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February 29th, 2016

Class 31 Learning Goals

Why We Get Sick: Immune Interactions

•  After this class, you should be able to:

–  Describe multiple pathways for human disease that involve the
immune system
–  Predict the general health outcome for a patient depending on
the binding targets of antibody-derived receptors
–  Predict the development of allergies and be able to describe a
model for allergic development in young humans
–  Choose and defend the better of two possible vaccination
How are memory B- and T-cells formed? Peer Instruction
Why are these memory cells useful?

Initial exposure to antigen Second exposure to antigen


is larger

Primary immune
A few cells
survive longer…

is faster
Peer Instruction
What if the 1st exposure to a virus is fatal?

Smallpox, caused by the variola virus, is an

example of a rapidly lethal disease.

10th century Chinese doctors took cotton plugs from the noses of
patients with mild smallpox infections. These were briefly inserted
into the noses of healthy people. Why?

In 1798, an English doctor observed that milkmaids rarely contracted

smallpox. They contracted the less dangerous but related cowpox.
How was this observation used to develop vaccination?
Peer Instruction
Usually, antibodies and immune cell
receptors bind only to non-self epitopes.

What would happen if a B-cell and T-cell

were created that bound to a common
epitope on the surface of a cell type in
arm and leg joints?

Would you expect to see this condition develop in old or

young patients more often? (hint: How often are B- and T-cells made?

Overall, would you expect to see evidence that the immune

system is overworking or underworking?
•  First produced
•  Heavy in antibodies
•  Absorbed through the
porous infant stomach
Analyze this disease-causing situation.

Has molecule
molecule D
D in blood
in blood

molecule D
in blood
What causes Rhesus Disease
(potentially fatal for infants)?
Peer Instruction

75-80% of all
antibodies in body Most common and
consistently abundant.

Not well understood.

Why is the Creates hypersensitivity

IgM:IgG ratio and allergies.
Most common in
breastmilk and for
creating immunity in
Made first to battle new
Peer Instruction
1) Explain how IgEs combine the innate
and adaptive immune responses.

This response is extremely

sensitive, and is needed to
defend against parasitic worms
which can otherwise hide from
the immune system.

2) How do IgEs cause allergies?

Peer Instruction
Prevalence of human-parasitic
worms in a country

1) What do these data say? Prevalence of


2) Hypothesize an explanation for this correlation.

Peer Instruction

So what?
Concept Questions
•  Virus survivors were often employed in earlier history to act as caregivers for the
sick. How were the bodies and cells of survivors different from their patients?
•  Byzantine doctors placed small pieces of scabs from small pox survivors under
the skin of young children. Why? What were the risks and benefits of this
•  What IgM:IgG ratio would you expect from:
•  A human with many commensal bacteria?
•  A human under attack by a new Martian virus?
•  A human under attack by common E. coli?
•  Which autoimmune disorder would be more likely to directly destroy the human
•  An autoimmune disorder where B cells were targeted at muscle cells
•  An autoimmune disorder where killer T cells bound to surface receptors on
dendritic cells
•  Would a molecule that implanted more ATP into T-cells be a good antibiotic?
What about a molecule that produced random epitopes that bound on the
outside of bacterial cells?
Flu vaccine production timeline Peer Instruction

Given this information:

When were flu viruses chosen to design the vaccine for
Winter 2016?

Assume that vaccine distribution requires 3-4 months of

processing. If a new pandemic flu emerged today, when could
the World Health Organization respond with new vaccine?
A new strategy for finding antibiotics?
Common strategy:

Try many, many molecules

See if they poison bacteria


A new hope?
House many, Isolate
“Isolation Chip” many microorganisms molecules
See if they prevent bacterial growth

Teixobactin (2015)
March 1st, 2016 Class 32 Learning Goals

Why We Get Sick: Human Diversity and Aging

•  After this class, you should be able to:
–  Describe human genetic diversity in terms of likely mutation
differences between individuals, localized groups, and races
–  Use a polymorphic locus or a microbiome tree to correctly judge
the identity of a human
–  Explain multiple models for parts of the overall progress of
aging, including:
•  Buildup of DNA
•  Telomere degradation
•  Radical oxidation
–  Assess the potential success of a proposal for prevention of
aging-related symptoms or for extending the human life span
Peer Instruction
The interleukin-2 protein-coding gene is 824 basepairs long, and is
relatively conserved between humans and mice (even though they
diverged ~80-100mya).
Draw a tree to describe DNA homology between a fly, a mouse, a
chimpanzee, you, your future child, and a random other person.

Human coding DNA is ~85% alignable with mouse DNA and 96%
alignable with the DNA of chimpanzees.
How many interleukin DNA differences would you expect:
Between humans and mice?
Between humans and chimps?
If two humans are 99.999% similar by DNA, do you expect to see any
differences in the DNA of the interleukin-2 gene?

The human genome contains 3.1 billion base pairs.

How many total DNA differences are likely between any two people?
Peer Instruction
Explain this data. •  Same as reference DNA
Are humans genetically identical? •  Common difference
•  Rare difference
A small chunk of a single human chromosome.

Two genes A single “race”

A name of a locus

Sequences from 1,092 individuals

The 1000 Genomes Project Consortium Nature 491, 56-65 (2012) doi:10.1038/nature11632
Peer Instruction

mtDNA map of an
indigenous population

Map of human migration based on mtDNA

1) What can mtDNA tell us about human history?

