The outreach quarterly connecting science with society

ISSN 2517-701X
ISSUE 106

FEATURING RESEARCH FROM:

Brown University and the National Marine Mammal Foundation; Sugar Research Australia; Technical University of Crete;
New Mexico Tech; Tokyo University of Marine Science and Technology; Research Origin for Dressed Photon; Collini Holding AG;
Yokohama National University; University of Indianapolis; Hungarian Academy of Science; Swiss Federal Institute of Technology;
Virginia Commonwealth University; University of Oklahoma; Geneva Institute of Landscape, Engineering and Architecture;
Tel Aviv University; International University Centre in Arezzo; Konkuk University; Radboud University Medical Centre; Sheffield
Hallam University; University of Liverpool; University of Utah School of Medicine, IBM Watson Health & NovartisResearch
Pharmaceuticals
Features 3
Corporation; Yale University School of Medicine; NOVA University of Lisbon; University of Denver; Case Western Reserve
University; Hungarian Academy of Sciences; National Institutes of Health; Amsterdam UMC, location VUmc; Western University
500 Women Scientists

RESEARCH OUTREACH ISSUE 106

WELCOME
The outreach quarterly connecting science with society

Serving society by making science

ISSN 2517-701X
ISSUE 106

open, inclusive, and accessible. TO ISSUE 106

The fields of science research are varied and diverse and FEATURING RESEARCH FROM:
Brown University and the National Marine Mammal Foundation; Sugar Research Australia; Technical University of Crete;
New Mexico Tech; Tokyo University of Marine Science and Technology; Research Origin for Dressed Photon; Collini Holding AG;

becoming increasingly global and collaborative. In this issue

Yokohama National University; University of Indianapolis; Hungarian Academy of Science; Swiss Federal Institute of Technology;
Virginia Commonwealth University; University of Oklahoma; Geneva Institute of Landscape, Engineering and Architecture;

ISSN 2517-701X
Tel Aviv University; International University Centre in Arezzo; Konkuk University; Radboud University Medical Centre; Sheffield
Hallam University; University of Liverpool; University of Utah School of Medicine, IBM Watson Health & Novartis Pharmaceuticals
Research Features 3
Corporation; Yale University School of Medicine; NOVA University of Lisbon; University of Denver; Case Western Reserve
University; Hungarian Academy of Sciences; National Institutes of Health; Amsterdam UMC, location VUmc; Western University

of Research Outreach, we feature researchers from across

the globe including Europe, the US, Australia and Japan. We
also speak to some of the people at the forefront of ensuring
THIS ISSUE
that the face of research truly reflects the society it serves.
Published by: Research Outreach

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and CEO Tara Chklovski, discussing how Iridescent’s goals James Harwood
james@researchoutreach.org
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www.researchoutreach.org 3
CONTENTS
6 READING BETWEEN
THE CLICKS: A NEW
APPROACH TO
ECHOLOCATION
Dr Alyssa Accomando
Understanding the precise
sound patterns produced
by bats and dolphins.
10 A RESEARCH MODEL
FOR CARBON-PARTITIONING
IN SUGARCANE
Dr Frederik (Frikkie) Botha
Examining Yellow Canopy
Syndrome in sugarcane to
better understand its impact
on plant health.
14 STRIPPING PAINTINGS
OF THEIR SECRETS WITH
HYPERSPECTRAL IMAGING
Professor Costas Balas
Using and developing
hyperspectral imaging
technology in art conservation.
18 THE POWER OF
LIGHT: PRODUCTION
OF SOLAR FUELS
Professor Michael D. Heagy
Work on novel nanostructures
aiming to improve the efficiency
of solar fuel production.
22 FORECASTING TSUNAMIS
USING SHIP NAVIGATION
RECORDS
Dr Daisuke Inazu
Developing effective
ways of monitoring
and forecasting tsunamis.
26 THE DRESSED PHOTON:
SHINING LIGHT ON THE
UNKNOWN USING THE
UNCONVENTIONAL AREA
OF OFF-SHELL SCIENCE
Professor Motoichi Ohtsu
Using the Dressed Photon
in a new method to create
silicon-based light emitting
diodes and lasers.
For 12 years, we have been
introducing children worldwide
to [...] new scientific advances.
TARA CHKLOVSKI, CEO OF IRIDESCENT
Page 126
4 www.researchoutreach.org
30 SETTING NEW HORIZONS
IN ELECTROPLATING
OF ZINC DIE CASTINGS
Valeriia Reveko
Investigating how to make zinc
alloys more sustainable.
34 EVALUATING STUDENTS’
PERCEPTIONS OF THE
ROLES OF MATHEMATICS
IN SOCIETY
Professor Toshikazu Ikeda
Developing an analytical tool
to evaluate the changes in
students’ perceptions of the
roles of mathematics in society.
38 FRANÇOIS VIÈTE’S
REVOLUTION IN ALGEBRA
Professor Jeffrey Oaks
Discovering the innovations
of François Viète that underpin
modern algebra.
42 GENERALISING THE
ENTROPY FORMULA
THROUGH MASTER
EQUATIONS
Dr Tamás Biró
Using statistics to study
problems as diverse as the
formation of hadrons, changes
in biodiversity, and patterns
in popularity on Facebook.
46 NMR : A HIGHLY ACCURATE
2
APPROACH TO PROTEIN-
LIGAND BINDING
Dr Julien Orts
Developing multidisciplinary
approaches to study protein-
small molecule complexes
using NMR spectroscopy,
X-ray crystallography and
computational methods.
50 LASER ABLATION
IN LIQUID: A POWERFUL
ROUTE TO NEW
NANOPARTICLE CATALYSTS
Dr Katharine Tibbetts
Dveloping a novel approach
for the synthesis of metal
nanoparticles, based
on a reactive laser ablation
in liquid technique.
54 ASSESSING PERFORMANCES
OF COMPUTER-AIDED
DIAGNOSIS OF BREAST
CANCER
Professor Bin Zheng
Harnessing the power
of Computer-Aided
58
Diagnosis technology.
DEVELOPING THE
GENEVA SOLAR CADASTER:
A DECISION SUPPORT
TOOL FOR SUSTAINABLE
ENERGY MANAGEMENT
IN URBAN AREAS
Professor Gilles Desthieux
Developing a tool for modelling
solar radiation and energy
production from building
rooftops and facades.
62 ENGINEERING THE FUTURE
Dr Margaret Bailey
How the WE@RIT programme
is encouraging more women
into the Engineering sector.
66 GENDER INEQUALITY:
OCCUPATIONAL
DEVALUATION
AND PAY GAPS
Professor Hadas Mandel
Addressing the analytical
and methodological distinctions
between structural and
individual aspects of gender
inequality.
70 THE DAWN OF MEMORY
MODULATION AND SELF-
PRESCRIBED FORGETTING –
A MORAL DILEMMA
Dr Andrea Lavazza
Examining the ethics
around memory modulation
and erasing.
74 EXTRACELLULAR VESICLE
DNA: A PROMISING CANCER
BIOMARKER
Professors Kye Young Lee
and Jae Young Hur
Studying and developing cancer
detection methods using liquid
biopsy with extracellular vesicles.
78 VALUES AND EVIDENCE
MEET: APPROPRIATE
HEALTHCARE ASSESSMENT
FOR VULNERABLE PATIENTS
Gert Jan van der Wilt
Exploring the ethical and social
implications of health care
technologies.
82 COUNTING THE COSTS OF
ANKYLOSING SPONDYLITIS
Dr Jessica Walsh, Dr Xue
Song, Dr Gilwan Kim
and Dr Yujin Park
Unveiling the direct costs
of healthcare for patients with
ankylosing spondylitis.
86 HOW DATA IS IMPROVING
DRIVING POLICIES
FOR EPILEPSY PATIENTS
Dr Laura Bonnett
Using prediction modelling
to inform driving regulations
for people with seizures
and epilepsy.
90 NEW INNOVATIONS IN
TRAUMATIC BRAIN INJURY
RESEARCH
Dr Lynne Ann Barker
Focusing on the effects of
brain injury on neural structures
and cognition and behaviour.
94 MACBRAINRESOURCE:
VIRTUAL ACCESS
TO DECADES-OLD
PRIMATE BRAINS
Drs Lynn Selemon
and Alvaro Duque
MacBrainResource is an online
repository of macaque brain
material available for the use
of researchers.
98 THE CAROTID BODY
Professor Silvia Conde
Examining the carotid body as a
candidate for regaining glucose
tolerance in Type 2 diabetes.
102 A POTENTIAL
NEW TREATMENT
FOR BRAIN INJURY
Dr Daniel Linseman
Exploring a prospective
nutritional supplement,
Immunocal®, for enhancing
RESEARCH AREAS
Biology Physical
Sciences
126
resilience and improving 122 EVOLUTIONARY ARMS RACE
recovery following traumatic A 400 MILLION-YEAR-OLD
brain injury. BATTLE BETWEEN HIV AND
ANCIENT GENES, HERC5
106 PLANT PHYTOCHEMICALS AND HERC6
Dr Sanjay Gupta Dr Stephen Barr
Identifying and developing Illuminating the evolution of the
cost-effective, minimally toxic HIV virus and the family of HERC
bioactive agents as cancer genes that inhibit HIV.
preventative agents for long-
term use and as adjuvants 126 IRIDESCENT: DISRUPTING
in various therapies with a focus THE CLASSROOM FOR THE
on epigenetic research. BETTER
Revolutionising education by
110 ADIPOSE STEM CELLS providing programmes that
MAY PROMOTE CANCER empower underserved children
PROGRESSION through technology and
Dr Robert Katona engineering.
Using a mouse adipose stem
cell model system to study 130 ACCIDENTAL SCIENCE!
cancer and cancer stem cell
development.
114 THE BIOLOGY OF AGEING
Dr Nan-ping Weng
Understanding the mechanism
of age-related changes
in immune function.
118 DREAM TEAM: IMPROVING
HEARTS AND BONES WITH
VITAMINS D AND K
Dr Hanne van Ballegooijen
14
Dr Hanne van Ballegooijen
has been working on vitamin D
for almost 10 years. Her work
suggests that vitamin D status
alone is not strongly related
to cardiovascular disease
and that combining vitamin D
with vitamin K might improve
its efficacy.
34
Enginering & Behavioural Health &
Technology Sciences Medicine
www.researchoutreach.org 5
Biology ︱ Dr Alyssa Accomando
Reading between
the clicks:
A new approach to echolocation
Biologists are increasingly
appreciating the importance of
bioacoustics in conservation. By
understanding the soundscape
of an environment we can
learn far more than previously
thought. This is also the case
for animal behaviour, a classic
example being echolocation in
bats and dolphins. Dr Alyssa
Accomando, from Brown
University and the National
Marine Mammal Foundation,
is studying echolocation to
determine how these animals
navigate the environment
around them and what we can
learn from this process.
6 www.researchoutreach.org
E
cholocation is one of nature’s
great superpowers. It is a type
of sonar, where sound is projected
by an animal and travels through the
environment interacting with objects on
the way. The sound is reflected by these
objects, producing echoes. Echoes from
these objects heard by the animal provide
information on each object’s size, distance,
and shape. Although we commonly
associate echolocation with bats and
dolphins, it’s also used by orcas, sperm
whales, and even some humans. There
are also studies of echolocation jamming
from tiger moths, who disrupt the sonar
emitted by bats to avoid detection.
But why is all of this important? First,
it is important to the animal because
it is how they navigate their environment
and find food. Unravelling the code
of echolocation will allow us to better
understand the behaviour of animals
such as the bat, and any differences
Bats like big brown bats, Eptesicus
fuscus, use echolocation to
navigate and locate food.
in echolocation techniques that
exist between species. This can help
conservationists improve environmental
design in areas such as reserves or zoos,
or to improve location choice for any
species reintroduction programmes.
It also helps zoologists understand
a species’ dietary preferences,
communication, and predator avoidance
and prey capture.
Secondly, we can use the principles
of echolocation in our everyday lives and
technological advancement. For example,
some fishing boats use sonar to locate
shoals of fish and the same technology
can be used to help people who are blind
to ‘see’. In fact, drones themselves are
used in conservation efforts, for example
searching for dolphin populations,
or studying rainforest canopy cover, so
the improvements to this technology that
come from nature positively feed back into
helping nature itself – quite fitting really.
BAT ECHOLOCATION
By using ultrasonic microphones,
scientists can record and analyse
bat echolocation sounds. Dr Alyssa
Accomando from Brown University
and the National Marine Mammal
Foundation is doing just this. She is
looking statistically at the relatedness
of patterns of bat echolocation pulses
in a way people haven’t tried before.
Dr Accomando had to first understand
how bats echolocate while performing
different behaviours. The normal way
to measure echolocation patterns is to
look at the time between pulses, or the
IPI (Inter-Pulse Interval). Differences in IPIs
can then be used to group echolocation
The frequency of bats’ sonar pulses
changes as they home in on their prey.
signals into different functions. For
example, when hunting, the bat emits
increasingly frequent pulses (shorter IPIs)
to home in on prey, and then a rapid
burst just before the catch. The same
behaviour is shown in dolphins. However,
these patterns can change when the
We are now coming to terms with the
fact that sounds in nature hold a huge
amount of information and can be
valuable indicators of ecosystem health,
change, and mechanism.
surrounding environment is cluttered
and contains many obstacles.
In these very “busy” environments,
bats emit ‘doublets’, or two echolocation
pulses, one just after the other. Each
pulse produces echoes that reflect back
to the bat from near and far objects.
But this produces a challenge because
it can be difficult to interpret which sound
is the first echo from the second pulse,
and which is the second echo from the
first pulse. This is also a common problem
in many technological sonar applications.
A CORRIDOR OF CHAINS
To understand how bats solve this
problem, Dr Accomando set up an
experiment. This involved a corridor lined
with chains hanging from the ceiling
and acting as obstacles. The bats would
fly through the corridor, and she designed
three corridors of decreasing width to
provide different degrees of challenge.
The species she used were big brown
bats, Eptesicus fuscus. Bats not only
produce doublets of echolocation signals,
but can also produce (less frequently)
singles, triplets and quadruplets. The first
task for Dr Accomando was to deduce
which pulses belonged to what group
and how many were produced under
the different corridor conditions. Bats
in the narrower corridors emitted fewer
doublets, and more singlets, triplets
and quadruplets relative to that observed
in uncluttered environments. Also,
the IPI decreased with corridor width, for
a more rapid stream of sound, suggesting
that it’s valuable for a bat to receive more
echoes, even if it means deciphering
Sonar uses the same concept as bats – by emitting pulses and then analysing the reflected echoes,
the location, distance and size of an object can be detected.
Still photographs taken from infrared video of
bats flying in the obstacle array. Obstacles were
plastic chains hanging from the ceiling of the
flight room.
the ambiguous source of echoes that
comes with a faster echolocation signal
production rate.
However, it could also be the case
that the alternation of IPIs might have
something to do with how the bats
ignore these echoes. The fact that
the IPI structure changed from primarily
doublets, to a greater mixture of pulse
groups suggests that by changing
the number of pulses per group, the
bats were able to more easily identify
the source of echoes – exactly how this
is done remains a mystery for now.
REMEMBERING PATHWAYS
Using something called a Spike Train
SIMilarity Space (SSIMS) analysis, Dr
Accomando spatially mapped the
different pulse patterns and compared
their similarity. SSIMS is a mathematical
www.researchoutreach.org 7

Dolphins also use echolocation to locate and catch prey.
Inset: the Tiger Moth disrupts bats’ sonar to avoid detection.
method used to analyse neural pulses
but can also be applied to echolocation.
It works by comparing two patterns
of pulses and attributing a ‘cost’ every
time a pulse has to be moved, inserted
or removed, in order to make the two
patterns identical.
Firstly, she changed the shape of the
corridors to see how adding a level of
difficulty (straight, S path, and reverse-S
path) would affect the bats’ echolocation
pulse patterns. Secondly, bats were tested
multiple times when the corridor shape
was consistent across trials, or when it
was randomly changed. This was done
to investigate whether bats remembered
their environment from trial to trial.
Interestingly, the bats hardly changed
their echolocation patterns in the curved
paths, whether random or fixed. However,
… [bats] can treat a space differently
when it is new compared to when
it is a path that was recently seen.
when the straight path was changed, the
bats’ echolocation pattern was different
compared to when the straight path was
maintained, suggesting they can treat a
space differently when it is new compared
to when it is a path that was recently seen.
Further study will involve testing
different species of bat. This will answer
the question of whether alternative
behaviours have evolved in different
species to deal with obstacles, and how
these species’ techniques might relate
to their specific environment.
8 www.researchoutreach.org
TAKING THINGS UNDERWATER
Dr Accomando also wants to apply
this knowledge under the water to
bottlenose dolphins (Tursiops truncatus).
Rather than obstacle avoidance, which
is not really an issue for dolphins in
the ocean, she wants to see whether
the click patterns in dolphins can
predict prey-catching behaviour. Little
is known about how the changing
ocean environment impacts the ability
of dolphins to catch fish. Dolphins,
much like bats, emit a ‘terminal buzz’
just before capturing prey. A more
rapid burst of clicks called a ‘burst-
pulse’ is emitted just after prey capture,
but it has been recorded that some
dolphins emit this early, pre-empting
a successful capture.
The echolocation sounds produced by
dolphins are commonly called “clicks.”
Using the same SSIMS analysis as with
the bats, Dr Accomando can compare
the ICIs (Inter Click Intervals) in the series
of clicks produced by each dolphin,
called the click train, and be able to
spatially separate different pre-, and
post-prey-capture echolocation patterns.
The experiment would involve using
a GoPro to confirm normal fish captures,
and ultrasonic hydrophones (underwater
microphones) to listen to echolocation
clicks. Dolphins would be trained and
rewarded for retrieving a target placed
in the water by an animal trainer. On
occasion, the target would be randomly
removed just before capture. The goal
of the study is to determine whether
dolphins produce different sound
patterns if the prey escapes compared
to if the prey is captured.
Burst-pulses are communication sounds
produced by dolphins, and SSIMS
analysis might also be able to help
quantify sounds that are not used for
echolocation but which are similar in
the way they are produced. For example,
new research suggests that burst pulses
have timing patterns that might be used
to identify individual narwhals in the wild
(Blackwell, et al., 2018).
Understanding echolocation behaviour
is an important step towards completing
a fuller picture of environmental
bioacoustics. Previous ecological and
zoological studies, which are primarily
terrestrial, have heavily focused on the
use of vision and olfaction in an animal’s
interaction with their environment.
There has been relatively little emphasis
on bioacoustics. We are now coming
to terms with the fact that sounds
in nature contain a huge amount
of information relevant to animals and
can be valuable indicators of ecosystem
health, change, and mechanism. The
work from ecologists and behavioural
neuroscientists such as Dr Alyssa
Accomando will not only help us better
understand how animals use sound
to obtain information about and interact
with their environment, but will also help
improve sonar technology and facilitate
wildlife conservation based on bio-
acoustic information.
Behind the Research
Dr Alyssa Accomando
E: alyssa.accomando@nmmf.org T: +1 877-360-5527 W: www.linkedin.com/in/alyssa-
accomando-phd-aa431146 W: www.nmmf.org/
Research Objectives References
Accomando AW, Vargas-Irwin CE, and Simmons JA (2018).
Dr Accomando specialises in understanding the precise
sound patterns produced by bats and dolphins. Neural spike train similarity algorithm detects effects of
obstacle proximity and experience on temporal patterning
of bat biosonar. Frontiers in Behavioral Neuroscience,
Detail https://doi.org/10.3389/fnbeh.2018.00013
2240 Shelter Island Dr., Ste 200 Wheeler AR, Fulton KA, Gaudette JE, Simmons RA,
San Diego Matsuo I and Simmons JA (2016) Echolocating Big
CA 92106 Brown Bats, Eptesicus fuscus, Modulate Pulse Intervals to
USA Overcome Range Ambiguity in Cluttered Surroundings.
Frontiers in Behavioral Neuroscience 10:125. doi: 10.3389/
Bio fnbeh.2016.00125
Alyssa Accomando is a research scientist at the National
Marine Mammal Foundation, where she conducts Blackwell, S.B. et al (2018). Burst-pulses in East Greenland
neuroscientific research with bottlenose dolphins. narwhals: Further evidence for unique, individual-specific
She earned her PhD studying big brown bat biosonar vocalizations. Paper presented to the 176th Meeting of
at Brown University. Her research aims to understand the Acoustical Society of America, Victoria, BC, Canada,
how dolphins and bats process acoustic signals resulting November 9th, 2018.)
from echolocation.
Funding
• Office of Naval Research (N00014-14-1-05880, awarded
Personal Response
to James A. Simmons)
• NINDS-Javits (NS025074, awarded to John Donoghue) Why do you think the bats’ echolocation pattern
differed on variable straight paths rather than
• Katie Samson Foundation grant (awarded to John
the curved paths?
Donoghue)
I think that, since they had the most experience
Collaborators
• Carlos E. Vargas-Irwin (coauthor)
flying the straight path, combined with fewer physical
demands like turning in a narrow space, this was the
• James A. Simmons (coauthor) least difficult for them to navigate. However, when the
bats flew down a straight path after having just flown in
• Ikuo Matsuo (collaborator)
more difficult curved paths only a minute beforehand,
that element of uncertainty about what they would
face when released into the flight room led them to
treat the relatively easier straight path more similarly
to the curved paths. This makes sense because bats
could collide with obstacles and emitting more sound
groups gives them more information to avoid that.
www.researchoutreach.org 9
Biology ︱ Dr Frederik (Frikkie) Botha
A research model for
carbon-partitioning
in sugarcane
Yellow Canopy Syndrome (YCS),
first observed in 2012, is an
undiagnosed condition affecting
Australian sugarcane. It causes
mid-canopy leaves to turn yellow,
decreasing crop sugar yields. Dr
Frederik Botha oversees YCS
research for Sugar Research
Australia (SRA). Focused on
gene expression and protein
and metabolite levels, this
research seeks molecular targets
to improve genetic tolerance
to YCS and enhance sugarcane
productivity in general. In
particular, a model of how
sucrose build-up regulates leaf
metabolism through feedback
control has been developed.
Understanding what elevates
leaf sucrose levels as YCS
develops could provide insights
into mechanisms underpinning
sugarcane diseases and
physiological disorders.
C
ommercial sugarcane (a hybrid
of Saccharum officinarum and S.
spontaneum) produces a higher
biomass yield than the other major world
crops, rice, wheat and maize. However,
sugarcane yields worldwide have not
improved significantly over the past three
decades. Good crop yields depend on
ensuring that, at each stage of plant
growth, the supply of assimilates from
the ‘source’ (leaves) to the ‘sink’ (growing
or filling tissues) is optimal. Although
sugarcane is one of the most efficient
crops in converting solar energy into
biomass, commercial yields remain half
that of experimental potential.
There are several reasons for inefficient
conversion of solar energy into biomass.
Of particular interest in sugarcane are
reduced photosynthetic rates in the leaves
and slowed biomass gain in the culms
due to feedback control of the plant’s
metabolism by high levels of sucrose and
other sugars in the leaves. It is difficult to
experimentally manipulate sugar levels
without changing light input or damaging
leaf and culm tissues. Since in YCS leaf
sucrose exceeds normal physiological
levels, discovering what causes this could
give clues to improving productivity.
Sugarcane turns yellow for various reasons
that can now be distinguished from
YCS, including herbicide application,
nutrition and known diseases. Indications
are that the syndrome is a combination
of abiotic and biotic factors leading
to a physiological disorder. Dr Botha
and colleagues have found that YCS
is especially associated with altered
carbon-partitioning in the leaf. Disruption
of the sink–source relationship causes
sugars to accumulate in leaves, and when
sugar exceeds a critical level it induces
senescence. High levels of sucrose
in sugarcane leaves are therefore an
indicator of compromised crop health.
THE SOURCE–SINK SYSTEM
How well a plant grows depends on
acquiring raw material (carbon fixation
and mineral uptake), distributing this
through plant organs and coping with
environmental stresses. The process
known as carbon-partitioning is critical
for distributing the energy captured by
plants through photosynthesis. In C4
plants like sugarcane, CO2 is converted
into four-carbon sugar compounds. These
then enter into chemical reactions that
take place in chloroplasts, the plant cell
organelles conducting photosynthesis.
Carbon fixed during photosynthesis and
converted into sugar in ‘source’ cells
is distributed to ‘sink’ cells. Phloem is
the tissue that transports the soluble
organic compounds (mainly sucrose),
made during photosynthesis and known
as photosynthates, to wherever they
are needed in the plant. The sugars
are imported into sink tissues for
consumption (providing energy for plant
functions) or storage. Some stored sugars
provide structural biomass as cellulose,
hemicelluloses and lignin.
Sucrose synthesis in source tissue, its
translocation and its partitioning between
storage, respiration and biosynthesis are
A field of sugarcane affected by yellow
canopy syndrome.
systemically coordinated in plants. Not
only is sucrose the primary product of
photosynthesis and the building block for
biomass accumulation but it also serves
as a sensitive metabolic switch controlling
photosynthesis and carbon-partitioning
in the plant. A model for the biochemical
process of carbon-partitioning in
sugarcane is being developed through
research on YCS.
Sugarcane has a unique source–sink
system. Stem-sinks store photosynthates
as soluble sucrose, which can reach
exceptionally high concentrations in
commercial sugarcane varieties. Most
other plant stems store carbon as
insoluble polysaccharides (such as starch
or cellulose) with low concentrations of
sucrose. In many
plants, sucrose
is stored (after
Sucrose serves as a sensitive metabolic
conversion to switch controlling photosynthesis and
carbon-partitioning in sugarcane.
insoluble starch) in
terminal sink organs
such as tubers,
grains or fruits, rather than in the stem.
Valuable sucrose from sugarcane culms is
extracted and purified for use in the food
industry or fermented to produce ethanol.
During development, sucrose synthesised
in sugarcane leaves is translocated via
phloem to internodes (the stem sections
that run between leaf-carrying nodes),
the storage sink. Sucrose accumulates
inside and outside the cell membranes,
in the symplast and apoplast respectively.
Immature sugarcane tissues partition
carbon into protein and fibre, whereas
mature culms mainly partition it to sucrose
storage. During maturation of commercial
sugarcane cultivars, leaf photosynthetic
activity decreases, as culm sucrose
content increases. Thus, sink regulation
of source capacity is taking place.
SUCROSE ACCUMULATION
IN SUGARCANE
In YCS, leaf yellowing occurs in the
late stage of sucrose accumulation,
senescence is induced and tissue
death begins. Normal diurnal changes
of sucrose concentrations (low in the
morning and high at the end of the day)
are absent in YCS affected plants, even
before yellowing. So, significant metabolic
changes occur well before visual signs.
Studies at SRA reveal that these changes
include an increase in soluble sugars,
a decrease in photosynthetic rate,
decreased internal leaf CO2, decreased
conductance through stomata (pores
in leaves and stems for gas exchange),
uncoupling of the photosynthetic
electron transport (PET) chain and altered
carbon-partitioning.
The mysterious yellow canopy
syndrome (YCS) of sugarcane.
The excessive increase in sucrose
suggests disruption of phloem transport.
Sugar is loaded into the phloem but
not exported from the leaf, since the
highest levels are found in the midrib
and sheath. Expression levels of genes
for sucrose transporters and SWEET
protein (not previously characterised in
sugarcane) are also greatest in these plant
parts. The sucrose accumulation could
be caused by physical blockage of the
phloem (for which
there is currently no
evidence) or arise
because the sink is
not using transported
sugar fast enough
which creates an
overflow into the surrounding leaf blade,
midrib, dewlap and sheath. Increased
sucrose also leads to elevated glucose,
fructose and trehalose, sugars that play
major roles in metabolic signalling.
Furthermore, sucrose synthesis slows
down which probably leads to a lowering
of available inorganic phosphate (Pi)
within chloroplasts. A feedback signalling
mechanism involving sucrose in the
symplast could result from chronic cellular
www.researchoutreach.org 11
 Behind the Research
INTERMEDIATE SUCROSE HIGH SUCROSE
• Over reduction of the PET
Light PSII 200mM
• Accelerated senescence initiated

