiction involves the progression of acute drug use to the development of drug-seeking
behavior, the vulnerability to relapse, and the decreased, slowed ability to respond to naturally
rewarding stimuli.
The Origin of Drug Addiction
Lets go over how drugs work. The four principal factors responsible for determining a drug user
are:
1. Pharmacological: Pharmacological factors take into account how a particular drug affects the
body (size, gender).
2. Cultural: Culture issues examine how societys views affect the use of a particular drug such
as the use of alcohol at parties.
3. Social: Social aspects include the specific reasons why a drug is taken.
4. Contextual issues: Contextual factors refer to how the drug use behavior develops.
Not all drugs are created equal and there is a hierarchy of drug induced effects that lead to
uncontrolled use. However, all illicit drugs can become addictive when abused. The four

principles listed below are part of the spectrum of psychoactive drug use and can give you an
idea of how drug use can become abuse.
1. Beneficial use would be considered any prescribed drug or over the counter medication that is
used for healing purposes, also coffee and tea would be included here as well as wine or
alcoholic drinks in a ceremony.
2. Casual use is non-problematic. It would be a recreational substance such as alcoholic drinks at
parties that do not lead to drunkenness.
3. Problematic use takes place when negative consequences are visible, such as drinking alcohol
every other day with your friends and results in an inability to do your homework or to keep up
with your daily life.
4. Chronic dependence is the most serious type of drug consumption. You would be considered a
drug addict at this point because you take the drug compulsively although it has become a threat
to your health and to society.
Once an individual has crossed the spectrum from left to right, he/she needs intervention to
combat addiction. The outcome of drug abuse differs from individuals since it reflects both
genetic and environmental influences and more importantly the nature of the drug abused.
There is no cure for drug addiction but it is a treatable disorder. Drug addiction therapy starts by
detoxification of the individual followed by a 9-12 step program seeking to change the persons
behavior. It is often that medications such as methadone (for heroin addicts) or antabuse (for
alcoholics) are prescribed.
Addiction and the Brain: Understanding the Reward Mechanism
The human brain (figure 5) is a very complex structure and it is the center of all human activities.
The brain can cope with complex tasks because of the way it is organized. It shapes your
thoughts, emotions, reality, and behavior by following a rule known as localization of function,
which means that specific regions of your brain are responsible for specific brain functions. For
example, the brain stem controls the basic functions of the body such as heart rate and breathing.
On the other hand, the limbic system (figure 6), another part of the brain, controls the brain
reward system and we will study this system carefully. The limbic system connects the parts of
your brain that are responsible for your ability to feel pleasure. Pleasure is a reward given to you
by doing an action necessary for your survival.
The brain has a sophisticated communication system. It utilizes neurons or nerve cells that have
networks that pass messages back and forth through the brain, the spinal column, and the
peripheral nervous system. Neurons communicate with each other through an electrochemical
process. Neurons contain some specialized structures known as synapses and chemicals known
as neurotransmitters (figure 7). These neurotransmitters or chemical messengers are sent from
one neuron to another. The receiving neuron has a receptor that the neurotransmitter dopamine
(which we will discuss later) binds to. Dopamine is the key player in the reward system of the

brain. It is released when you are experiencing something that will allow you to survive.
The Mesolimbic Dopaminergic System
The core of your brain reward system originates in the mesolimbic dopaminergic system (figure
8). This portion of the limbic system is thought to play a vital role in the development of
addiction. It is hypothesized that this system plays a role in the translation of motivation to motor
related behaviors and in reward learning. The reward system is controlled by the release of
dopamine (figure 9), which is a neurotransmitter found in regions of the brain that regulate
movement, emotion, cognition, motivation, and feelings of pleasure. Although different drugs
may act through different mechanisms, all addictive drugs increase the amount of dopamine in
the nucleus accumbens with profound consequences on peoples behavior. Dopamine makes you
feel good.
Different drugs have different initial targets in the brain, but all of them produce the same
outcome: activation of dopamine neurons. Although, the exact role of dopamine in reinforcement
remains an active research area, it is believed that the dopamines function is to enable rewardrelated stimuli to promote the learning of adaptive behavior that enables survival. This means
that dopamine triggers a cascade of reactions that allows a system to be motivated to perform a
task and repeat it if the reward is good. An example is eating chocolate. Lets say you are
motivated to eat chocolate. The mesolimbic system is responsible for the motivation to eat the
chocolate and the conversion of this motivation into the required motor movements to
accomplish this task such as getting you to the store to get it.
The mesolimbic system is also responsible for the feeling of reward after you eat the chocolate.
If you are happy after you eat the chocolate, you are likely to eat it again (positive reward). On
the other hand, if you throw up after you eat the chocolate, you are not likely to eat it again
(negative reward). The over stimulation of the reward system (when positive rewards are
received) leads to addiction. Addiction can then be defined as the necessity to repeat a behavior
that leads to euphoric effect.
The activation of the reward system is an important event in the brain so the brain seeks to repeat
that experience until it becomes a habit. Dopamine neurons are activated by natural rewards such
as food, drinks, and sex, all of which are necessary for the survival of the species. However,
drugs of abuse produce a much stronger elevation of dopamine and as a result, the regulation
mechanism used by the body to control this process is not followed. Illicit drugs of abuse can
lead to down regulation of the reward system which means that the neurons begin to reduce the
number of dopamine receptors because they sense an unnatural flood of neurotransmitters or
neurons may also make less dopamine. To alleviate down regulation, drug abusers start taking
higher doses of the drug causing some neurons to die due to the drugs toxicity.
All drugs of abuse alter dopamine in some way. Lets look at cocaine as a classical example and
how it influences the reward system. Cocaine is positive reinforcement to the reward system in
the brain. It causes the release of dopamine, which makes a person feel happy. Under normal
circumstances (figure 12), when a pleasurable event occurs dopamine is released. When the
stimulus is removed, the neurons that released the dopamine reabsorb it and repackage it into

vesicles for later use. This process is called reuptake. Cocaine acts to block the reuptake process.
The blocking of reuptake has two immediate consequences. As seen in figure 13, more dopamine
accumulates in the synapse because it cannot be removed. Second, the effect of dopamine lasts
longer again because it cannot be removed. The result is a prolonged euphoric feeling. Since this
activity makes individuals feel so good, the reward center of the brain wants to repeat the
experience.
However, after frequent use, the brain recognizes that there is too much dopamine floating
around and that dopamine overexposure is disruptive to the system. The brain will down regulate
the number of available dopamine receptors. This means that dopamine receptors on receiving
neurons will actually be removed. The consequence of down regulation is sensitization, which
leads to addiction. With a decrease in the number of receptors for dopamine, there will be a
decrease in how happy you feel when dopamine is released.
In order to feel the same euphoric effect as when you started using cocaine, you need to increase
the amount of cocaine. This leads to a cycle. The more cocaine you use, the more dopamine will
be released and the more your brain will down regulate dopamine receptors. In a short period of
time, you can become a cocaine addict and normal activities that once made you feel happy such
as eating or playing with friends will not make you feel happy. This is because not enough
dopamine is released when performing these activities in comparison to when you use cocaine.
You will become dependent on cocaine just to feel normal. Furthermore, the euphoria you once
felt when you initially used cocaine will not be achieved again as a result of down regulation and
unfortunately, this problem can lead to overdose.
Now, let us review: People use drugs because drugs activate the rewarding system in the limbic
system. Most drugs of abuse activate the brain reward system in a positive way. The exception is
LSD-like hallucinogens, which have been reported to produce negative experiences. Other
important facts that we need to remember:
1. Nicotine turns on dopamine neurons directly.
2. Opiates (morphine), depressants (valium), and alcohol turn on dopamine neurons indirectly by
inhibiting the inhibitory neurons that otherwise keep the dopamine neurons silent.
3. Stimulants (cocaine) increase dopamine levels in the nucleus accumbens by acting on the axon
terminal of dopamine-containing neurons to release or prevent the reuptake of dopamine.
4. PCP acts directly on the same nucleus accumbens neurons that receive the dopamine message.
5. It is not clear yet how marijuana activates the brain reward system, but whatever the
mechanism, the net result is an increase in dopamine levels in the synapses of the nucleus
accumbens.
Drug Delivery Methods

The method of drug delivery plays an important role in the development of drug addiction. Some
methods of drug delivery provide an almost immediate intense high while other methods slowly
get you high. Regardless of the method used to take a drug, mostly all drugs are distributed in the
body through the circulatory system in the blood. It requires approximately one minute for the
blood and consequently the administered drug to circulate completely throughout the body. The
rate at which a drug is distributed in the body depends on the drugs ability to pass across
membranes, its molecular size, its solubility properties (whether it dissolves in water or oil), and
its tendency to attach to proteins in tissues throughout the body.
Blood is carried to the nerve cells of the brain through capillaries. Drugs that are soluble in oily
solutions are most likely to pass through capillary membranes known as the blood brain barrier
into the brain tissue (figure 15). Many drugs are able to easily pass across the blood brain barrier
to the reward centers of the brain. Another biological barrier that most abused drugs can cross is
the placenta. This is why drug use during pregnancy has such detrimental effects (figures 15 and
16).
Most drugs do not take effect instantly because a certain amount of the drug needs to accumulate
in the body. This crucial concentration is known as its threshold.
1. Oral ingestion: This type of administration usually introduces the drug into the body by way of
stomach or intestines. The drug enters the bloodstream after passing through the wall of the
stomach or intestines without being destroyed. From the blood, the substance must diffuse to the
target area and remain there in sufficient concentration to have an effect. Thus, this is one of the
slowest ways to get high. Examples are alcohol and pills.
2. Inhalation: Inhalation into the lungs through the mouth or nose. Drugs can cross the
membranes and enter the bloodstream rapidly. Drug users may have to continually inhale the
substance to maintain the concentration necessary for an effect. This method represents one of
the fastest ways to get high. The effects are felt almost immediately with a peak high felt in
minutes. The effects usually do not last any longer than 15 minutes and thus while this method is
fast-acting, the effects are short-lived.
3. Injection (intravenous): IV is the fastest mode of action because the drug is delivered rapidly
and directly into your bloodstream. The high is brought on quickly, usually within 3-5 seconds.
However, the injection injures the vein and it collapses after repeated injections at the same
location. IV is often the method of choice for drug abusers who use heroin, cocaine, and
methamphetamine. The high is intense because blood concentration levels of the drug build up
quickly. However, because the concentration of the drug builds up so quickly, this is also a very
dangerous form of drug delivery leaving the user at high risk for overdose. The high comes on
quickly but also goes away quickly with the peak of the high felt in minutes as the body quickly
works to excrete the excessively high levels of the drug in the blood. This method of delivery
often leads to fast addiction as the user becomes physically and psychologically dependent on the
quick intense high.
Consequences of Drug Abuse

Addictive drugs produce short term changes in the brain, such as intoxication, and if drug use
continues, long term changes such as tolerance, sensitization, physical dependence, withdrawal,
psychological dependence, cravings and finally, addiction (in that order). Some of the
consequences of drug abuse are stress, poverty, domestic violence, and various sexually
transmitted diseases, such as HIV.
Small doses may not produce apparent damage, but continued use over long periods of time will
show effects years later. For example, occasional use of tobacco does not show immediate
negative effects but chronic use reveals its damage on the heart and the lungs. Studies have
shown temporary/permanent damage to the brain due to cocaine abuse (such as learning
disabilities), vein wasting due to heroin injections, and also the spread of viral disease (such as
sexually transmitted disease). Alcohol can directly damage cells and prolonged exposure to high
doses damages the brain, liver (figure 19), stomach, and other organs.
In the US alone, about 1 out of 4 deaths is attributed to drug abuse (primarily, alcohol, nicotine,
and some illicit drugs). Other nations also report high death rates but their numbers are not as
conclusive as in the US.
Treating Drug Dependence and Drug Abuse Prevention
Drug Addiction has been treated by using either therapeutic strategies or by less aggressive
treatments such as counseling and behavioral treatments. Good drug rehabilitation programs
consist of detoxification: learning and practicing a 9 or 12 step principle program that helps an
addicted person reshape his/her life. Psychological studies have shown that the principle program
is essential to their success. However, the program is not over after the patient goes back home.
These rehabilitative methods continue to be a part of the patients lifestyle and he/she must keep
in touch with the program or support group to avoid a possible relapse. This approach has
enjoyed a high success rate in the US. In addition, there is less likelihood of a relapse if family
and friends are involved and committed to help the individual. These programs are run by both
the private and public sectors of society on drug prevention/drug rehabilitation. If you need help
or know someone who needs help, please visit Drug Free.
Most countries provide community-based drug prevention, school-based drug prevention,
family-based drug prevention, and higher education drug-prevention. An outstanding program in
the US is DARE (Drug Abuse Resistance Education), has had a high success rate with children.
These programs have different levels of help and personalize programs for different groups in
society, such as low income teenagers and college students. Once the programs can address the
primary reasons for their desire to use drugs, they can provide alternatives.
Conclusion
In conclusion, drug abuse has devastating effects on not only the individual but also on society as
indicated by the following facts:
Tolerance to the drug-leads to drug wars in the streets

Impairment in cognitive functions-leads to accidents

 Negative effects of prenatal drug exposure on infants and children-hinders the future
generations

Negative effects of secondhand smoke-leads to innocent deaths

Increased spread of infectious diseases-leads to endemics, i.e. HIV endemic

Licit
Drugs

Legalized drugs

Illicit
Drugs

Illegal drugs

Addiction

Compulsive physiological and

psychological need for a habit-forming
substance, such as narcotics, to such an
extent that not having the substance can
cause severe trauma.

Chemical
dependency

A state resulting from habitual drug-use

where negative physical withdrawal
symptoms result from abrupt
discontinuation.

Withdrawal

The characteristic signs and symptoms

that appear when a drug that causes
physical (chemical) dependence is
regularly used for long periods of time
and then suddenly discontinued.

Psychoactive
drug

A chemical substance that acts primarily

upon the central nervous system where it
alters brain function, resulting in
temporary changes in perception, mood,
consciousness and behavior

Euphoria
Detoxification

Stimulant
(uppers)

Depressants
(downers)

A feeling of great happiness or well-being.

A period of medical treatment, usually
including counseling, during which a
person is helped to overcome physical and
psychological dependence on alcohol or
drugs.

Drugs that temporarily increase alertness and

wakefulness.

Cehmical agents that diminish the function or

activity of a specific part of the body.

Hallucinogens

Limbic
system

Dopamine

A psychoactive drug that induces

hallucinations or altered sensory
experiences.

Connects the parts of your brain that are

responsible for your ability to feel pleasure.

A neurotransmitter, which is the key player in

the reward system of the brain.

Diabetes/Obesity

Diabetes Mellitus (DM) is a condition in which the body either does not produce enough, or does
not properly respond to, insulin, a hormone produce in the pancreas. Insulin enables cells to
absorb glucose in order to turn it into energy. Glucose is an important molecule needed for
human survival. Glucose is our source of energy and several body organs are involved in its
regulation to maintain homeostasis. In diabetes, the body either fails to properly respond to its
own insulin, does not make enough insulin, or both. This causes glucose to accumulate in the
blood, often leading to various complications. DM causes irreversible physiological damage, and
over time it can disable the patient. DM disease is a worldwide problem and it is the leading
cause of death. In the United States, over a million people are affected and this number continues
to increase. It is estimated to affect over 366 million people worldwide by 2030.
Diabetes mellitus can be described as a spectrum that ranges from severe (irreversible) to mild
(reversible). DM can be classified into several forms of the disease:
Type 1 Diabetes: insulin dependent diabetes mellitus, irreversible
Type 2 Diabetes: insulin independent diabetes mellitus, reversible,affects both obese
and nonobese
Malnutrition related: very rare

 Gestational Diabetes: reversible, 2-7% of pregnant women develop it

Blood Glucose Levels and Glucose Metabolism
Blood glucose level refers to the amount of glucose present in the blood of a human. Normally in
mammals the blood glucose level is maintained at a reference range between 3.6 and 5.8 mM. It
is tightly regulated as a part of metabolic homeostasis. Glucose levels rise after meals for an hour
or two by a few grams and are usually lowest in the morning, before the first meal of the day.
Transported via the bloodstream from the intestines of liver to body cells, glucose (figure 1) is
the primary source of energy for bodys cells, fats and lipids being primarily a compact energy
store.
Before, we learn how glucose is regulated, lets first discuss glucose metabolism. The liver is
responsible for glucose metabolism. It absorbs, and produces/stores glucose in the form of
glycogen, which is released into the blood stream slowly between meals and this process is
known as gluconeogenesis (figure 2). Gluconeogenesis is a metabolic pathway that results in the
generation of glucose from non carbon sources, such as fat, glycogen, and protein. The liver
produces more than 90% of the needed glucose and the remainder comes from renal
gluconeogensis (in the kidneys). The rate of glucose utilization by peripheral tissues must match
the rate of glucose production to maintain homeostasis. The average person produces about 200g
glucose daily and the brain alone utilizes about 100 g every day. The uptake of glucose by the
brain is mandatory and does not seem to directly depend on insulin.
Regulation of Blood Glucose Levels
The homeostatic mechanism which keeps the blood value of glucose in a remarkably narrow
range is composed of several interacting systems, of which hormone regulation is the most
important. There are two types of mutually antagonistic metabolic hormones affecting blood
glucose levels (figure 3):
catabolic hormones-such as glucagon, which increase blood glucose
anabolic hormones- such as insulin, which decreases blood glucose
These two important hormones (i.e. insulin and glucagon) are produced in the pancreas (figure
4). More specifically, in the pancreas, the beta cells produce insulin and the alpha cells produce
glucagon. We will focus on insulin and its role in regulating glucose levels.
Insulin is the key regulator of glucose. Its action is predominant after a meal and the receptors
mediate its broad range. As depicted in figure 3 and 5, once glucose is released from the liver, it
is regulated by insulin that is discharge from the pancreas and it can be delivered to muscle or

adipose tissue, or any of the other organs. Insulin binds to receptors on target cells throughout the
body and only when bound can glucose get inside the cells. Briefly, as shown in figure 6, insulin
binds to its receptor, and as a result, turns on various signaling cascades. One of which, causes
glucose-4 transporter (GLUT-4) to translocate to the plasma membrane and leads to an influx of
glucose into the cell. Glycogen, lipid, and protein synthesis can now take place.
Type 1 vs. Type 2 DM
As mentioned before, DM is divided into four different classes. However, the two most common
forms of diabetes is Type 1 and Type 2 DM.
Type 1 DM
Type 1 DM is a chronic progressive autoimmune disease that leads to the lack of insulin
production (figure 8). This type of DM is most common in children and identification of
autoantibodies in the general population can predict type 1 diabetes. The following symptoms are
good signs of type 1 DM:
1. polyuria (frequent urination)
2. Thirst (due to loss of fluids)
3. Weight loss (due to rapid breakdown of fat and muscle)
Type 2 DM
Type 2 DM refers to a chronic progressive disease with either decreased insulin secretion, or
insulin resistance (figure 9). The risk of type 2 DM and glucose intolerance has been associated
with obesity. Type 2 DM is becoming a worldwide problem since obesity has become a global
epidemic. Type 2 DM is the most common type of diabetes (90-95% of diabetic patients).
Research has demonstrated that genetic factors are also associated with Type 2 DM. Nearly 6
million people in the US have type 2 DM and do not know it. Many have no signs or symptoms.
Symptoms can also be so mild that you might not even notice them. The following symptoms are
good indicators of type 2 DM:
1. increased thirst
2. increased hunger
3. fatigue
4. polyuria
5. weight loss
6. blurred vision
7. Sores that do not heal
Consequences of DM
People affected with DM are not able to use glucose efficiently because they make very little to
no insulin to meet their metabolic needs. The body, therefore, cannot use glucose for energy
without enough insulin. If glucose builds up in the bloodstream because it cannot get inside the
cells, it can damage the heart, kidneys, eyes, and feet.