2) Use these #s of polymorphic repeats to determine the guilty suspect.

DNA Region Crime Scene DNA Suspect 1 Suspect 2 Suspect 3 Suspect 4
Polymorphic locus 1 16 repeats 10 17 21 15

Polymorphic locus 2 33 8 33 19 91

Polymorphic locus 3 4 4 3 8 4
Peer Instruction
What is senescence?

Why do we age?

Thinking cynically: For people that can understand and assist

with aging, is the market increasing or decreasing?
Peer Instruction

Some cells absolutely need

Missing DNA on to keep all of the DNA intact.
lagging strand
Which cells?

How does telomerase help?

Telomerase with its

own RNA template

DNA polymerase

RNA primer

If you are interested:

Stress! Phospholipids!
Concept Questions

–  Draw a phylogenetic tree of the following alleles:

•  The ATP synthase gene in you, your parent, and an unrelated friend, and
a person from the other side of the planet to where you were raised
•  The homologous gene in a gorilla, a cat and a fish
•  The homologous gene in yeast and archaea
•  Estimate the % difference between each node
•  What is the likelihood (in your opinion) that each version of this gene
would work in each other species?
–  Write a 4-sentence explanation to a jury detailing:
•  How microbiome evidence is gathered and used to identify a person
•  How polymorphic loci evidence is gathered and used to identify a person
–  Explain why each of these drugs would not prevent aging:
•  A pill of telomerase
•  An injection of telomerase into the bloodstream
•  A protein that makes DNA un-bindable by any protein to protect it
•  A molecule that absorbs all free radical energy
•  A virus that inserts new, fresh mitochondria into every cell in your body
March 2nd, 2016 Class 33 Learning Goals

Why We Get Sick: Evolution

•  After this class, you should be able to:

–  Interpret disease-causing mutations in terms of selective
advantage and evolution

–  Discuss the time scale and likelihood for eradication of

evolved diseases

–  Categorize biologically relevant substances as ‘poisons’ or

‘safe’ at historical and present concentration
Babies in the US are screened for a deficiency Case Study
in glucose-6-phosphate dehydrogenase (G6PD). G6PD catalyzes an
important side reaction of early glycolysis in all cells.


If a G6PD-deficient patient eats the wrong

foods (like fava beans) then red blood cells
build up too much Glucose-6-phosphate.
Normal RBC G6PD-


Loss of red blood cells leads to weakness, anemia, heart

problems, and is fatal in 8% of children without treatment.
Peer Instruction

Cases of malaria Cases of G6PD deficiency

What narrative might explain this data?

The world is getting warmer:

What effect might this have on G6PD deficiency and malaria?
March 3rd, 2016 Class 34 Learning Goals

Why We Get Sick: Cancer

•  After this class, you should be able to:

–  Explain the recent rise in cancer in human populations

–  Assess a set of related mutations within a single cell

lineage and predict whether or not the organism is at risk
for cancer

–  Predict the likely effects on cancerous phenotypes based

on changes in human populations
A gene that pushes the cell cycle forward: Proto-oncogene

A mutation that pushes the cell cycle forward TOO MUCH: Oncogene

A gene that stops or slows the cell cycle: Tumor suppressor

A mutation that FAILS to stop or slow the cell cycle: Oncogene

Peer Instruction

Describe graphs of the following trends:

1) Frequency of violent deaths
2) Death by bacterial infection
3) Death by infectious disease
4) Amount of mutation-causing pollution

5) Average lifespan of humans

1650 1700 1750 1800 1850 1900 1950 2000

A very common
cancer mutation: p53
A problem of multi-cellularity: Cancer

•  Cancer-causing Cells Acquire:

–  Tissue-level characteristics:
•  Rapid mitosis and growth
•  Recruitment of blood vessels
•  Movement to other tissues (metastasis)
–  Cellular characteristics:
•  Lack of cell cycle controllers (tumor suppressor)
•  Telomerase activity
•  Increased cell cycle progression (oncogene)
•  Lack of a protective ‘off switch’ (apoptosis)

Cancerous level of mutations

# of Mutations

Normal progression
Age 10 20 30 40 50 60 70 80
A problem of multi-cellularity: Cancer

Cancerous level of mutations

# of Mutations

Normal progression

Age 10 20 30 40 50 60 70 80
Concept Questions

•  Is a reactive oxygen species a carcinogen? Is a mosquito? A radioactive

metal? A cigarette?
•  Would you expect to see more cancer in a population at war or at peace?
•  Would you expect to see more cancer in a population with better or worse
medicinal science? (This answer might be complicated…)

•  A cell can crawl, skip the G1 checkpoint, and recruit blood vessels. It is likely
to cause a cancer?
•  A cell cannot crawl but can completely pass through the cell cycle each hour.
Would this cell eventually cause damage to a multicellular organism?

•  What would happen to the rate of cancer if:

•  All p53 proteins were removed from an entire species?
•  All cells in an organism were able to turn on the promoter of the
telomerase gene?
•  A virus was bioengineered that could infect every cell and:
•  Insert randomly into the genome?
•  Insert copious nutrients into the cell?
•  Disable checkpoint-passing proteins?
•  The earth moved slightly closer to the sun?