Sucrose
• Transcription and translation of the major • Chloroplast and total protein
components of PSII down regulated PSI breakdown stimulated
• Physiological ‘fitness’ of PET reduced
Biomass • Major upregulation of components of

Dr Frederik (Frikkie) Botha

and photosynthetic reaction centres
inactivated (more heat production and
less reductant and ATP produced)
• Water splitting around PSII decreased
as a result of changes in gene expression
• Cyclic electron flow upregulated to
protect PSI
• Carbon partitioned to the
phenylpropanoid pathway to act
as antioxidants
• Carbon partitioned to β glucan to reduce
sucrose accumulation
• Stomata partially closed to reduce
photosynthesis
• Changes in both nuclear and plastid
gene expression
Leaf health is determined by the sucrose level in the photosynthetic mesophyll and bundle sheath cells. The sucrose level is determined by the difference
between production (R1) and utilisation in the culm (R2). Daily fluctuation between 20 and 100 mM is normal as a result of variation in photosynthetic rate.
Between 100 and 200mM sucrose (intermediate levels) a series of events are triggered that are aimed at protection of the photosynthetic electron transport
chain, reduction in carbon fixation and creation of an alternative sink for the reduced carbon. Prolonged levels above 200mM (high) triggers accelerated
senescence, collapse of the electron transport system, chlorophyll breakdown and cell death.
Pi limitation. Research shows that raised
sucrose also alters gene expression of key
photosynthetic proteins in leaf cells.
From the model developed so far, YCS
symptoms appear to be caused by down-
regulation of photosynthesis through
Pi limitation leading to chronic inability
to export reductant away from the PET
chain during cellular sugar accumulation.
Down-regulation of genes encoding
Photosystem (PS) II and I, cytochrome
and CP12 (an essential regulatory protein)
results in decreased synthesis of these
proteins, which then limits photosynthesis.
ADVANCING GENETIC STUDIES
OF SUGARCANE
The sugarcane genome has only recently
been mapped, owing to
100mM
NADPH
CO2 ATP Hexose-P
R1 R2
Leaf - Supply Culm - Demand
metabolism) and transcriptome
(messenger RNA molecules expressed
from the genes) analyses of the metabolic
pathways in the leaves and sink tissues
of sugarcane are helping researchers
to identify reactions that lead to YCS.
Comparing leaf transcriptomes of
symptomatic and asymptomatic plants
confirms that a complex network of
changes in gene expression underpin the
observed changes in the metabolome.
Fluorescence and gene expression data
from YCS studies indicate that PS II is
the sensitive process/component, linked
to reduced electron flow producing
reduced co-enzyme. The early change
in photosynthetic rate is accompanied
by changes in the expression of
the ubiquitin pathway
• Accumulation of amino acids and
amines
Respiration • Down regulation of the C4 and C3
carbon fixation pathways
• Increase in sugars associated with cell
wall degradation
• Major changes in both nuclear and
plastid gene expression
• Heat shock and other stress proteins
accumulate
• Up regulation of chlorophyll breakdown
• Yellowing of the leaf evident
• Respiration maintained to facilitate
senescence process
• Carotenoid retention
elevated sucrose. This increases caffeoyl-
quinic acids and quinate, compounds
that provide antioxidants to buffer free
radical production in the chloroplast
as a result of decreased electron flow
to the terminal electron acceptors of PS
I. Upregulation of the phenylpropanoid
pathway probably shifts carbon-
partitioning towards lignins, flavonoids
and anthocyanins.
In the early stages of sucrose
accumulation, several other changes also
occur: significant levels of metabolites
indicative of microorganisms that
associate with injured tissue, especially
where there are significant available
carbohydrates; significant increases
in caffeoyl/chlorogenic type compounds
indicative of wounding
E: fbotha@sugarresearch.com.au T: +61 488400074 / +61 7 33313318 W: https://sugarresearch.
com.au/team/dr-frikkie-botha/
Research Objectives
Dr Botha’s work examines leaf sucrose levels in
sugarcane, among other plants, and their impact
on overall plant health.
Detail
50 Meiers Road
Indooroopilly
Queensland 4078
Australia
Bio
Frederik (Frikkie) Botha is the Executive Manager Strategic
Initiatives at Sugar Research Australia and Honorary
Professor at the University of Queensland, Australia. His
research focus is on the genetic and molecular control of
carbon partitioning in the culm and leaves of sugarcane,
which is the driver of biomass composition and yield.
The research aims to understand the control of carbon
partitioning between the cell wall components, respiration
and sucrose accumulation in the culm and the impact of this
on sink strength. An early switch to sucrose accumulation
reduces biomass accumulation and reduces sink strength.
The limited capacity to buffer leaf sucrose through partition
of carbon to starch requires maintenance of a strong sink
demand to prevent induction of premature senescence
in the canopy.
References
Botha, F. (2019) Metabolic Changes Associated with the
Development of Yellow Canopy Syndrome in Sugarcane.
Conference: International Plant and Animal Genome
Conference XXIII 2015.
www.researchgate.net/publication/268116827_Metabolic_
Changes_Associated_with_the_Development_of_Yellow_
Canopy_Syndrome_in_Sugarcane
Marquardt, A., Scalia, G., Wathen-Dunn, K., Botha, F.C. (2017)
Yellow Canopy Syndrome (YCS) in sugarcane is associated
with altered carbon partitioning in the leaf. Sugar Tech, 19,
647–655.
Marquardt A., Scalia G., Joyce P., Basnayake J., Botha
F.C. (2016) Changes in photosynthesis and carbohydrate
metabolism in sugarcane during the development of Yellow
Canopy Syndrome (YCS). Funct Plant Biol 43:523–533.
Wang. J, Nayak, S., Koch, K., Ming, R. (2013) Carbon
partitioning in sugarcane (Saccharum species). Frontiers in
Plant Science, 4, 201.
Sugar Research Australia. Yellow Canopy Syndrome. https://
sugarresearch.com.au/growers-and-millers/pests-and-
diseases/yellow-canopy-syndrome/ [Accessed January 2019].

A model for the biochemical

sugarcane’s complexity:
high polyploidy (more
than two-paired sets of
chromosomes); aneuploidy
(varied numbers of
chromosomes); bispecific
origin of chromosomes;
and structural differences
and interspecific chromosome
recombinants. A reference genome
is now available for researchers. DNA
sequencing, development of gene-
expression technologies and improved
genetic/genomics resources for
Saccharum are enabling the regulatory
networks of carbon-partitioning
to be further elucidated.
Metabolome (low-molecular-weight
metabolites produced during
process of carbon-partitioning
in sugarcane is being developed
through research on YCS.
phosphoenolpyruvate carboxylase
(PEPC). NADP-malic dehydrogenase
expression is more sensitive to the
accumulation of sucrose than are
NAD-malic dehydrogenase and PEPC.
This demonstrates that chloroplast
metabolism is down-regulated when
sucrose levels rise.
Furthermore, genes in the shikimate and
phenylpropanoid metabolic pathways
are upregulated in early response to
and activation of plant
defence systems; and
increases in amino acids
and metabolites indicative
of stress metabolism
and of disruption of the
electron transport system,
which is dependent on fast
turnover of protein components.
A genomic approach is now being
pursued for YCS in sugarcane, using next-
generation RNA sequencing to compare
and analyse genetic data for affected
and unaffected plants from diverse field
locations. Genetic explorations of how
different tissue samples express different
proteins, continues to provide clues to
the cause of YCS and to understanding
sugarcane metabolism in general.
Funding Personal Response
• Sugar Research Australia
• Australian Research Council What impact do you hope this research will have over
• University of Queensland the next five years?
Co Authors
Conventional and genetic manipulation studies have
shown that accumulation of sucrose leads to biomass
• Annelie Marquardt (SRA) Sugar Research Australia penalties consistent with sucrose feedback control on
• Gerard Scalia (SRA) Sugar Research Australia photosynthesis. We need a better understanding of why
• Kate Wathen-Dunn (SRA) sucrose accumulates in the leaves of sugarcane during
Sugar Research Australia stress and what the impact of this is on leaf metabolism and
• Robert Henry (UQ) crop yield. This will contribute to the finding of management
Queensland Alliance for solutions for physiological disorders and biotic stress that
lead to sucrose accumulation. However, more importantly
Agriculture and Food
it could lead to genetic targets that provide an opportunity
Innovation, The University to break out of the current yield plateau that has frustrated
of Queensland sugarcane breeders for the past three decades.

12 www.researchoutreach.org www.researchoutreach.org 13
Physical Sciences ︱ Professor Costas Balas
Stripping paintings
of their secrets with
hyperspectral imaging
What lies beneath hundreds
of years of paint? Professor
Costas Balas at the Technical
University of Crete, Greece
is privy to some of the secrets
of the great Renaissance
masters with his hyperspectral
imaging devices. Such devices
can be used to identify not just
what chemicals are present
in pigments on the surface layers
of paintings, but also what lies
underneath.
14 www.researchoutreach.org
A
rt restoration is a difficult
business. A single painting
will use numerous pigments
to create a wealth of different colours
but while those colours might be
indistinguishable by eye, each of those
pigments may in fact have a different
chemical composition. Even worse,
different pigments or regions of the
painting may have been treated with
different binding materials and varnishes,
which will also affect the types of solvents
and materials that can be used for
cleaning or touching up certain areas.
If colour alone is not a reliable indicator
of the pigments and chemicals used
in a painting, how can art experts
and scientists identify what materials
have been used with a great degree of
accuracy, all in a non-destructive manner?
The answer lies in tools typically used
in analytical chemistry. Most of these
involve shining non-visible wavelengths
of light through the painting, including
X-rays and infra-red radiation, as these
are not completely absorbed by the
surface paint layers, unlike visible light.
Unfortunately, such spectroscopic
techniques are very expensive and
provide point-by-point information.
This means that each section of the
painting must be meticulously scanned
with the incoming X-rays or infra-red
to record all the chemical information
on different sections of the painting.
It may also be necessary to tune
the wavelengths of the incident light
to see different elements.
Given how time-consuming point-
by-point scanning is, one alternative
Fluorescence imaging combining spectral
images of El Greco’s St Francis of Assisi reveals
invisible conservation interventions. Materials
used for conservation are similar to the
background color but their different chemical
composition is evidenced by the different
fluorescence emission pattern.
approach is to combine spectroscopic
methods with imaging methods.
Spectroscopic methods are ideal for
accurately determining which chemical
elements are present in a particular
region but imaging methods have
very high spatial resolution and can
therefore disentangle differences
in even small, detailed areas of the
painting. This combination is known
as hyperspectral imaging and Professor
Costas Balas at the Technical University
of Crete, Greece and his research
group are experts in improving
and developing hyperspectral imaging
technologies for both medical
and art conservation applications.
HYPERSPECTRAL DEVICES
Professor Balas’s interest in
hyperspectral imaging was originally
motivated by his work in the field Hyperspectral analysis of the palimpsest (72 verso) (Mount Athos Monasteries-Greece). Regular colour
of cancer diagnosis and biomedicine. photography (top) shows only the newer script entitled “Mandona Anthems” which has been dated as
13th century AD. There is an older invisible script, however, dated between the 10-11th century AD, entitled
Here, there is a need for devices that “Porphyrogennetus”, which is revealed with hyperspectral imaging. The fusion of selected spectral
can successfully and accurately profile images made the visualisation of both the new (vertical script) and the old (horizontal script) possible.
and image tumours within the body
as part of the diagnostic process
but there are a number of features
The team found a number of surprising
of the technique that have meant
it can be applied to a diverse range
results that only hyperspectral imaging
of applications, including art restoration could have unearthed.
and identification.
the infra-red. Using these wavelengths with ultraviolet and infra-red detection
A hyperspectral imaging device of light in the infra-red allows Professor that provide more definitive chemical
works by simultaneously recording Balas to peel back the layers of paint assignments and are sensitive not just
spectral and spatial images to make to what lies on the canvas underneath. to the surface layers.
three-dimensional data sets. A spatial The flexibility of the wavelengths that
image is like a photograph that shows can be used with hyperspectral imaging SEEING THE CANVAS
the location of all the different objects has many advantages for dealing with Professor Balas and his team have been
in the frame. However, as the spectral complex materials such as paintings. able to use this technology to study
information can only be obtained for The use of visible light is important one of Doménikos Theotokópoulos’s,
a limited number of wavelengths per for identifying colours and pigments, otherwise known as El Greco,
spatial image, this means only certain
coloured objects are recorded in a
single image, so it would be like taking
a photograph which would only show
green objects. To make up a full three-
dimensional image, another photograph
would be taken, that would only show
blue objects, then red objects and
so forth until all the wavelengths of
interest had been covered and the full
scene could be created.
In practice, as the human body and
paint absorb visible light, the imaging
The hyperspectral camera, developed by Professor Balas and his team, (left) captures a series of
ranges of the hyperspectral imaging monochromatic images across the spectrum, building up the so-called spectral cube (right). This data
devices span from the ultraviolet to structure assigns a full spectrum to every point in a scene, giving information on its chemical composition.
www.researchoutreach.org 15

Hyperspectral analysis of “El Espolio” by Jorge Manuel (El Greco’s son). Spectral mapping of a detail, shown in the red frame, combined with machine learning
methods allows for the identification of malachite pigment non destructively. Areas with malachite are artificially colored with red for the purpose of facilitating
the visualisation of the pigment’s distribution in the painting
masterpieces, ‘The Baptism of Christ’.
Thought to have been painted in
the early 1600s, the painting depicts
a complex scene involving both the
heavens and the earth, where Christ
stands with St John the Baptist at
his right. Strikingly, a number of figures
are robed in bright greens, reds and
yellows, giving a small indication
of the complexity of the chemistry
occurring on the campus.
The goal of the project coordinated
by the Benaki Museum was to provide
technical information to art historians
to allow them to date and authenticate
the painting and to determine what
the physical condition of the painting
was to aid with conservation work.
During this process, the team found
a number of surprising results that only
hyperspectral imaging could have
unearthed, including the numerals
‘MDLXVI’, indicating the year 1566. This
date had gone previously unnoticed as
it had been overpainted, but the quality
of the spatial resolution from the imaging
made it possible to unambiguously
resolve most of the date.
There was one small complication to
this, though. Next to MDLXVI appeared
to be another I, which would indicate
the year to be 1567. Most other analysis
techniques would have suggested
the additional ‘I’-like feature was
intended to be part of the date, owing
to its location and similarities in colour.
However, the chemical information also
16 www.researchoutreach.org
Malachite
Verdigris
Green Earth
(1125)
Green Earth
(4081)
Green Earth
(4082)
Professor Balas’s interest in hyperspectral
imaging was originally motivated by his
work in the field of cancer diagnosis.
extracted from the hyperspectral imaging
indicated this ‘I’ was not a numeral as
part of the date, but actually intended
to be part of a nearby scene.
While hyperspectral imaging may
be more efficient than point-by-point
spectroscopic methods, the size of
the painting posed some problems
for Professor Balas and his team. They
were able to identify over ten different
pigments used by El Greco and his
contemporaries on the painting, including
lapis lazuli and azurite, but needed a
more efficient way of identifying them
over the full scale of the canvas. To
do this, they turned to machine learning
methods that, once they had been
trained to identify the spectroscopic
signatures of the various pigments, could
then automatically assign which pigments
had been used to paint specific regions,
speeding up the process immensely.
CAPTURING THE PAST
While not all paintings have dates
conveniently hidden under layers of
paint, hyperspectral imaging can be used
to date paintings through a different
approach. When chemists and artists
alike found ways to create new pigments,
this was often intimately related to the
development of new artistic styles. Their
colours and the techniques used to paint
them often provide art historians with
many visual clues as to a painting’s age,
which can in turn be verified by a more in-
depth chemical analysis of exactly which
compounds were used where.
Hyperspectral imaging can be used
not just for identification and dating
but also for historical preservation.
In cases where restoration is not possible
due to the fragile nature of the object,
imaging can be used to create digitised
records of particularly frail manuscripts.
One example is the Codex Sinaiticus,
the earliest manuscript containing
the complete New Testament which
dates from the mid-fourth-century.
The Codex Sinaiticus is currently kept
in four different locations, so as well
as historical preservation, the goal
of imaging the whole text also served
the purpose of allowing a reunification
of the complete text. The reunification
of the text through imaging gave some
ideas as to how the book may have
originally been bound and researchers
now have a wealth of information on
the composition of the different coloured
inks used in the text, all of which have
been made possible by developments
in hyperspectral imaging.
Behind the Research
Professor Costas Balas
E: balas@electronics.tuc.gr T: +30 28210 37212 W: www.linkedin.com/in/costas-balas-b4473236/
Research Objectives References
Balas, C., Epitropou G., Tsapras A. and Hadjinicolaou N.,
Professor Balas uses and develops hyperspectral imaging
technology in art conservation and in biomedical diagnosis. (2018) Hyperspectral imaging and spectral classification for
pigment identification and mapping in paintings by El Greco
and his workshop, Multimedia Tools and Applications, 77,
9737–9751.
Detail
Costas Balas PhD
Professor | Director Electronics Lab | School of Electrical &
Computer Engineering
Personal Response
Technical University of Crete
University Campus Acroterion 73100,
Chania, Crete
What are the unique challenges of imaging art pieces?
Greece Art pieces are very complex in nature with multiple
layers and chemicals contributing to image formation.
Bio When referring to historic art pieces, construction
Costas Balas is a full Professor at the Electrical and materials are often unknown and therefore it is very
difficult to develop material replicas to be used as
Computer Engineering department of the Technical
reference for the analysis.
University of Crete. He is a recognised expert and innovator
in biophotonics and hyperspectral imaging. He has Innovative platforms integrating hyperspectral imaging
patented and published life-saving, FDA-approved and machine learning methods emerge as a powerful
photonic methods and imaging technologies for tool for addressing these challenging diagnostic/
non-destructive analysis and for noninvasive diagnosis. He analytical tasks.
teaches both graduate and undergraduate courses.
Collaborators
The guidance and the data interpretation offered by
the eminent Art Historian Professor Emeritus Nicos
Hadjinicolaou and the experimental work conducted by my
graduate students are gratefully acknowledged.
Technical
University
of Crete
www.researchoutreach.org 17
Physical Sciences ︱ Professor Michael D. Heagy
The power of light:
Production of solar fuels
Harnessing the power of
the sun as a source of energy
is highly appealing for many
reasons, but primarily because
it is a renewable, clean source
of energy. Plants are already
incredibly proficient at not just
converting light to useable
energy but also at storing that
energy in the form of glucose,
which can be considered a
solar fuel. Professor Michael
D. Heagy at New Mexico Tech
has taken inspiration from plant
photosynthesis to develop
new materials, designed to
address some of the challenges
involved in efficiently converting
and storing solar energy.
W
hen it comes to solar
energy conversion, plants
are the experts. Through
photosynthesis, plants can use light
energy absorbed from the sun, in
combination with carbon dioxide and
water, to create glucose and oxygen.
Despite photosynthesis being a complex,
multi-step process, plants are able to
perform it with very high conversion
efficiencies, owing to their highly adapted
network of molecular machinery.
Glucose, the type of sugar produced
during photosynthesis, is a very energy-
dense fuel that the plant uses for two
main purposes. Firstly, glucose provides
the chemical building blocks for the plant
Liquid solar fuels have an advantage not
just in terms of their energy density but
can also be used as chemical feedstocks.
to be able to grow. Secondly, plants also
exploit glucose as part of respiration,
a process common to plants and humans,
which involves converting the energy
locked in the glucose fuel into
a useable form.
Trying to mimic the incredible
abilities of plants to convert and
store the energy from sunlight
has inspired the field of
artificial photosynthesis.
Artificial photosynthesis
attempts to recreate
a plant’s abilities for light harvesting,
conversion and storage by breaking
the photosynthetic process into two key
steps. Water splitting, where the key
goal is to oxidise water into hydrogen
and oxygen, followed by the reduction
of carbon dioxide to allow solar fuel
synthesis. Professor Michael D. Heagy
at New Mexico Tech and his research
team are experts at designing materials
tailored to promote the conversion of
carbon dioxide to solar fuels using the
power of light alone.
SOLAR FUELS
Recreating the energy conversion
efficiency of plants in the laboratory with
artificial photosynthesis is a tricky task
as well as overcoming one of the other
issues with solar energy: how to provide
a continuous, uninterrupted energy
supply from solar sources? The key to this
lies in finding a way to store the solar
energy, which is often done by using
photoinduced chemical processes
to create solar fuels.
Probably the most famous example
of a solar fuel, and the one created
during the water splitting stage of natural
photosynthesis, is hydrogen. After using
light-induced processes to form the
hydrogen, this then acts as a fuel reservoir,
as the hydrogen can later be burnt or
converted to release the stored energy
when required. However, while hydrogen
is now being used directly as a fuel by
hydrogen-powered cars, it is not an ideal
solar fuel. For practical purposes, the
hydrogen needs to be highly pressurised
Silver nanoparticles act as plasmonic sensitiser via Ag/Cu2O nanocomposite and augment solar-driven
bicarbonate formate conversion.
A B
Proposed mechanism for (a) Cu2O semiconductor and (b) Ag/Cu2O. (Blue block arrow represents resonant energy transfer from metal
to semiconductor.)
and is difficult to store safely owing the chemical reactants on their surface. One photocatalyst that Professor Heagy
to its flammability. Then, when they are illuminated, the has been investigating for solar fuel
photocatalyst helps to change the production is iron oxide. In his team’s
This is why Professor Heagy is interested charge distribution of electrons between work on iron oxide nanostructures, they
in using photochemical processes to itself and the reacting molecules. This found that the photocatalytic activity
create other kinds of solar fuels, including process results in significant acceleration for reducing bicarbonate to formate
finding ways to efficiently produce of the rate of chemical reactions such is strongly dependent on the shape
formate, the negatively charged version as the reduction of carbon dioxide. and structure of the material. By using
of the simplest carboxylic acid, formic
acid. Producing formate and other liquid
fuels not only is advantageous in terms
of their superior energy density, but they
can also be used as chemical feedstocks.
Part of our global reliance on fossil fuels
is not just using them as a source of
energy, but also as chemical feedstocks
for the manufacture of plastics and other
chemicals. The idea of using methanol Two crystal forms of ZnS were synthesised and evaluated for their photochemical properties. The
and dimethyl ether as alternatives for wurtzite crystal form showed the highest AQE of 0.9% when using IPA as the whole scavenger. The AQE
fossil fuels, for both energy and chemical increased to 3.2% when the electron donor was changed to glycerol. Given the large gain in productivity
and the potential renewable source, glycerol is a preferable solvent and positive hole scavenger.
synthesis, has been championed by
the Chemistry Nobel laureate George
Olah, who was a strong advocate for
encouraging the development of this
‘methanol economy’.
MAKING MATERIALS
Professor Heagy’s research focuses
on designing photocatalysts and
novel nanomaterials with specially SEM image of (left) micron Cu2O, and (centre) nano Cu2O. (right) TEM images of nano Cu2O and Ag/Cu2O.
designed structures for the reduction
of bicarbonate to solar fuels.
Bicarbonate exists in equilibrium with
dissolved CO2 and is the predominant
species at neutral pH. While plants
have specific cellular and chemical
architectures adapted for all the stages
of the photosynthetic cycle, in the
laboratory, driving the same processes
requires the use of photocatalysts. HR-TEM images of (left) micron Cu2O, (centre) nano Cu2O, and (right) Ag/Cu2O. (The inset shows
Photocatalysts work by capturing magnified Ag nanoparticles of ~5nm surrounded by Cu2O. Scale of insert is 5 nm.)
www.researchoutreach.org 19