Diabetes has a major negative effect on the circulatory system. DM causes both macrovascular
and microvascular disease. Macrovascular (large vessels) disease leads to strokes, cardiovascular
disease, renovascular, and peripheral vascular disease. Macrovascular disease is not specific to
diabetic patients. However, in DM, the microvascular (small blood vessels) system are affected
and cause three common complications: blood supply to the nerves (neuropathy), retina
(retinopathy), and renal glomerulus (nephropathy). Some of these complications can be
prevented by good medical care, particularly control of blood glucose levels and early detection
of health problems. After development of diabetes, an individual will suffer from tissue damage
that can lead to the following problems, limb amputation, blindness, and kidney disease. DM
also shortens lifespan by up to 1/3, it triples the risk of heart disease, and it increase infection
susceptibility.
In addition to the mentioned problems associated with high blood glucose levels, DM patients
also show minor symptoms, such as lack of energy, visual blurring, fungal infections, and
bacterial infections.
Neuropathy Disorder-The Diabetic Foot
Diabetic neuropathy is one of the most common diabetic disorderA diabetic neuropathy can
affect nearly any part of the body (figure 11), but the feet are typically affected first.
Neuropathies do not affect the central nervous system, which includes the brain and spinal
column, but the peripheral nerves, which transmit signals to the brain via the spinal column
(figure 12). Diabetic neuropathy can be acute sensory nerve, involving asymmetric transient
pain, chronic sensory nerve disorder involving symmetric pain, or autonomic neuropathy causing
erectile dysfunction. We will only cover one of the more severe causes of neuropathy in DM
patients-the diabetic foot (figure 13). The symptoms of diabetic neuropathy vary, depending on
which nerves or which area of the body are affected.

Since we are focusing here on diabetic foot care, the symptoms may include:
Decreased sensitivity to pain
Hypersensitivity to pain
Numbness
Tingling
Shooting, burning or electric pains
Cold feet/ inability to judge temperatures
Foot ulcers
Infections
Muscle and bone deformities
The diabetic foot is caused by damage to blood vessels and impairment of the immune system

(figure 14), which makes it difficult to heal these wounds. Bacterial infections can develop into
gangrene. Because of poor blood flow, antibiotics cannot get to the site of the infection easily.
Often, the only treatment for this is amputation of the foot or leg. For this reason DM patients
must be fully aware of how to examine their own feet in order to prevent foot problems.
Retinopathy: The Diabetic Eye
Diabetic retinopathy (figure 15) is another complication of DM that causes abnormality in the
tiny blood vessels nourishing the retina. As the vessels weaken, they leak fluid and blood, failing
to provide nutrients necessary for good health in the retina. This damages the retina, which can
eventually lead to blindness. It affects up to 80% of all patients who have had DM for 10 years or
more. Despite these intimidating statistics, research indicates that at least 90% of these cases
could be reduced if there was proper and vigilant treatment and monitoring of the eyes.
There are two forms of diabetic retinopathy: nonproliferative and proliferative. Nonproliferative
retinopathy is the most common form. It usually has no effect on vision and needs no treatment
after diagnosis. However, as it continues it can get worse because the capillary walls may lose
their ability to control the passage of substances between the blood and retina. As a result, the
retina becomes swollen and fatty deposits form within. If this swelling affects the center of the
retina, the problem is called macular edema. After several years, retinopathy progresses to a
more serious form called proliferative retinopathy (figure 16). In this form, the blood vessels are
so damaged that they close off, and in response, new blood vessels start growing in the retina. As
new blood vessels form at the back of the eye, they can bleed (hemorrhage) and blur vision. The
new blood vessels can also cause scar tissue to grow, which later shrinks and distorts the retina
(retinal detachment).
The retina can be badly damaged before the patient notices any changes in vision. Most people
with nonproliferative retinopathy have no symptoms and even patients with proliferative
retinopathy have sometimes reported no symptoms until it is to late to treat them. For this reason,
diabetic patients should have their eyes examined regularly by an eyecare professional.
Nephropathy: The Diabetic Kidney
The kidneys functions are vital to life and are regulated by hormones released by the endocrine
system. The kidneys main function is to regulate water and soluble substances by filtering the
blood, reabsorbing what is clean, and excreting the waste as urine. The kidney regulates blood
volume and pressure, controls levels of electrolytes and metabolites, and it also regulates blood
pH. Diabetic nephropathy is a progressive kidney disease caused by blockage of capillaries in the
kidney glomeruli. Kidney failure provoked by these blockages leads to fluid filtration deficits
and other disorders. There is an increase in blood pressure and fluid retention in the body.
Proteinuria, or high amounts of protein in the urine, is the hallmark of diabetic nephropathy.
These symptoms eventually lead to renal failure.
Patients with type 1 DM develop nephropathy more frequently than type 2 DM patients. It is
important for DM patients urine to be tested annually for protein since at the beginning of the
disease there might be no symptoms. Renal transplant is the treatment of choice and usually the

donor is a relative. However, a transplant is not possible for many patients, and the usual method
continues to be ambulatory peritoneal dialysis (CAPD). The patient receiving dialysis needs it 3
to 5 times a week depending on their condition. The procedure takes about 3-5 hours, and it is
slightly painful, but patients become accustomed to it.
Finally, blood pressure treatment, glucose control, and lifestyle modifications will slow down the
progression of kidney damage and reduce the risk of cardiovascular problems.
DM Treatments
The major goal in treating diabetes is to minimize any elevation of blood glucose without
causing abnormally low levels of blood sugar. Type 1 DM is treated with insulin, exercise, and a
diabetic diet. Type 2 DM is treated first with weight reduction, a diabetic diet, and exercise.
When these measures fail to control the elevated blood sugars, oral medications are used. If oral
medications are still insufficient, treatment with insulin is considered.
Adherence to a diabetic diet is an important aspect of controlling elevated blood sugar in patients
with diabetes. The American Diabetes Association (ADA) has provided guidelines for a diabetic
diet. The ADA recommends a plate approach to meal planning. Heres how it works: draw a
line down the center of your plate. One side of the plate is for non-starchy vegetables and the
other half is then divided again into two sections, starchy foods and protein foods (Figure 19).
Weight reduction and exercise are important treatments for DM. Weight reduction and exercise
increase the bodys sensitivity to insulin, thus helping to control blood sugar elevations.
DM Treatment: Medications
Based on what is known, medications for type 2 diabetes are designed to:
1. Increase the insulin output by the pancreas
2. Decrease the amount of glucose released from the liver.
3. Increase the sensitivity (response) of cells to insulin
4. Decrease the absorption of carbohydrates from the intestine
5. Slow emptying of the stomach to delay the presentation of carbohydrates for digestion and
absorption in the small intestine.
Oral treatment is the preferred method for type 2 DM. The administered medications are

hyperglycemic agents, such as Metformin, Sulphonyurea, and Acarbose. All of these drugs may
act through different mechanisms but their goal is to reduce increasing blood glucose and
minimize hyperglycemia. Weight gain plays an important role in the progression of DM, and
Orlistat (weight loss drug) is commonly prescribed to patients to help them achieve healthy
weights.
Insulin therapy is not a cure for DM, but it is a requirement for patients with type 1 DM or those
with type 2 DM who do not respond to oral medications. Insulin is destroyed in the
gastrointestinal tract so it must therefore be given subcutaneously, intravenously, or
intramuscularly. Insulin can be injected in three places in the body: the upper arms, the
inner/outer thighs, and the abdomen. Some of the complications associated with insulin
injections are wrong dose/timing, poor injection technique, and injection in the wrong place.
Insulin regimen and dosing is individualized because every persons body is different. Usually
medical doctors can estimate depending on age, weight, and diet, it typically requires a trial
period.
In the past, insulin was only available in an injectable form that involved carrying syringes.
Needless to say, patients often found it difficult to take multiple shots each day, and as a result,
good blood sugar control was often compromised. Many pharmaceutical companies are now
offering discreet and convenient methods of delivering insulin. One such method is the insulin
pen delivery system. This system is similar to an ink cartridge in a fountain pen. A small pensized device holds an insulin cartridge. The amount of insulin to be injected is dialed in by
turning the bottom of the pen until the required number of units is seen in the dose-viewing
window. The tip of the pen consists of a needle that is replaced with each injection. A release
mechanism allows the needle to penetrate just under the skin and deliver the required amount of
insulin.
The most recently available advance in insulin delivery is the insulin pump. An insulin pump is
composed of a pump reservoir similar to that of an insulin cartridge, a battery operated pump,
and a computer chip that allows the user to control the exact amount of insulin being delivered.
Currently, pumps on the market are about the size of a pager or beeper. The pump is attached to a
thin plastic tube that has a cannula (like a needle but soft) at the end through which insulin
passes. The cannula is inserted under the skin, usually on the abdomen and is changed every two
days. The pump is used for continuous insulin delivery, 24 hours a day. It allows the user to
program many different basal infusion rates to allow for variations in lifestyles. In addition, the
user can program the pump to deliver additional insulin during meals to cover the excess
demands for insulin caused by the ingestion of carbohydrates with the meal.
DM patients can also use an inhaled form of insulin. The insulin is packaged and then inserted
into an inhalation device. The device lances the powder packs allowing the insulin to enter a
chamber that has a mouth piece through which the user can inhale the insulin. This type of
insulin is very short acting and thus in patients with type 1 DM, the insulin should be combined
with a longer acting basal insulin.
Obesity

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may
have an adverse effect on health, leading to reduced life expectancy and/or increased health
problems. Current national statistics show that 65% of adults are overweight or obese and 30%
of children are overweight/obese. These statistics are alarming because obese individuals are at a
higher risk of chronic diseases such as heart disease type 2 DM, high blood pressure, stroke, and
cancer. Obesity in humans and most animals is not dependent on the amount of body weight but
on the amount of body fat.
Adipose tissue is loose connective tissue composed of adipocytes (fat cells) and its main role is
to store energy in the form of fat, but it also cushions and insulates the body. There are two types
of adipose tissue: white adipose tissue and brown adipose tissue. Adipose tissue serves as an
important endocrine organ by producing hormones such as leptin, resistin, and the cytokine TNF
alpha. Leptin and resistin are believed to regulate body fat, energy balance, and feeding behavior
and cytokine TNF alpha is involved in inflammation responses.
It might seem easy to determine whether a person is obese, but this task is a complicated matter.
The simple method is to measure the thickness of the layer of fat under the skin in several parts
of the body. However, the most common method is to use the Body Mass Index (BMI). The BMI
compares a persons weight and height. Though it does not actually measure the percentage of
body fat, it used to estimate a healthy body weight based on how tall a person is. BMI is defined
as the individuals body weight divided by the square of his or her height. This is a widely used
diagnostic tool to identify weight problems within a population, usually whether individuals are
underweight, overweight or obese. Figure 26 shows a typical BMI chart, which display BMI as
a function of weight (horizontal axis) and height (vertical axis) using contour lines for different
values of BMI or colors for different BMI categories.
Causes of Obesity
At an individual level, a combination of excessive caloric intake and a lack of physical activity is
thought to explain most cases of obesity. A limited number of cases are due primarily to genetics,
medical reasons, or psychiatric illnesses. A recent review article identified other possible
contributors to the recent increase of obesity:
(1) Insufficient sleep
(2) Endocrine disruptors (environmental pollutants that interfere with fat metabolism)
(3) Decrease variability in ambient temperature
(4) Decreased rates of smoking (smoking suppresses appetite)
(5) Increased use of medications that cause weight gain
Diet
The per capita dietary energy supply varies markedly between different regions and countries
and has changed significantly over time. From 1971 to 2000, obesity rates in the US increased
from 14.5% to 30.9%. During the same period, an increase occurred in the average amount of
calories consumed. As societies become increasingly reliant on energy-dense, big portion, fastfood meals, the association between fast-food consumption and obesity becomes more
concerning. In the US alone, consumption of fast-food meals tripled and calorie intake from

these meals quadrupled between 1977 and 1995.

Sedentary Lifestyles
A sedentary lifestyle plays a significant role in obesity. Worldwide there has been a shift towards
less physically demanding work, and currently 60% of the worlds population gets insufficient
exercise. This is primarily due to increasing use of mechanized transportation and a greater
prevalence of labor-saving technology. In children there appears to be declines in levels of
physical activity due to less walking and physical education. In both children and adults there is
an association between television viewing time and the risk of obesity. A study done in 2008
showed that 86% of people studied showed an increased rate of obesity with increase media
exposure, with rates increasing proportionally to time spent watching television.
Genetics
Like many other medical conditions, obesity is the result of an interplay between genetic and
environmental factors. Polymorphisms in various genes controlling appetite and metabolism
predispose to obesity when sufficient calories are present.
Medical and psychiatric illness
Certain physical and medical illnesses and the pharmaceutical substances used to treat them can
increase the risk of obesity. Medical illnesses that increase obesity risk include several rare
genetic syndromes as well as some congenital or acquired conditions, such as hypothyroidism
(which produces low thyroid hormone which leads to lower metabolic rate), Cushings syndrome
(which exposes body tissues to high levels of hormone cortisol), and the eating disorders, such as
binge eating and night eating syndrome. Certain medications may cause weight gain or changes
in body composition, these include antipsychotics, antidepressants, steroids, anticonvulsants, and
some forms of hormonal contraception.
Consequences of Obesity
The health risks associated with obesity are serious enough to be a national concern. Many
people think this is a cosmetic concern, but in reality, this is a life and death problem. Excessive
body weight is associated with various diseases, particularly cardiovascular diseases, type 2 DM,
obstructive sleep apnea, certain types of cancer, and osteoarthritis. As a result, obesity has been
found to reduce life expectancy. Studies have shown that obese men have a greater risk of
developing colon, rectum, and prostate cancer and obese women are more likely to develop
gallbladder, uterus, cervix, and ovarian cancer. Other diseases associated with obesity are
gallbladder disease, gallstones, fatty liver disease, gastroesophageal reflux, gout, and
reproductive problems in women.
Obesity does not only cause physiological disorders, but also psychological and social disorders.
Obesity can have a devastating psychological impact, especially in children. As a technologyadvanced society, we are obsessed with perfection and the media reminds us of it constantly. We
associate beauty and perfection with physical appearance: slimness and genetic makeup. Obese
and overweight people are often discriminated and ridiculed. Obese individuals complain they

are treated differently, ridiculed in public, perceived as dumb, lazy, and not accepted as a normal
citizens. Depression, shame, and feelings of rejection are the typical symptoms of psychological
damage. Unfortunately, these feelings can make it more difficult to lose weight since they eat
more food to comfort themselves and become more secluded.
Obesity Treatments
Even if you think you are predisposed to gain weight because of your genetic makeup, you will
still need to make sure that you eat a balance diet and get plenty of physical activity. Obese
individuals need to consult their professional health care providers before starting a diet and a
physical activity program.
It is up to the individual to make sure that you stay healthy. Be informed and take care of what
you eat. The following recommendations can help you live a longer, healthier life by maintaining
a healthy weight:
1. Eat sensible portions
2. Eat slowly and stop when you are full
3. Eat whole foods (i.e. apples instead of drinking apple juice)
4. Recognize and control your environment (do not buy large bags of M&Ms and leave them
next to you when you are reading this module)
5. Make sure you get at least 30 minutes of physical activity every day
6. Snack between meals (fruits and nuts, not chips and candy)
7. Do not eat in the car or in front of the computer. Sit at a table and look at your food. Do not
clean the plate if you are full, save it for later.
8. Keep a record of your food intake and do not skip meals
9. Do not eat out of desperation before finals, instead, study daily, and think twice before
overeating.

Diabetes Mellitus

A disease characterized by a chronic high blood glucose concentration a

insulin or insulin resistance.

Insulin

Helps transport glucose inside the bodys cells so it can be used for ener

Type 1 DM

A chronic progressive autoimmune disorder that leads to lack of insulin

Type 2 DM

Refers to a chronic progressive disease with either decreased insulin sec

sensitivity, or both.

Macrovascular Disease

Effects the large vessels; leads to strokes, cardiovascular disease, renova

peripheral vascular disease; not specific to diabetic patients.

Microvascular Disease

Effects the small vessels; specific to diabetic patients.

Retinopathy

A complication that causes abnormality in the tiny blood vessels nourish

Nephropathy

The term that describes kidney disease or damage to the kidney.

Neuropathy

The term refers to pain in the nerves or damage to the nerves.

Hypoglycemia

Develops when the blood glucose level falls extremely low.

Hyperglycemia

Develops when there is an excess amount of glucose in the blood.

Adipose tissue

Loose connective tissue composed of adipocytes (fat cells).