Hierarchical nanoflowers were synthesised from earth-abundant ZnO and evaluated
under solar AM 1.5 input as catalysts for the photochemical reduction of bicarbonate
to value-added formic acid.
arrangements for the iron and oxygen
atoms that gave the largest surface
area for the bicarbonate to interact
with, they could significantly increase
the productivity of the catalysts for
the production of formate. Iron oxide
is also an appealing choice of material
for this type of application as it is non-
toxic and low-cost.
THE NEW ECONOMY
Iron oxide is not the only material that
looks like a promising candidate for
photoreducing carbon dioxide to formic
acid. Professor Heagy’s group has also
been investigating zinc sulfide structures
and copper oxides to see whether these
would be more appealing photocatalysts
for the production of formate and how
the mechanism of the reaction differs,
or is influenced by the shape of the
particles, not just by changes in the
surface area. His work on zinc oxides
has shown that exotic nanostructures,
such as nanorods, nanobelts and
nanoflowers, seem to be better
20 www.researchoutreach.org
TEM and HR-TEM images of nP-Sphal (A, B) and nP-Wurtz (C, D).
Investigating how and where the carbon
dioxide molecules bind to the surface
will help to drive intelligent design
of photocatalysts.
catalysts than just having amorphous,
unstructured nanoparticles.
While Professor Heagy’s group are
developing new ways of controlling
the miniature architectures of
nanoparticles, a lot of their research
involves really trying to understand
why and how the different earth-abundant
photocatalysts work for these reduction
reactions. Investigating how and where
the dissolved carbon dioxide molecules
bind to the surface will help to drive
more intelligent, targeted design of
nanoparticle structures. Alongside this,
they are also investigating whether
changing the solvent environment for
the photocatalysis also has an impact
on the yield and rates of reaction.
This is important for such photocatalytic
reactions as one of the goals is not just
to have a practical, inexpensive reaction
that is only driven by light, but to ensure
all the reagents are non-toxic and
as environmentally friendly as possible.
While the reduction of carbon dioxide
to organic compounds using metal oxides
was first reported in 1979, it has become
a very hot area of research recently. With
the work of Professor Heagy and others
improving our fundamental understanding
of how some of the photocatalysts
involved work and designing more
efficient, effective materials that can be
used for such processes, we are one step
closer to realising the methanol economy.
Formate production in ppm
with ZnO rods and flowers
in 2-propanol and glycerol
(left) and productivity (right).
Behind the Research
Professor Michael D. Heagy
E: Michael.heagy@nmt.edu T: +1 575 835 6185 W: https://sites.google.com/nmt.edu/heagy-
home-page/home
Research Objectives References
Professor Michael D. Heagy’s work on novel nanostructures Leonard D., Pan H. and Heagy M., (2015), Photocatalyzed
aims to improve the efficiency of solar fuel production. Reduction of Bicarbonate to Formate: Effect of ZnS Crystal
Structure and Positive Hole Scavenger, ACS Applied Materials
and Interfaces, 7, 24543−24549
Detail Pan H., Chowdhury S., Premachandra D., Olguin S., Heagy
Dr Michael Heagy
NMT Department of Chemistry
M., (2018), Semiconductor Photocatalysis of Bicarbonate to
Solar Fuels: Formate Production from Copper(I) Oxide, ACS
801 Leroy Place Sustainable Chemistry and Engineering, 6, 1872-1880
Daniel H. Lopez Chemistry Rm 115
Socorro Pan H., Martindale K., Heagy M., (2018), Iron Oxide
NM 87801 Nanostructures for the Reduction of Bicarbonate to Solar
USA Fuels, Topics in Catalysis, 61, 601-609
Bio Pan H., Risley V., Martindale K., Heagy M.D., (2019)
Michael D. Heagy received an AB degree in Chemistry from Hierarchical Zinc Oxide Nanostructures for the Photochemical
Franklin & Marshall College, Lancaster, Pennsylvania and Reduction of Bicarbonate to Solar Fuels, ACS Sustainable
PhD under the direction of Nobel Laureate George A. Olah Chemistry and Engineering, 7, 1210-1219
at the University of Southern California, Los Angeles. At
the Massachusetts Institute of Technology, he conducted
postdoctoral research with Prof Julius Rebek, Jr.
Personal Response
Funding
National Science Foundation What are the remaining impediments to implementing
the methanol economy?
Collaborators Carbon dioxide capture remains a significant science
• Dr Hanqing Pan and engineering challenge. While CO2 exists at high
• Dr Sanchari Chowdhury concentrations from sources such as fossil fuel power plants
and often accompanies methane at oil-drilling operations,
automobile exhaust, and other diluted sources are difficult
to capture. Given the hydrophilic nature of methanol, if no
inhibitors are used, it can be corrosive to certain metals
such as aluminium and zinc. Existing pipelines designed
for petroleum products cannot handle methanol. Until new
pipeline infrastructure can be built, or existing pipelines
are retrofitted for methanol transport, methanol requires
shipment at higher energy cost in trucks and trains.
www.researchoutreach.org 21
Physical Sciences ︱ Dr Daisuke Inazu
Forecasting Tsunamis using
Ship Navigation Records
In recent years, the Earth has
been rocked by devastating
Tsunamis. The ability to predict
how intense they will be is crucial
in deciding how to mitigate their
effects. This is what makes the
work of Daisuke Inazu at Tokyo
University of Marine Science
and Technology and fellow
researchers so important. Their
pioneering work in using the
Automatic Identification Systems
(AIS) on ships to monitor tsunami
current has huge potential to
help developing countries to
forecast tsunamis so that they
may reduce loss of life and
infrastructure damage.
Our university vessel “Umitaka-Maru” is also transmitting AIS messages,
being one of AIS-derived tsunami current meters.
22 www.researchoutreach.org
T
sunamis are one of the most
devastating and destructive natural
occurrences and can cause mass
mortality and infrastructure damage
when they occur. Coastal cities have
to be able to find ways to reduce these
losses. Although some of these losses
can be mitigated through the use of
coastal defences, the immediate actions
of individuals and organisations after
the occurrence of a tsunami are critical
for reducing the loss of life that can often
directly occur.
This is why it is so important to be able
to tell when a tsunami is occurring, and
how intense it is likely to be. Real-time
forecasting of earthquakes and tsunamis
are useful when it comes to making
decisions for disaster mitigation. This is
what makes the work of Daisuke Inazu
at Tokyo University of Marine Science
and Technology and fellow researchers
so important. Daisuke Inazu is no
stranger to researching ways to predict
the intensity of natural disasters. His
research experiences centres around
using physics to understand and forecast
oceanic events, such as tsunamis, tides
and storm surges. Funded by the Japan
Society for the Promotion of Science and
the Nippon Foundation, he is perfectly
positioned to research the likelihood
of tsunami occurrences.
Most current systems in place to detect
tsunamis use seismic wave observations.
Seismic waves are usually generated
by movements of the earth’s tectonic
plates. However, they can also be caused
by volcanoes and landslides that occur
underwater. Seismic wave detection
technologies are useful in regards to
predicting the magnitude and intensity
of an earthquake but are not always
perfect when forecasting tsunamis.
This is because they estimate elastic
deformation that may be indirectly related
to tsunamis, and are sometimes unable
to accurately predict how a tsunami will
form. This is because tsunamis can be
formed by landslides that often occur
due to earthquakes and volcanic activities.
This, therefore, makes tsunami forecasting
much more difficult than simply predicting
the magnitude of an earthquake.
It is, therefore, better to use direct
observations of offshore sea level
to estimate the resultant size of
tsunamis. There are many systems that
use this method, such as the Deep-
ocean Assessment and Reporting
of Tsunami (DART) buoys forecasting
system. However, while these types
of observatories are reliable, they are
also incredibly expensive to maintain
and require regular replacements,
typically several decades after installation.
Ship distributions derived from terrestrial (orange) and satellite (blue) AIS. Adopted from Vesseltracker.com.
Since gigantic tsunamis may occur
once typically during tens to hundreds
of years at a certain place, the cost
of maintaining and replacing parts
of these observatories can add up.
Offshore tsunami forecasting needs
to be sustainable as well as reliable.
It is therefore important that other, more
sustainable, ways of monitoring and
forecasting tsunamis are developed.
Inazu and his fellow researchers
have conducted pioneering research
into solving this issue, looking at
the possibility of using Automatic
Identification System (AIS) data
to predict the current and height
of tsunamis.
WHAT IS AIS DATA?
AIS data is the navigation records
of ships. It includes the ship’s latitude
and longitude, speed over ground
(SOG), course over ground (COG)
and ship heading (HDG). All of this
information is used to determine the
ship’s position, and where it is going.
AIS data is collected under International
Maritime Organisation (IMO) regulations,
which means that all ships exceeding
300 gross tonnage, and all passenger
ships, are required to send this data
via very-high-frequency (VHF) radio
transmission. AIS data from ships close
to shore can be received by coastal
stations, and ships further ashore can
be received by low-Earth-orbit satellites.
The number of ships with recognised AIS
data is increasing annually with increases
in seaborne trade and in a number of
satellites. Real-time ship distributions
can be derived from AIS data on many deviations under tsunami conditions.
websites. For a price, AIS data is readily By conducting a quantitative investigation,
accessible, but there has been an effort these deviations were used as a proxy to
On ways in which to make AIS data more accurately measure the tsunami current,
accessible in the future. and could help to predict the tsunami
The number of ships recognised by the AIS
is continually increasing, meaning more and
more data can be used around to the world
to forecast and measure tsunamis.
HOW CAN AIS DATA HELP
TO FORECAST TSUNAMIS?
While AIS data has not been traditionally
used to forecast tsunamis, it is predicted
to be useful because it enables sudden
changes in the position of ships to be
seen, which could help to monitor tsunami
currents and predict wave heights. Inazu
and his research team are working on
contributing to the lack of research
regarding the use of AIS data to forecast
tsunamis. By using data from the
devastating 2011 Tohoku earthquake and
resultant tsunami, they have investigated
the relationship between ship horizontal
drift and tsunami current.
The 2011 Tohoku earthquake caused
a tsunami that reached coasts with
significant wave heights (greater than 10
m) a few tens of minutes after the tsunami
generation. Inazu and his research team
used AIS data obtained from 16 different
ships that were out at sea during this
tsunami. They found that measurements
obtained from AIS data during the
2011 Tohoku tsunami, had significant An image of tsunami current detection.
www.researchoutreach.org 23
 Behind the Research
Dr Daisuke Inazu
E: inazud@m.kaiyodai.ac.jp T: +81 3 5463 0417 W: https://sites.google.com/site/inazud4ocean/

Research Objectives References

Dr Inazu and his fellow researchers have conducted
pioneering research into developing effective ways of
monitoring and forecasting tsunamis by looking at the
possibility of using Automatic Identification System (AIS)
data of offshore navigating ships.
Tang, L., Titov, VV., Moore, C., Wei, Y. (2016). ‘Real-time
assessment of the 16 September 2015 Chile tsunami and
implications for near-field forecast’. Pure Applied Geophysics:
Volume 173, pages 369–387.
https://doi.org/10.1007/s00024-015-1226-3

Proud, R., Browning, P., Kocak, DM. (2016). ‘AIS-based mobile

Detail satellite service expands opportunities for affordable global

Department of Marine Resources and Energy,
Tokyo University of Marine Science and Technology
4-5-7 Konan, Minato, Tokyo 108-8477, Japan
Bio
Daisuke Inazu is an Associate Professor of the Department
Historical tsunami sources around the Pacific Ocean. Adopted from International Tsunami Information Center. of Marine Resources and Energy at Tokyo University
of Marine Science and Technology. He earned a PhD
source and wave height at the coast
of the 2011 Tohoku tsunami.
Inazu and his research team are in Geophysics from Tohoku University, Japan, in 2007. His
research experiences have been mainly based on numerical
working on contributing to the lack of simulation of physics of the ocean such as tsunamis, tides,
ocean observing and monitoring’. OCEANS 2016 MTS/IEEE
Monterey.
https://doi.org/10.1109/OCEANS.2016.7761069
Kong, Q., Allen, RM., Schreier, L., Kwon, Y-W. (2016)
‘MyShake: A smartphone seismic network for earthquake early
warning and beyond’. Science Advances: Volume 2, page
e1501055.
https://doi.org/10.1126/sciadv.1501055
Inazu, D., Ikeya, T., Waseda, T., Hibiya, T., Shigihara, Y. (2018).
‘Measuring Offshore Tsunami Currents using Ship Navigation

research regarding the use of AIS data

The AIS data obtained from these ships and storm surges. Records’. Progress in Earth and Planetary Science: Volume 5,
indicated that COG significantly deviates page 38.
from HDG as the tsunami passes the
ship. Using a mathematical model, they
to forecast tsunamis. Funding
• Japan Society for the Promotion of Science (JSPS)
https://doi.org/10.1186/s40645-018-0194-5

proved that ships immediately respond • The Nippon Foundation

to tsunami current by moving in a
diagonal direction with an equivalent
the source, magnitude and wave height
of a tsunami.
velocity. This research shows that crowd-
sourcing AIS data will help to predict What is so brilliant about this way
of measuring tsunamis is possible
Ship Heading in the current AIS framework. The number
of ships recognised by the AIS is
Course/Speed continually increasing, meaning more and
Over Ground more data can be used around the world
to forecast and measure tsunamis. This
novel method of crowd-sourcing data has
huge potential to change the way that
Ship velocity coastal populations forecast tsunamis.
component in
heading-normal
Although there is more that could
direction
be done to increase AIS data reliability,
Tsunami current Dr Inazu’s research team is seeking
component in to enhance the sensitivity of AIS data
heading-normal to tsunami currents by using real-time
direction coastal and satellite AIS data. Using
AIS data is a relatively cheap, promising
Ship velocity component in the heading-normal
direction is a clear proxy of tsunami current way of measuring and forecasting
in the same direction. tsunamis in the future.
THE FUTURE FOR THIS TECHNOLOGY
While countries such as Japan already Collaborators
Personal Response
employ offshore observatories to forecast • Tsuyoshi Ikeya, Tokyo University of Marine Science
What first piqued your interest in finding effective ways
and predict tsunamis, many developing and Technology, Tokyo, Japan
to forecast tsunamis?
countries do not have the economic • Takuji Waseda, Toshiyuki Hibiya, UTokyo Ocean Alliance,
resources needed in order to set these The University of Tokyo, Tokyo, Japan My research idea was actually inspired by the
up. However, due to the low cost of • Yoshinori Shigihara, National Defense Academy smartphone seismic network proposed by the University
obtaining AIS data, it is likely that Kanagawa, Japan of California, Berkeley. They utilise accelerometers
coastal cities in Southeast Asia and
embedded in our smartphones as seismic monitors from
crowd-sourced agents. Our smartphones are onshore.
South America will be able to use data How about offshore? I was speculating tsunami monitoring
obtained from ships in order to monitor using information from navigating ships over the global
and forecast tsunamis. ocean. Then I decided to study AIS data in detail. 
Tsunami disaster mitigation is of
paramount importance in many coastal
areas where large populations reside,
which is what makes the work of Inazu
and his fellow researchers so vital.
The use of AIS data for tsunami current
monitoring may be a sustainable way of
ensuring that tsunamis can be mitigated
in areas where life loss prevention and
infrastructure damage are so important.

24 www.researchoutreach.org
Physical Sciences ︱ Professor Motoichi Ohtsu
devices. He has achieved this by Fabrication and operation of a Si-LED.

The Dressed Photon:

exploiting the peculiarities of the recently
discovered Dressed Photon.

THE DRESSED PHOTON

To understand what a Dressed Photon
is, you first have to understand that the

Shining light on the unknown using the unconventional physical world is largely made up of tiny
building blocks of matter and energy.

area of off-shell science Atoms are the most widely known about,
but they too have their own constituent
parts: neutrons, electrons and protons
to name a few; and then there are their

B
The seas of science are
unrelenting: researchers have
spent lifetimes trying to attain
the unattainable – and fallen
overboard into obscurity when
they were unsuccessful. In the
disciplines of Quantum Field
Theory and Materials Science,
the ability to create light
emitting devices from silicon has
long been seen as a perpetual
white whale. But, as Professor
Motoichi Ohtsu, of Research
Origin for Dressed Photon
(Japan) has demonstrated,
anything can be achieved if you
choose the right tools. In his
case, an exotic particle known
as the Dressed Photon is exactly
ack in 1981, when the first CDs
were released, scientists had
inadvertently spawned an audio
revolution. Digital audio had already been
around for about a decade at that point,
but it was now possible to play it from a
storage device which could be held in
the hand. Records and audio cassettes
were relegated to the dusty cupboards
of history or the pristine shelves of
connoisseur collectors. In the mid-90s,
a similar thing happened with video: VHS
gave way to DVD and we could now
squeeze around four times the data that
a record could hold onto a disk taking
up less than 16% of the area. In 2004,
The Dressed Photon has a lot of unique
same small disk – that’s 60 times the data
that a record can contain. Have you ever
wondered what was behind these leaps
and bounds in home entertainment?
In this particular case, advances in laser
technology are what made the difference.
Data is etched onto such devices using
lasers – and read in the same way. The
size that one bit of data takes up on a CD,
DVD or Blu-ray depends on one thing
only: the wavelength of light used to read
and write it. For CDs, a 780 nanometre
(nm) laser was used (that’s a laser that
produces light with a wavelength of 780
thousand-millionths of a metre!). DVDs
more exotic cousins such as quarks,
muons, pions and bosons (amongst
others). You might even have heard of
the famous Higgs Boson, the so-called
God particle, whose existence was finally
proven at CERN in 2012. The fact is
that our universe, which is bigger than
we can possibly imagine, is absolutely
teeming with tiny particles that are so
small we can’t even see them. A photon
Top: Fabrication by the Dressed Photon-Phonon Assisted Annealing.
is simply a particle of light (when light Bottom: Operation, exhibiting Photon Breeding.
chooses to behave like a particle, that is).
few) – and one of the great problems of mechanics and is used to represent
Particles, of all shapes and sizes, interact our time is that these areas don’t always the world of sub-atomic particles.
with their environment in very specific play nicely with each other. Quantum
ways. For example, photons can – and Field Theory (QFT) was developed to try In QFT, when a particle obeys a set of
do – knock electrons out of their orbits and bridge the gap between classical field equations from classical physics, we say
on the outskirts of atoms – but only for theory, special relativity, and quantum that it is an example of on-shell science.

features which have never been described

what was needed to conquer
the unconquerable.
by the conventional quantum field theories.
when the first ever Blu-ray was released,
the quality of our home entertainment
catalogues rocketed, with a whopping
25GB of data now easily stored on that
Dispersion relation
of a quantum field
Dispersion relations for on-shell and off-shell
quantum fields.
and Blu-rays used 680nm and 405nm
laser light respectively. So why don’t
they just create a laser with a wavelength
of 1nm and be done with it?
Well, when it comes to light emitting
diodes (LEDs) and lasers, scientists
have long been struggling with the
same problem: the wavelength of light
emitted by a device is intrinsically linked
to the underlying atomic structure of the
materials used. In other words, scientists
can’t just decide which wavelengths
they want to produce: they have to
find materials, or engineer specific
combinations of materials, that will give
the results they are looking for. That’s
why advances in this technology come
in apparent sporadic leaps and jumps.
Professor Motoichi Ohtsu, of Research
Origin for Dressed Photon (Japan),
has been able to make another leap
forward in this field by creating the first
high powered Silicon (Si) LED and laser
a limited time: the ousted electron usually
returns to send the photon off with a swift Optical output powers and spectra of a Si-LED and a Si-laser
kick and a burst of light. Scientists call
this process excitation and emission. It is
a phenomenon that has been exploited
throughout science to produce many
of the technological wonders we currently
take for granted. How a particle interacts
with its surroundings can usually be
described in very precise, reliable ways.
Sometimes, though, particles behave
unexpectedly: they appear to break
the laws of conventional physics, having
more influence on their surroundings than
their size, or other measurable qualities,
indicates they should. Scientists call
these Dressed Particles and as Professor
Ohtsu has demonstrated by exploiting
a particularly special case, the Dressed
Photon, they are beginning to lead
us in completely new directions.
OFF-SHELL SCIENCE: SCOUTING
THE HINTERLANDS OF QUANTUM
FIELD THEORY
Physics can be divided into many different
Top left: Optical output power of the Si-LED. Top right: Spectral profile of the light emitted from the
areas – classical physics, relativistic Si-LED. Bottom left: Output optical power of the Si-laser of 15 mm-length. Bottom right: Output optical
physics, quantum physics (to name a power of the Si-laser of 30 mm-length. Open squares are copies of those in the left figure.

26 www.researchoutreach.org www.researchoutreach.org 27
Dressed photon

Behind the Research

Creation (left) and detection (right).

Professor Motoichi Ohtsu

E: ohtsu@rodrep.or.jp T: +81 90 1603 0562 W: http://rodrep.or.jp/

Research Objectives References

The terminology comes from the fact
that these specific equations relate to
the particle’s energy, momentum and
what physicists like to call its mass-shell
(but which can be thought of as plain old
mass for our purposes). When a particle
entertainment systems and so much
more: laser technology is central to
our current push towards nuclear fusion
which will unlock an essentially limitless
energy supply. If achieved, it will change
the course of history forever.
is thought of as an extremely difficult
material to work with when creating light
emitting devices. Rather than be put off by
such a seemingly unattainable challenge,
scientists around the world have set it as
their target – intent on catching the white
Professor Motoichi Ohtsu uses the Dressed Photon in his Sakuma, H., Ojima, I. and Ohtsu, M. (2017). Dressed photons
new method to create silicon-based light emitting diodes in a new paradigm of off-shell quantum fields. Progress in
and lasers. Quantum Electronics 55 (2017) 74-87.
Ohtsu, M. (2016). Silicon Light-Emitting Diodes and Lasers.
Detail (Springer, Heidelberg) 2106.

doesn’t obey these equations of motion, whale of materials science.

it is an example of off-shell science—
an area of physics we still have much
to learn about. ‘The Dressed Photon has
a lot of unique features which have never
In one process, Professor Ohtsu has
simultaneously achieved the apparently
unachievable and unlocked new information.
been described by the conventional
quantum field theories that treat only the
phenomena of on-shell science,’ explains
Professor Ohtsu.
Off-shell science is an extremely fertile
area of physics and nobody really
knows what secrets it might unlock in
the future. Back in the year 1960 when
a couple of unassuming physicists
built the first laser, it didn’t really have
a purpose. Today, as we have already
seen, it is at the heart of our home
Structure and photograph of a Si-laser
Cross-sectional structure (top) and a photograph (bottom) of a high-power Si laser of 15 mm device length.
HIGH-POWERED LEDS AND LASERS
USING SILICON CRYSTALS
Professor Ohtsu has used this fertile area
of science to develop the world’s first
high-powered LEDs and lasers from silicon
crystals. This is important because, after
oxygen, silicon is the most abundant
material in the Earth’s crust: for more than
half a century it has been the primary
material used in electronics and, as a
result, a worldwide infrastructure is already
in place for creating silicon-based devices.
In other words, it would be extremely cost
effective to develop light emitting devices
based on silicon. On the other hand,
silicon is widely believed to have a low
light emitting efficiency and, as a result,
To create his devices, Professor Ohtsu
has not engineered a new combination
of materials to achieve the light emitting
devices required but developed a new
method for engineering them. His new
approach, which he calls Dressed Photon-
Phonon Assisted Annealing is a nano-
fabrication technique which uses off-shell
science to produce light emitting materials
in a novel way. Using a technique called
Joule-heating, and flooding the material
with light during the process, he is able
to lock-in specific wavelengths in a way
that has never been seen before. ‘The
unique feature of the fabricated device
is that the wavelength of the emitted light
is equivalent to that of the light irradiated
during the annealing,’ explains Professor
Ohtsu. ‘This surprising feature is named
the “Photon Breeding”, which has never
been observed in conventional LED
and laser devices.’
In one process, Professor Ohtsu has
simultaneously achieved the apparently
unachievable and unlocked new
information about the world that we live
in. Not only will his devices be extremely
useful in many aspects of science and
technology, but the surprising new science
he has uncovered provides a new direction
for researchers to head in their efforts to
understand the unknown. Chipping away
at the vast wall of the undefined and filling
the small cracks with knowledge and
understanding is how science progresses.
Who knows what else might be uncovered
by shining the light that Professor Ohtsu
has created with his research?
Prof Dr Motoichi Ohtsu
(General Incorporated Association)
Research Origin for Dressed Photon (RODreP)
3-13-19 Moriya-cho
Kanagawa-ku
Yokohama
Kanagawa 221-0022
Japan
Bio
Motoichi Ohtsu was awarded his Dr. Eng. from the Tokyo
Institute of Technology where he went on to become
an Associate Professor and Professor. Later, he became
Professor at the University of Tokyo. He is now Professor
Emeritus at both the University of Tokyo and the Tokyo
Institute of Technology. Professor Ohtsu is also Director-in-
chief of research institute, the “Research Origin for Dressed
Photon”. Professor Ohtsu has published 560 papers and
80 books. He has received 87 patents and been awarded
20 prizes.
Collaborators
• Dr I. Ojima (RODreP)
• Dr H. Sakuma (RODreP)
• Prof T. Kawazoe (Tokyo Denki Univ.)
Personal Response
Your work takes place in an extremely multidisciplinary
area, simultaneously uncovering new phenomena in
science and having practical uses in technologies around
the world – which do you find most interesting?
It is most interesting to draw a precise physical picture
of a dressed photon. Also, from the technical point of view,
it is essential to investigate the mechanism of fabricating
and operating Si-LEDs and Si-lasers.
Do you feel that one area is more beneficial
to the public?
No, I do not think so because all the areas I have
developed are based on off-shell science and are mutually
correlated. Their progression in an organised manner will
be effective to establish novel industries and markets,
which may be more beneficial to the public.
What do you think are the main differences between
carrying out research within industry and academia?
On-shell science has been almost saturated. Industry
and academia should keep going in different directions
until they get new products from the fertile field of off-shell
science. They are:
Academia: Focus on original basic research! Do not hop
on the latest fashion!
Industry: Produce novel technology! Encourage young
engineers!
Industry-academia collaboration is nothing more
than a by-product of basic research.

28 www.researchoutreach.org www.researchoutreach.org 29
Physical Sciences ︱ Valeriia Reveko

Setting new horizons

strong alkaline environments. Therefore
SPECIAL ASPECTS OF
certain elements, like aluminium or
ELECTRODEPOSITION ON ZINC
copper, are added to obtain zinc alloys
DIE CASTINGS
with superior properties. Although,

in electroplating
Zinc die casting part in cross section: difference
adding those dissimilar elements opens in structure between the surface and the bulk.
the way to corrosion, a process of metal
deterioration. In this way, electroplating
coatings are a necessity in order to

of zinc die castings

change surface properties: reduce metal
cations from a solution with the help
of electric current, and hence form a
protective metallic coating. Furthermore,
and disregarding the long usage of
electroplating as the surface treatment for
it, zinc die casting persistently generates

Our supply of zinc, a metal
abundant in our planet’s crust,
could run out by 2100 unless we
begin to change the way we use
it. Collini Holding AG creates a
step change in uncovering and
addressing the core causes of
common faults of plating on
zinc die cast by investigating
this material and the ways of
it surface finishing in a more
sustainable way.
W
ith over 7 billion people on
the planet – theoretically
from today – there will be an
inevitable increase in the demand on the
world’s natural resources. Natural gas,
oil, and coal are some of the key natural
resources that are in danger of being
diminished. Yet, there are additional
resources provided to us by our planet
that although their existence is an integral
part of our daily lives, they will eventually
vanish; that is unless we begin to change
the way we use them.
Zinc and its alloys are essential to
manufacturing processes because of
their respective properties such as
castability and performance while also
offering significant energy and cost
savings. However, this metallic element
is a profound example of a vanishing
natural resource because its supply
from our planet’s crust is predicted to
last only until 2100. This is exactly why
Collini Holding AG, the leading group
of companies in coating metals and
plastics in Europe, has been investigating
and developing surface solutions to
render zinc alloys more sustainable and
efficient. Founded as a grinding shop
over 120 years ago, Collini is now an
industrial surface treatment company,
creating surfaces for fittings, electrical
and automotive industry, machine, plant
and building construction, and also for
medicine and various consumer goods.
The company has thirteen production sites
in Austria, Germany, Italy, Russia, Mexico
and Switzerland that specialise in a wide
range of surface technologies including
electroplating, hot-dip galvanizing,
anodizing and organic coating.
ZINC DIE CASTING
From toy cars that children play with to
the metal parts used in actual cars, there
is a huge variety of consumer parts made
using the die casting process. In fact, die
casting is a manufacturing process that has
been around for more than 180 years and
was initially invented in order to develop
portable typewriters. Essentially, this
process involves heating metal alloys until
they become molten and consequently
pressed between steel moulds until they
cool down and solidify in the required
shape. One of the most popular alloys to
use in the die casting process is zinc alloys
because they are easier to cast and solidify
at a lower temperature in comparison to
alternatives such as aluminium, therefore,
the die casting process is cheaper and
more efficient.
several challenges for plating, especially
when it comes to decorative use (Reveko
and Møller, 2018). Consequently, there are
a variety of challenges associated with zinc
die casting that has recently become the
primary research of the Austrian surface
treatment company Collini Holding AG in
By 2100, it is anticipated the supply
of most metals will run out.
conjunction with the Technical University
of Denmark (DTU). Their work has resulted
in the completion of a series of studies by
Collini scientist Valeriia Reveko.
ZINC PLATING COLOUR CHANGE
Valeriia Reveko, a PhD candidate in the
Department of Mechanical Engineering,
DTU, has published several peer-reviewed
research studies that highlight the distinct
challenges that are associated with the
electroplating of zinc die-casted parts.
More specifically, Reveko has conducted
thorough morphological and
compositional tests and analyses to verify
the performance and safety of zinc
galvanic coatings on zinc die-cast items to
improve the plating quality. For instance,
and as noted in Reveko, Lampert, Winther
Electron Image 1
and Møller (2018), one of the most
common issues with zinc coating over zinc
die-cast components involves a distinct
blue discolouration – blue areas on the
surface of the electroplated zinc coatings.
In this study, Reveko and co-workers
suggest that aluminium from the
substrates will gradually diffuse through
the coating and will propel the
manifestation of these blue areas as a
result of oxidation under the influence of
ambient moisture and potential
contaminants. Furthermore, and perhaps
more importantly, the environment within
which zinc plating occurs – from alkaline or
acidic solution– directly influences the rate
of aluminium diffusion: alkaline zinc
demonstrates higher rates of diffusion
compared to acidic zinc due to its
AI K Series Electron Image 1
morphology. Hence, and as suggested
by Collini team, a viable and attractive
solution can be a double-layered zinc
coating in which the inner layer is
mildly acid zinc and the outer layer
is alkaline zinc.
INACCURATE ANALYSIS
OF CHROMIUM-PASSIVATED
ZINC SURFACES
In principle, trivalent chromium conversion
coating is a very efficient way to anticipate
corrosion of zinc coating while meeting
environmental and safety requirements.
However, some recent research studies
reported the presence of hexavalent
chromium in the surface passivation layers.
AI K Series

Zinc is a hard, ductile, self-lubricating

material that has high thermal conductivity
and dimensional stability. However,
unalloyed zinc is brittle, is weaker and it is Scanning electron microscope images with Energy-dispersive X-ray spectroscopy analysis showing Al presence in zinc plated, zinc die-casted component
susceptible to corrosion in acidic and/or before (left) and after (right) blue discolouration.

30 www.researchoutreach.org www.researchoutreach.org 31
 The Registration, Evaluation, Authorisation
and Restriction of Chemicals (REACH) has
banned hexavalent Cr coatings because
they are carcinogenic. In addition, 4% of
ZINC PRESSURE DIE CASTING
Conventional Hot Chamber Machine Behind the Research
people in Europe and 5% in America are
allergic to chromium, and hexavalent Cr is
Valeriia Reveko
much more likely to cause a skin reaction
such as dermatitis than the trivalent one. E: vreveko@collini.eu T: +43 664 6105 729 www.linkedin.com/in/valeriia-reveko-10047a118/
W: collini.eu
In general, colourimetric
1,5-diphenylcarbazide (DPC)-based
spot test is one of the principal methods
used to identify hexavalent chromium
Research Objectives References
on various metallic and leather surfaces. PhD candidate Valeriia Reveko from the Austrian Valeriia Reveko and Per Møller (2018). ‘Special Aspects
However, and as noted in Reveko, electroplating company Collini, has led a series of studies of Electrodeposition on Zinc Die Castings’. NASF Surface
Lampert, Din, Thyssen and Møller (2018), looking into how to make zinc alloys more sustainable. Technology White Papers, 82 (8), pp. 1-9, Article Post:
DPC testing on trivalent chromium Zinc die casting machine. 3/19/2018.

Research in Collini intends to reveal SUSTAINABLE SOLUTIONS

This research would be remiss if it did
Detail Valeriia Reveko, Felix Lampert, Grethe Winther and Per
Møller (2018).’Change of The Decorative Properties Of Zinc-
and address the causes of common not consider the present-day ecological Collini GmbH, Plated Zinc Die Castings Over Time’. International Journal of

plating faults and support sustainable sustainability challenges. Coated metal

alloys consist of parts with multiple coating
Schweizer Str. 59,
6845 Hohenems
Metalcasting, pp. 1-7, https://doi.org/10.1007/s40962-018-
0237-0.
use of materials. layers of different metals that are tricky to Austria
recycle. This is because separating metals Valeriia Reveko, Felix Lampert, Rameez Ud Din, Jacob P.
passivated zinc surfaces can actually on the surface because of atmospheric such as chromium and nickel – metals Bio Thyssen, Per Møller (2018) ‘False-positive result when a
be misleading. X-ray photoelectron corrosion can be the reason for these false- that are traditionally used to coat zinc Valeriia Reveko is a Product- and Process Development diphenylcarbazide spot test is used on trivalent chromium-
spectroscopy (XPS) measurements positive results. The importance of this metal alloys – is a process with increased engineer in Collini GmbH, Austria. She holds an MSc degree passivated zinc surfaces.’ Contact Dermatitis, Volume 78: Issue
performed in this research study did study is not limited to the impeccable level energy demands. Therefore, researchers in technical electrochemistry from Kiev Polytechnic Institute 5, pp. 315-320, doi:10.1111/cod.12955.
not verify the presence of hexavalent of quality control needed in the European have shifted their focus on coating zinc and is conducting a PhD project in materials science and
chromium previously identified on such metal industry, but also because these alloys with zinc coatings because this surface technology at the Technical University of Denmark
surfaces by DPC. The study suggests that
unintended oxidation of the DPC indicator
false-positive results can unavoidably result
in the prescription of erroneous treatment
process reduces the overall number of
metals used, thus rendering the recycling
(DTU).
Personal Response
in reaction with the substances present to patients with contact dermatitis. process easier. This is exactly why Collini Funding
has turned its attention towards improved The research was funded by Collini GmbH, Hohenems. Why do you think it’s important to find ways
ZINC RESPONSIBLE USAGE CYCLE approaches of the surface treatment of to recycle zinc?
zinc die-cast parts. The usage of recycled Collaborators It is my position that in today’s world, we cannot
zinc is an energetically favouring process • Professor Per Møller, Technical University of Denmark (DTU). continue to use natural resources in such an exploiting
because its energy requirements are less manner as we currently do at the moment. Our planet has
than 10% compared to the production given us a great deal, and the least we can do in return is
SUSTAINABLE
INCREASED to use these resources wisely. Zinc, copper, nickel, steel,
of primary zinc. Essentially, the research
SERVICE LIFE aluminium, plastic – before putting those materials to the
presented in this article is directly market, we must carefully consider the whole product
connected to the increasing industrial lifecycle, aiming for sustainable solutions; and the surface
need for recyclable zinc components. treatment industry can be a conductor who make a real
impact on this.
SIB
LE CONSUMPTIO
N
CONCLUSIONS
ON
SP
This research conducted by Collini intends ‘Applied surface intelligence’ is the motto at Collini,
RE

SUSTAINABLE and we all work together with the aim of using materials

Zn
IMPROVED to identify and evaluate the core causes of
PROFITABILITY more effectively.
common plating faults while supporting
N

RECYCIN
UCTIO

ABUNDANT
NATURAL the sustainable use of materials. Valeriia
OD

RESOURCES
PR

EFFICIENT ZINC Reveko’s study provides greater insight

LE

AB
AIN RECYCLING
SUST
into the electroplating of zinc die castings
while at the same time, it manages to
SUSTAINABLE evaluate the hidden challenges of zinc-
PRODUCTION
plated and zinc die-casted components,
and trivalent chromium-passivated zinc
surfaces.
DECREASED
CO2 ENVIRONMENTAL
IMPACTS
COSTS
REDUCTION

32 www.researchoutreach.org www.researchoutreach.org 33
Physical Sciences ︱ Professor Toshikazu Ikeda
Mathematical Modelling Ex. Night time in Norway

Evaluating students’ Real

World
Concrete
Model
Geometric
Model
Symbolic
Model

perceptions of the roles

66.6°
x° 90° y=(2/15).cos-1
0° {tan(23.4).tan x}

of mathematics in society Graphic

Model

Y: Hours of night time

Toshikazu Ikeda, Professor
of Mathematics Education
at Yokohama National
University, has found that while
mathematical modelling is
often evaluated with respect
to mathematical attributes,
little academic consideration
has been given to the non-
mathematical viewpoint. To fill
this knowledge void, he has
developed an analytical tool
to evaluate the changes in
students’ perceptions of the
roles of mathematics in society
following an experimental
teaching program.
aving students recognise the roles
that mathematics takes in society
is a significant aim in the teaching
and learning of mathematical modelling.
This issue has been considered by
academics since the 1980s. There have
been several studies investigating student
belief about the value of mathematics
in society, but little has changed in
the literature regarding the many roles
of mathematics in society.
CLASSIFICATION OF
MATHEMATICAL MODELS
Mathematical models are often classified
according to their various attributes:
whether they are concrete or abstract,
descriptive or analytical, together with
their underlying mathematical basis, such
as algebra, geometry or statistics. While
useful, these categories are essentially
founded on mathematical perceptions.
Toshikazu Ikeda, a Professor of
Mathematics Education at Yokohama
National University, considers the non-
mathematical viewpoint in his study
Experimental teaching: the number
of years to double their savings.
and has developed an analytical tool
to assess how students perceive the roles
of mathematics in society.
METHODOLOGY
The Likert-scales method, where items
are usually rated from ‘strongly agree’
to ‘strongly disagree’, is often used to
assess students’ awareness of how useful
mathematics is in the real world. While this
is a simple and effective tool, it does not
capture detailed information regarding
students’ perceptions of the roles
of mathematics in society.
Professor Ikeda has developed four
categories which are centred on why
mathematical models are used in society.
These combine three standpoints:
personal-societal perspectives, clarity of role
statements, and specific-general contexts.
CATEGORIES
In the first category, students see
mathematical modelling only from
a personal perspective. For example,
they realise the usefulness of
carrying out their personal
financial calculations, but ignore
the impact on society.
The second category has students
adopting some social perspective;
however, their responses are not
specific. For instance, they will
acknowledge that mathematics is
useful in society but not mention
how it is useful or provide examples.
In the third category, students
assume a societal viewpoint
and refer to a specific context,
such as how mathematics can
help a particular company reduce its
manufacturing costs, but they do not
include a general context.
NIGHT TIME
IN NORWAY
Why is daytime so long? In Japan,
it is pitch-dark at 10:40pm
An example of using mathematics to explain and predict phenomena.
The fourth category has students
adopting a societal perspective and
referencing a general context, such
as using mathematics to explain
phenomena, contribute to decision
making, or assist with designing objects.
INVESTIGATION
Professor Ikeda conducted an
experimental program with a ninth-grade
class of approximately 30 students. The
procedure was carried out over two years
(2007–2008) at a junior high school in
Japan with the same teacher during both
years. A teaching program comprising
nine lessons was devised. These lessons
took place once a week from September
to November each year and were carried
out by the classroom teacher. The first
eight lessons each lasted 100 minutes
and the ninth lesson took 50 minutes.
THE EXPERIMENTAL
TEACHING PROGRAM
The program of lessons concentrated
on three roles of mathematics in society:
understanding, making decisions, and
designing. Eight modelling tasks were
selected. The ‘understanding’ tasks
involved investigating reflections of a face
in a mirror and calculating probabilities
in rock-paper-scissors. During the ‘making
decisions’ tasks, students examined
X: North Latitude
From the mathematical model, we can understand that
the hours of night time dramatically decrease in Norway
Having students recognise the roles
that mathematics takes in society is
a significant aim in the teaching and
learning of mathematical modelling.
a bank interest system, calculated when we examine real-world problems
the number of years to double their from various perspectives?’ before
savings and explored the position of commencing the program of nine lessons.
tennis serves. The ‘designing’ tasks
included investigating the shapes of During the first seven lessons, the teacher
cans, exploring the structure of a bicycle conducted group discussions regarding
reflector and designing a parking space. the modelling process. These were
followed by problem-solving periods
The students were asked to write down where the teacher presented one of the
their responses to the pre-program modelling problems. The students worked
question: ‘How is mathematics useful on the problem in groups of 4 or 5 and
TO MAKE MONEY DOUBLE
X 1 2 3 4 5 6 7 8 9 10
Y 70 36 24 18 15 12 11 10 9 8
a 70 72 72 72 75 72 77 80 81 80
VALUE OF A
Calculation of average: a = 75.1 A simple model to calculate the number
of years to double their savings.
y = 75.1/x

34 www.researchoutreach.org www.researchoutreach.org 35
then came together to discuss it as a class.
In the seventh and eighth lessons, three
tasks were introduced and each group
of students selected one to work on.
Throughout the lessons, emphasis was
put on the reason for solving problems
and students were encouraged to reflect
on the roles of mathematics in order to
identify the significant aspects of the roles
of mathematics in society. The students
first reflected prior to the teaching
program; followed by reflection after
each lesson; and finally, after the teaching
program was completed.
During the ninth lesson, the students
reviewed the eight modelling tasks. They
reflected on the modelling processes and
identified the common points in order to
ascertain the roles of mathematics. The
students discussed the problems they
faced during the eight tasks and how they
solved them. The students then broke
into groups to the post-program question:
‘How is mathematics useful when we
examine real-world problems from various
perspectives?’. Then the teacher asked
each of the students to write down their
answer without any teacher-led discussion
so that the students could provide their
own answers supported by their group
discussion, but without any influence from
the teacher.
ANALYSIS
A total of 57 students took part in the
study, 31 students during the first year
and 26 students during the second.
The students’ responses to the pre- and
post-program questions regarding their
perception of the roles of mathematics
in society were coded and then analysed.
Ikeda’s analytical tool revealed that
students’ opinions concerning the roles
of mathematics in society changed
significantly over the course of the nine-
week experimental teaching program.
Analysis of the students’ perception
relating to personal-societal perspectives,
clarity of role statements, and specific-
Students’ opinions concerning the roles
of mathematics in society changed
significantly over the course of the nine-
week experimental teaching program.
36 www.researchoutreach.org
Experimental teaching: investigating reflections
of a face in a mirror.
general contexts was carried out. A few
students continued to adhere only to their
personal perspectives or provide vague
statements, insisting that mathematics
was not useful in their lives, even though
they acknowledged that it might be useful
for others.
With respect to the personal-societal
perspective, only a few students adopted
a personal perspective without also
developing a societal perspective.
Regarding the clarity of role statements,
several students still only used vague,
general statements. From the specific-
general contexts, the analytical tool
revealed that some students were able
to clearly identify several purposes
of mathematical modelling.
Professor Ikeda found that by using
the analytical tool he could start to
distinguish between the qualitative
differences of the various students’
perceptions of the roles of mathematics
in society as well as whether students
were able to appreciate the roles from
both personal and societal perspectives
or only a personal perspective. He also
discovered that students, who were able
to perceive the roles of mathematics in
society, did not automatically appreciate
the utility of mathematics.
CONCLUSION
Professor Ikeda found strong evidence
to suggest that this type of teaching
program is significantly effective in
developing students’ thinking and their
appreciation of mathematical modelling.
This was reinforced when he examined
the work that students produced in
the study, demonstrating their thoughts
on solving the set tasks. Ikeda found
that these written examples of students’
thinking consistently demonstrated
a marked increase in the quality
and depth of the students’ insight into
the mathematical modelling process.
This study also revealed that Professor
Ikeda’s analytical tool enabled the
clarification of students’ perceptions of
the roles of mathematics in society, both
before and after the teaching program
was performed. This revealed how
students’ perceptions regarding the roles
and utilisation of mathematics in society
changed significantly over the course
of the nine-week teaching program.
Professor Ikeda recommends that further
attention should be paid to both the
validity and reliability of his analytical
tool, particularly when setting up the
pre- and post-program question and
interpreting of the students’ response.
He suggests that samples of students
are interviewed to check the validity
of the results. Keeping these points in
mind, this analytical model still merits
further use in future studies, particularly
those involving student belief regarding
the value of mathematics in society.
Behind the Research
Professor Toshikazu Ikeda
E: toshi@ynu.ac.jp T: +81 45 339 3371 W: http://er-web.jmk.ynu.ac.jp/html/IKEDA_Toshikazu/en.html
W: www.researchgate.net/profile/Toshikazu_Ikeda W: https://slideplayer.com/slide/8309101/
W: https://link.springer.com/article/10.1007/s11858-018-0927-3
Research Objectives
Toshikazu Ikeda, Professor of Mathematics Education
at Yokohama National University, work focuses on
teaching mathematical modelling and its applications.
He has recently developed an analytical tool to evaluate
the changes in students’ perceptions of the roles
of mathematics in society following an experimental
teaching program.
Detail
Yokohama National University
40-8501 Kanagawa Prefecture,
Yokohama, Hodogaya-ku,
Japan
Bio
Toshikazu Ikeda is a Professor of Mathematics Education
at Yokohama National University. He received his PhD in
education at Waseda University in 2014. Since 1999, he
has studied the teaching of mathematical modelling and
applications, funded by a Grant-in-aid for Science Research
in Japan.
Funding
Grant-in-aid for Science Research in Japan
References
Ikeda, T. (2018). ‘Evaluating student perceptions of the roles
of mathematics in society following an experimental teaching
program’. ZDM Mathematics Education, 50(1-2), 259-271.
Ikeda,T. and Stephens, M. (2010). ‘Three teaching principles
for fostering students’ thinking about modelling: An
experimental teaching program for 9th grade students in
Japan’. Journal of Mathematical Modelling and Applications,
2(1), 49-59. Available at: http://proxy.furb.br/ojs/index.php/
modelling [accessed 02/01/19].
Ikeda,T. (2009). ‘Didactical Reflections on the teaching of
mathematical modelling-Suggestions from concepts of ‘time’
and ‘place’’. In Morten BlomhØj and Susana Carreira, Roskilde
University, Department of Science, Systems and Models,
Mathematical applications and modelling in the teaching
and learning of mathematics, 217-228. IMFUFA tekst nr.461.
Ikeda, T., & Stephens, M. (2017). ‘Modelling as interactive
translations among plural worlds: Experimental teaching using
the night-time problem’. In G.A. Stillman, W. Blum, & G. Kaiser
(Eds.), Mathematical modelling and applications – Crossing
and researching boundaries in mathematics education
(pp.399-409), Springer International Publishing.
Personal Response
What initially prompted you to investigate students’
perceptions of the roles of mathematics in society?
In Japan, there has been the tendency where students
have not realised the usefulness of mathematics in society
from the result of PISA. To overcome this tendency,
mathematical modelling has been gradually emphasised
in the teaching of mathematics. However, I am uncertain
that students will realise the usefulness of mathematics
by focusing on mathematical modelling in mathematics
lessons. If students thought that mathematics might not
be used in his/her future life, he/she might not realise the
usefulness of mathematics even though he/she realises
that mathematics is applied in the real world. This study
starts from this question.
www.researchoutreach.org 37
Physical Sciences ︱ Professor Jeffrey Oaks

François Viète’s A geometric polynomial

revolution in algebra
from Viète’s De Recognitione
Aequationum (1615), which
can be translated into our
notation as A4+2B∙ A3+B2∙ A2.
Among other differences,
note the prepositions “in” for
multiplication, and the lack of
the coefficient “1” before the
“A quad. quad.”

François Viète is considered
by many historians to be the
founder of modern algebra,
but his work has not received
the academic attention it
deserves. Professor Jeffrey
Oaks from the University of
Indianapolis seeks to redress this
imbalance. Through his study
of Medieval and Renaissance
mathematics, Professor Oaks
shows how Viète reestablished
algebra on a geometrical
foundation; and in the process
created an entirely new notation.
His work inspired Fermat’s
and Descartes’ developments
and led to algebra becoming
the language of science.
T
he word algebra derives from
the Arabic al-jabr, which means
restoration, or the reunion of
broken parts. Algebra can be traced back
to ninth century CE Arabic books on
the topic, and prior to that, we find that
it was practised in India, Greece, and even
ancient Babylonia.
Algebra before 1500, whether in Arabic,
Latin, or Italian, was used predominantly
for numerical problem-solving by
practitioners such as merchants,
government secretaries and surveyors.
Only a few mathematicians employed
it for more ‘scientific’ exploits, such
as Diophantus in the 3rd century CE,
Omar Khayyam in the 11th century, and
Jordanus de Nemore in the 13th century.
Algebra began to attract the attention
of theoretically-minded mathematicians
in sixteenth-century Italy. Mathematicians
such as Scipione del Ferro, Niccolò
Tartaglia, Girolamo Cardano and Rafael
Bombelli had finally solved irreducible
cubic and quartic equations, and in
the process, they had begun to explore
negative and complex numbers.
from his predecessors. Beginning in 1591,
he published a series of short treatises
in which his algebraic knowns and
unknowns, which he calls ‘magnitudes’,
possess dimension without limit, and,
for the first time, arbitrary knowns are
represented in notation. It is mainly
because of his notational innovations that
he has been credited by some historians
as being the founder of modern algebra.
A MISUNDERSTOOD
MATHEMATICIAN
Despite Viète’s importance, and partly
due to his own terse and sometimes
confusing style, his work has been
misunderstood and has not received the
serious attention it warrants. For starters,
just what are these capital letters he
employs in his new algebra? Jeffrey
Oaks, Professor of Mathematics at
the University of Indianapolis, however,
is redressing this. Nearly two decades
ago he decided to combine his two
main interests, Mathematics and History,
in the study of Medieval Arabic
mathematics. Professor Oaks enlisted
the help of a Palestinian colleague to
teach him Arabic and embarked on the
PREMODERN POLYNOMIALS
Oaks discovered that algebraists before
Viète conceived of the objects of their
study, that is monomials, polynomials,
and equations, differently than we do
today. A premodern polynomial was
considered to be a collection of different
kinds of numbers or powers, without
any operations present. Where our x2
+ 3x, for example, is constructed from
the operations of exponentiation, scalar
multiplication, and addition, the medieval
equivalent ‘a māl and three things’ (here
translated from Arabic) was simply a
collection of four items of two kinds, like
saying ‘an apple and three bananas’. This
interpretation lay behind the algebra in
Ancient Greek, medieval Arabic, Latin,
and Italian, and even in the algebra of
sixteenth-century Europe.
A NEW ALGEBRA FOR GEOMETRY
Prior to Viète, the knowns and unknowns
in algebra were positive numbers. Viète
diverged from this norm, but in a way
Viète was also the first mathematician
to explore beyond the third dimension
What drove Viète was his interest in
producing accurate astronomical tables.
He was faithful to the Greek tradition
exemplified in Ptolemy’s Almagest (2nd
century CE) by regarding geometry
as providing the theoretical footing
for calculations in astronomy. (Even if
magnitudes have no intrinsic numerical
measure, one can assign numerical
measures to them.) Ptolemy had not
used algebra to express his theorems
or to perform his calculations, but Viète,
through his investigations in trigonometry,
found a way to adapt the numerical
algebra of his time to a geometrical
setting. By working abstractly with higher-
dimensional magnitudes and by resolving
proportions into equations, he laid
the foundation for a new algebra. This
new algebra, which he called logistice Portrait of Viète from Savérien’s 1773 Histoire des
speciosa, wasn’t just another step towards Philosophes.
modern algebra. It was a complete
overhaul of the very foundation of the operations. Before Viète, the powers of
art. It inspired Fermat’s and Descartes’ the unknown in algebra were considered
developments, which ultimately led to the to be different types of numbers and were
given individual names. For instance,
in 1575, Xylander called the first-degree
unknown “numerus” and the second
degree unknown “quadratum”, which

FRANÇOIS VIÈTE
François Viète (1540 -1603), a French
lawyer in the court of Henry IV, took
algebra in a completely different direction
study of Arabic algebra. His early work
exposed the conceptual differences
between medieval and modern algebra,
and those studies laid the foundation
for his later work on Viète.
in geometry.
that had not been properly analysed
before. Professor Oaks has reviewed
the whole of Viète’s output, along with
an extensive range of mathematical
literature from the period, and has
determined that Viète’s letters, standing
for his knowns and unknowns, represent
instead geometric magnitudes such as
lines and surfaces. More specifically,
they represent the relative sizes that
geometric magnitudes have with respect
to one another, without any regard to
possible numerical measures. In other
words, Viète created an algebra for
classical geometry.
replacement of Euclidean geometry with
algebra as the standard way to express
scientific results.
A RADICALLY NEW CONCEPT
OF POLYNOMIAL, AND A NEW
NOTATION TO GO WITH IT
One natural consequence of the shift
from an arithmetical to a geometrical
foundation is that Viète’s polynomials
were understood in an entirely new way.
Where premodern polynomials were
simply aggregations of the powers,
Viète’s polynomials are modern in the
sense that they are now constructed from
he abbreviated as “N” and “Q”. In
one problem, for example, he wrote
“1Q+6N+36” for what would be our
x 2+6x+36. While Xylander’s notation
may look modern, the letters function
differently than our powers of x. The “Q”
is a denomination or type (like “euro”),
and only with a coefficient (here a “1”)
does it assume a value (like “1 euro”). This
is how all the various algebras preceding
Viète functioned, both rhetorically
and in notation.
The notation of Viète’s logistice speciosa
performs differently from its premodern
counterpart. Viète expressed Xylander’s
polynomial as “A quadratum, + B in A, +
B quadrato”, or translated into English,