Environment:Don't be lazy

It was a busy day at the waffle bar in Portland and two men were discussing climate change as
they waited for their order to arrive. The children were restless waiting for their food while the
fathers drank their coffee and waited and waited. One was dressed with informal clothing that
yelled out that it was expensive but made to look inexpensive. He was an individualisticoriented businessman who claimed that climate change was an exaggerated exploitation of
scientific data. All you had to do was look at the data and see that there was a change but
whether it was due to mankinds influence or just the normal flux of temperature over the years
was hard to prove. Since he was in the oil business, he wanted to keep people's house warm in
the winter and give them gasoline. He claimed that people would not want any restrictions on
gasoline or heating oil for their homes. His new found acquaintance countered that the climate
changes are just beginning and that the human race needs to find a way to take care of itself now
and in the future. This man was a community-oriented person who was suspicious of individual
initiative since he thought they did everything for money. He said- Think about your kids!
The businessman said that is exactly what he was doing. And so it goes.
How does one present climate change?
There is the science in terms of what the data documents that there are major changes in our
environment. This data will be presented in the next two modules.
However, once we document the climate change, what should we do about it?
Is climate change a bigger issue than AIDS or the obesity epidemic? One would think so since it

affects all of mankind.

If there was a plague that killed 45% of the human population would that be worse than climate
change?
How many people will climate change kill, injure, etc?
The predictions are that the heating of the globe will cause climate change throughout the world.
The climate system is similar to any other system you have studied and it have has five major
components.
(a) Atmosphere;
(b) Ocean;
(c) Land surface;
(d) Ice and snow surfaces (both land and ocean areas);
(e) Biosphere (both terrestrial and marine).
Keep in mind there are other factors such as change in the suns heating pattern and land/ocean
distribution in the event of some geological event that changes the land/water scape. For all
intensive purposes the five listed above are the major ones.
It is obvious that the sole source of life on earth is the sun. It has been worshiped since the dawn
of man and the giver of life. Now to some physics. Electromagnetic wave energy transfer
(radiation) accounts for nearly all energy transfer from the sun, and is the primary source of
energy for the atmosphere and the entire climate system. For energy to reach the world it has to
be radiant. The other means of heat transfer are conduction and convection both of which would
not work in outer space. For the earth to maintain a steady climate the radiant heat from the sun
must equal the radiant heat emitted by the globe. Incoming radiant heat must equal outgoing
radiant heat.Such transfer is also the only way in which significant amounts of energy can leave
the climate system. The primary human impact on the energy balance is to alter the radiative
properties of the atmosphere with respect to these two energy streams. This effect far outshadows other anthropogenic (human) energy sources and sink effects such as the heating due to
combustion and nuclear processes.
There are two primary forms of radiation relevant to the energy balance properties of the climate
system. The first is the solar or short-wave form predominant in the radiation from the sun. This
is primarily in the wavelength range from 0.2 to 4.0 microns (a micron is one-millionth of a
meter, .000001 m) which encompasses the visible part of the spectrum. This short-wave radiation
provides a source of energy for the climate system as it is absorbed in the atmosphere, clouds,
ocean, land surface, and by living matter. The second form is the terrestrial or long-wave type

predominant in the radiation emitted by matter in the climate system. The primary wavelength
range for this form is from 4 to 60 microns which is entirely in the invisible infrared part of the
spectrum. Sometimes the solar and terrestrial radiation forms are called visible and invisible,
respectively.
Solar radiation incident upon the Earth system coming into the atmosphere from above leads to
heating as it is absorbed by gases, aerosols and clouds in the atmosphere, and by the ocean, land,
ice and biosphere elements at the Earths surface. The absorption is proportional to the intensity
of the solar radiation and depends on the properties of these substances. As the solar radiation is
absorbed, there is less radiation available to be absorbed at lower levels. Although the radiation
is initially in a narrow beam traveling in one direction from the sun, reflection at surfaces and
scattering within the atmosphere sends the solar radiation all directions. For this reason, when
one looks outdoors in the daytime one sees light coming from all directions.The intensity
depends on the temperature of the sun and the distance from the sun to the Earth. The angle of
the solar beam to the local vertical varies according to a number of astronomical factors: latitude
on Earth (distance from the equator), longitude on Earth (time of day), and the orientation of the
Earths axis with respect to the sun (the solar declination angle) which varies according to the
time of year. Variations in these factors lead to large variations in heating from day to night, from
equatorial to polar regions, and from summer to winter. The albedo (reflectivity) of sunlight from
the Earths surface is indicative of (inversely related to) the absorption of radiation by that
surface. A surface with a high albedo (high visible brightness) is heated much less than one with
a low albedo (low visible brightness). At the Earths surface, the albedo ranges from about five
percent for ocean surfaces (with the sun high in the sky) and the top surface of dark thick
coniferous forests to 90% for fresh snow.Thick clouds in the atmosphere can also have an albedo
nearly as high as fresh snow. Since much of the reflected and back scattered solar radiation
travels back out to space, it is never converted to heat in the climate system. The atmosphere
(gases, aerosols, and clouds) absorbs less of the incident radiation than the Earth surface, so that
solar heating effects are greater at the Earth surface than in the atmosphere.
Terrestrial (long-wave) radiation is both emitted and absorbed by material substances in the
climate system. The Earths surface and clouds have radiative properties that tend to produce the
maximum amount of terrestrial radiation given by black body values and to absorb incident
terrestrial radiation completely. On the other hand, the radiation emission and absorption
characteristics of atmospheric gases have a large variability depending on wavelength. The
strongest effects are exhibited by minor constituents in the atmosphere: water vapor, carbon
dioxide, ozone, nitrous oxide, and methane. These gases occur naturally and are known as
greenhouse gases. The greenhouse gas radiative properties just noted are much more
pronounced for terrestrial radiation than for solar radiation.On a globally-averaged basis the
observed surface temperature is about 33K above the 255K expected with no atmosphere at all.
This enhancement value would be even greater (over 80K) if radiative effects for the clear
atmosphere were the only modifying factors [Manabe and Strickler, 1964]. Sensible and latent
heat fluxes from the Earths surface to the atmosphere along with atmospheric convection
partially offset the surface temperature enhancement due to radiation transfer back from the
atmosphere.A basic aspect of radiation forcing is the systematic variation with latitude. There is
generally an overall reduction with distance from the equator in the daily total solar radiation
coming into the Earthatmosphere system, being more extreme in the winter season and nearly

absent at the time of the summer solstice. Seasonal and annual means for solar radiation
absorbed in the Earth-atmosphere system show poleward decreases in both the summer and
winter hemispheres.The resulting net radiation forcing for the Earthatmosphere system has a net
excess in the tropical latitudes and a deficit in the polar latitudes. If radiation transfer were the
only process occurring, the equatorial regions would be hotter than observed and the polar
regions colder than observed. However, the transport of heat from the equatorial to polar regions
by atmospheric and oceanic circulations offsets this radiation imbalance and provides an overall
energy balance at each latitude. In conclusion and as stated before, the primary connection
between human activity and climate change is the alteration of the radiation transfer
characteristics of the atmosphere. The change in greenhouse gas concentration and the addition
of other gases with similar characteristics will change the terrestrial radiation transfer. In
addition, a change in aerosol concentration and perhaps related change in cloud cover will
change the solar radiation transfer. Except on a very local scale, the energy transferred by
radiation is far greater than any production rate of energy due to human activity.
A number of factors make the atmosphere a very complex fluid system. As a gas, it has
compressibility and great mobility. It extends well above topographic barriers and can sustain
global-scale circulations. A number of forcing factors including radiative heating and cooling,
latent heat sources and sinks (reservoirs) due to phase change of water, and variations in Earths
surface temperature give rise to significant temperature variations in all three space dimensions
and in time. These temperature variations give rise to horizontal pressure gradient forces
approximately consistent with the hydrostatic relationship, which are the basis for horizontal
atmospheric motions.
The hydrological cycle is an important part of the atmospheric system. Evaporation and
condensation of water can transfer considerable amounts of energy by both vertically and
horizontally. The cloud component of the hydrological cycle strongly affects transfers of both
solar and terrestrial radiation. The precipitation is the source of fresh water needed for life on
land surfaces.The circulation in the atmosphere is sufficiently vigorous that material injected into
one part of the atmosphere can be spread quickly over broad regions. It may take just days for a
volcanic smoke plume or radioactive products to circle the Earth. Constituents with sufficiently
long lifetimes, such as carbon dioxide, would be expected to have relatively uniform
concentration throughout the atmosphere. The large-scale north-south circulations are less
vigorous than those in the the east-west direction. Vertical motions generally are much smaller
than horizontal motions so the vertical transport of atmospheric constituents may be quite
limited. This accentuates the buildup of atmospheric pollutants in the lower layers of the
atmosphere especially in local areas with large sources of the pollutants.
The ocean has a major impact on the climate of the atmosphere. It covers approximately 71
percent of the Earths surface and thus has a dominant role for transfers of energy and other
properties between the atmosphere and the Earths surface. Its large heat capacity, made
accessible for surface energy transfers by circulations within the ocean, provides a moderating
effect on temperature variability in the atmosphere. Oceanic currents transfer large amounts of
heat energy away from equatorial regions. Finally, the ocean is an important source for
atmospheric water vapor, as well as a source and sink for other greenhouse gases.However, the

oceanic condition is different from the atmosphere in two fundamental ways. First, the primary
forcing of the ocean is at the upper boundary, whereas the primary forcing for the atmosphere is
at its lower boundary. Atmospheric winds above the ocean are a major factor in causing ocean
surface currents through surface friction processes. In contrast, for the atmosphere frictional
conditions at its lower boundary tend to reduce atmospheric motion.
Second, the density of the ocean water is determined primarily by its salinity and temperature
instead of pressure, temperature and water vapor content as in the atmosphere.The oceans play a
significant role as a source and sink for atmospheric gases, including greenhouse gases. Changes
in ocean temperature can change the holding capacity for gases and can result in a net outflow or
intake from the atmosphere. Particularly noteworthy is the case for carbon dioxide. It is
estimated that the carbon dioxide dissolved in the upper layers of the ocean is nearly 50 percent
more than the total amount in the atmosphere (1020 versus 750 gigatons of carbon content).
Thus, there is much potential for effects on the atmospheric carbon dioxide concentrations and
the resulting radiation impacts due to changes in the ocean.
Land surface is an important interactive component of the climate system. It covers 29% of the
Earths surface. Significant exchanges of heat, moisture, and momentum occur between the
atmosphere and the land surface, including its biosphere. It is also the surface on which people
live. The heat storage factor of land surface with respect to atmospheric temperature variations is
much less than that for the oceans. Land has a lower specific heat than the ocean, and its rigidity
restricts heat transport to deeper levels. As a result, the depth of the soil layer which is important
for energy exchange interactions with the atmosphere is only several meters for the annual-cycle
time scale. A cave 20 meters underground will remain at the same temperature all year round.
Because of the small heat capacity of the land surface, variations in atmospheric temperature just
above the surface are much larger over the land than over the ocean.Topography of the land
surface has a pronounced effect on large-scale atmospheric circulations. particularly in the
Northern Hemisphere. The Rocky Mountains, which are oriented north-south transect the
Northern Hemisphere westerlies, and the Tibetan Plateau with its extreme height and aerial
extent affects flow over a large area. Topography is a factor in the wave patterns in the upper
tropospheric horizontal wind flow, and also has major effects on surface temperature and
rainfall.Alteration of land surface by human activity is an important factor in climate change that
adds to the effects of human-produced changes in the radiative characteristics of the atmosphere.
Urbanization, cultivation for agriculture, irrigation, and deforestation change the albedo of land
surfaces and the surface sensible and latent heat transfers. These factors can also greatly
influence the local aspects of climate change.
The cryosphere the ice component has significant impacts on the climate system in
several ways. It affects radiative and sensible heat transfers at the Earths surface. It influences
temperatures in the ocean and at the Earths surface due to transfers between latent and sensible
energy during melting and freezing.Finally, its melting and freezing influences water runoff from
land and ocean salinity. Ice and snow exist primarily in the latitudes poleward of 30 degrees
latitude and are thus are unfamiliar to the majority of the worlds human population. Although
only about two percent of all the water on Earth is frozen, it covers an average of 11% of the
worlds land surface and seven percent of its oceans. Note that although Antarctica and

Greenland between them account for 98% of the worlds land ice, the total area covered by ice
and snow can be much larger in the Northern Hemisphere winter. The Northern Hemisphere has
a much larger seasonal range than the Southern Hemisphere because of the larger amount of land
area. Cryosphere conditions may not be directly evident to most people of the world. However,
because of the global nature of the climate system, the cryosphere component also influences
lower latitudes.
The biosphere is a component of the climate system that has a distinct role in the interactions of
both the oceans and land surface with the atmosphere. Vegetation on the land surface and both
plant and animal life in the oceans are all relevant elements of the biosphere component that
interact with the atmosphere. Climate conditions of the atmosphere have a direct effect on the
type of terrestrial plant growth at the Earths surface. The nature of the plant cover in turn feeds
back on the atmospheric condition by influencing the sensible and latent energy transfers from a
land surface, as well as surface layer turbulence in the atmosphere (through its roughness
properties). Furthermore, land vegetation is a significant reservoir for carbon with a total carbon
content nearly equal to that in the atmosphere. Changes in the amount of land vegetation due, for
instance, to forest cutting and burning or simply seasonal changes have a direct impact on the
carbon dioxide concentration in the atmosphere. Along with dissolved inorganic carbon and
calcium carbonate solids, plant and animal life have key roles in the ocean, in the carbon cycle
which influences the concentration of the greenhouse gas, and carbon dioxide in the atmosphere
and results in a loss of carbon due to sedimentation of carbonates at the ocean bottom.The
interactions between the biosphere and atmospheric climate have produced a record of past
climate conditions. Tree rings, fossil patterns, pollen counts in ocean and lake bottom sediments,
and coal and oil deposits are records which give us information on past climates. Humans,
themselves, are members of the biosphere. Humans alter the biosphere directly by agricultural
and forestry activities and indirectly by altering the climate system in which the biosphere exists.
It is important to understand these various impacts of human activity in order to understand
climate change. The biosphere must be included in the climate system analysis in order to
understand climate change. It is a component that interacts with other climate system
components, and is the component where the effects of climate change will be clearly evident to
people.

Global Warming

The earth is supposedly getting hotter than normal. Is it the earth or the climate? It is the climate.
This is a very controversial issue in that there is no disagreement that the climate is getting
warmer. What is controversial is what is causing it and what can we do about it. More broadly
speaking, why should we care about global warming? The experts contend that if the overall
climate temperature increases an additional 2C that there will be widespread drought, famine,
civil unrest, and possibly a major change in the entire political and financial picture of the world.

The cause of global warming is the greenhouse effect which is the heat absorption by certain
gases in the atmosphere which effectively trap heat in the lower atmosphere and re-radiation
downward of some of that heat. Where does this heat come from? The sun! As the suns
shortwave energy (the visible and ultraviolet portion of the spectra) heats the surface, longerwave (infrared) energy (heat) from the earth is re-radiated to the atmosphere. Greenhouse gases
absorb this energy, thereby allowing less heat to escape back to space, and trapping it in the
lower atmosphere.
Water vapor is the most abundant greenhouse gas, followed by carbon dioxide,methane, nitrous
oxide and synthetic ones. The synthetic ones are chlorofluorocarbons (CFCs),
hydrofluorocarbons (HFCs) and Perfluorocarbons (PFCs), as well as sulfur hexafluoride (SF6).
Atmospheric concentrations of both the natural and man-made gases have been rising over the
last few centuries due to the industrial revolution. As the global population has increased and our

reliance on fossil fuels (such as coal, oil, and natural gas) has been firmly solidified, so emissions
of these gases have risen. Without a natural greenhouse effect, the temperature of the Earth
would be about 0F (-18C) instead of its present 57F (14C). So, the concern is not with the
fact that we have a greenhouse effect, but whether the temperature rise is injurious to the
population as a whole and what factors that influence global warming we want to control. The
biggest challenge is that the human race is continuing to grow and as it does, the population
wants to have all the benefits of a modern society.
The following are the major gases produced and their effects on global warming:
Water Vapor
Water vapor is a by-product of respiration in plants and animals. Gaseous water represents a
small but environmentally significant constituent of the atmosphere. The percentage of water
vapor in surface air varies from a trace in desert regions, to about 4% over oceans.
Approximately 99.13% of it is contained in the troposphere. Water vapor is also the most potent
greenhouse gas owing to the presence of the hydroxyl bond which strongly absorbs in the infrared region of the light spectrum.
Carbon Dioxide
The natural production and absorption of carbon dioxide (CO2) is achieved through the terrestrial
biosphere and the ocean. However, humankind has altered the natural carbon cycle by burning
coal, oil, natural gas, and wood and since the industrial revolution began in the mid 1700s, each
of these activities has increased in scale and distribution. Carbon dioxide was the first
greenhouse gas demonstrated to be increasing in atmospheric concentration with the first
conclusive measurements being made in the last half of the 20th century. Prior to the industrial
revolution, concentrations were fairly stable at 280 ppm. Today, they are around 370 ppm, an
increase of well over 30 percent. In 2010, CO2 accounted for about 84% of all U.S. greenhouse
gas emissions from human activities. Here are the major contributors to carbon dioxide:
1. The carbon cycle as photosynthesis, plants, algae, and cyanobacteria absorb carbon dioxide,
light, and water to produce carbohydrates, energy, and oxygen as a waste product. But in
darkness, photosynthesis cannot occur, and during the resultant respiration small amounts of
carbon dioxide are produced;
2. Carbon dioxide is also produced by combustion of coal or hydrocarbons;
3. The fermentation of liquids (wine!);
4. The respiration of humans and animals;
5. In addition it is emitted from volcanoes, hot springs, geysers and other places where the
earths crust is thin;
6. CO2 is also commingled with oil and gas deposits.