38 www.researchoutreach.org www.researchoutreach.org 39

A polynomial from Michael
Stifel’s book Arithmetica Integra
(1544), showing premodern
notation. We would write it as
150x-√(4500x2)+x2. Note the
coefficient of “1” on the last term.
Compare with the notation on the
preceding page.
“A squared + B (multiplied)
by A + B squared”. While
Viète’s notation may look
a little less symbolic, his
letters were the first in
algebra to denote values,
thus the lack of a “1”
before the “A quadratum”.
This term represents the
size of a square relative
to other magnitudes. This
reconception opened
the door to operations
in algebraic expressions beyond
polynomials that had been absent before.
Further, because Viète’s algebra is
founded in geometry, his coefficients
are necessarily arbitrary geometric
magnitudes (here “B” and “B quadrato”
instead of “6” and “36”). This enabled
the structure of solutions to be depicted
Viète’s geometrical algebra, built
on a new foundation, would eventually
oust the old premodern algebra.
René Descartes, whose 1637 La Geometrie
built on Viète’s new algebra.
40 www.researchoutreach.org
Title page to Vasset’s 1630 French translation of two
of Viète’s works, showing Viète on the right.
in a simplified equation, or formula;
and because Viète’s goal was ultimately
numerical calculation, this formula could
be reused, substituting different knowns
to generate tables.
BEYOND THE THIRD DIMENSION
Prior to Oaks, the only serious study
of the ontology of Viète’s logistice
speciosa was a 1936
article by the German-
trained philosopher
Jacob Klein. Klein,
searching for the origins
of modern, axiom-
based mathematics, saw
the objects of Viète’s
algebra not as geometric
magnitudes, nor as
numbers, but as abstract
entities that transcend
the two. Klein’s thesis
gained traction with its
translation into English
in 1968. Although not
universally accepted, it
has remained until now
the only serious study of
the ontology underlying
Viète’s algebra.
According to Oaks, Klein probably went
astray largely because he (and other
historians as well) failed to notice that
Viète worked with four-dimensional
geometric magnitudes in two of his
propositions. No mathematician
before Viète had gone beyond the
third dimension. Viète made this leap,
not by some deep insight into the nature
of geometry, but simply because it gives
correct values when applied to numerical
calculation. Like other impossible objects
of his century, such as negative and
complex numbers, higher dimensions in
geometry were admitted because they
proved to be useful.
IMPACT
Viète’s new geometrical algebra would
eventually oust the old algebra. His
concept of polynomial, together with
his novel notation, was taken up in
modified form in Descartes’ 1637 La
Geometrie. Descartes presumed an
intrinsic numerical measure for his
magnitudes, and thus re-introduced
numbers to algebra. He also preferred
the lower case x and y, which we still
use today, to Viète’s capital A, E, etc.
It is the algebra of Descartes that became,
and remains today, the standard mode
of expressing mathematics, physics,
and other fields. With Viète’s work,
what had been a practical technique
of merchants and surveyors was
on its way to becoming the language
of science.
Behind the Research
Professor Jeffrey Oaks
E: oaks@uindy.edu T: 1 317 788 3454 W: https://www.uindy.edu/cas/mathematics/oaks/
W: https://www.uindy.edu/cas/mathematics/faculty W: https://www.researchgate.net/profile/Jeff_Oaks
Research Objectives
Professor Jeffrey Oaks’ study of Medieval Arabic Algebra at
the University of Indianapolis has led to his discovery of the
innovations of François Viète that underpin modern algebra.
Detail
Department of Mathematical Sciences
University of Indianapolis
1400 E. Hanna Ave.
Indianapolis, IN 46227 USA
Bio
Jeffrey Oaks received his PhD in Mathematics from the
University of Rochester in 1991. Since 1992, he has been
a Mathematics Professor at the University of Indianapolis.
Oaks originally worked in differential geometry, but
switched to history of mathematics in 1999. Since then,
he has focused mainly on medieval Arabic algebra.
References
Oaks, J.A. (2018). ‘François Viète’s revolution in algebra’.
Archive for History of Exact Sciences, 72 (3), 245-302.
Oaks, Jeffrey A. (2017). ’Irrational ‘coefficients’ in Renaissance
algebra’. Science in Context, 30, 141–172.
Klein, J. (1968). ‘Greek Mathematical Thought and the Origin
of Algebra’ (trans: Brann, Eva). Cambridge: MIT.
Klein, J. (1936). ‘Die griechische Logistik und die Entstehung
der Algebra. II’. Teil. Quellen un Studien zur Geschichte der
Mathematik Astronomie und Physic, 3(2), 122–235.
Personal Response
What initially prompted your research into medieval
Arabic mathematics?
I knew even as an undergraduate student that Arabic
mathematics is as important as it is understudied. While
many people are working on, say, eighteenth-century
mathematics, very few are reading the Arabic manuscripts.
I am currently one of the few people in the world working
on Arabic algebra.
What are your plans for future research in this area?
At the moment, I am working on a translation
and commentary of the Arithmetica of Diophantus of
Alexandria with a co-author, Jean Christianidis. I am also
planning other studies on Arabic mathematics, and I will
eventually look beyond Viète to investigate the algebra
of 17th c. Europe.
www.researchoutreach.org 41
Physical Sciences ︱ Dr Tamás Biró
Generalising the
Entropy Formula through
Master Equations
Entropy is one of the most
important and most widely
studied quantities in physics,
and for centuries, its value
has been robustly described
using simple mathematical
relationships. Yet however
elegant, Tamás Biró at the
Hungarian Academy of
Science believes the formula
is hiding a more complex
array of relationships. Through
constructing ‘master equations’
to describe these relationships,
Biró and his colleagues are using
statistics to study problems
as diverse as the formation of
hadrons, changes in biodiversity,
and patterns in popularity
on Facebook.
Energy, Entropy, the 2nd law of Thermodynamics
High Randomness,
High Entropy, High Disorder
42 www.researchoutreach.org
E
very system around us has
a different degree of chaos
associated with it. While atoms
within metals are arranged in neat,
highly ordered lattices, the movements
of gas molecules in the air are far more
chaotic and unpredictable. Since the
19th century, physicists have described
this chaos using a quantity known as
‘entropy’. The changes in entropy which
take place during physical processes form
the basis of one of the most fundamental
laws of physics: The Second Law of
Thermodynamics. The law states that
in any system closed off from the outside,
entropy must not decrease over time; as
such, the universe becomes more chaotic
as a whole.
As Dr Biró describes, this inevitable
increase in entropy represents a decrease
in the number of possible leftover
arrangements of particles, or ‘states’,
that a system can find itself in as the
one-way passage of time progresses.
“Macroscopically, entropy has proved
never to decrease spontaneously;
an idea related to the ‘arrow of time’,
or irreversibility,” he explains. “Many
processes in nature end up only
Low Randomness,
Low Entropy, Low Disorder
in some selected states while they may
begin in any of a vastly larger amount
of possible states. All microscopic
changes in a complicated closed system
conspire in a way that the total entropy
never decreases.”
To quantify entropy, physicists ultimately
need to use statistics to study how
particles move around into different
arrangements over time. “Kinetic theory
and its follower, statistical physics, depend
on our knowledge about entropy,” Dr
Biró continues. “They can be viewed
as given mathematical formulae based
on the probability of being in a given
state. All random, or ‘stochastic’ models
are now checked for satisfying such
a theorem, accounting for random
forces in their calculations.” Even after
centuries of scrutiny, these mathematical
descriptions have proved time and
again to robustly describe real physical
systems. However, in their research, Dr
Biró and his colleagues now want to take
the theory a step further.
GENERALISING
BOLTZMANN’S FORMULA
In the 1870s, Austrian physicist Ludwig
Boltzmann was able to reduce the
quantity of entropy down to a remarkably
simple, elegant formula. He proposed
that its value simply has a logarithmic
relationship with the number of possible
states a system can have under its
current conditions. Yet although the
formula is so effective in mathematically
predicting changes in entropy, Dr
Biró and colleagues believe it cannot
completely account for the more complex
physical processes which underlay
it. In their research, the researchers
aim to generalize Boltzmann’s simple
equation; identifying mathematical
relationships which build up to the overall
logarithmic relationship.
All microscopic changes in a complicated
closed system conspire in a way that
“Our research couples to the novel efforts
to generalize Boltzmann’s original formula, the total entropy never decreases.
containing the logarithm – a neat function
mapping products to sums,” says Dr Biró. In their research, Dr Biró and colleagues particles in a system to be in a certain
“What are the more general dynamical have proposed a new way of looking place. The probability distributions
processes which make it unavoidable to at the problem, based on the earlier work derived by Tsallis could describe the
use Boltzmann’s logarithm?” Through of Brazilian physicist Constantino Tsallis. entropy of physical systems far more
several studies, the researchers have used In the 1980s, Tsallis drew up a new set realistically than previous models.
real-world examples of entropy changes of statistical parameters to generalise
to study how Boltzmann’s logarithm can Boltzmann’s formula, resulting in a Based on Tsallis’ work, Dr Biró’s team
be generalised in this way. The problems new branch of statistics for the specific could construct a set of ‘master equations’
they have analysed so far range from case of entropy. In particular, his equations – mathematical relationships which build
fundamental questions of particle physics resulted in new sets of probability up to Boltzmann’s formula collectively but
to patterns of interaction on social media. distributions – statistical formulae which better describe the behaviour of physical
describe how likely it is for individual systems individually.
SOLVING THE
HADRONIZATION PROBLEM Number Dynamics Probability Dynamics
In the dynamic first moments of the
universe, fundamental particles known
as quarks and gluons existed as freely-
flowing elements of a gas-like soup,
or plasma. However, these particles
ultimately cannot exist by themselves;
within octillionths of a second after the
Big Bang, they grouped together to form
stable structures named hadrons – made
from three quarks bound together by
gluons. Yet the process of ‘hadronization’
throws up a problem for physicists: since
hadrons appear to be far more ordered
than a quark-gluon plasma, how could
Schematic representation of the coarse-grained random growth model. Previously published in Zoltán
the overall entropy of the universe Néda et al. https://doi.org/10.1371/journal.pone.0179656 and is under the Creative Commons Licence
have increased? CC BY 4.0.
www.researchoutreach.org 43
 Rescaled distribution of the citation (share) numbers.
Previously published in Zoltán Néda et al. https://doi.org/10.1371/journal.pone.0179656 and is under
the Creative Commons Licence CC BY 4.0.
This allowed the researchers to approach
the hadronization problem from a new
angle; providing new insights into how
entropy could have increased as a whole
in the earliest moments of the universe.
Dr Biró and colleagues also applied their
mathematics to other situations; testing
the effectiveness of their model on
systems including patterns of popularity
on social media, distributions in income
and wealth, along with size distributions
of settlements and ecosystems.
A SET OF MASTER EQUATIONS
Through these studies, Dr Biró and
colleagues have made strides towards
generalizing Boltzmann’s original
formula, using mathematics adapted
from the principles of statistical physics
which Tsallis first generalized for the
case of entropy. As Dr Biró explains,
“We found that nonlinear master
equations: dynamical equations treating
the probabilities of systems being
in given states not linearly, but via some
more complicated function, lead to the
use of non-logarithmic formulas for
the entropy.” Using such sophisticated
mathematics, the researchers could
Dr Biró and colleagues have made
strides towards generalizing Boltzmann’s
original formula.
44 www.researchoutreach.org
construct entropic probability
distributions which more closely reflect
those which can be observed in nature.
Ultimately, these master equations
allowed Dr Biró and colleagues to
model how the probability distributions
of systems evolve as time progresses,
and entropy increases. Over time,
an increase in entropy will mean the
probability distribution associated with
a system can be expected to shift. “Our
way of showing this relied on the use
of an ‘entropic divergence’: a non-
symmetric distance formula between
two probability distributions,” Dr Biró
continues. “Stable nonlinear master
equation models describe a change of
probabilities always towards a no-more-
changing, stationary distribution.” As
such, the team’s master equations could
model the changes in entropy of real
systems over time.
Through this work, Dr Biró and
colleagues could construct a ’non-
extensive’ entropy formula, which
accounted for how the probability
distribution of a system after a process
Left: scheme for processes with local changes
(e.g. diffusion). Mid: scheme for locally one-way
processes with resets to the ground state (e.g.
popularity). Right: scheme for general processes
with long jumps (e.g. stress in earthquakes).
has played out will be independent
of the initial probability distribution
for most materials. Since this entropic
distance relationship more closely
reflected reality, the master equations
could be used to construct a highly
generalized formula for calculating
entropy. “A number of physical
systems are described by stochastic
master equations,” explains Dr Biró.
“Their corresponding stationary
distributions belong to maximal entropy;
therefore, entropy can also be defined
as the entropic divergence from
the uniform distribution.”
APPLYING THE MODEL
The mathematics described by Dr Biró
and colleagues can already be used to
model the entropy changes which unfold
in a wide variety of different systems.
“We apply our mathematical model
to various physical systems, including
complex networks of popularity
like citations or Facebook likes, city
size distributions, produced hadron
energies in big collider experiments,
student exchange networks between
universities, among others,” Dr Biró
concludes. Yet the team’s mathematical
description is still far from complete.
In future work, the researchers will
study more complex nonlinear master
equations; enabling for an even greater
understanding of how entropy works.
Behind the Research
Dr Tamás Biró
E: Biro.Tamas@wigner.mta.hu T: +36 20 435 1283
Research Objectives
Biró and his colleagues are using statistics to study
problems as diverse as the formation of hadrons, changes
in biodiversity, and patterns in popularity on Facebook.
Detail
H-2081 Piliscsaba, Tó sétány 5A, Hungary
Bio
Tamás studied physics at Eotvos University from 1975
til 1980, and received an MSc in physics and biophysics.
He later received his PhD degree at the same university.
Tamás is the vice director of the Institute for Particle
and Nuclear Physics, the half of the Wigner Research
Centre for Physics, in Budapest.
Funding
• Ministry for Innovation and Technology
• National Research Development and Innovation
Office (both in Hungary)
Collaborators
• Zoltán Néda (UBB Cluj, Romania)
• András Telcs (Wigner RCP, Budapest, Hungary)
W: www.rmki.kfki.hu/~tsbiro
References
Biró, T.S., Barnaföldi, G.G., Biró, G., Shen, K.M. (2017).
‘Near and Far from Equilibrium Power-Law Statistics’.
Journal of Physics: Conference Series, 779(1), 012081.
Biró, T.S., Schram, Z., Jenkovszky, L. (2018). ‘Entropy
production during hadronization of a quark-gluon
plasma’. The European Physical Journal A, 54(2), 17.
Biró, T.S., Neda, Z. (2018). ‘Unidirectional random
growth with resetting’. Physica A: Statistical Mechanics
and its Applications.
Biró, T.S., Telcs, A., Néda, Z. (2018). ‘Entropic Distance
for Nonlinear Master Equation’. Universe, 4(1), 10.
Personal Response
What future research studies do you have planned?
So far, we have discovered that whenever a
dynamical master equation uses non-linear functions
of probabilities, then the general way of constructing
entropic divergence and through this the entropy –
probability relation leads to new formulae. On the
other hand, more trivially, transition rates depending
on the state properties (including linear preference
rates) also determine the stationary distribution having
a non-exponential, non-Boltzmannian form.
Our plans include to study systems where both
the initial and the target state influences the micro-
transition rate between them. Here the increase of
entropy is highly a nontrivial question, and no definite
answer has been found so far – except for cases
restricted by the detailed balance condition. Another
future development is to study processes where no
detailed balance is possible, due to asymmetric big
jumps occurring as easily as small transitions. Such
physical systems can show avalanches or earthquakes.
For these questions, we concentrate not on the
final distribution of stress (which describes a state),
but on the distribution of the size of the jumps
in the dynamics.
www.researchoutreach.org 45
Physical Sciences ︱ Dr Julien Orts
NMR :
A highly accurate approach to protein-ligand binding
A novel method to determine
accurately and efficiently the
structure of the receptor binding
sites in protein-ligand complexes
promises to revolutionize drug
discovery. Dr Julien Orts and
his collaborators at the Swiss
Federal Institute of Technology
are developing a powerful
and general technique, based
on liquid nuclear magnetic
resonance (NMR), to shed light
on the details of how proteins
interact with drugs.
46 www.researchoutreach.org
2
P
roteins are the fundamental
building blocks of all living matter,
from microscopic viruses and
bacteria to highly evolved multicellular
organisms, plants, animals and humans.
They play a role virtually in all phenomena
associated with life, including providing
structural support to individual cells
and tissues, enabling motion in complex
organisms, producing energy and
regulating signalling between cells in
the body. Frequently, the physiological
function of proteins is modulated by the
interaction with small molecules (ligands),
which can bind to specific receptor sites
in a protein and trigger a response, e.g.
in the form of a structural change or of
a chemical reaction. For instance, ligands
like hormones can promote cell growth by
increasing the rate of protein production
or they can induce relaxation in muscle
Understanding the nature of the
interactions between proteins and ligands
is a crucial issue in drug discovery.
tissue. Similarly, cofactors are
ligands that play an essential role
in a number of complex chemical
reactions involved in the metabolic
processes that keep an organism
alive. Most drugs can themselves
be classified as artificial ligands.
They work in the same way as
natural ligands, by binding to
specific sites in proteins and
modifying the protein’s function.
A famous example of this is
penicillin (an antibiotic, and one of
the first medications found to be effective
against many bacterial infections caused
by staphylococci and streptococci),
discovered by Alexander Fleming in 1928.
Penicillin acts by binding to receptor
sites in bacterial cell membrane proteins,
which drastically affects the bacterial cell
wall growth and eventually leads to its
degradation and to bacterial death. Some
anti-cancer drugs act in a similar way, by
blocking the proteins responsible for DNA
synthesis and hindering the growth of
new cancerous tissue. Understanding how
proteins involved in bacterial infections
or ontogenesis are affected by specific
drugs, and how we can optimise these
drugs to maximise their effects is currently
one of the crucial and most far-reaching
issues in pharmacological research
and drug discovery.
PROTEIN STRUCTURE
DETERMINATION
Proteins are typically large and complex
macromolecules, composed of thousands
of atoms, which are arranged in chains
of subunits, called amino acids. Proteins
fold into 3D structures, which are
characteristic of each protein and are
connected at a fundamental level to the
protein’s function. Accurate knowledge
of a protein’s structure is the first step
toward understanding how the protein
works and how the chemico-physical
processes that it carries out can be
influenced by means of drugs. Nowadays,
drug discovery typically starts by
screening large databases of molecules
or molecular fragments as potential
ligands for a selected drug target. This
approach is very error-prone and it
requires validation, e.g. by comparison
to refined 3D complex structures. The
gold standard in 3D protein structure
determination is currently provided
by X-ray crystallography, a powerful
Method
The challenge is to derive, rapidly and reliably, protein-
ligand complex structures
1: W ithout any protein assignment
2: W ithout knowing the location of the binding site
3: W ith receptor (side chains & backbone) and ligand flexibility
Experimental inter-molecular NOEs measured on a high field spectrometer: Top: 13C,15N-filtered 2D-[1H,1H]-NOESY spectrum showing inter-molecular NOEs
between the ligand and unknown methyl groups of HDMX. Bottom: Ligand 1H magnetization auto-relaxation curves (left) and inter-molecular cross-peak
build-up curves (right) versus the mixing time of the filtered NOESY experiments.
approach that is frequently used date using these two complementary and size of the pocket), electrostatic
to work out the structure of protein- techniques. The new method developed or chemical interactions. The global
ligand complexes, essentially at an by Dr Orts and his collaborators aim structure of the protein is initially largely
atomic level. This technique requires to bridge the gap between X-rays unaffected by the ligand binding. Based
crystalline samples, which can be and NMR, in order to expand the power on this observation, Dr Orts and his
expensive and time-consuming to and applicability of NMR and to make collaborators have developed a powerful
obtain. X-ray crystallography can also it a robust tool for drug discovery. protocol to work out in great detail the
run into problems with specific classes structure of the protein-ligand binding
of proteins, including membrane proteins NMR2: A ZOOM site, using existing information about the
and flexible receptors. The efficiency ON THE BINDING SITES global structure of the protein obtained
of X-ray crystallography can be improved The protein-ligand binding arises from in separate X-ray diffraction or liquid
substantially using the Molecular very local interactions: ligands only bind NMR measurements. This method, the
Replacement (MR) method, which to very specific sites in a protein, which Nuclear Magnetic Resonance Molecular
relies on the existence of a previously typically involve only a relatively small replacement (NMR2), is based on solution-
resolved structure that is similar to the
protein-complex under study. However,
number of atoms compared to the
whole protein. Binding sites are just like
state NMR structure determination, but it
focusses on the structure of the binding-
some classes of proteins (like membrane pockets in the protein, which a ligand can site alone, rather than on the full protein,
proteins and flexible receptors) remain enter and in which it can be stabilised and therefore it circumvents the lengthy
beyond the capabilities of X-rays, and by steric (i.e. depending on the shape and tedious analysis required to resolve
a radically different technique, nuclear
magnetic resonance (NMR), has been
proposed as a potential alternative for
these cases. NMR uses magnetic fields to
gain information about the environment
of each individual atom in a protein, for
example, its chemical shift and dipole-
dipole interaction. The main limitation
of NMR is that this technique requires
long measurements and extensive data
analysis. A recently proposed and fast-
developing technique, cryo-electron
microscopic, has also been shown to have
great potential in drug discovery for large
systems. Currently, however, X-ray
BINDING INTERMOLECULAR ALLOSTERIC SIGNAL
crystallography and, to a lesser extent, COMMUNICATION TRANSDUCTION
NMR are by far the most widely used
approaches to structural determination,
and hundreds of thousands of protein From drug design to intermolecular communication and biological function via signal transduction.
structures have been resolved to
www.researchoutreach.org 47
the whole protein structure from NMR
data. NMR2 drastically reduces the time
and effort required to obtain an atomically
resolved structure of a binding pocket
by using previously determined protein
structures, from a couple of months to
a couple of days. It can also be partially
automated, and therefore it provides
a natural tool for high-throughput
workflows, which can be used to screen
thousands of potential new drugs in
sequence and to analyse the nature of
their interaction with a target protein.
A typical NMR2 protein-ligand structure
determination requires a preliminary
preparation of the sample, in which either
the protein or the ligand are isotopically
substituted (13C, 15N) or selectively
labelled (e.g. isoleucine, leucine and
valine methyl labelling). NMR experiments
are then used to measure intra-molecular
(ligand) and inter-molecular (ligand-
protein) atomic distances, which in turn
provide a model of the ligand structure
in the binding pocket. To understand
the exact nature of the ligand-protein
interaction, protein structures from
existing databases (obtained from X-ray
or NMR measurements) are then used as
The NMR2 methods reduce the time
required to determine protein-ligand
structures from months to a few days.
RMSD 0.9 Å
A B
C D
RMSD 1.1 Å
NMR structures of HDMX in complex with cmpd2 under different starting scenarios using either a)
2
the 3D structure of the native holo-protein (3fea), b) the X-ray crystallography structure of HDMX in
complex with a different ligand (3fe7), c) a homology model of an X-ray crystallography structure of
HDM2 bound to a different ligand (2axi), or d) a homology model derived from the NMR structure
of the homologous protein HDM2 (1z1m) in its ligand-free state. The reference X-ray structure of the
HDMX – cmpd2 complex is coloured green. The NMR2-derived structures are colour coded red for the
ligand and blue for the protein with the exception of the protein structure in a) because the structure is
identical to the reference structure.
48 www.researchoutreach.org
Binding Site Opening
HDMX binds to p53 and inhibits the transactivation of p53 target genes. HDMX binds to ligands via a
mechanism where disordered regions become structured. Left: Protein binding pocket (circled in red)
opening upon p53-peptidomimetic binding. Right: Effect on the protein NMR spectrum upon ligand
binding (blue = protein bound, red = free protein).
input information. The structures selected
can be either that of the protein in the
absence of the ligand or those of similar
(homolog) proteins. The NMR2 program
then screens all possible assignment
groups in the protein and calculates the
protein-ligand complex structure for all
options. At this stage, it is essential to
reduce as much as possible the number
of configurations to screen. This can
be achieved by initially restricting the
assignment groups in the protein to only
3 or 4 relevant ones. False assignments
RMSD 0.9 Å
21 intermolecular
distances
RMSD 1.8 Å
can be ruled out using geometric
considerations, based on the knowledge
of the input structures. This substantially
reduces the calculation time. At the end
of this procedure, the resulting complex
structures have to be analysed carefully,
to detect potential errors arising from
the unconstrained relaxation of the
protein backbone during the refinement
procedure. It is important that a sufficient
number of inter-molecular distances are
taken into account, typically at least 12
or 15. A high signal-to-noise in the NMR
spectra and a good signal resolution
are also crucial.
A NEW TOOL FOR
DRUG DISCOVERY
The NMR2 method has been applied
successfully to the resolution of various
classes of protein-ligand complexes.
Several structures containing strong
binders or small ligands have been
determined with an accuracy of 0.9-
1.5 angstroms relative to the reference
structure. The applicability of NMR2 to
complexes with ligands in fast exchange
or weak affinity binding has also been
demonstrated. In the case of the weak
affinity binding complex HDM2-#845,
a new complex has been characterised,
never observed before. The efficiency
NMR2 is well represented by the complex
structure of SJ212-MDMX, which could
be resolved at 1.35-angstrom accuracy
within a day using a desktop computer.
These are a few initial examples of the
great potential of NMR2 in the study of
protein-ligand interactions and protein
function and they pave the way for its
application as a fast, reliable and accurate
protocol for drug discovery.
Behind the Research
Dr Julien Orts
E: julien.orts@phys.chem.ethz.ch T: +41(0) 44 632 28 64 @JulienOrts
Research Objectives References
Dr Orts and his collaborators have developed Orts, J (2018). Research profile. [online]. Available at: https://
multidisciplinary approaches to study protein-small twitter.com/JulienOrts http://n.ethz.ch/~ortsj/JulienOrts/
Interests.html [Accessed 28 Jan 2019].
molecules complexes using NMR spectroscopy, X-ray
crystallography and computational methods.
Orts, J; Wälti MA; Marsh, M; Vera, L; Gossert, AD; Güntert,
P; Riek, R. (2016). ‘NMR-Based Determination of the 3D
Detail Structure of the Ligand−Protein Interaction Site without
Protein Resonance Assignment’. J. Am. Chem. Soc., 138,
Dr Julien Orts 4393-4400.
Laboratory of Physical Chemistry
Swiss Federal Institute of Technology Wälti MA; Riek, R.; Orts, J. (2017). ‘Fast NMR-Based
ETH Determination of the 3D Structure of the Binding Site of
Protein–Ligand Complexes with Weak Affinity Binders’.
HCI F217, Vladimir-Prelog-Weg 2 Angew. Chem. Int. Ed., 56, 5208-5211.
8093 Zürich,
Switzerland Wälti MA; Orts, J. (2018). ‘The NMR2 Method to Determine
Rapidly the Structure of the Binding Pocket of a Protein–
Bio Ligand Complex with High Accuracy’. Magnetochemistry,
Julien Orts graduated in Physics and Biophysics jointly 4, 12.
from the Max Planck Institute and the European Molecular
Biology Laboratory. He is currently a junior group leader
at the ETH Zürich. He develops methods for structure-
Personal Response
based drug design and demonstrated for the first time that
The accuracy and efficiency of the NMR2 methods
3D structure determination of a protein-ligand complex
have been documented in a number of protein-ligand
can be achieved from solution NMR data fully automatically.
complexes. What are the remaining challenges of
NMR2 that need to be addressed in order to make your
Collaborators method a robust and easy to use routine tool for high-
• Peter Güntert throughput molecular screening in drug discovery?
• May Marsh
Fragment-based drug discovery is becoming a major
• Roland Riek approach in both pharmaceutical companies and academic
• Dean Strotz laboratories. Fragment-based methods need fewer
• Felix Torres compounds to be screened, synthesized and the fragment
• Marielle Aulikki Wälti hits show usually high ligand efficiencies (potency per atom).
Currently, no fast and robust NMR method can handle
small fragments due to a lack of protons “probes”.
We need to develop the current NMR2 method to
create a new approach, that can automatically and
simultaneously determine multiple structures of fragment-
protein complexes.
Having access to the structure of the binding site for each
binder allows investigating chemical scaffolds that would
otherwise be discarded and to broaden the chemical
knowledge as well as the drug-ability of the receptors.
www.researchoutreach.org 49
Laser ablation
Physical Sciences ︱ Dr Katharine Tibbetts
in liquid:
A powerful route to new nanoparticle catalysts
Dr Katharine Tibbetts (Virginia
Commonwealth University)
has been developing a novel
approach for the synthesis of
metal nanoparticles, based
on a reactive laser ablation
in liquid technique. She uses
ultra-short laser pulses to ionise
water molecules and generate
a highly energetic plasma of
electrons capable of reducing
soluble metal ions to neutral
atoms, which then coalesce
to generate a nanoparticle
suspension. At variance with
traditional chemical approaches
based on strong reducing
agents and surfactants, the
laser ablation technique is fast,
environmentally friendly and
it can be used to control the
nanoparticle size and properties.
Solvent, metal
salt(s), additives
fs laser
50 www.researchoutreach.org
N
anomaterials exhibit characteristic
structures containing particles
of sizes between 1 and 100 nm
(1 nm=10-9 m), in an unbound state or
in the form of aggregates. Examples of
natural nanomaterials include the capsid
structures of viruses, some butterfly
wing scale patterns and colloidal fluids,
such as milk and blood. Synthetic
nanomaterials, on the other hand,
are engineered and manufactured to
have well-defined mechanical, physical
or chemical properties, which makes
them suitable for technology and
in industrial processes. In particular,
metal nanomaterials and metal oxide
nanocomposites have important
applications in optoelectronics, sensing,
drug delivery and catalysis. Bimetallic
nanoparticles have for instance been
shown to be promising catalysts for
processes including the water-splitting
reaction and the reduction of CO2, and
they represent a highly promising path
towards sustainable energy generation,
storage, transmission and utilisation
Solid target
Plasma reactions
on a global scale. The enhanced
activity of bimetallic nanoparticles has
been attributed to synergistic effects
between the metals and defect sites
in nanocrystal structures.
In order for nanomaterials to be
chemically effective, the size of their
constituent nanoparticles has to be tightly
controlled. For instance, in catalytic
processes, smaller nanoparticles yield
better catalytic turnover, because the
ratio between their surface area (where
chemical reactions occur) and their
volume is large. Traditional approaches
to metal nanomaterial synthesis typically
use strong reducing agents to produce
nanoparticle seeds and surfactants
to prevent excessive growth. Surfactants,
however, are toxic and they can have
a substantial environmental impact.
Furthermore, surfactant molecules
can hinder catalytic reactions by binding
strongly to a nanoparticle’s active sites
and making them inaccessible to potential
reactant molecules. Finally, chemical
Schematic illustration of femtosecond reactive
laser ablation in liquid method.
Nanostructured products
Au nanoparticles synthesised in 10 mM Au nanoparticles stabilised by amorphous silica. Au nanoparticles synthesized with 532 nm
isopropyl alcohol. nanosecond laser pulses.
methods are slow, and they require hours,
or even days, to grow nanoparticles
Plasma synthesis operates in highly non-
of the desired size. equilibrium conditions and affords the
PLASMA SYNTHESIS controlled and efficient creation of novel
OF NANOPARTICLES
nanoparticle phases.
WITH LASER LIGHT
The reactive laser ablation in liquid
method pioneered by Dr Tibbetts directly proportional to the production OH radicals react with each other to
and her collaborators offers a powerful of electrons in the laser-induced plasma, produce hydrogen peroxide (H2O2),
and flexible alternative to the purely as has been demonstrated in the case which can act as a reducing agent for
chemical approaches to nanomaterial of the reduction of Au3+ in [AuCl4]- in species like Au3+ (therefore further
synthesis currently in use. It is a fast water solution. Furthermore, the rapid promoting the formation of Au
and “green” method, which generates cooling following the reduction caused nanoparticles), but also as an oxidising
nanomaterials within minutes, does by the solution mixing can determine agent for reduced metal atoms, like Ag.
not require toxic reducing agents the formation of novel metastable As a consequence of the formation of
and surfactants, and enables the nanoparticle structures, which are not H2O2, fast growth of Au nanoparticles
formation of nanostructures with observed in chemical synthesis carried is therefore typically observed, whereas
novel morphologies and bonding out in milder conditions. no Ag nanoparticles form at all because
environments. The key idea of this the Ag atoms are quickly back-oxidised
method is that laser light, rather than a CONTROLLING NANOPARTICLE to Ag+ ions. To prevent the formation
chemical agent, can be used to provide SIZE AND COMPOSITION of H2O2, OH. scavengers, which
the electrons required to reduce soluble In addition to creating the reducing include ammonia, sodium acetate and
metal ions to their neutral metal atom electron plasma, the laser radiation isopropyl alcohol, can be added to the
counterparts, which then assemble also forms hydroxyl radicals (OH.) solution. This enables superior control
themselves to form a nanoparticle phase. by breaking apart water molecules. over the formation of both Au and Ag
A typical synthesis uses water solutions
of metal ions (e.g. Au3+ or Ag+), and it
can include a solid target, such as a silicon
wafer. Laser light is applied in the form
of very short (ca. 30 fs, or 30 quadrillionths
of a second) and intense pulses, which
exchange enough energy with the water
molecules to induce the emission of
electrons from them. These electrons
are highly energetic and form a dense
plasma with transient temperatures
as high as 5000-7000 K, comparable
to the surface of the Sun. These free
electrons reduce the Au3+ and Ag+ ions
in solution to insoluble Au or Ag atoms,
Ag nanoparticles synthesised in 0.25 mM Ag nanoparticles synthesised in 1 mM ammonia.
which assemble to form the nanoparticles. ammonia.
The rate of metal-ion reduction is
www.researchoutreach.org 51

Current understanding of reaction mechanisms forming stabilised nanoparticles from femtosecond reactive laser ablation in liquid.
nanoparticles. For instance, Dr Tibbetts
and collaborators have shown that
adding isopropyl alcohol reduces
the size of Au nanoparticles from 4.9
to 3.8 nm and makes them significantly
more monodisperse (the same size).
This has been attributed to the reduced
production of H2O2 in the presence
of isopropyl alcohol, which prevents
the formation of large particles. For Ag,
different morphologies are observed
depending on the amount of ammonia
added to the solution. The presence
of the silicon
wafer can also
be exploited to
Nanostructured catalysts exhibit
reduce the rate of exceptional activity in several chemical
back-oxidation,
as the laser
processes for energy production
pulses cause the and storage, including water splitting
and CO2 reduction.
photo-ejection
of silicon atoms
and clusters
from the wafer, which can both react with
the forming OH radicals and stabilise
the incipient nanoparticles by attaching
to them.
CHALLENGES AND OPPORTUNITIES
OF PLASMA SYNTHESIS
Although a general model of the physical
and chemical phenomena occurring
during laser ablation in liquid has been
developed, based on the chemical
and morphological characterisation
of the synthesis products along with
in situ measurements (optical emission
spectroscopy, cavitation bubbles with
shadowgraphy and small-angle X-ray
scattering) and quantum mechanical
(DFT) simulations, a number of details
concerning the kinetics of the reactions
induced by laser irradiation remain largely
52 www.researchoutreach.org
obscure. The team lead by Dr Tibbetts
has been pioneering the use of in-situ UV-
vis spectroscopy measurements carried
out during plasma synthesis to unravel
the complexity of the chemical reactions
involved in the process and the dynamics
of nanoparticle growth. Understanding
the real-time dynamics of the species
generated during laser ablation and
the kinetics of the metal-ion conversion
to nanoparticles, as well as establishing
a correlation between the observed
reaction rates and the properties
of the products are important steps
toward the optimisation of the synthetic
conditions for generating nanoparticles
with wide varieties of compositions,
sizes and chemical reactivities. In
particular, the ability to synthesise sub-5
nm nanoparticles composed of earth-
abundant metals (Cu, Fe and Ni), in place
of the noble metals Au and Ag, is an
ambitious and far-reaching goal, which
has the ability to transform laser ablation
in liquid from a cutting-edge technique
for the synthesis of metal nanoparticles
into a practical, general and sustainable
approach to develop new catalytic
species for large (potentially industrial)
scale chemical processes.
A current significant limitation
of bimetallic nanoparticle catalysts is that
their chemical activity deteriorates over
time, owing to metal leaching and particle
agglomeration. A promising approach
to hinder the occurrence of these adverse
processes is to support the nanoparticles
on thermally stable and chemically inert
oxides, such as silica (SiO2). Chemical
approaches have been proposed to this
aim, which use commercially available
silica supports. These methods do
not use surfactants, but they require
a separate precursor synthesis and
they are relatively slow (typically their
duration is at least
two days). Recently,
Dr Tibbetts’s group
has demonstrated
that the reactive laser
ablation in liquid
technique can be
used to promote
the formation of Au
nanoparticles with
diameters as small as 1.9 nm supported
on an amorphous silica matrix. This
is the first report of laser-synthesised
supported sub-3 nm metal nanoparticles,
which paves the way for the development
of a clean, fast and highly tunable
approach for the synthesis of metal oxide
nanocomposites with enhanced catalytic
activity. Plasma synthesis can also be
extended to the creation of catalytically
active multimetallic nanostructured
materials with morphologies and
physico-chemical properties not
accessible to other methods. The work
initiated by Dr Tibbetts will provide
a more detailed and insightful picture
of the plasma synthesis processes
in a variety of conditions and enable
better control of the properties
of the resulting nanomaterials.
Behind the Research
Dr Katharine Tibbetts
E: kmtibbetts@vcu.edu T: +1 804 828 7515 W: https://chemistry.vcu.edu/people/faculty/tibbetts.html
Research Objectives
Dr Tibbetts Current research areas focus on (1) synthesising
metal-based nanoparticles from metal salt precursors and
elucidating reaction mechanisms for these transformations
in the condensed phase, and (2) probing and controlling
the dissociation dynamics of polyatomic radical cations
in the gas phase.
Detail
Department of Chemistry, Virginia Commonwealth
University 1001 W. Main St.
Richmond, VA 23284 USA
Bio
Katharine Tibbetts received her PhD in Chemistry at
Princeton University with Herschel Rabitz. She was a
postdoctoral fellow at the Center for Advanced Photonics
Research at Temple University with Robert Levis. She
began her independent career at Virginia Commonwealth
University (VCU) in 2015.
Funding
American Chemical Society Petroleum Research Fund; US
Army Research Office
Collaborators
• M. Samy El-Shall, VCU Chemistry
• Puru Jena, VCU Physics
• Gennady Gutsev, Florida A&M Physics
References
Tibbetts, K (2018). Research profile. [online] College of
Humanities & Sciences, Chemistry – Virginia Commonwealth
University. Available at: https://chemistry.vcu.edu/people/
faculty/tibbetts.html [Accessed 21 Jan 2019].
John, MG; Tibbetts, KM. (2019). ‘One-step femtosecond laser
ablation synthesis of sub-3 nm gold nanoparticles stabilized by
silica’. Applied Surface Science, 475, 1048-1057.
Rodrigues, CJ; Bobb, JA; John, MG; Fisenko, SP; El-Shall, MS;
Moore; Tibbetts, KM. (2018). ‘Nucleation and growth of gold
nanoparticles initiated by nanosecond and femtosecond laser
irradiation of aqueous [AuCl4]-’. Physical Chemistry Chemical
Physics, 20, 28465-28475.
Meader, VK; John, MG; Rodrigues, C; Tibbetts, KM. (2017).
‘Roles of Free Electrons and H2O2 in the Optical Breakdown-
Induced Photochemical Reduction of Aqueous [AuCl4]-’. The
Journal of Physical Chemistry, A, 121, 6742-6754.
Meader, VK; John, MG; Frias Batista, LM; Ahsan, S.; Tibbetts
KM. (2018). ‘Radical Chemistry in a Femtosecond Laser
Plasma: Photochemical Reduction of Ag+ in Liquid Ammonia
Solution’. Molecules, 23, 532.
Personal Response
How do you expect your method evolve in the near
future, and do you expect it to see it applied to
industrial or commercial processes in the short term?
As we learn how to manipulate the concentrations
of reactive species in the plasma, we expect to gain
greater control over nanoparticle sizes, compositions,
oxidation states, and surface properties, as well as expand
the scope of accessible metals. For instance, if we can’t
remove enough hydroxyl radicals to make copper or iron
nanoparticles in water, we could switch to a different solvent
like methanol. Right now, our method can’t make sufficient
nanoparticle quantities for commercial applications, but
it is only a matter of time before a laser ablation in liquid
method will achieve this. A group in Germany recently
reported production of gold nanoparticles at a rate of
4 g/hr by ablating gold foil with a specialised high-
repetition-rate laser.
www.researchoutreach.org 53
Engineering and Technology ︱ Professor Bin Zheng
Assessing performances of
Computer-Aided Diagnosis
of breast cancer
S
In under two decades, the
techniques used to image,
classify and diagnose breast
cancer have significantly
improved with the help of
rapidly advancing computer-
based digital image processing
and machine learning
technologies. Since the early
days of developing Computer-
Aided Diagnosis technology
in the 1990s, Professor Bin
Zheng at the University of
Pittsburgh and then the
University of Oklahoma has
dedicated his research to
assess its capabilities. His
work has allowed for advances
ranging from confirmations
of the success of some of the
first detections of cancer from
digitised mammograms to the
use of MRI in assessing the
responses of breast tumours
to chemotherapy.
A GUI of the short-term breast cancer risk prediction model.
54 www.researchoutreach.org
ince the late 1990s, Computer-Aided
Detection and/or Diagnosis (CAD)
has become an indispensable tool
for clinicians as they attempt to identify
and diagnose cancer in their patients.
Through processing and analysing medical
images taken through methods including
X-ray and MRI scans, CAD is now capable
of identifying and quantifying the image
patterns that highly associate with cancer
risk, characteristics and prognosis; more
effectively than the human eye in many
cases. Breast cancer is one area where
CAD has become particularly important;
in recent years, the technology has made
it far easier to identify dangerous growths
from digital mammograms and MRI scans.
Since its emergence, Professor Zheng
and his colleagues have been at the
forefront of assessing the capabilities
of CAD mammography.
THE POTENTIAL OF COMPUTER-AIDED
DETECTION AND DIAGNOSIS (CAD)
In the past, doctors (in particular
radiologists) have faced many difficulties
in reading and interpreting mammograms
to detect suspicious breast lesions, and to
classify the difference between malignant
and benign lesions, simply through their
trained intuition. When it first emerged
in the 1990s, CAD showed the promising
potential to provide radiologists with
useful decision-making supporting tools
to reduce errors in cancer detection
and diagnosis, but it was far from certain
whether the technology would be able
to help radiologists more accurately identify
cancers (or distinguish between malignant
and benign lesions).
In his research, Professor Zheng has
strived to develop new ways to assess
how effectively CAD can be used to
diagnose and treat instances of breast
cancer. Through rigorous testing involving
the mammograms of real breast cancer
patients, his work has provided crucial
assessments of where CAD technologies
are working, and has identified areas
where they need to be improved. In
earlier studies, this involved evaluating
the performance of CAD in identifying
breast cancer from mammograms taken
by rapidly-improving imaging techniques.
Based on this earlier work, Professor
Zheng is now working towards assessing
the abilities of CAD to image quantitative
cancer image markers. Imaging these
markers would allow radiologists both
to predict short-term breast cancer risk
for improving the efficacy of cancer
screening, and to assess cancer prognosis;
improving the efficacy of cancer treatment.
ASSESSING LIMITATION OF EARLY CAD
Professor Zheng and his colleagues carried
out their first significant study in 2001 [1],
as CAD was emerging as an important new
diagnostic tool. In the study, the researchers
investigated the potential clinical utility
of using CAD to help improve radiologists’
performance in detecting breast cancer
through mammograms. To do this,
the team carried out a multi-mode based
observer performance study involving
screening mammograms acquired
from 209 women. While some of these
patients had tested positive for breast
cancer according to several reputable
radiologists, the rest were confirmed
to be cancer-free. For each screening,
Professor Zheng’s team programmed
the CAD scheme to four different levels
of detection sensitivity and specificity A B
(or false-positive rates) in detecting breast
lesions, which were represented by both
soft tissue masses and micro-calcification
clusters. Afterwards, eight radiologists
independently read and interpreted
this set of mammograms five times; first
without using CAD, and then using CAD
at four different performance levels. The
researchers then quantified the rates of
correct diagnoses through comparisons
with the radiologists’ conclusions in five C D
reading modes. Showing intermediate results of image processing steps including (A) the computed breast density maps,
(B) detected focal density regions, (C) local density fluctuation maps, and (D) image maps generated
using Gaussian bandpass filtering. Colour bars show volumetric density levels of the pixel values.
The team found that when using high-
Professor Zheng hopes that clinicians will soon
performance CAD schemes with both
high sensitivity and low false-positive
rates, the radiologists’ performance
in detecting breast cancer from screening
be able to use CAD-generated markers to predict
mammograms was significantly improved. the risk of breast cancer in individual patients.
At the same time, using CAD with lower
performance levels, including either First, in developing a multi-view CAD (or lesion) based score. This technique
low sensitivity or higher false-positive scheme, the team proposed and applied produced a new CAD cueing method,
rates, actually reduced radiologists’ a new narrow matching strip method, namely, an adaptive cueing method,
performance. This laboratory study based which significantly improved accuracy to help detect more difficult or subtle
finding was appraised by an editorial when matching two suspicious lesions cancers without increasing overall false-
article of an expert in mammography [2], detected in two view mammograms. positive rate [6].
and has later been confirmed by a number As a result, the new CAD scheme enables
of clinical studies (e.g., [3] ). Thus, Professor radiologists to detect more lesions on In addition to detecting suspicious
Zheng’s study revealed the importance two views, without increasing false-positive lesions, Professor Zheng and his team
of reducing false-positive rates when rates [5]. Second, the team developed also developed CAD schemes to classify
CAD is used in clinical practice. a new case-based CAD scheme to predict between malignant and benign breast
the risk of a given case being positive lesions. For example, the team has
ADAPTING TO ADVANCING CAD for cancer, then fusing the case-based performed pioneering work in applying
TECHNOLOGY risk score with the conventional region content-based image retrieval (CBIR)
This finding promoted great research
interest to explore and develop new
technologies and approaches in the
CAD research field. For example,
Professor Zheng and his collaborators
have not only converted the CAD scheme
from the previous screen-film based
digitized mammograms to full-field
digital mammograms (FFDM) [4]. The
team has also been working towards
developing and evaluating a number
of novel approaches, which include
but are not limited to multi-image based
CAD schemes [5] and adaptive CAD
cueing methods [6]. A multilayer topographic region growing algorithm is implemented to segment lesions on CEDM images.
www.researchoutreach.org 55

technology to develop CAD schemes using
a large, diverse and balanced reference
dataset. This data showed more than 4,000
regions of interest (ROIs) that depict biopsy-
verified malignant and benign lesions.
This CBIR-based CAD scheme not only
achieves higher classification performance,
but also pursues higher visual similarity,
aiming to increase radiologists’ confidence
in accepting CAD-generated classification
results [7].
Recently, Professor Zheng and his team
identified and investigated a new short-
term breast cancer risk factor, or prediction
model, based on the quantitative analysis
of bilateral mammographic density and
tissue asymmetry. Several studies (i.e.,
[8]), have demonstrated that using this
new model had the potential to increase
discriminatory power to predict short-term
breast cancer risk, and thus, to help improve
the efficacy of mammography screening.
TRANSITION TO A
NEW IMAGING MODALITY
Recently, contrast-enhanced digital
mammograms (CEDM) have emerged
as a promising new imaging modality in
breast cancer imaging. The technique takes
advantage of both DDDM, which provides
high spatial resolution, and breast magnetic
resonance imaging (MRI), which provides
physiologically functional information with
significantly fast scanning and low cost.
However, the possibility of developing CAD
schemes of CEDM to assist radiologists
in more accurately diagnosing suspicious
lesions has not been investigated before.
Professor Zheng and his collaborators
in Mayor Clinic Arizona and Arizona
State University have been working to
develop new CAD schemes of CEDM.
The work reported in the ABME paper [9]
presents the first fully-automated CAD
scheme of CEDM to classify between
malignant and benign breast lesions.
The study results showed, firstly, that
the segmentation of lesions from dual
energy subtraction (DES) images was much
Professor Zheng’s study revealed that
even in the first years of its development,
CAD already showed significant potential
to improve rates of a successful breast
cancer diagnosis.
56 www.researchoutreach.org
A
B
(a) Workflow of CEDM imaging and (b) Four images from left to right: high energy image, low energy
image, and dual energy subtraction image displayed at the original and the adjusted window and level
for improving visibility, respectively.
easier and more accurate if lesions are
enhanced. Secondly, however, DES lost
lesion density heterogeneity information,
which may be a disadvantage Finally,
CAD yielded a significantly improved
performance by mapping better lesion
segmentation results from DES images
to low-energy FFDM images. If the results
can be further validated in future large-
scale studies, using CEDM and CAD
will play an important role in reducing
unnecessary biopsies in future breast
cancer diagnoses.
GENERATING NEW
CAD-BASED IMAGE MARKERS
Currently, Professor Zheng and a team
of researchers are developing CAD
of breast MR images, aiming to identify
new image markers for assessing the
response of breast lesions to neoadjuvant
chemotherapy. For example, in a 2016
study, Professor Zheng and his colleagues
used CAD to assess MR images of 151
women undergoing neoadjuvant
chemotherapy for breast cancer; some
of whom showed a complete response
to the treatment, and others displaying
only a partial response. This time, CAD
generated image markers by checking
for bilateral asymmetry of dynamic
contrast enhancement signals between
the left and right breasts of each patient.
These markers were computed, and then
selected to build a multi-feature, fusion-
based machine learning model to
distinguish between complete and partial
responses to neoadjuvant chemotherapy,
using MRI acquired pre-therapy [10 ].
The study demonstrated that even with
a large number of MR images, CAD
remained a reliable technique not only
in identifying time-varying cancers from
the images, but also for classifying
between different responses of breast
cancers to chemotherapy. This result
reveals a promising potential for CAD
to be used to generate quantitative cancer
image markers in patients undergoing
chemotherapy. With the insights provided
by this latest development, Professor
Zheng hopes that clinicians will soon
be able to use CAD-generated markers
to predict the risk of breast cancer in
individual patients, to classify between
malignant and benign tumours, and to
assess patient responses to chemotherapy
more effectively than ever before.
Behind the Research
Professor Bin Zheng
E: bin.zheng-1@ou.edu T: +1 405 325 3597 W: www.Medical-imaging.rccc.ou.edu/zheng
www.linkedin.com/in/bin-zheng-49ba3232/ W: https://scholar.google.com/citations?user=FnKrwz0AAAAJ&hl=en
W: www.ou.edu/coe/ece/faculty_directory/dr_zheng
Research Objectives
Professor Zheng’s research aims to provide clinicians with “visual-aided” tools in cancer diagnosis, developing and validating
the computerised biomarkers extracted from the biomedical images and electrical signals in order to help improve accuracy
and reliability of predicting cancer risk, classifying suspicious lesions, assessing cancer prognosis and treatment efficacy.
Detail
101 David L. Boren Blvd, Suite 1001, Norman, OK 73072, USA
Bio
Bin Zheng received PhD from the University of Delaware.
Currently, he is a professor of Electrical and Computer
Engineering and Oklahoma TSET cancer research scholar at
the University of Oklahoma. His research interest is to develop
and evaluate novel medical imaging informatics tools for disease
risk prediction, early detection and prognosis assessment.
Funding
Current work is supported in part from Grant R01 CA197150 from
the National Cancer Institute, National Institutes of Health, USA, as
well as Oklahoma Tobacco Settlement Endowment Trust, Peggy
and Charles Stephenson Cancer Center, University of Oklahoma.
Collaborators
• Dr Bhavika Patel in Mayo Clinic Arizona
• Drs Teresa Wu and Jing Li at Arizona
State University
Co-PIs of grant R01 CA197150:
• Dr Alan Hollingsworth in Mercy
Health Center
• Dr Hong Liu at the University of Oklahoma
Personal Response
What are your future plans for research in this area?
Developing novel quantitative image markers using
CAD technology has demonstrated its potential to help
clinicians (i.e., radiologists, pathologists, oncologists
and surgeons) make more accurate and consistent decision
in cancer diagnosis and treatment. Thus, Professor Zheng
and his research team will continue their research effort
to explore and identify new image features from different
imaging modalities, as well as develop and test new
machine learning models that can optimally fuse multiple
images features to produce new image markers that can
achieve higher discriminatory power in prediction of cancer
risk, diagnosis of suspicious lesions, and assessment of
cancer prognosis and treatment efficacy.
References
[1] Zheng, B. Ganott, M.A. Britton, C.A. Hakim, C.M.
Hardesty, L.A. Chang, T.S. Rockette, H.E. Gur, D. (2001).
‘Soft-copy mammographic readings with different
computer-assisted detection cuing environments:
preliminary findings’. Radiology, 221(3), 633-640.
[2 ] D’Orsl C. (2001). ‘Computer-aided detection: There is no
free lunch’. Radiology, 221:585-586.
[3] Fenton J, Abraham L, Taplin S, Geller B, Carney P,
D’Orsl C, Elmore J, Barlow W, (2011). ‘Effectiveness
of computer-aided detection in community
mammography practice’. Journal of National Cancer
Institute, 103:1152-1161.
[4] Zheng B, Sumkin JH, Zuley M, Lederman D, Wang X,
Gur D, (2012). ‘Computer-aided detection of breast
masses depicted on full-field digital mammograms:
a performance assessment’. British Journal of Radiology,
85:e153-161.
[5] Zheng B, Leader JK, Abrams GS, Lu AH, Wallace LP,
Maitz GS, Gur D, (2006). ‘Multiview based computer-
aided detection scheme for breast masses’. Medical
Physics, 33:3135-3143.
[6] Wang X, Li L, Xu W, Liu W, Lederman D, Zheng B, (2012).
‘Improving performance of computer-aided detection of 
subtle breast masses using an adaptive cueing method’.
Physics in Medicine and Biology, 57:561-575.
[7] Zheng B, Lu A, Hardesty LA, Sumkin JH, Hakim CM,
Ganott MA, Gur D, (2006). ‘A method to improve visual
similarity of breast masses for an interactive computer-
aided diagnosis environment’. Medical Physics, 33:111-
117
[8] Wang X, Li L, Liu W, Xu W, Lederman D, Zheng B, (2012).
‘An interactive system for computer-aided diagnosis of
breast masses’. Journal of Digital Imaging, 25:570-579.
[9] Danala G, Patel B, Aghaei F, Heidari M, Li J, Wu T,
Zheng B, (2018). ‘Classification of breast masses
using a computer-aided diagnosis scheme of contrast
enhanced digital mammograms’. Annals of Biomedical
Engineering, 46:1419-1431.
[10] Aghaei, F. Tan, M. Hollingsworth, A.B. Zheng, B.
(2016). ‘Applying a new quantitative global breast
MRI feature analysis scheme to assess tumor response
to chemotherapy’. Journal of Magnetic Resonance
Imaging, 44(5), 1099-1106.
www.researchoutreach.org 57
Engineering and Technology ︱ Professor Gilles Desthieux

Developing the
2D and 3D cadastral data. (In Switzerland,
plots of land are registered in a cadaster
or cadastre, and their geometric details,
structures, current situation and ownership
are recorded.)

Geneva Solar Cadaster:

Around ten public and private stakeholders
collaborated on this R&D project that was
supported by several funders: the State
of Geneva and Geneva Energy Company –

A decision support tool for sustainable energy SIG (in the framework of the Geneva’s solar
cadaster), the Swiss Federal Agency for the

management in urban areas Promotion of Innovation Based on Science

(iCeBOUND project - Cloud-Based Design 3D representation of the solar radiation outputs (in kWh/m2/year) on existing building facades and roofs
Support System for Urban Numeric Data) in the “Meyrin Cité” neighbourhood (Geneva). This figure was previously published in Desthieux G, et
and the University of Applied Sciences al. (2018). ‘Solar Energy Potential Assessment on Rooftops and Facades in Large Built Environments

Gilles Desthieux, Associate
Professor at the Geneva Institute
of Landscape, Engineering
and Architecture and a
Consultant in Urban Energy
Planning with Amstein+Walthert
Geneva, leads a team of
researchers who have developed
the Geneva Solar Cadaster, a
tool for modelling solar radiation
and energy production from
building rooftops and facades.
R
ecent urban studies have shown
that our cities play a significant
role in environmental issues and,
in particular, energy transition. One of
the targets of the EU 2030 Framework
for climate and energy is to reach a
minimum of 27% renewable energy
consumption and reduce carbon emission.
In order to achieve this target, cities
will have to accurately evaluate their
renewable energy sources.
SOLAR PANELS
The use of solar panels on building
rooftops is now widespread. In built-
up areas, however, incoming sunlight
is limited and restricts the deployment
of solar power plants. The recent
improvements in solar panel efficiency,
together with innovative concepts such
as Nearly Zero Energy Buildings and
Building Integrated PhotoVoltaics,
have enabled the exploration
Building facades are particularly
appealing for producing solar energy
of other usable surfaces including
highway roofs and walls for potential
energy production. Building facades
are particularly appealing for producing
solar energy during the winter months
when the sun is lower in the sky.
MODELLING POTENTIAL
SOLAR ENERGY
Modelling the accessibility of solar
energy within the fabric of the built
environment can be carried out using
available 3D information about cities
and image processing. Facade modelling
for solar analysis, however, has received
less consideration than rooftops, as it
requires much more complex tools based
on 3D GIS data.
Gilles Desthieux, Associate Professor
at the Geneva Institute of Landscape,
Engineering and Architecture and a
Consultant in Urban Energy Planning
Western Switzerland – HES –SO (joint
research program Energy District 2050).
AIMS
The project aims to design and develop
a Decision Support System, based on
the use of 3D digital urban data, that
facilitates environmental analyses in large
built areas such as the assessment of solar
energy potential. The project targets
building rooftops and facades in urban
areas so as to provide relevant indicators
for decision makers in city planning
and energy management and boost solar
energy production.
Two key goals of this project are
to allow residents to check the solar
energy potential of their building and to
promote the installation of PhotoVoltaics,
encouraging energy transition away from
nuclear power.
METHODOLOGY
The methodology is underpinned by
the researchers’ previous work on ‘Solar
Energy Potential’, where they evaluated
Based on LiDAR Data, Image Processing, and Cloud Computing. Methodological Background,
Application, and Validation in Geneva (Solar Cadaster)’. Front. Built Environ. 4:14. doi 10.3389/
fbuil.2018.00014 and is under the Creative Commons Attribution License (CC BY 4.0).
The data is stored in a georeferenced TIFF FACADE COMPONENT
raster format and is made up of a Digital The Digital Urban Surface Model does
Urban Surface Model, a slope matrix and not permit the modelling of building
an orientation matrix. The Digital Urban facades, so the researchers have
Surface Model is constructed from LiDAR developed a facade component. This
data and represents the structure of the generates a grid of facade ‘hyperpoints’
city, such as buildings and houses. The at 1-meter intervals using building
slope matrix describes the slope of each outlines in the form of 2D vector data.
point using values between 0 and 90°. The shading algorithm is then applied to
The orientation matrix describes the calculate hourly shading and the Sky View
orientation of each point with values Factor in a similar way to the rooftops.
between 0 and 360°. These two matrices
are produced using common GIS software. APPLICATION TO THE SOLAR
CADASTER FOR GENEVA
The researchers calculate solar radiation In 2011, Gilles Desthieux and the
by adding its three main components and research team started working on a
related shading indices: direct radiation solar cadaster for the Canton (or State)
which is directly proportional to the sun of Geneva, an area of about 300 km2,
visibility, diffuse radiation derived from as a support to boost solar energy
the sky visibility and reflected radiation production (in accordance with both
from the ground and nearby objects. the Geneva Energy Law and the Master
Solar maps can then be produced enabling
Energy Plan of Geneva). The new solar
cadaster, highlighting raw solar radiation
the accurate evaluation of urban areas for on building roofs, was made available

during the winter months when

the potential of urban buildings’ roofs the installation of renewable energy, such to the public. During the second phase
and facades to produce solar energy using as PhotoVoltaics and thermal solar panels of the project, in 2014, the researchers

the sun is lower in the sky. both thermal and photovoltaic technology. on building rooftops. developed indicators relating to solar

Solar energy potential for a particular

in Amstein+Walthert Geneva, leads a
team of researchers who have developed
a tool for modelling radiation and energy
production on inner-city building rooftops
and vertical facades.
This integrated tool uses Light Detection
and Ranging (LiDAR)
data together with
building is computed by summing
the estimated value of the solar radiation
in kWh for every hour during a given
period of time. Data is input comprising
location, meteorological data (statistics
or measurements), average solar radiation
parameters and the 3D surrounding relief
and landscape. A Shading Algorithm, Web-based tool developed by arx is under the 3D representation of the solar radiation outputs
based on image processing techniques, mandate of SITG; an example of the display for main (intensity in kWh/m2/year) on building facades in a
rooftop characteristics. Reproduced from SITG – sector of the Municipality of Carouge, mixing new tall
is used to calculate the hourly shading
https://sitg-lab.ch/solaire (2017). building developments and existing industrial areas.
and the ratio of visible sky, also known This figure was previously published in Desthieux G,
as the Sky View Factor. et al. Front. Built Environ. (2018). (CC BY 4.0).