Also a major source of ocean acidification is CO2 which dissolves in water forming carbonic
acid, which is a weak acid, because CO2 molecule ionization in water is incomplete. The effects
on the pH of the oceans and marine life will be discussed later.
The part carbon dioxide plays in biological environmental processes
Carbon dioxide is one of the most abundant gasses in the atmosphere. Carbon dioxide plays an
important part in in photosynthesis and respiration. As you may recall from earlier modules,
plants convert carbon dioxide and water into food compounds, such as glucose, proteins, lipids,
and oxygen. This process is called photosynthesis.
The overall reaction of photosynthesis is as follows:
6 CO2+ 6 H2O --> C6H12O6+ 6 O2
Plants and animals, in turn, convert the food compounds by combining it with oxygen to release
energy for development of ATP which is used to power anabolism and catabolism. This is the
respiration process which is the reverse of photosynthesis.
The respiration reaction is as follows:
C6H12O6+ 6 O2--> 6 CO2+ 6 H2O
In essence, living systems do a control burn of carbon products. Remember the terms oxidation
and reduction. Carbohydrates are oxidized in the cells and the resulting chemical is carbon
dioxide. We are using carbohydrates as an example of a compound that can be oxidized to
produce energy in the form of heat and ATP. However any compound that can be oxidized can
produce heat. There are different kinds of combustion:
Rapid (explosive weapons)
Rapid combustion is a form of oxidation otherwise known as a fire, in which large amounts of
heat and light energy are released, which often results in a flame. This is used in a form of
machinery such as internal combustion engines and in thermobaric weapons. Sometimes, a large
volume of gas is liberated in combustion besides the production of heat and light. The sudden
evolution of large quantities of gas creates excessive pressure that produces a loud noise. Such a
combustion is known as an explosion.
Complete combustion (Industrial applications)

In complete combustion, the reactant burns in oxygen, producing a limited number of products.
When a hydrocarbon burns in oxygen, the reaction will only yield carbon dioxide and water.
When elements are burned, the products are primarily the most common oxides. Complete
combustion is almost impossible to achieve. In reality, as actual combustion reactions come to
equilibrium (constant), a wide variety of major and minor species will be present such as carbon
monoxide and pure carbon (soot or ash). In a complete combustion reaction, a compound reacts
with an oxidizing element, such as oxygen , and the products are compounds of each element in
the fuel with the oxidizing element. For example: CH4 + 2 O2 = CO2 + 2 H2O + energy. In most
industrial applications and in fires, air is the source of oxygen (O2).
Incomplete combustion ( in thermal power plants)
Incomplete combustion will only occur when there isn't enough oxygen to allow the fuel to react
completely to produce carbon dioxide and water. It also happens when the combustion is
quenched by a heat sink such as a solid surface or flame trap. For most fuels, such as diesel oil,
coal or wood, pyrolysis (thermo-chemical decomposition of organic material) occurs before
combustion. In incomplete combustion, products of pyrolysis remain un-burnt and contaminate
the smoke with noxious particulate matter and gases. The quality of combustion can be improved
by design of combustion devices, such as burners and internal combustion engines. Further
improvements are achievable by catalytic (change in rate of a chemical reaction) after-burning
devices (such as catalytic converters) or by the simple partial return of the exhaust gases into the
combustion process. Such devices are required by environmental legislation for cars in most
countries, and may be necessary in large combustion devices, such as thermal power plants, to
reach legal emission standards.
Smoldering (in residential fire)
Smoldering is the slow, low-temperature, flameless form of combustion, sustained by the heat
evolved when oxygen directly attacks the surface of a condensed-phase fuel. Common examples
of smoldering phenomena are the initiation of residential fires on upholstered furniture by weak
heat sources (e.g., a cigarette, a short-circuited wire), and the persistent combustion of biomass
behind the flaming front of wildfires.
Turbulent (gas turbines)
Combustion resulting in a turbulent flame is the most used for industrial application (e.g. gas
turbines, gasoline engines, etc.) because the turbulence helps the mixing process between the fuel
and oxidizer.
Modern Living and Carbon Dioxide Production

Automobiles
Burning one gallon of gas creates approximately 20 pounds of carbon dioxide, and the average
car emits about six tons of carbon dioxide every year. But averages don't tell you much about
your own carbon footprint, which is as personal as your fingerprint. What you drive, how you
drive, and how much you drive all make a huge difference. Some people reliably get 58 miles per
gallon in their hybrids, which perform best in city driving while others get eight miles per
gallon.
Heating a House
Heating a house produces about four tons of carbon dioxide per year on a national average, in
addition to eight tons for electricity use.
Travel
Flying non-stop round trip from Boston to Wichita creates about 1,400 pounds of carbon dioxide
emissions, but the total impact is actually twice that, due to other gases, the contrails, and the
altitude at which the carbon dioxide is emitted. Since the plane is already at high altitudes, the
carbon dioxide that it emits is directly injected into the atmosphere.
Monday Night Football
A large-screen plasma can produce as much carbon dioxide as a big refrigerator. A plasma TV
can draw 400 watts of power which equivalent to about 1,500 pounds of carbon dioxide over the
course of a year.
The Hot Tub!
The average hot tub, uses about 2,300-kilowatt hours per year, producing more than 3,000
pounds of carbon dioxide.
Instead of making this personal, lets look at the major picture in the USA.
Electricity
Electricity is a significant source of energy in the United States and is used to power homes,
businesses, and industries. The combustion of fossil fuels to generate electricity is the largest
single source of CO2 emissions in the nation, accounting for about 40% of total U.S.
CO2 emissions and 33% of total U.S. greenhouse gas emissions in 2009. The type of fossil fuel
used to generate electricity will emit different amounts of CO2. To produce a given amount of
electricity, burning coal will produce more CO2 than oil or natural gas.
Transportation

The combustion of fossil fuels. such as gasoline and diesel to transport people and goods is the
second largest source of CO2 emissions, accounting for about 31% of total U.S. CO2 emissions
and 26% of total U.S. greenhouse gas emissions in 2010. This category includes transportation
sources such as highway vehicles, air travel, marine transportation, and rail.
Industry
Many industrial processes emit CO2 through fossil fuel combustion. Several processes also
produce CO2 emissions through chemical reactions that do not involve combustion, for example,
the production and consumption of mineral products such as cement, the production of metals
such as iron and steel, and the production of chemicals. Various industrial processes accounted
for about 14% of total U.S. CO2 emissions and 20% of total U.S. greenhouse gas emissions in
2010.
Methane
Methane is an extremely effective absorber of radiation, though its atmospheric concentration is
less than CO2 and its lifetime in the atmosphere is brief (10-12 years), compared to some other
greenhouse gases (such as CO2, N2O, CFCs). Methane (CH4) has both natural and man made
(anthropogenic) sources. It is released from swamplands or in rice production. Over the last 50
years, human activities such as growing rice, raising cattle, using natural gas and mining coal
have added to the atmospheric concentration of methane. This is a list of sources for methane:
1. Wetlands account for 20% of atmospheric methane
2. Ruminant animals such as sheep and cows contain bacteria that break down plant material. As
a consequence of this activity, when the animals burps or defecates, methane is produced.
3. Permafrost, which releases methane when it is heated.
4. Rice cultivation, rice is grown in swamp like conditions and contributes, to a large extent,
methane production.
5. Landfills (AKA dumps), in the United states are the largest source of methane.
6. Biomass burning, such as burning to clear out land.
7. Natural Gas: Methane is a component of natural gas.
Natural sources of CH4 are estimated to produce 37 percent of the total CH4 flux into the
atmosphere every year. The largest source of natural CH4emissions is natural wetlands, which
contribute 170 Tg CH4/yr (per year). Several other sources contribute substantially as well,
including geologic emissions (now estimated at 42 to 64 Tg CH4/yr), lakes (estimated at 30 Tg
CH4/yr), and vegetation (which potentially contributes 20 to 60 Tg CH4/yr)
Natural Sinks of Atmospheric Methane:
Troposphere

The most effective sink of atmospheric methane is the hydroxyl radical in the lowest portion of
the earth's atmosphere, known as the troposphere. As methane rises into the air, it reacts with the
hydroxyl radical to create water vapor and carbon dioxide. The lifespan of methane in the
atmosphere was estimated at 9.6 years as of 2001; however, increasing emissions of methane
over time reduce the concentration of the hydroxyl radical in the atmosphere.
Stratosphere
Even if it is not destroyed in the troposphere, methane can usually only last 12 years before it is
eventually destroyed in Earths next atmospheric layer: the stratosphere. Destruction in the
stratosphere occurs the same way that it does in the troposphere: methane is oxidized to produce
carbon dioxide and water vapor.
Hydrofluorocarbons, Perfluorocarbons, Sulfur hexafluoride
Even though hydrofluorocarbons and perfluorocarbons are emitted in relatively small quantities,
they have a disproportionate effect on the greenhouse effect. As a greenhouse gas, the most
potent hydrofluorocarbons and perfluorocarbons are 11,700 times and 7,000 to 9,000 times per
molecule as effective as a molecule of carbon dioxide, respectively. Also, perfluorocarbons have
relatively long atmospheric lifetimes (up to 50,000 years). Rated as the most powerful
greenhouse gas ever released to the atmosphere, sulfur hexafluoride is used as an electric
insulator, heat conductor, and a freezing agent. In comparison to one molecule of carbon dioxide,
the global warming potential of one sulfur hexafluoride molecule is approximately 24,000 times
greater. Sulfur hexafluoride has now been banned from use due to its global warming potential.
Chlorofluorocarbons (CFCs) are nontoxic, nonflammable chemicals containing atoms of carbon,
chlorine, and fluorine. They are used in the manufacture of aerosol sprays, blowing agents for
foams and packing materials, as solvents, and as refrigerants. They have been banned since they
contribute to Ozone depletion.
Atmospheric methane
From Wikipedia, the free encyclopedia
Main article: Methane
Atmospheric methane is the methane present in Earth's atmosphere. Atmospheric methane
concentrations are of interest due to methane's impact on climate change, as it is one of the most
potent greenhouse gases in Earth's atmosphere. The 100-year global warming potential of
methane is 29[1] (i.e., over a 100-year period, it traps 29 times more heat per mass unit
than carbon dioxide and 32 times the effect when accounted for aerosol interactions.[2]) Global
methane levels, have risen to 1800 parts per billion (ppb) by 2011, an increase by a factor of 2.5
since pre-industrial times, from 722 ppb, the highest value in at least 800,000 years.[3] Its
concentration is higher in the Northern Hemisphere since most sources (both natural and human)
are located on land and the Northern Hemisphere has more land mass. The concentrations vary
seasonally, with a minimum in the late summer mainly due to removal by the hydroxyl radical.

Methane concentrations up till 2011.

Early in the Earth's historyabout 3.5 billion years agothere was 1,000 times as much
methane in the atmosphere as there is now, released into the atmosphere by volcanic activity.
During this time, Earth's earliest life appeared. These first, ancient bacteria added to the methane
concentration by converting hydrogen and carbon dioxide into methane and water. Oxygen did
not become a major part of the atmosphere until photosynthetic organisms evolved later in
Earth's history. With no oxygen, methane stayed in the atmosphere longer and at higher
concentrations than it does today.
Methane is created near the surface, and it is carried into the stratosphere by rising air in
the tropics. Uncontrolled build-up of methane in Earth's atmosphere is naturally checked
although human influence can upset this natural regulationby methane's reaction with
hydroxyl radicals formed fromsinglet oxygen atoms and with water vapor.

Methane concentrations (green curve) in 420,000 years of ice core data from Vostok, Antarctica
research station. Current period is at the left.

Methane concentrations graph.

Contents
[hide]

1 Methane as a greenhouse gas

2 Global methane cycle
3 Emissions accounting of methane
3.1 Natural sources of atmospheric methane

3.1.1 Methanogens

3.1.2 Wetlands

3.1.3 Animals

3.1.4 Plants
3.1.5 Methane gas from methane clathrates
3.1.6 Permafrost
3.2 Anthropogenic sources of atmospheric methane

3.2.1 Ecological conversion

3.2.2 Farm animals

3.2.3 Rice agriculture

3.2.4 Landfills

3.2.5 Waste water treatment

3.2.6 Biomass burning

3.2.7 Natural gas distribution

3.3 Coal mining
4 Removal processes
4.1 Natural sinks of atmospheric methane

4.1.1 Methanotrophs in soils

4.1.2 Troposphere

4.1.3 Stratosphere

4.1.4 Reaction with free chlorine

4.2 Anthropogenic sinks of atmospheric methane
5 Patterns of methane change over time
5.1 Natural methane cycles
5.2 Changes in anthropogenic sources
6 Impacts
7 Methane management techniques
8 See also
9 References
10 External links

o
o

Methane as a greenhouse gas[edit]

A 550ppm CO
2 level correlates to +9 C temperature rise, which was previously enough to trigger selfreinforcing climate change feedback loops leading to the Permian Extinction Event with 95%
planetary die-off. Even more worrying is that current levels of atmospheric methane (>1820ppb)
indicate near-term human extinction.
Methane in the Earth's atmosphere is a stronggreenhouse gas with a global warming potential of
34 over a 100-year period. This means that a methane emission will have 34 times the impact on
temperature of a carbon dioxide emission of the same mass over the following 100 years.
Methane has a large effect (100 times as strong as carbon dioxide) for a brief period (having a
half-life of 7 years in the atmosphere[4]), whereas carbon dioxide has a small effect for a long
period (over 100 years). Because of this difference in effect and time period, the global warming
potential of methane over a 20 year time period is 86.
The concentration of methane in Earth's atmosphere has increased by about 150% since 1750,
and it now accounts for 20% of the total radiative forcing from all of the long-lived and globally
mixed greenhouse gases.[5] According to NOAA the atmospheric methane concentration is now
above 1820ppb - largely due to the arctic methane release from melting methane clathrates.
Atmospheric methane concentration has not been this high for over 420,000 years and correlates
to 9 C average Earth temperature increase (see graph, which shows the close correlation
between CH4concentrations, CO
2 concentrations, and Earth's temperature variations).
Global methane cycle[edit]

This simple diagram depicts the flow of methane from sources into the atmosphere as well as the
sinks that consume methane. More detailed explanations of each source and sink are covered in
later sections.
A. Permafrost, glaciers, and ice cores A source that slowly releases methane trapped in frozen
environments as global temperatures rise.
B. Wetlands Warm temperatures and moist environments are ideal for methane production.
Most of the methane makes it past methane-consuming microorganisms.[citation needed]
C. Forest fire Mass burning of organic matter releases methane into the atmosphere.[6]
D. Rice paddies The warmer and moister the rice field, the more methane is produced.
E. Animals Microorganisms breaking down difficult to digest material in the guts of ruminant
livestock and termites produce methane that is then released during defecation.
F. Plants While methane can be consumed in soil before being released into the atmosphere,
plants allow for direct travel of methane up through the roots and leaves and into the atmosphere.
[citation needed]
Plants may also be direct producers of methane.[citation needed]
G. Landfills Decaying organic matter and anaerobic conditions cause landfills to be a
significant source of methane.
H. Waste water treatment facilities Anaerobic treatment of organic compounds in the water
results in the production of methane.
I. Hydroxyl radical OH in the atmosphere is the largest sink for atmospheric methane as well as
one of the most significant sources of water vapor in the upper atmosphere.
J. Chlorine radical Free chlorine in the atmosphere also reacts with methane.
Emissions accounting of methane[edit]

Computer models showing the amount of methane (parts per million by volume) at the surface
(top) and in the stratosphere (bottom).[7]

Mauna Loa methane concentrations from ERSL measurements

The balance between sources and sinks of methane is not yet fully understood. The IPCC
Working Group I stated in chapter 2 of the Fourth Assessment Report that there are "large
uncertainties in the current bottom-up estimates of components of the global source", and the
balance between sources and sinks is not yet well known. The most important sink in the

methane cycle is reaction with the hydroxyl radical, which is produced photochemically in the
atmosphere. Production of this radical is not fully understood and has a large effect on
atmospheric concentrations. This uncertainty is exemplified by observations that have shown
between the year 2000 and 2006 increases in atmospheric concentration of methane ceased
without reduction in anthropogenic sources, showing that methane accounting does not
accurately predict methane observations.[citation needed]
Houweling et al. (1999) give the following values for methane emissions (Tg/a=teragrams per
year):[8]

Origin

CH
4 Emission
Mass (Tg/a) Type (%/a)

Total (%/a)

Wetlands (incl. Rice agriculture)

225

83

37

Termites

20

Ocean

15

Hydrates

10

Natural Total

270

100

45

Energy

110

33

18

Landfills

40

12

Ruminants (Livestock)

115

35

19

Natural Emissions

Anthropogenic Emissions

Waste treatment

25

Biomass burning

40

12

Anthropogenic Total

330

100

55

Soils

-30

-5

-5

Tropospheric OH

-510

-88

-85

Stratospheric loss

-40

-7

-7

Sink Total

-580

-100

-97

+20

~2.78 Tg/(nmol/mol) +7.19 (nmol/mol)/a

Sinks

Emissions + Sinks
Imbalance (trend)

Any process that results in the production of methane and its release into the atmosphere can be
considered a "source." The two main processes that are responsible for methane production occur
as a result of microorganisms anaerobically converting organic compounds into methane.
Methanogenesis, the scientific term for methane production, occurs primarily in anaerobic
conditions because of the lack of availability of other oxidants. In these conditions, microscopic
organisms calledarchaea use acetate and hydrogen to break down essential resources in a process
calledfermentation.
Acetoclastic methanogenesis- certain archaea cleave acetate produced during anaerobic
fermentation to yield methane and carbon dioxide.
H3C-COOH CH4 + CO2
Hydrogenotrophic methanogenesis- archaea oxidize hydrogen with carbon dioxide to yield

methane and water.