58 www.researchoutreach.org www.researchoutreach.org 59
energy production, environmental
assessment, economic investment
and payback.
In 2016, during the third phase of
the Geneva solar cadaster project,
the research team updated the 2011 solar
cadaster using new LiDAR data and 3D
urban models. They also refined the
solar modelling algorithms and improved
the computational models, using cloud
computing, in order to provide decision-
makers with the relevant indicators for city
planning and energy management.
The outputs from the revised Geneva
solar cadaster have been scientifically
validated by an international expert
on solar modelling.
CLOUD COMPUTING
The majority of urban solar cadasters
available in Europe are based on restricted
areas, usually less than 100 km2. Geneva’s
solar cadaster, however, covers the whole
Canton of Geneva, not just the city,
extending to around 300 km2. This brings
challenges for Desthieux and the team with
regards to computation time. Their original
Geneva solar cadaster calculation in 2011
was computed by a single server machine
and took approximately 2000 hours.
In order to reduce the computation time
of solar analysis on large urban areas, the
researchers opted to use cloud computing
in the framework of the iCeBOUND project
mentioned above. This has reduced the
overall computation time for the whole
state of Geneva to about 350 hours.
RESULTS
The solar cadaster of Geneva has shown
that a potential solar electricity production
of 700 MWe could be achieved if
PhotoVoltaics were installed on all the
Generation of facades’ “hyperpoints” using 2D vector data of building outlines. This figure
was previously published in Desthieux G, et al. Front. Built Environ. (2018). (CC BY 4.0).
60 www.researchoutreach.org
The principle of the shadow casting algorithm,
adapted with permission from ©2018 Front. Built
Environ. (Desthieux et al., 2018).
Sharing this data and information is
essential to promote an open energy
transition strategy in order to move away
from nuclear power.
suitable rooftops of the Canton. At the
end of 2016, Geneva solar electricity
production was approximately 45 MWe.
Desthieux mentions that while achieving
100% of this potential solar electricity
production might not be realistic,
it remains a significant target.
DISSEMINATION
Results are communicated via the
Geneva official geoportal (SITG – Geneva
Territorial Information System) and a
Web-based interface that has been
customised for public use. The geoportal,
aimed at professionals working with solar
energy, allows users to extract the whole
solar database on any perimeter or group
of buildings, supporting solar energy
planning on various scales.
Interactive maps together with information
identifying suitable rooftops are published
on the public web interface for various
end-users, such as energy planning
authorities, energy companies’ marketing
and investing departments and the
general public, to promote awareness
and encourage the installation of
PhotoVoltaics and thermal solar panels.
Gilles Desthieux states that sharing
this data and information is essential
to promote an open energy transition
strategy in order to move away from
nuclear power to green technologies.
The public web interface is used between
80 and 100 times per week. This is in line
with the number of applications for public
funds, particularly the Geneva funding
program for the renovation of buildings.
PERSPECTIVES
The researchers are planning to develop
workshops, seminars and training sessions
for potential stakeholders as well as
targeted information on the Web to boost
the solar market.
They also intend to extend the solar
cadaster to cover the whole agglomeration
of Geneva, including French municipalities
(new project “G2 Solaire” supported
by the European program Interreg V
for French-Swiss collaborationships).
It is anticipated that the computation time
can be further reduced through the use
of a Graphics Processing Unit which
accelerates computing and is adapted
to matrix processing.
The research team are planning the
next version of the solar cadaster and
aim to produce a collaborative platform
for everyone involved with solar energy
in order to increase the number of
installations and boost the solar market.
Behind the Research
Professor Gilles Desthieux
E: gilles.desthieux@hesge.ch T: +41 22 546 26 80 W: www.hesge.ch/hepia/ W: https://sitg-lab.ch/solaire/
Research Objectives References
Gilles Desthieux’s current research & consultancy activities Desthieux G. et al. (2018). ‘Solar Cadaster of Geneva:
deal with integrated urban and energy planning at A Decision Support System for Sustainable Energy
district and municipal levels, development of GIS tools for Management’. From Science to Society, Springer, 129-137.
energy mapping and planning, 3D urban modelling for
environmental assessment – solar energy (application to the
solar cadaster in Geneva) and flood risks, platforms for eco-
Desthieux G. et al. (2018). ‘Solar Energy Potential Assessment
on Rooftops and Facades in Large Built Environments Based
neighbourhood development support, collaborative urban
on LiDAR Data, Image Processing, and Cloud Computing.
planning support based on geographical indicator systems.
Methodological Background, Application, and Validation in
Geneva (Solar Cadaster)’. Frontiers in Built Environment, 4,
14. Available at: https://doi.org/10.3389/fbuil.2018.00014
Detail [Accessed 7/12/18].
Geneva Institute of Engineering,
Architecture and Landscape Personal Response
HEPIA Geneva
Prairie Street 4 How much will installing PhotoVoltaics on building
CH-1202 Geneva facades in Geneva increase potential solar electricity
Switzerland production?
Considering the potential installation of solar PV panels
Bio on a small part of the existing building facades in Geneva
Gilles Desthieux, PhD and MSc from EPFL, is an associate (like 5% of the total of the facades), this would represent a
professor at the Geneva Institute of Landscape, Engineering potential of about 250 MWe in addition of the potential on
and Architecture and a consultant in urban energy planning the roofs, which is significant. However, solar installations on
facades are easier to anticipate on new building projects.
in Amstein+Walthert Geneva. His research & consultancy
Therefore, in some new planned districts analysed, it was
activities deal with urban and energy planning, GIS tools for estimated that solar PV on facades could cover until 50%
energy mapping, and collaborative urban planning support. of the electricity needs in the district.
Funding Can this model be applied to other urban areas outside
• State of Geneva (Energy, Topographic, Geomatics of Switzerland?
agencies) In this article, the application of the solar potential
• Geneva energy service agency (SIG) tool was illustrated through the solar cadaster in Geneva.
• Swiss Innovation Agency However, this experience can be reproduced without any
problem in other cities, provided 3D digital and cadastral
Collaborators data are available.
• Claudio Carneiro (State of Vaud, Switzerland)
• Reto Camponovo, (HES SO /hepia, Switzerland)
• Peter Gallinelli, (HES SO /hepia, Switzerland)
• Nabil Abdennadher, (HES SO /hepia, Switzerland)
• Anthony Boulmier, (HES SO /hepia, Switzerland)
• Eugenio Morello, (Politecnico di Milano, Italy)
• Phelan Leverington, (State of Geneva, Switzerland)
• Alberto Susini, (State of Geneva, Switzerland)
• Christelle Anthoine-Bourgeois,
(Geneva energy service agency, Switzerland)
• David Beni (arx iT, Switzerland)
www.researchoutreach.org 61
Thought Leader
The AdvanceRIT project involves initiatives aimed at refining university structures and practices. In the
spring of 2018, AdvanceRIT hosted a salary workshop for RIT faculty titled: “Let’s Talk about Money:
Understanding RIT Pay Practices”. Participants explored salary-related resources which could help
to shape future thinking and discussions regarding salary. They also discussed what RIT has learned
from past studies regarding faculty salary. All the survey respondents agreed with the following: ”This
session enhanced the way I think about the issues/topics discussed.”

In academic fields, going for tenure

Engineering the future:

The AdvanceRIT project involves cultural
change focused workshops. Here, Dr

occurs at the same time as we are having

Bailey is facilitating a bystander awareness
and action workshop in the fall of 2016
which was attended by a large audience
of women and men on the RIT faculty and
staff. Over 80% of participants asked for children, and women remain the primary
care-giver in most cases.
more workshops to continue to learn how to

How the WE@RIT programme is encouraging more become an effective and active bystander.
The two-week after-event survey revealed
that 100% of respondents agreed with the

women into the sector following: ”I think I can make a difference in

making the campus more inclusive by being
an active bystander.”
The Kate Gleason College of Engineering at Rochester Institute of Technology (RIT) is the only engineering college in
the United States to be named solely after a woman engineer. Inspired by Kate Gleason’s legacy as an innovative and (http://www.wepan.org/). During my
entrepreneurial scholar, the Women in Engineering at RIT (WE@RIT) programme was initiated by Professor of Mechanical leadership, the Kate Gleason College
Engineering Margaret Bailey in 2003. Since then, it has become a bastion of support for female students in an academic witnessed a three-fold increase in the
field that remains even now, vastly male-dominated. number of incoming female students
annually (from approximately 50 to 150).
In addition, external funding for the
proposals; and created a thorough
programme evaluation system.
Can you explain your current roles as
the Senior Faculty Associate to the
Provost for ADVANCE and Principal
Investigator (PI) and co-chair for the
President’s Commission on Women?
I serve as the PI of the NSF ADVANCE
a set of strategic initiatives focused on
refining campus culture, improving career
navigation and creating new institutional
structures. Complementary social science
research efforts adapt interventions to
address the needs of key sub-populations
including women of colour and deaf and
hard-of-hearing women faculty.

S
ince its inception in 2003, the
Women in Engineering at Rochester
Institute of Technology (WE@RIT)
programme has directly led to an increase
in female students at the Kate Gleason
College of Engineering at the institution,
and the setting up of hugely successful
projects such as the Establishing the
Foundation for Future Organizational
Reform and Transformation (EFFORT@
RIT) and Advancement of Women
Faculty (AdvanceRIT). WE@RIT continues
to act today as an example for other
science, technology, engineering and
mathematics (STEM) departments across
the United States and beyond, proving
that it is possible to change campus
culture through well-planned and well-led
strategic policies. We caught up with
Founder of WE@RIT Professor Margaret
Bailey to find out a bit more.
Hi Margaret! Can you tell us a little
bit more about the WE@RIT, its core
mission and heritage and your previous
leadership role?
I led the creation of the programme ‘WE@
RIT’, which is dedicated to expanding the
representation of women engineers and
leaders within the engineering profession.
In support of this mission, WE@RIT
provides opportunities for girls and young
women to explore engineering, create an
engineering community and lead within
an engineering environment. I served as
the Founding Executive Director from
2003-2011 during which time WE@
RIT received the ‘WEPAN 2008 Women
in Engineering Program Award’
organisation reached an annual level
of $400K.
As the Executive Director, I advised the
Dean on issues related to gender diversity
within the college; created strategies
with Admissions to improve recruitment
of women engineering students;
managed programme staff including a
full-time programme manager; oversaw
financial activities; created/maintained
a governance body; established key
partnerships; prepared successful funding
Institutional Transformation project
at RIT titled ‘Creating Opportunity
Networks for Engagement and
Collective Transformation: Increasing
the Representation and Advancement
of Women Faculty at RIT’ or AdvanceRIT
(http://nsfadvance.rit.edu/).
The other positions you mention
closely align with this effort. The
AdvanceRIT project aims to increase
the representation and advancement
of female STEM faculty at RIT through
What are your personal achievements
and highlights at RIT?
Significant grassroots engagement in
AdvanceRIT’s work over the past years has
added positive and amplifying energy to
the programme, helping to demonstrate
the ongoing necessity and value of the
work, while engaging a wider group of
RIT faculty. Policy and practice changes in
support of managing work-life integration
have also occurred. AdvanceRIT has been
a model of the organisational agility that
is a part of the university’s strategic plan.

62 www.researchoutreach.org www.researchoutreach.org 63

What challenges might women face in
STEM education and careers? Would
you say that these challenges have
dramatically changed since you were
studying and starting out in your career?
Isolation and cultural/climate-related
issues and challenges around work-life
integration are rife. In academic fields,
going for tenure occurs at the same time
as we are having children, and women
remain the primary care-giver in most
cases. In addition, some fields are still
male-dominated, so there are a lack of
role models for both students and faculty.
When I was an undergraduate at
Pennsylvania State, there was no women
faculty in my STEM classes. The Society
Cultural change efforts often challenge people to
be reflective, sometimes a bit vulnerable, and open
to the possibility of alternative models of behaviour.
of Women Engineers (SWE) had recently
started but the programming was
minimal. We actually thought it was
strange that they had programmes for
us, back then, people did not talk about
it. Currently, 25% of faculty are women
in my department. The numbers have
changed dramatically and so have
programmes and initiatives focused on
work-life integration, reducing isolation
and supporting building community
networks for women faculty and students.
What has your personal experience
been as a woman in a leading role?
It has been wonderful to work with a team
of predominantly women leaders, and
many energised male leaders on campus
around issues focused on inclusivity.
Leading an institutional transformation
project is challenging. Some of the things
I have had to learn along the way include
financial and managerial type skills and
knowledge, but they also include things
that I find exciting and very complex.
Things like cultural change and changing
structures within the university.
Prior to joining the RIT, you were an
Assistant and Associate Professor at
the United States Military Academy
located in West Point, New York.
64 www.researchoutreach.org
Dr Margaret Bailey has been on
the faculty at RIT in Mechanical
Engineering since 2003.
You created the first student section
of the SWE to exist at West Point and
served as its faculty advisor – can you
tell us about your time there?
I was at West Point for five years and
the students were great to work with.
It was very male-dominated. There were
about ten civilian women on the whole
faculty, and being a young civilian woman,
I would get a lot of attention. I sometimes
felt as if I was in the spotlight.
West Point was created, designed and
refined over the years to be a place where
leadership development happens. A vital
part of leadership development is the
presence of role models around students.
I looked around myself, to the students
who were amazing young people and
faculty colleagues who had been in
the military for many years and I found
many role models to also watch and
learn from. I think I spent those five years
transforming who I was, and what that
model of leadership looked like for me.
You have received many awards
in recognition of leadership and
significant contributions in supporting
gender diversity initiatives, such as
the Maria Mitchell Women in Science
Award, Edwina Award for Gender
Diversity, and most recently, the
Isaac Jordan Award for Inclusion and
Pluralism – how do these awards and
events help celebrate and promote
women in science?
They are very visible; symbolically and
politically they highlight accomplishments
and achievements, and often encourage
other women and men to do this kind
of work. The simple exercise of putting
together packets for these awards
require a great deal of effort and helps
the nominee or the person doing the
nomination to tell their own story clearly.
This helps with self-awareness and how to
talk about impacts that have been made.
Can you tell us about the NSF
Pathways Project and the research
investigations in relation to the topic
of gender within STEM? What did you
establish with this project and how did
it create an impact?
Since 2008, I have served as the RIT lead
researcher on a cross-university effort
to investigate the relationship between
undergraduate engineering student
participation in cooperative (co-op)
educational experiences and self-efficacy
development. The NSF Pathways
Project involves researchers from RIT,
Northeastern University (lead), Virginia
Tech and the University of Wyoming. The
overarching model for the study proposes
that self-efficacy is based on the impact
of students’ demographic characteristics,
the effect of work experience and the
contextual support provided by the
university. This research has resulted
in several award-winning publications
and findings verify the pathways model.
Academic self-efficacy and contextual
support in all time periods are found
to be critical to retention. Contextual
support is found to be particularly
important to women.
How important were both the
Establishing the Foundation for
Future Organizational Reform and
Transformation (EFFORT@RIT) and
Advancement of Women Faculty
(AdvanceRIT) projects at RIT?
Extremely important! The EFFORT grant
was the catalyst for RIT obtaining the
much larger institutional transformation
grant. It involved objective data, working
with human resources to collect the
data, as well as the creation of the
climate survey to collect and analyse
job satisfaction type data, as well as
Thought Leader
Over the past five years, the AdvanceRIT project has hosted over
30 workshops focused on cultural change through unconscious bias
education. Many of these sessions have used interactive theatre as
the delivery approach. In the academic year of 2017/2018, nearly 400
participants from the RIT faculty and staff attended one of the workshops.
Here, RIT faculty participate in a mentoring workshop in the spring of 2018 which Dr Bailey co-
facilitated. Participants explored different models of mentoring learned how to design and implement
a networked mentoring programme.
benchmarking where RIT’s practices and To find out more about WE@RIT, please
policies compared with other schools’. visit the following website www.rit.edu/
Without the EFFORT grant, AdvanceRIT kgcoe/women/.
may not have been possible.
What needs to be done to ensure
that women continue to enter STEM
education and careers?
Efforts need to continue as long as
women are under-represented in these
areas, efforts focused on reducing Rochester Institute
isolation and promoting the growth of Technology
of networks and cultural change for all One Lomb Memorial Drive,
members of the campus community. Rochester, NY 14623-5603
I would say out of all of those, cultural USA
change is the most important and the E: Margaret.Bailey@rit.edu
most difficult. Cultural change efforts
T: +1 585 475 2960
often challenge people to be reflective,
W: www.rit.edu/
sometimes a bit vulnerable and open W: www.rit.edu/kgcoe/staff/
to the possibility of alternative models margaret-bailey
of behaviour. This type of organisational W: https://nsfadvance.rit.edu/
development is challenging to create,
and administer; however, the results
can be well worth the effort.
www.researchoutreach.org 65
Behavioural Sciences ︱ Professor Hadas Mandel
Gender inequality:
occupational devaluation
and pay gaps
T
The comparative research of
long-term trends of gender
inequality largely neglects
structural mechanisms. As
more women reach positions
of power, structural elements
will become more significant.
Despite the growing body
of literature in this area,
the long-term effect of the
changing gender composition
of occupations on their
relative pay has been largely
neglected. Hadas Mandel,
an Associate Professor in the
Department of Sociology
and Anthropology at Tel Aviv
University, has addressed
this gap in the literature by
exploring the negative effect
of occupational feminisation
on occupational pay in the US
and the mechanisms underlying
these trends.
66 www.researchoutreach.org
he theoretical argument for
understanding long-term trends
of the association between
feminisation and occupational pay rests
on a distinction between two processes
related to gender inequality, that have
occurred in recent decades in the labour
markets of most western democracies.
The first process, which relates to
women as individuals, addresses the
upward occupational mobility of women,
meaning that women are incrementally
entering higher rungs of the occupational
hierarchy. The second process – which
is conceptualized as a structural process
– refers to the criteria for rewarding
occupations. The question in this regard
Structural mechanisms of gender/race
inequality are not directed at any specific
individual and thus are more ambiguous
and more difficult to track empirically.
is whether gender is one of the criteria
and if so whether occupations are
devaluated following the entry of women.
The literature documenting long-term
trends in gender inequality has tended
to focus heavily on the former – i.e. the
upward occupational mobility of women
on the occupational ladder. The latter,
i.e. the structural implications are
largely overlooked. However, the two
are inherently
connected,
as a notable consequence of the growing
occupational attainments of women
over recent decades is evident in the
way occupational feminisation affects
the pay level of occupations. Although
a considerable amount of research has
highlighted the negative association
between the percentage of women in
occupations and their rewards, most of
these studies have focused on the causal
mechanisms of the process rather than
on the dynamics over an extended period
of time.
Prof Hadas Mandel sought to address
this lacuna in the literature by examining
trends in the effect of occupational
feminisation on occupational pay over
several decades in the US and exploring
the mechanisms underlying these trends.
Using integrated data on individuals and
occupations from the US Census (1960-
2010) and the ACS surveys (2001-2015),
her findings show, similarly to previous
studies, that in recent decades, and
especially from 1980 onwards, a growing
number of women in the US have
approached the head of the occupational
ladder (see the first figure below). This
shift has been fuelled by women’s
growing educational attainments, which,
together with the rising economic
premium to education, have greatly
contributed to the decline in gender
wage gaps. Furthermore, based on
these changes, the negative association
between female percentage in
occupations and occupational pay levels Trends in female proportion in occupations
declines over time (see model 1 in the by levels of average occupational pay.
second figure below). This decline is most
0.6
apparent from 1980 onward, a period in
which US women witnessed a significant
improvement in their occupational 0.5
standing, and a period where
occupations requiring higher education
0.4
Proportion of females in occupations
enjoyed a large wage premium.
However, when examining the effect of
gender composition of the occupation
0.3
after accounting for women’s higher
education and for the level of education
in occupations, the trend is reversed; the 0.2
negative net effect of female percentage
on occupational pay intensifies over time
(see model 2 in the second figure below). 0.1
These two opposite processes reflect the
upward occupational mobility of women,
0.0
on the one hand, and its gendered 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
consequences, on the other hand.
Low pay Tertile Mid pay Tertile High pay Tertile
The major role education plays
in explaining the divergent trends
Trends in the effect of gender composition (% female)
is twofold. The entry of women into
occupations requiring higher education,
on the average pay of occupations, before (Model 1)
and the growing economic reward to high and after (Models 2) accounting for education.
education and to occupations with higher 0.0
educational requirements, may both
conceal the trend in the devaluation
-0.1
effect as they contribute to weakening
the correlation between the percentage
Effect of % of females in occupations
of women and pay across occupations -0.2
over the course of time. Thus, the
intensification of the devaluation effect
-0.3
is revealed only after controlling for
education (at both the occupational and
individual level), because the growing -0.4
educational level of women, and the
growing rewards to education, are -0.5
processes that run counter to devaluation
and thus conceal its intensification.
-0.6
Let’s consider the example of industrial 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
engineers and electrical engineers. Both
Model 1 Model 2
occupations demand high education
(more than 70% of incumbent workers
in 2010 had an academic degree), and feminization is associated with a smaller provide concrete evidence that gender
both enjoyed a wage premium during wage premium relative to comparable stratification operates differently at
the period studied. However, while in highly educated occupations. Thus the individual and at the structural/
both occupations the percentage of controlling for education is essential for occupational level. The split between
women in 1960 was negligible (2% and revealing the devaluation process. Indeed, individual and occupational forms of
1%, respectively), 50 years later only 10% we see that while electrical engineers gender in/equality and the divergent
of electrical engineers were women, enjoyed a premium of 25% during the trend of each are crucial for our
compared to 19% – almost double – of period studied, industrial engineers understanding of gender inequality
industrial engineers. As both occupations enjoyed a premium of less than 19%. in theory as well as in practice. This is
enjoyed wage premiums, the devaluation because structural mechanisms are not
effects may not be observed because the The findings demonstrate the directed at any specific individual and
process of feminization was not followed interrelationship between two thus are more ambiguous and more
by an absolute wage reduction. Rather, opposing gendered processes and difficult to track empirically. The danger is
www.researchoutreach.org 67
therefore that the importance of gender
as a determinant of economic inequality
in the labour market will be less visible,
less amenable to empirical assessment,
and not sufficiently acknowledged.
GENDER AND RACIAL PAY GAPS
A different topic that Prof Mandel
Average Weekly Wage
investigates deals with the intersection
between race and gender in earnings
inequality. Segregation and earnings
disparities between blacks and whites
observed at the turn of the 21st century
in the US, are considerably lower than
those documented in the middle
of the 20th century. The rate of decline
in racial pay disparities was fairly rapid
following the enactment of the Civil
Rights Act but has slowed in recent
decades. Despite the wide consensus
that racial economic disparities are
declining, researchers do not fully agree
on the sources, causes, and trajectory
of the decline or whether the trends
are similar for both men and women.
Although the literature on racial earnings
disparities has grown, most studies on
the topic focus on the male population.
To address this issue, Prof Mandel,
in collaboration with Moshe Semyonov,
used IPUMS data between 1970 and
2010 to examine the trends and sources
of the racial pay gap among men and
women in the US labour force. Findings
highlighted the significance of the
intersection between gender and race.
They found that gender differences in the
racial pay gaps were so pronounced that
it was not possible to reach conclusions
regarding racial
Shifts in income distribution during the
pay gaps based
first decade of the millennium were more
on data for only
one of the two
gender groups. detrimental to the earnings of blacks,
particularly black men, than to those of whites.
Racial pay gaps
were substantially
larger among
men than among women at all time
points. Although this demonstrates the
significance of the intersection of gender
and race, the findings do not support
a double disadvantage hypothesis.
Instead, they show that black men,
not black women, are the prime target
of economic discrimination in the US
labour market. However, the findings
also show that earning inequality is
more gendered than racialized. They
find that women of both races have an
68 www.researchoutreach.org
1000
Average Weekly wage by Race and Gender.
900
800
700
600
500
400
300
1970 1980
White Male Black Male
economic disadvantage in comparison
with men. The ‘racial advantage’ of black
women compared with black men should
thus be understood within their overall
gender disadvantage.
Despite these differences between
the genders, the trend over time
was very similar for both genders; racial
gaps sharply declined between 1970
and 1980 and continued to decline
at a slower rate until 2000. However,
at the turn of the millennium, the trend
reversed for both gender groups. Given
that earning inequality was found to be
“more gendered than racialized” the
similar trends is intriguing. The post-1970
decline in the gap can be understood as
resulting from the enactment of the Civil
Rights Act and the implementation of
affirmative action policies. The reversal
of the trend at the turn of the millennium
may have several explanations.
One possible explanation relates the
widening racial gaps to the sharp
increase in overall income inequality
during the 2000s. The findings showed
that, in the case of men (but not
women), once variations in income
1990 2000 2010
White Female Black Female
inequality across decades were
statistically controlled, the increase
in the racial pay gap during the 2000s
was much smaller. This implies that
in addition to changes that are directly
related to race, shifts in income
distribution during the first decade
of the millennium were more detrimental
to the earnings of blacks, particularly
black men, than to those of whites.
Some evidence also implies an increase
in market discrimination against blacks
at the beginning of the new millennium.
During the 2000s, rewards to academic
degree increased for whites more than
for blacks and thus whites benefited
more from higher education relative
to blacks. This
was followed
by stagnation
in the processes
of occupational
desegregation,
which may also
indirectly indicate
a rise in economic discrimination
against blacks. Although different
pay rewards of higher education
for blacks and whites, as well as
stagnation in desegregation, are only
implicit indicators for discrimination,
the simultaneous changes in the two
trends – i.e., the reversal of the trend
among the two gender groups, coupled
with our knowledge of government
reforms during this very period–
may point to growing discrimination.
Behind the Research
Professor Hadas Mandel
E: hadasm@tauex.tau.ac.il T: +972 3 640 7922 W: http://people.socsci.tau.ac.il/mu/hadasm/ W: https://scholar.google.co.il/
citations?user=GUGugqEAAAAJ&hl=en&oi=ao W: www.researchgate.net/scientific-contributions/2009968734_Hadas_Mandel
Research Objectives
Professor Mandel’s research addresses the analytical
and methodological distinctions between structural and
individual aspects of gender inequality, underpinning
the development of gender inequality over time
and across societies.
Detail
The Department of Sociology and Anthropology
Faculty of Social Science Naftali Building, Tel Aviv University.
Ramat Aviv. Israel
Bio
Hadas Mandel is an Associate Professor in the Department
of Sociology and Anthropology at Tel Aviv University.
Her research focuses on the intersection between gender,
class, race and the complex implications of welfare
state policies on women’s economic attainments. Since
2017, she is the Principal Investigator of the ERC-funded
‘Structural vs. Individual’ project addressing the analytical
and methodological distinction between structural and
individual aspects of gender inequality underpinning
the development of gender inequality over time
and across societies.
Funding
The European Research Council (ERC) under the European
Union’s Horizon 2020 research and innovation program
(Grant 641 Agreement No. 724351).
Collaborators
• Amit Lazarus
• Assaf Rotman
• Adi Moreno
References
Mandel H. (2013). ‘Up the Down Staircase: Women’s Upward
Mobility and the Wage Penalty for Occupational Feminization,
1970-2007’. Social Forces, 91 (4):1183-1207.
Mandel, H. (2016). ‘The role of occupational attributes
in gender earnings inequality, 1970–2010’. Social science
research, 55,122-138.
Mandel, H., & Semyonov, M. (2016). ‘Going back in time?
Gender differences in trends and sources of the racial pay
gap, 1970 to 2010’. American Sociological Review, 81(5),
1039-1068.
Mandel, H. (2018). ‘A Second Look at the Process
of Occupational Feminization and Pay Reduction
in Occupations’. Demography, 55(2), 669-690.
Personal Response
What is the focus of your future research in this area?
I expect the dynamic of the structural vs. individual
processes to vary between countries and also by class.
I thus seek to examine the processes in four representative
countries – Sweden, Germany, Spain and the United
States – that differ in many of the institutional aspects that
affect gender inequality, including the provision of welfare,
gender ideology, wage structure, and political economy
factors. Therefore, gender in/equality processes in these
countries are expected to take different forms in both
structural and individual appearances. That said, in all
countries I expect gender in/equality processes to vary
by class, and I thus seek to examine the processes after
distinguishing between classes of workers. I expect gender
equality to be more pronounced and rapid for advantaged
women. At the structural level, however, the rapid upward
occupational mobility of skilled and educated women
may expose highly rewarded occupations to devaluation
and pay reduction more than others. 
www.researchoutreach.org 69
Behavioural Sciences ︱ Dr Andrea Lavazza
The dawn of memory
modulation and self-prescribed
forgetting – a moral dilemma
Human memory is an incredible
feat of the brain, storing all of
our fondest memories, and
all of our greatest heartaches,
nightmares and frankly
memories we would maybe
rather do without. What was
once considered an idea bound
to science fiction may be a
possibility, at least theoretically.
Advances in Neuroscience
and Psychology have allowed
the idea of physically and
intentionally altering memory
and inducing forgetting. Andrea
Lavazza, a research fellow at the
International University Centre in
Arezzo, Italy, focuses on bringing
these ideas to light to allow
proper debate on a powerful,
and controversial topic.
H
umans often pride ourselves on
being the ‘Top’ species, ever
more creative, intelligent and
sophisticated than even our closest
relative species. We possess a number
of seemingly unique, complex, and
powerful abilities: imagination, will,
language, consciousness and morality.
Perhaps the most integral is memory.
Memory, whilst shared by many species,
is particularly important to humans – it
truly holds the key to individuality and
development of “The Self”. You are an
amalgamation of experiences in time;
thousands, even millions of moments,
some trivial, others life changing,
all stored by the brain. Your fondest
moments are remembered, and can
be replayed at will (for most of us at
least), bringing a smile to your face. By
the same token, your worst moments can
do the same with quite different results.
For many, childhood experiences and
memories shape later lives and identity.
For those fortunate enough to have a
pleasant upbringing, this can provide
stability and security. However, for
others, where early experiences were
acutely negative and traumatic, this can
create difficult problems to navigate.
The impact of painful memories on later
life and the self can be seen in Post-
Traumatic Stress Disorder
(PTSD): an acutely
traumatic memory
(resulting from
an accident, an aggression, or a
war episode) can cause anguish long after
the event. People can spend many hours
and a lot of money on psychotherapies
addressing negative memories in
attempts to resolve them. The value
of these approaches is unquestioned
but perhaps newer science can offer
an alternative method.
SCIENCE FICTION MATERIALISES
Altering memory has been a common
trope of science fiction films for decades
(think of “Total Recall”, “Strange Days” or
“Eternal Sunshine of the Spotless Mind”).
For most, it remains a fictional idea, rather
than a possible reality. But not for all.
Andrea Lavazza of Centro Universitario
Internazionale (Arezzo, Italy) specialises
in the field of neuroethics – a new field
that examines the wider implications
of neuroscience research. His recent work
has focused on the question of memory
modulation – Is it possible? Should we
do it? What might the implications be?
CAN WE?
Lavazza highlights the interesting finding
that a drug named Propranolol has been
found to modulate emotional response
to certain memories. Propranolol is
a beta blocker typically prescribed for
hypertension and anxiety. Studies have
found that if taken within six hours
of an emotionally salient event, the
emotional response to that memory
is mitigated (Brunet et al, 2008). The
drug works by inhibiting or reducing
the release of stress hormones such as
adrenaline and cortisol. This inhibition,
by proxy, means the negative response
associated with the memory of the event
will be reduced. The actual memory
itself is no less detailed. Instead, it is
the evoked emotional or stress response
which is lessened.
Post-Traumatic Stress Disorder can be more
prevalent in service personnel due to their
experiences of conflict.
The possible impact on a person’s mind,
self and identity caused by deleting
memories must be considered.
Recent work with animal models has CAN THE SELF SURVIVE Bullying can also leave children with negative
provided some more powerful examples UNNATURAL CHANGE?
and disruptive memories.
of memory modulation. For instance, rats Lavazza raises the issue of how memories
have been conditioned to associate a of all forms, including the negatively
particular stimulus, such as a cage, with charged, shape each person. If we begin time ago. However, imagine Elisabeth can
pain. Then, the rat’s brain is physically to alter how we remember negative now alter this memory of her bullies, or
altered via pharmaceuticals to stop the events, this can lead to a cascade of at least reduce the associated emotional
consolidation and storing of that memory; following decisions that may not have impact. She can now interact positively
the valence (positive or negative) occurred without that initial alteration. with the bullies, perhaps even ‘forgive’
of a memory was even switched by Lavazza alludes to a thought experiment them. This seems like a positive outcome
researchers using optogenetics (Redondo suggested by Erler (2011) where it but the question it raises is: Was it really
et al, 2014). As with all animal model is imagined a girl named Elisabeth Elisabeth making that decision? Wouldn’t
studies, the ability to transfer this to encounters her former childhood bullies. she have asked her friends to repent or
humans is not direct nor is it always Now ordinarily most of us as adults would have confronted the bullies if she had not
advisable. However, the possibility to not want to spend much time with anyone had her memories altered? Our genetic
perform such modifications with humans who caused us harm, even if it was a long makeup and life experiences shape the
is certainly real. So to the question “Is
memory modulation possible?”, the Post-Traumatic Stress Disorder was first widely
answer is yes – although the area currently recognised as ‘shell shock’ in soldiers in WWI.
lacks finesse and certainty.
SHOULD WE?
Moving beyond the practical ability
to modulate or delete memories – the
real question Lavazza deals with is: Should
we? Assume the existence of perfectly
accurate and reliable methods of memory
modulation and deleting. We could
now, in an extreme example, remove
the traumatic memories that cause PTSD.
On the surface, this sounds like a positive
use of a potential technology. However,
the possible impact of memory deletion
on a person’s mind, self and identity must
be considered.
www.researchoutreach.org 71