4H2 + CO2 CH4 + 2H2O
While acetoclastic methanogenesis and hydrogenotrophic methanogenesis are the two major
source reactions for atmospheric methane, other minor biological methane source reactions also
occur.
Natural sources of atmospheric methane[edit]
Most ecological emissions of methane relate directly to methanogens generating methane in
warm, moist soils as well as in the digestive tracts of certain animals.
Methanogens[edit]
Methanogens are methane producing microorganisms. In order to produce energy, they use an
anaerobic process called methanogenesis. This process is used in lieu of aerobic, or with oxygen,
processes because methanogens are unable to metabolise in the presence of even small
concentrations of oxygen. When acetate is broken down in methanogenesis, the result is the
release of methane into the surrounding environment.
Wetlands[edit]
Main article: Wetland Methane Emissions
Wetlands account for approximately 20 percent of atmospheric methane through emissions from
soils and plants.[9] Wetlands counteract the sinking action that normally occurs with soil because
of the high water table. When the water table is low, the methane generated within the wetland
soil has to come up through the soil and get past multitudes of methanotrophic bacteria. When
the water table is higher, then the methane produced in the soil can more easily diffuse through
the water and escape into the atmosphere.[citation needed]
Animals[edit]
Ruminant animals, particularly cows and sheep, contain bacteria in their gastrointestinal systems
that help to break down plant material. Some of these microorganisms use the acetate from the
plant material to produce methane, and because these bacteria live in the stomachs and intestines
of ruminants, whenever the animal burps or defecates, it emits methane as well. The amount of
methane emitted by one cow is equivalent to the amount of methane that 2.5 acres
ofmethanotrophic bacteria can consume.
Termites also contain methanogenic microorganisms in their gut. However, some of these
microorganisms are so unique that they live nowhere else in the world except in the third gut of
termites. These microorganisms also break down biotic components to produce ethanol, as well
as methane byproduct. However, unlike ruminants who lose 20 percent of the energy from the
plants they eat, termites only lose 2 percent of their energy in the process.[10] Thus comparatively,

termites do not have to eat as much food as ruminants to obtain the same amount of energy, and
give off proportionally less methane.
Plants[edit]
Living plants (e.g. forests) have recently been identified as a potentially important source of
methane, possibly being responsible for approximately 10 to 30 percent of atmospheric methane.
[11]
A 2006 paper calculated emissions of 62236 Tg a1, and "this newly identified source may
have important implications".[12] [13] However the authors stress "our findings are preliminary
with regard to the methane emission strength".[14]
These findings have been called into question in a 2007 paper which found "there is no evidence
for substantial aerobic methane emission by terrestrial plants, maximally 0.3% of the previously
published values".[15]
While the details of plant methane emissions have yet to be confirmed, plants as a significant
methane source would help fill in the gaps of previous global methane budgets as well as explain
large plumes of methane that have been observed over the tropics.[11][16]
In wetlands, where rate of methane production are high, plants help methane travel into the
atmosphereacting like inverted lightning rods as they direct the gas up through the soil and
into the air. They are also suspected to produce methane themselves, but because the plants
would have to use aerobic conditions to produce methane, the process itself is still unidentified.
Methane gas from methane clathrates[edit]
See also: Arctic methane release and Clathrate gun effect
At high pressures, such as are found on the bottom of the ocean, methane forms a
solid clathratewith water, known as methane hydrate. An unknown, but possibly very large
quantity of methane is trapped in this form in ocean sediments. The release of large volumes of
methane gas from such sediments into the atmosphere has been suggested as a possible cause for
rapid global warmingevents in the Earth's distant past, such as the PaleoceneEocene Thermal
Maximum of 55 million years ago, and the Great Dying.
Theories suggest that should global warming cause them to heat up sufficiently, all of this
methane gas could again be released into the atmosphere. Since methane gas is twenty-five times
stronger (for a given weight, averaged over 100 years) than CO
2 as a greenhouse gas; this would immensely magnify the greenhouse effect.
Permafrost[edit]
Methane that gets frozen in permafrost land that is frozen for several years at a time is slowly
released from bogs as the permafrost melts. With rising global temperatures, the amount of
permafrost melting and releasing methane continues to increase.
Although records of permafrost are limited, recent years (1999 to 2007) have seen record
thawing of permafrost in Alaska and Siberia. Recent measurements in Siberia show that the

methane released is five times greater than previously estimated.[17] Melting yedoma, a type of
permafrost, is a significant source of atmospheric methane (about 4 Tg of CH4 per year).
Anthropogenic sources of atmospheric methane[edit]
Slightly over half of the total emission is due to human activity.[5] Since the Industrial
Revolutionhumans have had a major impact on concentrations of atmospheric methane. As a
result, humans have acquired the ability to affect concentrations of other gases in the atmosphere
as well. For example, because methane traps heat in the atmosphere, increased methane
emissions increase the temperature of the atmosphere. And, because warmer climates hold more
water vapor, through methane emissions humans can indirectly increase the amount of water
vapor in the atmosphere as well.[11]
Ecological conversion[edit]
Conversion of forests and natural environments into agricultural plots increases the amount of
nitrogen in the soil, which inhibits methane oxidation, weakening the ability of the
methanotrophic bacteria in the soil to act as sinks. Additionally, by changing the level of the
water table, humans can directly affect the soils ability to act as a source or sink. The
relationship between water table levels and methane emission is explained in the wetlands
section of natural sources.
Farm animals[edit]
A 2006 UN FAO report reported that livestock generate more greenhouse gases as measured in
CO2equivalents than the entire transportation sector. Livestock accounts for 9 percent of
anthropogenic CO2, 65 percent of anthropogenic nitrous oxide and 37 percent of anthropogenic
methane. A senior UN official and co-author of the report, Henning Steinfeld, said "Livestock are
one of the most significant contributors to today's most serious environmental problems."[18]
Recent NASA research has confirmed the vital role of livestock eructation (burping) in global
warming. "We understand that other greenhouse gases apart from carbon dioxide are important
for climate change today," said Gavin Schmidt, the lead author of the study and a researcher at
NASA's Goddard Institute for Space Studies in New York, NY and Columbia University's Center
for Climate Systems Research.[19] Other recent peer reviewed NASA research published in the
journal Sciencehas also indicated that the contribution of methane to global warming has been
underestimated.[20][21]
Nicholas Stern, the author of the 2006 Stern Review on climate change has stated "people will
need to turn vegetarian if the world is to conquer climate change".[22] President of the National
Academy of Sciences Ralph Cicerone (an atmospheric scientist), has indicated the contribution
of methane by livestock flatulence and eructation to global warming is a serious topic.
Cicerone states Methane is the second-most-important greenhouse gas in the atmosphere now.

The population of beef cattle and dairy cattle has grown so much that methane from cows now is
big. This is not a trivial issue."[23]
Approximately 5% of the methane is released via the flatus, whereas the other 95% is released
viaeructation. Vaccines are under development to reduce the amount introduced through
eructation.[24]
Rice agriculture[edit]
Due to a continuously growing world population, rice agriculture has become one of the most
powerful anthropogenic sources of methane. With warm weather and water-logged soil, rice
paddies act like wetlands, but are generated by humans for the purpose of food production. Due
to the swamp-like environment of rice fields, this crop alone is responsible for approximately 50100 million metric tons of methane emission each year.[25] This means that rice agriculture is
responsible for approximately 15 to 20 percent of anthropogenic methane emissions.[26] An
article written by William F. Ruddiman explores the possibility that methane emissions started to
rise as a result of anthropogenic activity 5000 years ago when ancient cultures started to settle
and use agriculture, rice irrigation in particular, as a primary food source.[27]
Landfills[edit]
Due to the large collections of organic matter and availability of anaerobic conditions, landfills
are the third largest source of atmospheric methane in the United States.[28] Even after a landfill is
closed, the mass amount of decaying matter continues to emit methane for years. Although the
methanotrophic bacteria in the surrounding soil does oxidize some of the methane,
approximately 90 percent of the methane produced in landfills escapes through the landfill cover
and into the atmosphere.[29]
Waste water treatment[edit]
Waste water treatment facilities act to remove organic matter, solids, pathogens, and chemical
hazards as a result of human contamination. Methane emission in waste treatment facilities
occurs as a result of anaerobic treatments of organic compounds and anaerobic biodegradation of
sludge.[30]
Biomass burning[edit]
Incomplete burning of both living and dead organic matter results in the emission of methane.
While natural wildfires can contribute to methane emissions, the bulk majority of biomass
burning occurs as a result of humans- including everything from accidental burnings by civilians
to deliberate burnings used to clear out land to biomass burnings occurring as a result of
destroying waste.[16]

Natural gas distribution[edit]

Methane is a primary component of natural gas, and thus during the production, processing,
storage, transmission, and distribution of natural gas, a significant amount of methane is lost into
the atmosphere.[30]
According to the EPA Inventory of U.S Greenhouse Gases and Sinks: 1990-2009 report, dated
April 2011, methane emissions from oil and natural gas systems make up 3.8 percent of total
greenhouse gas emissions in the United States. Methane emissions occur in all sectors of the
natural gas industry, from drilling and production, through gathering and processing and
transmission, to distribution. These emissions occur through normal operation, routine
maintenance, fugitive leaks, system upsets, and venting of equipment. In the oil industry, some
underground crude contains natural gas that is entrained in the oil at high reservoir pressures.
When oil is removed from the reservoir, associated natural gas is produced.[31][32]
Additionally, the inventory shows that the oil and natural gas industry emitted 624 billion cubic
feet (Bcf) of methane in 2009. Of this amount, 63% was from production operations, 7% from
processing, 18% from transmission and storage systems, and 12% from distribution systems. Oil
and natural gas systems are the largest human-made source of methane emissions (37 percent) in
the United States.[31][32]
Similarly, according to the EPA Global Anthropogenic Non CO2 Greenhouse Gas Emissions:
1990-2020 report, dated June 2006, oil and natural gas operations are a significant source of
global methane emissions, constituting approximately 18 percent of total human-made methane
emissions. The report also indicates that in 2005, global oil and natural gas methane emissions
totaled approximately 82 billion cubic meters (Bcm), or 2,896 billion cubic feet (Bcf), equivalent
to about 1,165 million tonnes carbon dioxide equivalent (MtCO2e).[32][33]
Recent estimates of natural gas losses during distribution are as high as 9%[34]
Coal mining[edit]
In 2014 NASA researchers reported the discovery of a 2,500 square miles
(6,500 km2) methane cloud floating over the Basin. The discovery was based on data from
the European Space Agencys Scanning Imaging Absorption Spectrometer for Atmospheric
Chartography instrument from 2002 to 2012.[35]
The report concluded that the source is likely from established gas, coal, and coalbed
methanemining and processing. The region emitted 590,000 metric tons of methane every year
between 2002 and 2012almost 3.5 times the widely used estimates in the European Unions
Emissions Database for Global Atmospheric Research.[35]
Removal processes[edit]
Any process that consumes methane from the atmosphere can be considered a "sink" of
atmospheric methane. The most prominent of these processes occur as a result of methane either
being destroyed in the atmosphere or broken down in soil.

A pie chart demonstrating the relative effects of various sinks of atmopsheric methane.
Reaction with the hydroxyl radical- The major removal mechanism of methane from the
atmosphere involves radical chemistry; it reacts with the hydroxyl radical (OH) in
thetroposphere or stratosphere to create the CH3 radical and water vapor. In addition to being the
largest known sink for atmospheric methane, this reaction is one of the most important sources of
water vapor in the upper atmosphere.
CH
4 + OH CH
3+H
2O
This reaction in the troposphere gives a methane lifetime of 9.6 years. Two more minor sinks are
soil sinks (160 year lifetime) and stratospheric loss by reaction with OH, Cl andO1D in the
stratosphere (120 year lifetime), giving a net lifetime of 8.4 years.[8] Oxidation of methane is the
main source of water vapor in the upper stratosphere (beginning at pressure levels around
10 kPa).
The methyl radical formed in the above reaction will, during normal daytime conditions in the
troposphere, usually react with another hydroxyl radical to form formaldehyde. Note that this is
not strictly oxidative pyrolysis as described previously. Formaldehyde can react again with a
hydroxyl radical to form carbon dioxide and more water vapor. Note that sidechains in these
reactions may interact with nitrogen compounds that will likely produce ozone, thus supplanting
radicals required in the initial reaction.[36]
Methanotrophic bacteria in soils- Methanotrophic bacteria that reside within soil use methane as
a source of carbon in methane oxidation.[37] Methane oxidation allows methanotrophic bacteria to
use methane as a source of energy, reacting methane with oxygen and as a result producing
carbon dioxide and water.
CH4 + 2O2 CO2 + 2H2O
Natural sinks of atmospheric methane[edit]
Most natural sinks occur as a result of chemical reactions in the atmosphere as well as oxidation

by methane consuming bacteria in Earths soils.

Methanotrophs in soils[edit]
Soils act as a major sink for atmospheric methane through the methanotrophic bacteria that
reside within them. This occurs with two different types of bacteria. High capacity-low affinity
methanotrophic bacteria grow in areas of high methane concentration, such as waterlogged soils
in wetlands and other moist environments. And in areas of low methane concentration, low
capacity-high affinity methanotrophic bacteria make use of the methane in the atmosphere to
grow, rather than relying on methane in their immediate environment.[37]
Forest soils act as good sinks for atmospheric methane because soils are optimally moist for
methanotroph activity, and the movement of gases between soil and atmosphere (soil diffusivity)
is high.[37] With a lower water table, any methane in the soil has to make it past the
methanotrophic bacteria before it can reach the atmosphere.
Wetland soils, however, are often sources of atmospheric methane rather than sinks because the
water table is much higher, and the methane can be diffused fairly easily into the air without have
to compete with the soils methanotrophs.
Troposphere[edit]
The most effective sink of atmospheric methane is the hydroxyl radical in the troposphere, or the
lowest portion of Earths atmosphere. As methane rises into the air, it reacts with the hydroxyl
radical to create water vapor and carbon dioxide. The lifespan of methane in the atmosphere was
estimated at 9.6 years as of 2001; however, increasing emissions of methane over time reduce the
concentration of the hydroxyl radical in the atmosphere.[16] With less OH to react with, the
lifespan of methane could also increase, resulting in greater concentrations of atmospheric
methane.
Stratosphere[edit]
Even if it is not destroyed in the troposphere, methane can usually only last 12 years before it is
eventually destroyed in Earths next atmospheric layer: the stratosphere. Destruction in the
stratosphere occurs the same way that it does in the troposphere: methane is oxidized to produce
carbon dioxide and water vapor.
Reaction with free chlorine[edit]
Methane also reacts with natural chlorine gas in the atmosphere to
produce chloromethane andhydrochloric acid (HCl). This process is known as free radical
halogenations.[38]
CH4 + Cl2 CH3Cl + HCl

Anthropogenic sinks of atmospheric methane[edit]

Humans have yet to act as any significant sink of atmospheric methane.
Patterns of methane change over time[edit]
Since the 1800s, atmospheric methane concentrations have increased annually at a rate of about
0.9%.[9] Long term atmospheric measurements of methane by NOAA show that the build up of
methane has slowed dramatically over the last decade, after nearly tripling since pre-industrial
times.[39] Although scientists have yet to pinpoint the exact reason(s) for this sudden drop in
growth rates, it is thought that this reduction is due to reduced industrial emissions and drought
in wetland areas.
The only exceptions to this drop in growth rate occurred in 1991 and 1998 when growth rates
increased suddenly to 14-15 nmol/mol per year for those years, nearly double the growth rates of
the years before.[11]
The 1991 spike is believed to have occurred due to the volcanic eruption of Mt. Pinatubo in June
of that year. Volcanoes affect atmospheric methane emissions when they erupt, releasing ash and
sulfur dioxide into the air. As a result, photochemistry of plants is affected and the removal of
methane via the tropospheric hydroxyl radical is reduced. However, growth rates quickly fell due
to lower temperatures and global reduction in rainfall.
The cause of the 1998 spike is unresolved, but scientists are currently attributing it to a
combination of increased wetland and rice field emissions as well as an increased amount of
biomass burning. 1998 was also the warmest year since surface temperatures were first recorded,
suggesting that anomalously high temperatures can induce elevated methane emission.[40]
Data from 2007 suggested methane concentrations were beginning to rise again.[41] This was
confirmed in 2010 when a study showed methane levels were on the rise for the 3 years 2007 to
2009. After a decade of near-zero growth in methane levels, "globally averaged atmospheric
methane increased by [approximately] 7 nmol/mol per year during 2007 and 2008. During the
first half of 2009, globally averaged atmospheric CH4 was [approximately] 7 nmol/mol greater
than it was in 2008, suggesting that the increase will continue in 2009."[42]
Methane emissions levels vary greatly depending on the local geography. For both natural and
anthropogenic sources, higher temperatures and higher water levels result in the anaerobic
environment that is necessary for methane production.
Natural methane cycles[edit]
Emissions of methane into the atmosphere are directly related to temperature and moisture. Thus,
the natural environmental changes that occur during seasonal change act as a major control of
methane emission. Additionally, even changes in temperature during the day can affect the
amount of methane that is produced and consumed.
For example, plants that produce methane can emit as much as two to four times more methane
during the day than during the night.[9] This is directly related to the fact that plants tend to rely

on solar energy to enact chemical processes.

Additionally, methane emissions are affected by the level of water sources. Seasonal flooding
during the spring and summer naturally increases the amount of methane released into the air.
Changes in anthropogenic sources[edit]
The most clearly identified rise in atmospheric methane as a result of human activity occurred in
the 1700s during the industrial revolution. As technology increased at a considerable rate,
humans began to build factories and plants, burn fossil fuels for energy, and clear out forests and
other vegetation for the purpose of building and agriculture. This growth continued to rise at a
rate of almost 1 percent per year until around 1990 when growth rates dropped to almost zero.[11]
A recent article from William F. Ruddiman, however, indicates that the anthropogenic change in
methane may have started 5000 years prior to the industrial revolution.[27] The
methane insolationcycles of the ice core remained stable and predictable until 5000 years ago,
most likely due to some anthropogenic effect.[27] Ruddiman suggests that the transition of humans
from hunter gatherers into agricultural farming was the first instance of humans affecting
methane concentration in the atmosphere. Ruddimans hypothesis is supported by the fact that
early rice irrigation occurred approximately 5000 years agothe same time the ice core cycles
lost their predictability. Due to the inefficiency of humans first learning how to grow rice,
extensive rice paddies would have been needed to feed even a small population. These, overflooded and filled with weeds, would have resulted in huge methane emitting wetlands.[27]
Another source of methane emissions has been identified in Russia. Near Yamburg and Urengoy
exist gas fields with a methane concentration of 97 percent.[43] The gas obtained from these fields
is taken and exported to Western and Central Europe through an extensive pipeline system
known as the Trans-Siberian natural gas pipeline system. In accordance with the IPCC and other
natural gas emissions control groups, measurements had to be taken throughout the pipeline to
measure methane emissions from technological discharges and leaks at the pipeline fittings and
vents. Although the majority of the natural gas leaks were carbon dioxide, a significant amount
of methane was also being consistently released from the pipeline as a result of leaks and
breakdowns. In 2001, natural gas emissions from the pipeline and natural gas transportation
system accounted for 1 percent of the natural gas produced.[43] Fortunately, between 2001 and
2005, this number reduced to 0.7 percent, and even the 2001 value is still significantly less than
that of 1996.[43] Thus, it is suggested that while natural gas transportation is a significant
anthropogenic source of methane, over time as technology advances and greenhouse gas
emission awareness increases, methane emission growth rates decrease and natural gases are
overall better managed and controlled.[citation needed]
However that may be, transportation is only part of the problem. Indeed, Howarth [44] et al. have
argued that:
We believe the preponderance of evidence indicates shale gas has a larger GHG [green house
gas] footprint than conventional gas, considered over any time scale. The GHG footprint of shale
gas also exceeds that of oil or coal when considered at decadal time scales, []
As a recent study [45] by Miller et al. shows, current greenhouse gas reduction policies in the US

are based on what appear to be significant underestimates of anthropogenic methane emissions.

As the authors state:
We find greenhouse gas emissions from agriculture and fossil fuel extraction and processing
(i.e., oil and/or natural gas) are likely a factor of two or greater than cited in existing studies.
Impacts[edit]
The direct radiative greenhouse gas forcing effect has been estimated at 0.5 W/m^2.[46]
In addition to the direct heating effect and the normal feedbacks, the methane breaks down to
carbon dioxide and water. This water is often above the tropopause where little water usually
reaches. Ramanathan (1988)[47] notes that both water and ice clouds, when formed at cold lower
stratospheric temperatures, are extremely efficient in enhancing the atmospheric greenhouse
effect. He also notes that there is a distinct possibility that large increases in future methane may
lead to a surface warming that increases nonlinearly with the methane concentration.
Methane management techniques[edit]
In an effort to mitigate climate change, humans have started to develop alternative methods and
medicines.
For example, in order to counteract the immense amount of methane that ruminants give off, a
type of drug called monensin (marketed as rumensin) has been developed. This drug is
classified as an ionophore, which is an antibiotic that is naturally produced by a harmless
bacteria strain. This drug not only improves feed efficiency but also reduces the amount of
methane gas emitted from the animal and its manure.[48]
In addition to medicine, specific manure management techniques have been developed to
counteract harmful emissions from livestock manure. Educational resources have even begun to
be provided for small farms run by owners who do not realize the harmful effects of livestock
manure on the environment. Management techniques include daily pickup and storage of manure
in a completely closed off storage facility that will prevent runoff from making it into bodies of
water. The manure can then be kept in storage until it is either reused for fertilizer or taken away
and stored in an offsite compost. Nutrient levels of various animal manures are even provided for
optimal use as compost for gardens and agriculture.[49]
In order to reduce effects on methane oxidation in soil, several steps can be taken. Controlling
the usage of nitrogen enhancing fertilizer and reducing the amount of nitrogen pollution into the
air can both lower inhibition of methane oxidationa major sink of atmospheric methane.
Additionally, using drier growing conditions for crops such as rice and selecting strains of crops
that produce more food per unit area can reduce the amount of land with ideal conditions for
methanogenesis. Careful selection of areas of land conversion (for example, plowing down
forests to create agricultural fields) can also reduce the destruction of major areas of methane
oxidation.
To counteract methane emissions from landfills, on March 12, 1996, the EPA (Environmental
Protection Agency) added the Landfill Rule to the Clean Air Act. This rule requires large

landfills that have ever accepted municipal solid waste, have been used as of November 8, 1987,
can hold at least 2.5 million metric tons of waste with a volume greater than 2.5 million cubic
meters, and/or have nonmethane organic compound (NMOC) emissions of at least 50 metric tons
per year to collect and combust emitted landfill gas.[29] This set of requirements excludes 96% of
the landfills in the USA. While the direct result of this is landfills reducing emission of
nonmethane compounds that form smog, the indirect result is reduction of methane emissions as
well.
To reduce emissions from the natural gas industries, the EPA developed the Natural Gas STAR
Program, also known as Gas STAR.[30]
Another program was also developed by the EPA to reduce emissions from coal mining. The
Coalbed Methane Outreach Program (CMOP) helps and encourages the mining industry to find
ways to use or sell methane that would otherwise be released from the coal mine into the
atmosphere.[30]
A portable methane detector has been developed which, mounted in a vehicle, can detect excess
levels of methane in the ambient atmosphere and differentiate between natural methane from
rotting vegetation or manure and gas leaks. As of 2013 the technology was being deployed
by Pacific Gas & Electric.[50]

Introduction
Chlorofluorocarbons (CFCs), hydrofluorocarbons (HFCs), perfluorocarbons (PFCs), and
aerosols are very important greenhouse gases. CFCs, HFCs, and PFCs are all human made and
are not produced by any other process but our activities. Chlorofluorocarbons (CFCs) are
nontoxic, nonflammable chemicals containing atoms of carbon, chlorine, and fluorine. They are
used in the manufacture of aerosol sprays, blowing agents for foams and packing materials, as
solvents, and as refrigerants. CFCs owe their existence to accidents that occurred in the early
1900s. Refrigerators in the late 1800s and early 1900s used the toxic gases, ammonia (NH3),
methyl chloride, and sulfur dioxide, as refrigerants. After a series of fatal accidents in the 1920s
when methyl chloride leaked out of refrigerators, a search for a less toxic replacement begun as a
collaborative effort of three American corporations - Frigidaire, General Motors, and Du Pont.
CFCs were first synthesized in 1928 by Thomas Midgley, Jr. of General Motors, as safer
chemicals for refrigerators used in large commercial applications.
Hydrofluorocarbons - HFCs, Perfluorocarbons - PFCs, Sulfur Hexafluoride - SF6

Hydrofluorocarbons (composed of hydrogen, fluorine, and carbon) and perfluorocarbons

(composed of fluorine and carbon) have been created for industrial applications and been
adopted as ozone safe replacements for chlorofluorocarbons and thus are growing in atmospheric
concentration (Figure 13). Even though hydrofluorocarbons and perfluorocarbons are emitted in
relatively small quantities, they have a disproportionate effect on the greenhouse effect. As a
greenhouse gas, the most potent hydrofluorocarbons and perfluorocarbons are 11,700 times and
7000 to 9000 times per molecule as effective as a molecule of carbon dioxide, respectively. Also,
perfluorocarbons have relatively long atmospheric lifetimes (up to 50,000 years). Rated as the
most powerful greenhouse gas ever released to the atmosphere, sulfur hexafluoride is used as an
electric insulator, heat conductor, and a freezing agent. In comparison to one molecule of carbon
dioxide, the global warming potential of one sulfur hexafluoride molecule is approximately
24,000 times greater. Sulfur hexafluoride has now been banned from use due to its global
warming potential.
Figure 13. Hydrofluorocarbons (HFCs) and hydrochlorofluorocarbons (HCFCs) atmospheric
concentrations.. Concentrations given in parts per trillion (ppt).

Natural sources of N2O (Nitrous oxide) are estimated to contribute about 64% of the total inputs
to the atmosphere. The largest sources of natural N2O emissions are soils (contributing 6.6 Tg
N/yr) and oceans, rivers, and estuaries (contributing 5.4 Tg N/yr). However, there is some
controversy as to what fraction of the emissions associated with rivers and estuaries should be
considered natural source emissions, as they are driven primarily by anthropogenic contributions
of nitrogen to the water bodies (e.g., from agricultural runoff) Global average atmospheric
concentrations of N2O have increased from about 270 parts per billion by volume (ppbv) in 1750
to 314 ppb in 1998, which equates to a 16% increase for the period.
Predictions
The Southwest region stretches from the southern Rocky Mountains to the Pacific Coast.
Elevations range from the lowest in the country to among the highest, with climates ranging from
excessively dry to very wet. Past climate records based on changes in Colorado River flows

indicate that drought is a frequent feature of the Southwest, with some of the longest documented
megadroughts on Earth. Since the 1940s, the region has experienced its most rapid population
and urban growth. During this time, there were both unusually wet periods (including much of
1980s and 1990s) and dry periods (including much of 1950s and 1960s).The prospect of future
droughts becoming more severe as a result of global warming is a significant concern, especially
because the Southwest continues to lead the nation in population growth.
1.Water supplies are projected to become increasingly scarce, calling for trade-offs among
competing uses, and potentially leading to conflict. Water is vital to agriculture, hydroelectric
power production, the growing human population, and ecosystems. Water supplies in some areas
are already becoming limited. Large reductions in spring precipitation are projected for the
Southwest. Continued temperature increases combined with river flow reductions and rapid
population growth will increase competition for water supplies.
2. Increasing temperature, drought, wildfire, and invasive species will accelerate transformation
of the landscape.
3. Unique tourism and recreation opportunities are likely to suffer. Decreases from 40 to almost
90% are likely in end-of-season snow pack under high emissions scenarios in states with major
ski resorts from New Mexico to California.
4. Cities and agriculture face increasing risks from a changing climate. With more intense,
longer-lasting heat waves projected to occur over this century, demands for air conditioning are
expected to deplete electricity supplies, increasing risks of brownouts and blackouts. Much of the
regions agriculture will experience detrimental impacts in a warmer future, particularly specialty
crops in California such as apricots, almonds, artichokes, figs, kiwis, olives, and walnuts. These
and other such crops require a minimum number of hours below a chilling temperature threshold
in the winter to set fruit for the following year.
Building Climate Resilience on the Ground

On Monday, the Administration released the U.S. Climate Resilience Toolkit, a suite of resources
to help communities prepare for and respond to the impacts of climate change. The Toolkit,
which was called for in the Presidents Climate Action Plan, provides decision makers with easy
access to information ranging from which neighborhoods are likely to flood in future storm
surges to how future droughtconditions could affect regional crop growth. The Toolkit also

includes case studies that feature examples of how decision makers have used these tools,
lessons learned, and best practices.
The Toolkits initial focus is on coastal flood risk, food resilience, ecosystems, and human health.
In the coming months, it will be updated to include more resources and address additional topics
such as water and transportation.
Some features of the Toolkit include:

The Climate Explorer: A visualization tool that offers maps of climate stressors and
impacts, as well as interactive graphs showing daily observations and long-term averages from
thousands of weather stations across the country.

Steps to Resilience: A five-step process that users can follow to initiate, plan, and
implement projects to help make their homes, communities, and infrastructure more resilient to
climate-related hazards.

Taking Action stories: More than 20 real-world case studies describing climaterelated risks and opportunities that communities and businesses face, steps theyre taking to plan
and respond, and tools and techniques theyre using to improve resilience.

Federal resources and tools: Centralized access to Federal sites for future climate
projections, as well as freely available tools for accessing and analyzing climate data, generating
visualizations, exploring climate projections, estimating hazards, and engaging stakeholders in
resilience-building efforts.
The Toolkit was premiered at a meeting of the State, Local, and Tribal Leaders Task Force on
Climate Preparedness and Resilience, which was established by President Obama last year as
part of the Climate Action Plan. The Task Force concurrently submitted
theirrecommendations for how the Federal Government can support resilience at the state, local,
and tribal levels. The recommendations are the culmination of a year of work to solicit input

from across governments, trade associations, academic organizations, civil society, and other
stakeholders. They offer guidance on how the Federal Government should modernize programs
and policies to incorporate climate change, remove barriers to and incentivize community
resilience, and provide actionable information and tools. The recommendations are intended to
reflect the diverse needs of communities nationwide on issues ranging from health to natural
resources management to infrastructure and building design.
The solution?
Since we cannot completely reduce our carbon dioxide production (aka carbon footprint) by
reducing the amount of fuel and energy we consume we can compensate for this production by
having offsets. A carbon offset is a reduction of carbon dioxide or other greenhouse gases made
in order to compensate for or to offset a greenhouse gas emission made elsewhere.
Carbon offsets are measured in metric tons of carbon dioxide-equivalent (CO2e) and
may represent six primary categories of greenhouse gases which include:
Carbon dioxide (CO2),
Methane (CH4),
Nitrous oxide (N2O),
Perfluorocarbons (PFCs),
Hydrofluorocarbons (HFCs), and
Sulfur Hexafluoride (SF6).
One carbon offset represents the reduction of one metric ton of carbon dioxide or its equivalent
in other greenhouse gases.
Now here comes the tricky part. While voluntary purchases of offsets can play an important role
in reducing the threat, since global warming is international in scope we also need a massive
international effort to move from a fossil fuel-based economy to a renewable energy economy.
Or Do we?
Biologically we are primates and are programmed to be social and to help. Consider the case of
having a job in China selling cars. Cars contribute to global warming whereas bikes do not. What
do you do? Sell Bikes?

Drought:

In 2000 to 2004, the American west experienced a drought which causes the crop yield to be
decreased by 13% and river basins showed large decreases of 5 to 50% of inflow. These
reductions continued after the drought ended even though there was a relatively wet period but it
took three years for the lakes and reservoirs to be recharged.
What caused the drought? Global warming?
If you want to know how severe the drought was, it exceeded the conditions for the Dust Bowl in
the 1930s. I am sure most of you and your grandparents have no idea what the Dust Bowl was
and its implication. Simply stated, the climatic conditions in the 1930's caused such a dramatic
reduction in crops so that it prompted a massive migratiminions of people from the midwest to
California. Steinbeck's Grapes of Wrath" was based on the conditions the emigrants from the
midwest faced when they came west. According to experts, the climatic conditions we face in
the southwest part of the country is nothing compared to what is coming.
Overall, climate models point to a warmer planet due largely to greenhouse gases. This warming
trend will create extremely dry conditions across western North America as global winds and
atmospheric pressures respond to the warming.
But is this really a new phenomenon? Hardly. Scientists have studied the rings of more than 200

Ponderosa pine and Douglas fir trees. Widely spaced rings indicate wetter seasons; narrower
rings indicate parched years. Researchers created a history of rainfall in El Malpais National
Monument in New Mexico. They produced a two thousand year timeline starting from 1371
BC.Scientists have detected a relationship between warming and drought in western North
America by analyzing trends over the last 100 years. From a common sense point of view, they
documented that frequent drought and low precipitation events observed are associated with
increasing temperatures across the Northern Hemisphere. It makes sense. More heat, less water
due to evaporation and human use. How serious is this? In June 2012, 3,200 heat records were
broken. Some scientists are thinking about a Megadrought! But how new is this phenomenon?
You will hear different sides to this story1. The drought is due to the dramatic increase in green house gases in the atmosphere due to the
rapacious appetite mankind has for land, food, and water that are playing a major role in global
warming; and/or
2. The drought is part of a cycle of drought and wetness that is characteristic of cycles induced
by major forces besides mankinds influence and we are unfortunate to be in the dry cycle.
Wrong place, wrong time.
3. Combination of 1 and 2
As you read this material, do not get discouraged! We are having a major increase in global
warming and what mankind can effectively do to weather this challenge is not clear. Creative
new thinking will be needed to counter this problem!
Some scientists contend that climate changes may have had a more profound effect on the
stability of past societies. Climate change may not have been the only force that caused the
toppling of old societies but it played a critical role. Marshall, Michael (2012), "Ruined, Climate
may have had a far more profound impact on past societies than we realized" (New Scientist
August 4, 2012 Vol 215 No. 2876).
Besides the Middle East, let's consider China. Did drought play a role in the demise of various
Chinese Dynasties?
The Chinese depended on monsoons for their rice crops. If there was a decrease in the number of
monsoons, the rice crop would fail. China suffered three periods of drought from 860-960, 13401380, 1580-1630 in the 2000 years that were sampled. Every time the monsoons failed, there
was not enough water to support the chemical reactions in plants such as photosynthesis, crops
failed, people became hungry and rioted and the ruling group in power would be removed. For
example, the Yuan Dynasty was founded in 1271 by Kublai Khan, a grandson of Genghis Khan.
Despite the best efforts of the Yuan Emperors, this dynasty lasted only until 1368 due to the lack
of monsoons.
Let's fast forward to the present century. A major drought is affecting the southwest. Future

precipitation trends, based on climate model projections for the coming fifth assessment from the
Intergovernmental Panel on Climate Change, indicate that droughts of this length and severity
will be commonplace through the end of the century unless human-induced carbon emissions are
significantly reduced. Indeed, assuming business as usual, each of the next 80 years in the
American West is expected to see less rainfall than the average of the five years of the drought
that hit the region from 2000 to 2004. The report puts the increase in global warming as a
function of mankind- calling it anthropogenic climate change along with natural variability.
Anthropogenic means that it was caused by humans. The effects of the drought whatever its
origin would be as follows:
Agriculture (Biological Concepts: Carbohydrates, Proteins and Lipids, Hunger)
Russia and the United States have major droughts that are decreasing the production of wheat to
feed themselves and the world. The biology behind this fact is that mankind must eat. It is our
primordial drive and we depend on photosynthesis to produce the heat, rice etc. Without
photosynthesis, life as we know it would not exist. Photosynthesis depends on water for growth
and development. The hydrogen ion from water is key for producing the ATP that the plant needs
to develop its own protein, carbohydrates and lipids. Without water, there is no photosynthesis
and the end result is a desert. In the United States, pressure for action intensified last week as the
US department of agriculture (USDA) warned food prices were set to soar. USDA said the worst
drought in 50 years had forced farmers to abandon corn fields covering an area larger than
Belgium and Luxembourg combined. The department slashed its forecasts for key crops
including corn and soybeans and lowered production forecast for eggs, milk, and pork. Blaming
"extreme dryness" in the Central Plains and the Corn Belt, the USDA said it now expects this
year's corn harvest to be the lowest since 1995-1996.
Let's discuss water and how it is circulated through the world. It is by far the most important
chemical in the world. More important than gold.
The water cycle, also called the hydrologic cycle, operates similarly to other biogeochemical
cycles in which the chemicals associated with plant and animal nutrients move through the
atmosphere, the earth, and through living things and repeat the cycle. The water cycle includes
water in the forms of solid, liquid, and gas with the Sun providing the energy to power the
continuous cycle of water among these three forms. The largest component of the water cycle
occurs in oceans, bays, lakes, ponds, rivers, and streams. The ocean covers most of the Earths
surface and so contributes the largest share to the water cycle; more than 85% of the water that
evaporates from the Earths surface into the atmosphere does so from the ocean. About 80% of
the worlds precipitation enters oceans.
The water cycle contains five components that transfer moisture either from the Earths surface
to the atmosphere or from the atmosphere back to Earth. These components are the following:

 Condensationconversion of water vapor into droplets of liquid water

Precipitationwater that falls from the atmosphere to land or to surface waters as rain, snow,
sleet, or hail
Infiltrationdownward movement of liquid water through soil
Evaporationconversion of liquid water into gas, or water vapor
Transpirationmovement of liquid water from plant roots, upward in vessels, and into the
atmosphere from the leaves as water vapor
Forests serve in the water cycle in two critical ways: transpiration and water storage. Both
animals and plants transpire water vapor into the air, but animals transpire as part of aerobic
respiration when they exhale moisture from their lungs. As we discussed in the module on
respiration, the air that you inhale has to be humidified. As a consequence when you exhale,
there is moisture in the expired air. Keep in mind that the air you breathe already has a certain
amount of moisture.
Plants and trees possess special cells on the underside of their leaves, called guard cells, that
release water vapor from the plant into the atmosphere. The transpiration process begins when
trees draw water from the soil through their roots and transport it upward in vesselsxylem
carries water and nutrients upward and phloem distributes water and nutrients throughout the
plant. Trees, depending on size and species, transpire from 5,000 gallons to almost 50,000
gallons of water per year, more in warmer weather and less in colder weather. Low relative
humidity and increased air movement caused by wind or breezes also increase the transpiration
rate. During drought or in the desert where only drought-tolerant plant life lives, a trees
transpiration rate decreases so that it can conserve water. Soil also affects water transpiration.
When soil moisture levels are low, as in drought, trees slow their transpiration rate to conserve
water. Trees undergoing the normal aging process, called senescence, give way to new trees
ready to take their place. Prolonged drought, however, puts all trees into a premature senescence,
an event that may eventually kill a forest. Global warming has exerted a critical effect on forest
health because it increases the incidence and severity of droughts worldwide, and in doing so it
accelerates the death of drought-vulnerable trees.
Forests second major activity involves the capacity of trees to store water. Trees act as a
watershed by absorbing water during floods and storing and slowly releasing water in times of
low rainfall. Surface waters, groundwaters (or aquifers), and plant life comprise the Earths total
watershed. Part of trees role in the watershed involves regulation of the water table, which is the
area underground where water has completely filled the spaces between rocks and soil particles.
Beneath the water table lies an area of higher density where all the air has been squeezed out to
make room for water. This location, called the zone of saturation, holds water undisturbed for
longer periods than the water table. Therefore, water moves through three layers in the earth: the
upper unsaturated zone, where soils hold varying amounts of moisture (also called the soil zone);
the water table, where water exchanges from the saturated layer below to the unsaturated layer
above; and the zone of saturation. Tree roots pull water from either the unsaturated zone or the
water table. If the water tables are decreasing, then the plants that depend on that source of water

will die.
The Los Angeles Times had a number of articles that dealt with the great decrease in water tables
throughout the United States. Human activities interfere with the water cycle in the three
following ways: by drawing large amounts from surface sources and groundwaters, by polluting
water, and by removing or damaging the worlds forests. Part of the problem of water use by the
Earths human population resides in the fact that water is a very poorly managed resource. Water
covers 71% of the Earth and makes up at least 60% of living cells, but only 0.014% is available
for peoples use. Yet humans continue to waste water, pollute it, or otherwise treat it as if it were
free. Benjamin Franklin once said, When the wells dry, we know the worth of water. The
world has been progressing toward ever greater water shortages since the acceleration of global
warming. Some countries have already entered a dangerous condition known as water stress,
meaning their water requirements exceed the water they have available. A solution that addresses
this issue is the waterless toilet. Toilets require a huge infrastructure of water, sewage treatment
plants and electricity. The Melinda Gates Foundation awarded a major grant to University of
California which demonstrated a prototype waterless toilet that generated hydrogen gas and
electricity every time it was flushed. It might not be the most creative solution to water shortage
but consider that 2.5 billion people in the world do not have access to toilets which lead to major
illness.
Since every living thing needs water and cannot exist without it for more than a few days,
maintaining a clean supply is paramount to maintaining biodiversity. Forests play a vital role in
maintaining a continuous supply of available water, so this represents one way in which forests
maintain biodiversity. The bottom line is that the destruction of forests for the sake of farming in
the long run dramatically influences the water cycle.
Water is always on the move! The Suns energy causes water to evaporate from oceans and lakes
into the atmosphere. Plants and animals also release water vapor into the atmosphere as they
breathe. When the atmosphere cools, water vapor condenses, making clouds that might produce
rain or snow. Water has been recycled in its different forms as ice, liquid, or vapor --for more
than 3.5 billion years.
Influence of carbon dioxide on the pH of the earths water.
The water cycle is intimately tied in with the carbon dioxide cycle.
Carbon dioxide can change the pH of water. Recall that pH determines the rate at which
chemical reactions can occur. If the pH becomes too alkaline or acidic the reactions stop. Carbon
dioxide dissolves slightly in water to form a weak acid called carbonic acid, H2CO3, according to
the following reaction:

CO2 + H2O --> H2CO3

After that, carbonic acid reacts slightly and reversibly in water to form a hydronium cation,
H3O+, and the bicarbonate ion, HCO3-, according to the following reaction:
H2CO3 + H2O --> HCO3- + H3O+
This chemical behavior explains why water, which normally has a neutral pH of 7 has an acidic
pH of approximately 5.5 when it has been exposed to air. If the carbon dioxide level increases
the consequence is that the pH will change influencing the life in the sea.
Carbon dioxide
What is carbon dioxide and how is it discovered?
Joseph Black, a Scottish chemist and physician, first identified carbon dioxide in the
1750s. At room temperatures (20-25 oC), carbon dioxide is an odourless, colourless gas,
which is faintly acidic and non-flammable.
Carbon dioxide is a molecule with the molecular formula CO2. The linear molecule
consists of acarbon atom that is doubly bonded to two oxygen atoms, O=C=O.
Although carbon dioxide mainly consists in the gaseous form, it also has a solid and a
liquid form. It can only be solid when temperatures are below -78 oC. Liquid carbon
dioxide mainly exists when carbon dioxide is dissolved in water. Carbon dioxide is only
water-soluble, when pressure is maintained. After pressure drops the CO2 gas will try to
escape to air. This event is characterised by the CO2 bubbles forming into water.
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Properties of carbon dioxide
There are several physical and chemical properties, which belong to carbon dioxide.
Here we will sum them up in a table.

Property

Value

Molecular weight

44.01

CO2-molecule

Specific gravity

1.53 at 21 oC

Critical density

468 kg/m3

Concentration in air

370,3 * 107 ppm

Stability

High

Liquid

Pressure < 415.8 kPa

Solid

Temperature < -78 oC

Henry constant for solubility

298.15 mol/ kg * bar

Water solubility

0.9 vol/vol at 20 oC

Where on earth do we find carbon dioxide?

Carbon dioxide can be found mainly in air, but also in water as a part of the carbon cycle. We
can show you how the carbon cycle works, by means of an explanation and a schematic
representation. --> Move to the Carbon Cycle.
Applications of carbon dioxide by humans
Humans use carbon dioxide in many different ways. The most familiar example is its use in soft
drinks and beer, to make them fizzy. Carbon dioxide released by baking powder or yeast makes
cake batter rise.
Some fire extinguishers use carbon dioxide because it is denser than air. Carbon dioxide can
blanket a fire, because of its heaviness. It prevents oxygen from getting to the fire and as a result,
the burning material is deprived of the oxygen it needs to continue burning.
Carbon dioxide is also used in a technology called supercritical fluid extraction that is used to
decaffeinate coffee. The solid form of carbon dioxide, commonly known as Dry Ice, is used in
theatres to create stage fogs and make things like "magic potions" bubble.

The part carbon dioxide plays in environmental processes

Carbon dioxide is one of the most abundant gasses in the atmosphere. Carbon dioxide plays an
important part in vital plant and animal process, such as photosynthesis and respiration. These
processes will be briefly explained here.
Green plants convert carbon dioxide and water into food compounds, such as glucose, and
oxygen. This process is called photosynthesis.
The reaction of photosynthesis is as follows:
6 CO2 + 6 H2O --> C6H12O6 + 6 O2
Plants and animals, in turn, convert the food compounds by combining it with oxygen to release
energy for growth and other life activities. This is the respiration process, the reverse of
photosynthesis.
The respiration reaction is as follows:
C6H12O6 + 6 O2 --> 6 CO2 + 6 H2O
Photosynthesis and respiration play an important role in the carbon cycle and are at equilibrium
with one another.
Photosynthesis dominates during the warmer part of the year and respiration dominates during
the colder part of the year. However, both processes occur the entire year. Overall, then, carbon
dioxide in the atmosphere decreases during the growing season and increases during the rest of
the year.
Because the seasons in the northern and southern hemispheres are opposite, carbon dioxide in
the atmosphere is increasing in the north while decreasing in the south, and vice versa. The cycle
is more clearly present in the northern hemisphere; because it has relatively more land mass and
terrestrial vegetation. Oceans dominate the southern hemisphere.
Influence of carbon dioxide on alkalinity
Carbon dioxide can change the pH of water. This is how it works:
Carbon dioxide dissolves slightly in water to form a weak acid called carbonic acid, H2CO3,
according to the following reaction:
CO2 + H2O --> H2CO3
After that, carbonic acid reacts slightly and reversibly in water to form a hydronium cation,
H3O+, and the bicarbonate ion, HCO3-, according to the following reaction:
H2CO3 + H2O --> HCO3- + H3O+

This chemical behaviour explains why water, which normally has a neutral pH of 7 has an acidic
pH of approximately 5.5 when it has been exposed to air.
Carbon dioxide emissions by humans
Due to human activities, the amount of CO2 released into the
atmosphere has been rising extensively during the last 150 years. As a
result, it has exceeded the amount sequestered in biomass, the oceans,
and other sinks.
There has been a climb in carbon dioxide concentrations in the
atmosphere of about 280 ppm in 1850 to 364 ppm in 1998, mainly
due to human activities during and after the industrial revolution,
which began in 1850.
Humans have been increasing the amount of carbon dioxide in air by
burning of fossil fuels, by producing cement and by carrying out land
clearing and forest combustion. About 22% of the current atmospheric
CO2concentrations exist due to these human activities, considered that
there is no change in natural amounts of carbon dioxide. We will take
a closer look at these effects in the next paragraph.
Environmental problems - the greenhouse effect
The troposphere is the lower part of the atmosphere, of about 10-15 kilometres thick. Within the
troposphere there are gasses called greenhouse gasses. When sunlight reaches the earth, some of
it is converted to heat. Greenhouse gasses absorb some of the heat and trap it near the earth's
surface, so that the earth is warmed up. This process, commonly known as the greenhouse effect,
has been discovered many years ago and was later confirmed by means of laboratory
experiments and atmospheric measurements.
Life as we know it exists only because of this natural greenhouse effect, because this process
regulates the earth's temperature. When the greenhouse effect would not exist, the whole earth
would be covered in ice.
The amount of heat trapped in the troposphere determines the temperature on earth. The amount
of heat in the troposphere depends on concentrations of atmospheric greenhouse gasses and the
amount of time these gasses remain in the atmosphere. The most important greenhouse gasses
are carbon dioxide, CFC's (Chlor-Fluoro-Carbons), nitrogen oxides and methane.
Since the industrial revolution in 1850 began, human processes have been causing emissions of
greenhouse gasses, such as CFC's and carbon dioxide. This has caused an environmental
problem: the amounts of greenhouse gasses grew so extensively, that the earth's climate is
changing because the temperatures are rising. This unnatural addition to the greenhouse effect is
known as global warming. It is suspected that global warming may cause increases in storm

activity, Melting of ice caps on the poles, which will cause flooding of the inhabited continents,
and other environmental problems.
Together with hydrogen, carbon dioxide is the main greenhouse gas. However, hydrogen is not
emitted during industrial processes. Humans do not contribute to the hydrogen amount in the air,
this is only changing naturally during the hydrological cycle, and as a result it is not a cause of
global warming.
Increasing carbon dioxide emissions cause about 50-60% of the global warming. Carbon dioxide
emissions have risen from 280 ppm in 1850 to 364 ppm in the 1990s.
In the previous paragraph various human activities that contribute to the emission of carbon
dioxide gas have been mentioned. Of these activities fossil fuel combustion for energy
generation causes about 70-75% of the carbon dioxide emissions, being the main source of
carbon dioxide emissions. The remaining 20-25% of the emissions are caused by land clearing
and burning and by emission from motor vehicle exhausts.
Most carbon dioxide emissions derive from industrial processes in developed countries, such as
in the United States and in Europe. However, carbon dioxide emissions from developing
countries are rising. In this century, carbon dioxide emissions are expected to double and they
are expected to continue to rise and cause problems after that.
Carbon dioxide remains in the troposphere about fifty up to two hundred years.
The first person who predicted that emissions of carbon dioxide from the burning of fossil fuels
and other burning processes would cause global warming was Svante Arrhenius, who published
the paper "On the influence of carbonic acid in the air upon the temperature of the ground" in
1896.
In the beginning of the 1930 it was confirmed that atmospheric carbon dioxide was actually
increasing. In the late 1950s when highly accurate measurement techniques were developed,
even more confirmation was found. By the 1990s, the global warming theory was widely
accepted, although not by everyone. Whether global warming is truly caused by increasing
carbon dioxide in the atmosphere, is still debated.

Rising carbon dioxide concentrations in air in the past decades

The Kyoto treaty
World leaders gathered in Kyoto, Japan, in December 1997 to consider a world treaty restricting
emissions of greenhouse gases, mainly of carbon dioxide, that are thought to cause global
warming. Unfortunately, while the Kyoto treaties have worked for a while America is now trying
to evade them.
Carbon dioxide and health
Carbon dioxide is essential for internal respiration in a human body. Internal respiration is a
process, by which oxygen is transported to body tissues and carbon dioxide is carried away from
them.
Carbon dioxide is a guardian of the pH of the blood, which is essential for survival.
The buffer system in which carbon dioxide plays an important role is called the carbonate buffer.
It is made up of bicarbonate ions and dissolved carbon dioxide, with carbonic acid. The carbonic
acid can neutralize hydroxide ions, which would increase the pH of the blood when added. The
bicarbonate ion can neutralize hydrogen ions, which would cause a decrease in the pH of the
blood when added. Both increasing and decreasing pH is life threatening.
Apart from being an essential buffer in the human system, carbon dioxide is also known to cause
health effects when the concentrations exceed a certain limit.
The primary health dangers of carbon dioxide are:
- Asphyxiation. Caused by the release of carbon dioxide in a confined or unventilated area. This
can lower the concentration of oxygen to a level that is immediately dangerous for human health.
- Frostbite. Solid carbon dioxide is always below -78 oC at regular atmospheric pressure,
regardless of the air temperature. Handling this material for more than a second or two without
proper protection can cause serious blisters, and other unwanted effects. Carbon dioxide gas

released from a steel cylinder, such as a fire extinguisher, causes similar effects.
- Kidney damage or coma. This is caused by a disturbance in chemical equilibrium of the
carbonate buffer. When carbon dioxide concentrations increase or decrease, causing the
equilibrium to be disturbed, a life threatening situation may occur.
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Read more: http://www.lenntech.com/carbon-dioxide.htm#ixzz3LLfEDAAC

Be fruitful and multiply (Food; hunger)
No discussion about global warming would be complete without a discussion about the worlds
population. The reason that droughts are so important is that as consequence of a decrease in
wheat, rice, cattle, etc, people will eat less and die of starvation. It would seem reasonable to
assume the population control would be a major emphasis of various countries. However, the
story is not that simple.
All cultures concern themselves with a birth rate that will increase. This drive is not purely
political. One of the great drives for biological systems is to reproduce. Humans have the means
to control their rate of reproduction but many factors influence their decision. Life span was not
that long in medieval times. In 1810, due to advances in agriculture and the industrial revolution,
there were a billion people on the globe. With advances in the biological sciences, sanitation was
improved, food supplies were more reliable and vaccines help to boost the number to two billion
by 1974. From 1810 to 1974, 164 years elapsed to put 2 billion people on the planet requiring
food and water. In 2012, the population passed 7 billion. In thirty eight years we have more
tripled the entire world population with people producing carbon dioxide from the Krebs Cycle,
their cars, their industries, and cattle. What is interesting is that the nations continued to grow.
By the year 2043, the world population will be billion. (what number do you want to put here?)
Part of the reason that the societies did not collapse was due to more scientific ways to raise
crops and population control. Birth control in poor countries is not administered well, cultural
differences, etc. for example, Nigeria only 8% of the women use birth control vs 72% in the
USA. By 2050, Nigeria might exceed the United state in terms of population. According to some
experts, three billion people are under the age of 25 and are entering child bearing year. If left
unchecked, the number of babies they will produce will raise the population from to 9 11
billion people.
In rankings, China is #1 with 1.339 Billion, India is #2 with 1.184 Billion, USA is 309,975
Million.
If the population of the earth continues to grow there will not be enough work for the young

populations in developing countries.

An interactive list of countries including their (2012-2014 estimated) populations, as well as
land sizes and densities.
100 largest cities - by population
Capital cities of the world - with population
Click on any of the bolded headings to sort this country list.
Type the name of a country you're looking for in the search bar to find its individual stats.
Show

entries

Search:

Population
Density
(Sq. Km.)

Area
(Sq. Mi.)

Country Name:

Population

Area
(Sq. Km.)

China

1,339,190,00
0

9,596,960.00

139.54

3,705,405.45

India

1,184,639,00
0

3,287,590.00

360.34

1,269,345.07

United States of America

309,975,000

9,629,091.00

32.19

3,717,811.29

Indonesia

234,181,400

1,919,440.00

122.01

741,099.62

Brazil

193,364,000

8,511,965.00

22.72

3,286,486.71

Population
Density
(Sq. Km.)

Area
(Sq. Mi.)

Country Name:

Population

Area
(Sq. Km.)

Pakistan

170,260,000

803,940.00

211.78

310,402.84

Nigeria

170,123,000

923,768.00

171.32

356,668.67

Bangladesh

164,425,000

144,000.00

1,141.84

55,598.69

Russia

141,927,297

17,075,200.0
0

8.31

6,592,768.87

10

Japan

127,380,000

377,835.00

337.13

145,882.85

11

Mexico

108,396,211

1,972,550.00

54.95

761,605.50

12

Phillipines

94,013,200

300,000.00

313.38

115,830.60

13

Vietnam

85,789,573

329,560.00

260.32

127,243.78

14

Germany

81,757,600

357,021.00

229.00

137,846.52

15

Ethiopia

79,221,000

1,127,127.00

70.29

435,185.99

16

Egypt

78,848,000

1,001,450.00

78.73

386,661.85

17

Iran

75,078,000

1,648,000.00

45.56

636,296.10

Population
Density
(Sq. Km.)

Area
(Sq. Mi.)

Country Name:

Population

Area
(Sq. Km.)

18

Turkey

72,561,312

780,580.00

92.96

301,383.50

19

Congo (Dem. Rep. of )

67,827,000

2,345,410.00

28.92

905,567.49

20

France

65,447,374

547,030.00

119.64

211,209.38

21

Thailand

63,525,062

514,000.00

123.59

198,456.43

22

United Kingdom (UK)

62,041,708

244,820.00

253.42

94,525.49

23

Italy

60,340,328

301,230.00

200.31

116,305.51

24

Myanmar

50,496,000

678,500.00

74.42

261,970.21

25

South Africa

49,991,300

1,219,912.00

40.98

471,010.46

Population matters from a number of biological points of view:

1. It is one of the major drivers for the growth of greenhouse gases. More people more demands
on everything run on energy: water, food, clothing, housing, transportation, etc. If the population
does not grow too fast, agricultural production loss and an increase in prices will put 90-125
million people at risk of hunger by 2080.
2. The poorest countries and the poorest groups within this population are most vulnerable to
climate related hazards such as floods, droughts, and landslides.
3. Poor people will play a major role in deforestation. People need to stay warm, cook their food
and possibly sell the timber for food and shelter. Examples are Sierra Leone, Solomon Islands,
Rwanda, Uganda
4. Population will impact the world's limited water supply. Experts point to Africa as being one
of the continents most impacted by water scarcity. However in the United States, the southwest
drought will impact as well
5. Global warming will bring about sea level increase and those change will have a significant

effect on the high population density near coastlines. Low elevation zones account for two
percent of the worlds land area but contain 10% of the worlds population which is growing fast.
6. Global warming and increase in population will affect women the most. In many societies,
women are the providers for water, food, and fuel.
In the long run, it would be cheaper to finance family planning rather than inventing or
enhancing technological changes to generate solar energy, capture and store carbon dioxide. As
a consequence it would also be more effective in minimizing global warming. However,
religious, cultural, and social norms will make it very difficult to slow the human population
explosion, especially in developing countries.

40. Innate Immune System

Immune system: innate and adaptive immune response of white blood cells
First defense mechanism consisting of physical and chemical barriers of the surface
Secondary defense mechanism through a process called inflammation
Macrophages fight against microbial infection, are responsible for harmful particles and
bacteria engulf
You ever wondered what your life would be if you could not touch your breast or go play
with your friends. This was the story of David Vetter, the "boy in a bubble". He had no
immune system and died when I was 12 but never left his bubble until the day of his death.
To understand this we must remember that our body not only nourishes but we must also
be protected through a system of active defense. This system uses a mechanism of
regulation and recognition to distinguish between self cells and foreign agents. White cells
of the innate immune system are phagocytes and NK cells
Defense
We have three lines of defense: the first two are associated with the innate system and the
adaptive third. The first line is nonspecific and involves surface defenses are physical
barriers. The second occurs within the fabric and refers to inflammation.
The third line of defense consists of the human flora, consisting of fungi and bacteria that
established a symbiotic relationship with our body.
The skin is the largest organ in vertebrates, form 15% of the total weight in humans and its
primary function is to keep the water inside and outside microbes.
Additional input port of microbes and bacteria is by inhalation into the respiratory tracts,
secreting airway mucus to trap the microbes before they reach the warm, moist areas deep
in the lungs. The cilia of the respiratory mucosa drag these microbes to facilitate its
removal sneezing, coughing or swallowing into the gastrointestinal tract where the
stomach acid kills them.
Lysozyme is abundant in secretions such as tears; saliva and mucus will destroy the
bacterial cell wall polysaccharides and thus provides protection against infection.
Inflammation occurs as a consequence of infection accelerates the death of the microbes,
and changes in the walls of blood vessels that allow local additional molecules to pass from
the blood into the infected tissue, and dilate the capillaries and increase the blood flow.
This is very important because without inflammation the body could not heal wounds and
infections.
Have you ever wondered why we have a fever?
Although it is hard to believe fever is another defense mechanism of the body to treat
infections. Fever helps the body creating a less favorable environment for the growth of
microbes. Fever also stimulates phagocytosis and reduces levels of iron that bacteria need
to grow.What are phagocytes?
They are a type of cells kill microbes by ingestion, this process is called phagocytosis.
One of the most important phagocytes in our body is the macrophage to engulf anything
that looks abnormal including dust and infected cells.

41. Adaptive Immune System

Key elements of successful immune defense are recognition, activation, and response
Immune system organs lymphoid organs are divided into primary and secondary
lymphoid organs
The cell mediated immunity using mediating T cells (activated macrophages)
Humoral immunity works through the natural activation of B cells (antibodies) and
activation by vaccines
This system is more specialized than the innate, has the ability to recognize specific
bacteria. The adaptive system responds quickly after encountering a microbe like
remember previous encounters with microbes (chickenpox suffer through it alone once in
a lifetime).
The adaptive immune system is closely related to the circulatory system, the immune
system cells that circulate blood throughout the body. This movement ensures that the B
and T cells are exposed to foreign antigens. Part lymphocytes 20-40% of the white cells of
the body and its total mass is equivalent to the brain or liver.
The most important processes are the adaptive immune system recognize, activate, and
quickly respond to unknown organisms.
What are the organs of the immune system?
Primary lymphoid organs were bone marrow and thymus where they mature B and T
lymphocytes, and where is the identification of antigens. When these lymphocytes have
matured migration occurs from the primary organs to the blood and secondary organs
(lymph nodes, spleen, etc.). In these secondary organs the lymphocytes keep dividing and
differentiate. The adaptive immune system operates primarily through secondary organs.
Microbes enter the blood stimulates an immune response in the spleen. All immune cells
originally derived from the bone marrow through a process called hematopoiesis. In bone
marrow B cells mature in the thymus and T cells.
Two fundamental adaptive mechanisms:
Cellular immunity refers to surrounding macrophage antigens, and displays the
processed internally of them on its surface. This allows T cell recognition.
Humoral immunity refers to an immature B cell is stimulated and mature when an
antigen binds to the surface of the receptor, a T cell cytokine release to help.T cells are most
important because without them we could not live. In the absence of B
cells, T cells are responsible. When a baby is born without T cells, the first weeks showed
no abnormalities, but later acquired infectious diseases and died in his childhood because B
cells cannot function without the help of T cells.
42. Infectious Diseases
Microbial pathogens are bacteria, viruses, protozoa, and prions
Host-microbe interaction depends on virulence factors and host immunity
Sexually transmitted diseases, HIV / HPV
Treatment and prevention of the disease by vaccination and antibiotic
Have you ever wondered why cold or flu sick when the weather changes? Well, the cause is
usually opportunistic pathogens are microbes that are in contact with the host or the
person is infected. Infectious diseases are diseases caused by the presence of a microbial
pathogen such as a bacterium, fungus, protozoan, virus, multicellular parasites and
modified proteins as prions.
What happens when a pathogen is in contact with the host? The pathogen can enter and

multiply or die if the host has a strong immune system.

Transmission
Infectious diseases can be transmitted by various means such as fluids, body fluids,
contaminated objects and inhalation air. Some examples are: respiratory diseases
transmitted by sneezing or kissing, gastrointestinal disease caused by ingesting
contaminated food and sexual diseases by body fluids.
There are two vectors in the transmission of infectious diseases: biological and mechanical.
- The biological vector if the pathogen is located within it, (eg mosquito) and introduced
into the host.
- The vector is mechanical if only carries the parasite to the host (eg fly).
Virulence Factors
Virulence factors are molecules expressed and secreted by pathogens that help you adhere
to the host, evade the immune response of the same and feed him.
Other things you'll learn in this module are:
- H.Pylori bacteria, which causes gastritis and ulcers and it is considered that half of the
population in the world has.
- Sexually transmitted diseases, the virus HPV (human papilloma virus) disease is the most
common sexually transmitted.
- The prevention of these diseases, the role of antibiotics.
- And the recent emergence of swine flu which quickly became infected and was the cause
of approximately 17,000 deaths.
43. HIV/AIDS
Retrovirus ribonucleic acid using a reverse transcriptase to make a DNA copy of its RNA
genome
Collapse of the immune system caused by infection and death of CD4 T cell help
Examinations Preventions and try to limit the spread of HIV
Blocking of the immune system allows opportunistic infections
HIV / AIDS have become a pandemic as it has spread throughout the world. Between 25 to
30 million people have died of AIDS to date. In fact every day 5,000 people die of AIDS, and
every 7 deaths 1 is a child. This means that 30 children die of AIDS every 30 minutes.
Viruses consist of two basic components:
- The genome (a core of genetic material (DNA or RNA)) and
- Capsid (protein surrounding layer that protects the genome).
HIV is a retrovirus, meaning that it is a virus with an RNA genome using a reverse
transcriptase to make a DNA copy of its RNA genome. This DNA copy of the genome is then
integrated into the host cell DNA.
The HIV virus infects and destroys T-helper cells (CD4 T cells), an important part of the
immune system. This leaves an ineffective immune system in the host (patient HIV +). This
inefficient immune system allows the invasion of bacteria, mold and fungi in the body. The
collapse of the immune system is caused by the infection and death of CD4 helper T cells.
This collapse of the immune system allows opportunistic infections.
Prevention and diagnostic tests try to limit the spread of HIV. To stop the spread of the
virus requires information and changes in cultural practices and social customs, such as
promoting safe sex, use of condoms, not sharing needles, etc.
44. Drug Addiction
Drugs are divided into two categories: the drugs or prescription drugs and nonprescribed

drugs: cocaine, heroin, etc.

Drug classifications according to the chemical structure and physical effects
(hallucinatory, depressive etc.)
Drug addiction caused by overflow of dopamine in the limbic system and changes in the
reward mechanism
Drug abuse / addiction leads diseases (cardiovascular), psychiatric diseases, social
problems (abuse, crimes)
A drug, generally speaking, is any substance (natural or synthetic compounds) that, when
absorbed by a living organism, alters normal function. Drugs have been used for centuries
for medicinal purposes. When people abuse their consumption, become addicted to both
drugs and recreational drugs. Drug abuse is toxic to the body.
Drugs are grouped into two categories: prescription drugs and OTC drugs without
prescription. Drugs may be classified according to their chemical structure, but this classification
does not provide information on its effects. Some drugs of the same class of
chemistry can produce different effects.
Drugs that act on the CNS can be classified into four categories: depressants, narcotics,
stimulants and hallucinogens:
- Depressants: slow the CNS and produces a feeling of relaxation (e.g. barbiturates and
alcohol).
- Narcotics: slowing blocks pain and CNS (eg morphine and heroin)
- Stimulant speeds increase CNS alertness, producing a sense of euphoria (e.g. caffeine and
cocaine).
- Hallucinogens: slows and speeds up the central nervous system and the perception are
altered (e.g. LSD and marijuana)
Drug addictions are caused by overflow of dopamine in the limbic system and alterations in
the reward mechanism. The limbic system is the part of the brain responsible for the ability
to feel pleasure. Neurons or nerve cells form networks to transmit messages back and forth
through the brain, spinal cord and peripheral nervous system. The drug abuse / addiction
causes disease (cardiovascular, psychiatric ...) and social problems (abuse, crimes).
45. Diabetes and obesity
Levels of blood glucose, regulated, catabolic hormones (glucagon) increases levels of
blood glucose and anabolic hormones (insulin) decreases blood glucose
Diabetes is divided into two categories, type 1 diabetes mellitus: no insulin production,
type 2 diabetes mellitus: insulin resistant
Obesity-induced genetic diseases (hypothyroidism), but especially the imbalance of
energy intake and energy expenditure
Diabetes / obesity treatment administered, pharmacologically (stabilizing glucose),
behavioral changes and daily living (eating and exercise), surgery (gastric banding, gastric
bypass, etc.)
Diabetes mellitus (DM) is a disease in which the body does not produce enough insulin or
does not respond properly to insulin, a hormone produced by the pancreas. Insulin enables
cells to absorb glucose for energy. Diabetes mellitus can be described as a broad-spectrum
disease ranging from mild to severe. Meaning of reversible to irreversible. Firstly
differentiate type 1 diabetes, which is insulin dependent and irreversible. Type 2 diabetes
is diabetes mellitus, non-insulin dependent and reversible, affects both obese and nonobese.
Malnutrition can have some sort of connection with the development of diabetes,

although it is very rare. Gastrointestinal diabetes develops in pregnant women and is

reversible from 2 to 7% of cases.
The blood glucose level refers to the amount of glucose in the blood. The liver is
responsible for the metabolism of glucose, glucose stored as glycogen, which is released
slowly into the bloodstream between meals and this process known as gluconeogenesis. Glucose
levels in the blood are regulated by catabolic hormones (glucagon) and anabolic
(insulin). Increasing blood glucose is controlled by insulin which reduces blood glucose
level.
Obesity are in excess body fat and this accumulation of fat can have an adverse effect on
health, leading to a reduction in life expectancy and the increased health problems. Obesity
is induced by genetics, disease (e.g. hypothyroidism), but mostly by the imbalance between
energy intake and energy expenditure. Obesity is the result of the interaction of genetic and
environmental factors. Polymorphisms in various genes controlling appetite and
metabolism predispose to obesity when ingested calories suficientes. Tambin some
diseases and the drugs used for treatment may increase the risk of obesity. Diseases that
increase obesity risk include several rare genetic syndromes and a congenital or acquired,
such as hypothyroidism (low thyroid hormone, leading to reduced metabolic rate).
Diabetes and obesity can be treated pharmacologically (stabilizing glucose), by changes in
daily living habits (diet and exercise), or surgery (gastric banding, gastric bypass, etc.)
46. The Climate System
Climate system is affected by the ocean
Climate system is affected by the atmosphere
Climate system is affected by the biosphere
Climate system is affected by the earth, ice, and snow surface
(Any of these factors that influence the climate will have major effects on plants and
animals)
The climate system has five main components: atmosphere, oceans, land surface, snow and
ice surfaces, and biosphere.
- Atmosphere: is a large and very complex fluid system and it extends far above
topographic barriers and can support large scale circulations. A large number of factors,
including heating and cooling lead to significant temperature variations.
- Oceans: the seas have a large impact on the climate of the atmosphere. It covers
approximately 71 percent of the land surface and therefore has a dominant role in the
energy transfer between the atmosphere and the surface of the earth.
- Land surface: the surface of the earth is an important interactive component of the
climate system since it covers 29% of the surface of the earth. Significant exchanges of heat
and humidity occur between the atmosphere and the earth's surface
- Areas of ice and snow: the cryosphere is the ice component that affects the heat transfer
on the surface of the earth due to the latent energy transfer during melting and freezing.- The
biosphere: the biosphere is a component of the climate system which is composed of
oceans and the land surface . The vegetation on the land as well as plant and animal life in
the oceans are elements of the biosphere and therefore the plants and animal life in the
oceans are important elements of the biosphere.
48. Global Warming
Evaporated water is the most common gas in the atmosphere
Carbon dioxide is produced biologically and industrially

 Methane is produced by the biosphere

Hydrofluorocarbons, perfluorocarbons, sulfur hexafluoride are synthetic (manmade)
greenhouse gases.
There is an increase in global warming which is considered to be induced by
greenhouse gases which hold in the heat from the sun similar to a greenhouse.
Water vapor represents a small but environmentally significant constituent of the
atmosphere.
Carbon dioxide is produced biologically and industrially. The natural production
and absorption of carbon dioxide occurs in the terrestrial biosphere and the oceans but the
natural carbon cycle has been dramatically increased due to the burning of coal, oil,
natural gas, and wood resulting in a large increase of carbon dioxide in the atmosphere.
Methane is produced by the biosphere and is extremely more effective as a
greenhouse gas than carbon dioxide. Methane has both natural and artificial origins. During
the past 50 years, human activities such as rice cultivation, livestock rearing, burning
natural gas, and coal mining have greatly increased the atmospheric concentration of
methane thereby increasing global warming.
Although hydrofluorocarbons and perfluorocarbons are produced in relatively small
quantities, they have a disproportionate impact as a greenhouse gas.
48. Drought
Drought is conditioned by several components: condensation, precipitation, infiltration,
evaporation, transpiration
Climate change affects cultural variations
Carbon dioxide and water affect ocean pH Population supposed demand on water sources
Why so serious drought? Exceeded dust conditions in the 1930s. I'm sure most of you and
your grandparents have no idea what it was the dust bowl and its implication. In short, the
climatic conditions in the 1930s caused a drastic reduction of crops that caused a massive
migration of people from the Midwest to California. Although, experts say weather
conditions currently affecting the southwestern part of the country are not bad when
compared to what is forecast coming.
The drought is due to the dramatic increase in greenhouse gases in the atmosphere, this is
due to the voracious appetite that humanity has for land, food and water, all of which are
playing an important role in global warming. Another reason is that drought is part of a
cycle that alternates induced drought and humidity are the main forces condensation,
precipitation, infiltration, evaporation and transpiration. Besides the influence of humanity
and we are unfortunately in the drying cycle in the wrong place and the wrong time.
In drought influenced by several factors: condensation, precipitation, infiltration,
evaporation, transpiration:
- Condensation conversion steam into liquid water droplets
- Precipitation rain water falls from the atmosphere to land or surface water as rain, snow,
sleet or hail
- Infiltration downward movement of liquid water through the soil
- Evaporation: conversion of liquid water into gas, or steam
- Transpiration: water circulation liquid from plant roots, upwards in the vessels, and in the
atmosphere of the leaves as water vapor.
Climate change affects everyone in general. Carbon dioxide and water alter the pH of the
ocean. This chemical behavior explains why the water, which typically has a natural pH of 7

changes to an acidic pH of about 5.5 when it is exposed to air. If the level of carbon dioxide
increases, the consequence is that the pH change and influence life in the sea. A component
that affects water sources on our planet as well as chemical and cultural influence is the
demand of the population on the sources of water on our planet earth.