Problematic memories may make up integral
parts of our ‘Self’.
self and to alter these can possibly change
our self. Therefore, Elisabeth, by altering
her ‘natural’ response to negative
experiences, has altered Elisabeth
as a person.
Another hypothetical situation deserves a
mention. Imagine exploited or ill-treated
people were induced to take drugs that
would alleviate their negative memories.
They would suffer less but they might also
lose the urge to try to challenge injustice.
Not only would they “betray” their true
self, but the whole of society could be
damaged. Lavazza acknowledges that
while a single memory may not impact
a person’s core self, the possibility that
it might do remains open. The impact
of memory modulation and deletion at
present depends on one’s position on
what ‘The Self’ is: a hotly debated topic.
Supporters of certain narrative-based
theories of self argue that memory
is crucial to the self as it allows the
construction of one’s narrative within the
realms of reality (see Schechtman, 2014).
This means an accurate and truthful
representation of reality is integral and
hence sensitive to changes. Under this
perspective, altering any memory can
damage the ‘natural’ or truthful reality
which shapes formation of the self.
Narrative theories would suggest any
natural changes to self are gradual with
72 www.researchoutreach.org
room for foresight from the individual, i.e.
they can predict how these changes may
take effect, preserving the continuity of
self. Following this reasoning, any attempt
to introduce immediate modulation
or literal erasing of memories is a very
dangerous game to play. Lavazza refers
If we begin to alter how we remember
negative events, this can lead to a cascade
of following decisions that may not have
occurred without that initial alteration.
to this kind of formulation of the self
as ‘Rigid Identity’.
Constructionist viewpoints, on the other
hand, view the self as a more fluid,
emergent property which will not be lost
by changes to memory alone. In fact, the
alteration of unpleasant memories could
be seen as a form of self-improvement
akin to any approach to achieve such. The
possible damage of memory deletion and
modulation is far less pronounced if this
viewpoint – called ‘Extended Identity’ –
is held.
WHAT NEXT?
Lavazza’s work highlights the current
position of the debates surrounding
memory modulation and deletion to be
dependent on how the self is defined.
At present, popular theories are rooted
in ‘normative’ conceptualisations of the
self, rather than being based on empirical
research. Generally, the consensus is
either memory modulation could lead
to self-improvement or it could lead to
the opposite, self-deletion. As is often
the case with newly emerging fields,
progression of technology and scientific
research is going to be decisive here.
A world where negative memories and
experiences are eradicated may seem
attractive to the imagination, but it’s
dubious that anyone would seriously
consider it a desirable reality. Learning
from negative experiences is natural
and crucial to human development.
Empathy, compassion and many
complex human emotions could be lost
without natural responses to negative
stimuli. This is truly a fascinating topic,
which will require deliberate debate and
formation of good science to investigate
the implications fully.
Behind the Research
Dr Andrea Lavazza
E: lavazza67@gmail.com T: 0039 02 67 38 29 34 W: www.cui.org/andrea-lavazza/
W: www.researchgate.net/profile/Andrea_Lavazza2
Research Objectives Personal Response
Dr Lavazza’s work examines the ethics around memory How accurate do you think memory deletion can
modulation and erasing. actually be? Can a single, specific memory be deleted?
We must be clear in saying that today there is no
Detail safe and effective way to modulate memories at will. But
research in this field is taking rapid steps forward. Moreover,
Centro Universitario Internazionale, a single memory, closely embedded into a semantic
via A. Garbasso, network of other memories, seems almost impossible
42 - 52100 Arezzo (I) to remove completely at the current state of knowledge.
Italy
What one potential benefit to memory modulation
Bio would you highlight to the general public?
Andrea Lavazza is a senior research fellow at the Centro There are situations of suffering related to psychological
Universitario Internazionale, Arezzo, Italy. He specialises in traumas that can paralyze a person and literally prevent
moral philosophy and neuroethics. His interests focus on them from living. The ability to modulate negative
the social and legal implications of science and technology. memories – making them neutral – could reduce many
His publications include the book “Frontiers in Neuroethics. pains that today have no real cure.
Conceptual and Empirical Advancements” (Cambridge
Scholars Publishing). What are the potential risks of unregulated
memory-modulation?
Collaborators
• Silvia Inglese,Fondazione IRCCS Ca’ Granda Ospedale One can think a duty to remember exists. A witness
Maggiore Policlinico, Milan, Italy to a crime should keep her memories in good shape in
order to testify in the courtroom. But should an individual
who participated in a historical event remember and tell
other people what she saw even though the event was
shocking? Think of survivors of Nazi lagers. Should they
remember the facts in order to transmit the vivid story
of Shoah, with its capacity to mobilise people to prevent
a similar tragedy from happening again? Or do they have
the right to forget and live a happier life?
References
• L avazza A (2018) Memory-Modulation: • L avazza A and Inglese S (2013). • M
 uravieva E,V, Alberini C, M, (2010)
Self-Improvement or Self-Depletion? Manipolare la memoria. Scienza ed Limited efficacy of propranolol on the
Front. Psychol. 9:469. doi: 10.3389/ etica della rimozione dei ricordi. Milano: reconsolidation of fear memories. Learn
fpsyg.2018.00469 Mondadori Università. Mem.17:306–13.
• L avazza A (2015) Erasing traumatic • B
 runet A, Orr SP, Tremblay J, Robertson • R
 edondo R,L, Kim J, Arons AL,
memories: when context and social K, Nader K, Pitman RK. (2008) Effect Ramirez S, Liu X, Tonegawa S.(2014).
interests can outweigh personal of post-retrieval propranolol on Bidirectional switch of the valence
autonomy. Philos. Ethics Humanit. Med. psychophysiologic responding during associated with a hippocampal
10:3 DOI 10.1186/s13010-014-0021-6 subsequent script-driven traumatic contextual memory engram. Nat.
imagery in post-traumatic stress 513:426–30.
• L avazza A (2017) Moral Bioenhancement disorder. J Psychiatr Res.(42):503–6.
Through Memory-editing: A Risk for • S
 chechtman, M (2014). Staying Alive:
Identity and Authenticity? Topoi DOI • E
 rler A (2011). Does memory Personal Identity, Practical Concerns,
10.1007/s11245-017-9465-9 modification threaten our and the Unity of a Life. New York, NY:
authenticity?. Neuroethics, 4(3), 235-249. Oxford University Press.
www.researchoutreach.org 73
Health and Medicine ︱ Professors Kye Young Lee and Jae Young Hur EGFR genotyping results
The first lane shows primary tumour

Extracellular vesicle DNA:

tissue biopsy results. Second to
fourth lane compares the tissue re-
biopsy results of resistance acquired
patients with liquid biopsy using
BALF cfDNA and BALF EV DNA. Primary tissue biopsy
(Abbreviations; E19 del: exon 19
deletion, WT: wild type.)

A promising cancer biomarker p. T790M: 2/9 (22.2%)

Rebiopsy tissue

Lung cancer patients could
one day receive faster, cheaper
and more accurate diagnoses
thanks to extracellular vesicle
DNA found in liquid biopsies.
These were the findings of a
research team led by Professors
Kye Young Lee and Jae Young
Hur of Konkuk University’s
School of Medicine. Their work
offers an alternative to invasive
tissue biopsies which are
currently used to detect cancer
and determine treatments.
L
ung cancer is the biggest tumour-
related killer worldwide, accounting
for 1.6 million deaths per year.
Currently, doctors rely on biopsies
– invasive procedures that involve
taking tissue samples to determine
the presence and extent of disease –
to diagnose cancers and define the best
course of treatment. In fact, patients
are increasingly having multiple biopsies
during treatment as doctors try to prevent
or detect cancers’ resistance to targeted
drugs and immunotherapies.
However, while demand for biopsies
increases, the chances of obtaining
adequate tissue samples in later stages
decreases, as patients become more
susceptible to infection and other
diseases, preventing them from having
the procedure. Furthermore, the
asymptomatic nature of lung cancer
and lack of efficient diagnostic methods
means the disease can often reach
its later stages before a patient sees
a doctor for their first biopsy, leading
to poor prognosis.
As a result, researchers have turned
to liquid biopsies, such as blood tests,
to detect cancerous DNA. The more
efficient and less invasive nature of these
tests mean that cancers can be detected
with minimal risk to the patient and – once
optimised – could even become a routine
measure to help doctors detect cancers
sooner and improve patient outcomes.
However, finding enough cancerous DNA
in blood to achieve truly efficient and
accurate testing is challenging. Initially,
researchers focused on circulating tumour
DNA (ctDNA), however, there is only
a very small amount of ctDNA in the
blood, making it difficult to detect. And
while some studies have shown relatively
high rates of detection – or sensitivity –
ranging from 66% to 78%, others have
only achieved sensitivities ranging from
28.8% to 46%, rendering it unsuitable
for diagnostic use.
Now, a team of researchers led by
Professors Kye Young Lee and Jae
Young Hur at Konkuk University’s School
of Medicine are looking to extracellular
vesicle DNA (EV DNA) for faster,
cheaper and more accurate and reliable
cancer diagnosis.
WHAT ARE
EXTRACELLULAR VESICLES?
Extracellular vesicles (EVs) are
nanoparticles that are secreted by cells
into body fluids such as blood, urine or
saliva. They contain bioactive molecules
including DNA, RNA, proteins and
lipids (fats).
Fortunately for researchers, doctors and
patients, cancer cells secrete more EVs
than healthy cells, making them – and the
cancerous DNA – more abundant in body
fluids. This, combined with the protection
EVs offer DNA from degradation, make
EV DNA easier to detect and a better
target than cell-free DNA (cfDNA)
BALF cfDNA
BALF EV DNA
E19 del &
E19 del
p. T790M
time using a fibre optic cable so that
pulmonologists and surgeons can
see any diseased tissue.)
Once isolated, the EVs were broken
up and the cancerous DNA retrieved
for sequencing. In particular, the
researchers wanted to check that the
sequences of the epidermal growth factor
receptor gene (EGFR) found in plasma
and BALF EV DNA matched those found
in existing tissue samples. They chose
the EGFR gene because its encoded
protein helps control cell growth, division
and survival and mutations in the gene
have been associated with lung cancer.
Lung cancer is the biggest tumour-related
killer worldwide, accounting for 1.6
p. T790M: 3/9 (33.3%)
p. T790M: 5/9 (55.5%)
Not available,
p.L858R WT not done
The hope was that the three sample
types would be in complete agreement
for each patient and show that liquid
biopsies could definitively replace solid
tissue biopsies.
They found that BALF liquid biopsies
could. In fact, EGFR sequences in 23
BALF EV DNA samples matched 100%
of those obtained from tissue biopsies
from the same patients. In contrast,
cfDNA EGFR sequences only matched
71.4% of those from tissue biopsies.
Meanwhile, EGFR sequences from 20
plasma EV DNA samples matched 55%

TESTING IN NON-SMALL million deaths per year.

CELL LUNG CANCER PATIENTS
To see if EV DNA lived up to its promise,
Professors Lee and Hur decided to
explore it in non-small cell lung cancer
(NSCLC) patients, which account for
85% of lung cancer cases. Here, EVs
were obtained through liquid biopsies
of plasma and bronchoalveolar lavage
fluid (BALF). (A bronchoalveolar lavage
is a saline wash of the bronchial and
alveolar spaces in the lungs, where
saline displaces the EVs and any other
extracellular material and the resulting
Electron microscope image of EVs in BALF sample. The red arrow indicates double stranded DNA (dsDNA)
mixture is sucked up for examination. inside of an EV collected from BALF. DsDNA specific
A bronchoscopy is done at the same antibodies were used to performing immuno-EM.

74 www.researchoutreach.org www.researchoutreach.org 75
of sequences from corresponding tissue
biopsies. While this is significantly lower
than the BALF results, it is still higher than
those achieved with plasma cfDNA, which
only matched 30% of EGFR sequences in
corresponding tissue biopsies.
Professor Lee and his team chalk plasma
EV DNA’s reduced sensitivity down to
sample contamination. In their 2018
paper, they explain that lipoproteins
present in the plasma are very similar
to those of EVs, preventing them from
completely isolating EVs and interfering
with analysis.
They also suggest that distance could play
a role in a sample’s ability to demonstrate
cancer status, where BALF EV DNA’s
close proximity to the lung cancer helped
it to better display tumour status than
circulating EVs and DNA.
DETECTING ACQUIRED
DRUG RESISTANCE
With such remarkable results, Professors
Lee and Hur wanted to see whether BALF
EV DNA could also be used to detect
acquired drug resistance.
Often, EGFR-tyrosine kinase inhibitors
(TKIs) – anticancer drugs that prevent
an enzyme called tyrosine kinase from
transmitting signals that result in cell
growth and division, and thus, prohibit
Membrane
Protein
Protein mRNA
miRNA DNA
Mutant DNA
Phospholipid Bilayer
Diagram of tumour-derived EV containing RNA;
DNA, including mutant DNA; and proteins.
76 www.researchoutreach.org
Lung cancer patients could one day
receive faster, cheaper and more accurate
diagnoses thanks to extracellular vesicle
DNA found in liquid biopsies.
further growth or spread of cancer – can
be used to successfully treat NSCLC
patients.
However, after about a year of use,
patients with EGFR mutations such as
Exon 19 deletion and p. L858 R often
acquires resistance to EGFR-TKIs and
need alternative treatments.
To ensure the next set of treatments will
be effective, doctors need to confirm
that patients have the mechanism
of resistance caused by a mutation in
p. T790 M.
As a result, the researchers surveyed
biopsies from nine patients with
acquired resistance to EGFR-TKIs
for the p. T790 M mutation. Of
these, six were tested using BALF EV
DNA and cfDNA obtained from liquid
biopsies as well as a conventional
tissue biopsy. The remaining three
patients only had the BALF EV DNA
and cfDNA samples as tissue samples
were unattainable for various reasons.
Here, BALF EV DNA revealed that five
of the nine patients had the p. T790 M
mutation while cfDNA only detected
it in three out of nine patients. However,
these tests are still more sensitive than
tissue biopsies which only exposed the
mutation in two patients – including two
from the BALF EV DNA and cfDNA test.
Furthermore, two of the patients newly
identified as pT790M carriers by liquid
biopsy showed positive responses to
the subsequent Osimertinib, a third-
generation TKI designed to target
the pT790M mutation.
THE FUTURE
Despite the small sample size, these early
findings demonstrate BALF EV DNA’s
increased sensitivity to the p.T790M
mutation, compared to tissue biopsies
which are normally used to detect this
mutation. One day, BALF EV DNA tests
could help doctors optimise treatment
plans sooner and significantly improve
patient prognosis.
Finally, while further studies into EV DNA
is needed to confirm their ability to detect
other cancers and mutations, Professors
Lee and Hur believe that their research
could lead to the identification of new
biomarkers and help the advancement
of precision medicine.
Behind the Research
Professor Kye
Young Lee
E: 20050690@kuh.ac.kr E: 20160475@kuh.ac.kr T: +82 2 2030 7521 W: www.kuh.ac.kr/medical/dept/centerDoctor.do?dept_cd=100011
Detail
Konkuk University Medical Center
Gwangjingu neungdongro 120-1
Seoul, Korea 05030
Bio
Kye Young Lee MD PhD is a
Pulmonologist and chief of Precision
Medicine Lung Cancer Center at
Konkuk University Medical Center. He received his MD and
PhD from Seoul National University Medical School.
Jae Young Hur PhD runs the Liquid Biopsy lab in the
Department of Pathology and Precision Medicine Lung
Cancer Center at Konkuk University Medical Center.
He received his PhD from Seoul National University.
Funding
AstraZeneca Korea Ltd
Collaborators
• Hee Joung Kim at Konkuk University Medical Center
• Chang-Min Choi at Asan Medical Center
• Jae Cheol Lee at Asan Medical Center
• Min Kyo Jung at Korea Brain Research Institute
• Wan Seup Kim at Konkuk University Medical Center
Personal Response
How long do you think it will take before liquid
biopsies overtake tissue biopsies in cancer
diagnosis and treatment?
At present, liquid biopsies require advanced
technology not widely available in hospitals and
medical labs. Most liquid biopsies are performed
with blood, as it is the most conveniently drawn and
frequently tested body fluid. However, because of its
complex composition, results are often inconclusive
or complicated. Therefore, liquid biopsy technique
should be able to reduce cost, solve the problem of
interpreting complicated results, and explore other
bodily fluids to widen the use for cancer diagnosis.
Discovery of a new technique and then application
into the actual field often takes years, but liquid
biopsy technique seems to have reached the level
applicable to undiagnosed patients. There is currently
lots of excitement in the field of liquid biopsy as
we are sure this could lead to further research and
advancement in the early detection and treatments
of cancer patients.
Professor Jae
Young Hur
Research Objectives
Professors Kye Young Lee’s and Jae Young Hur’s research team’s
focus on studying and developing cancer detection methods
using liquid biopsy with extracellular vesicles.
References
Hartmaan, J., Haap, M., Kopp, H. and Lipp, H. (2009). ‘Tyrosine
kinase inhibitors – a review on pharmacology, metabolism and
side effects’. Current Drug Metabolism, [online] 10(5), 470-
481. Available at: www.ncbi.nlm.nih.gov/pubmed/19689244
[Accessed 20/01/2019].
Hur, J., Kim, H., Lee, J., Choi, C., et al. (2018). ‘Extracellular
vesicle-derived DNA for performing EFGR genotyping of
NSCLC patients’. Molecular Cancer, [online] 17(1), 15-20.
Available at: www.ncbi.nlm.nih.gov/pubmed/29374476
[Accessed 20/01/2019].
Jiang, T., Su, C., Ren, S., C., F., et al. (2018). ‘A consensus on
the role of osimertinib in non-small cell lung cancer from the
AME Lung Cancer Collaborative Group’. Journal of Thoracic
Disease, [online] 10(7), 3909-3921. Available at: www.ncbi.nlm.
nih.gov/pmc/articles/PMC6106007/ [Accessed 20/01/2019].
Lee, J., Hur, J., Kim, I., Choi, C., et al. (2018). ‘Liquid biopsy
using the supernatant of a pleural effusion for EGFR
genotyping in pulmonary adenocarcinoma patients: a
comparison between cell-free DNA and extracellular vesicle-
derived DNA’. BMC Cancer, [online] 18, 1236-1243. Available
at: bmccancer.biomedcentral.com/articles/10.1186/s12885-
018-5138-3 [Accessed 20/01/2019].
Paul, M. and M, A. (2004). ‘Tyrosine kinase – Role and
significance in cancer.’ International Journal of Medical
Sciences, [online] 1(2), 101-15. Available at: www.ncbi.nlm.nih.
gov/pmc/articles/PMC1074718/ [Accessed 20/01/2019].
Radha, S., Afroz, T., Prasad, S. and Ravindra, N. (2014).
‘Diagnostic utility of bronchoalveolar lavage’. Journal of
Cytology, [online] 31(3), 136-138. Available at: www.ncbi.nlm.
nih.gov/pmc/articles/PMC4274523/ [Accessed 20/01/2019].
Reck, M. and Rabe, K. (2017). ‘Precision Diagnosis and
Treatment for Advanced Non–Small-Cell Lung Cancer’. The
New England Journal of Medicine, [online] 377, 849-861.
Available at: www.nejm.org/doi/full/10.1056/NEJMra1703413
[Accessed on 20/01/2019].
US National Department of Health Services. (2019). EFGR
Gene. [online] Genetics Home Reference. Available at: https://
ghr.nlm.nih.gov/gene/EGFR#resources [Accessed 20/01/2019].
Williams, E. Amino acid single letter code. [online] UW
Hematology. Available at: http://williams.medicine.wisc.edu/
aminoacidcodes.pdf [Accessed 20/01/2019].
www.researchoutreach.org 77
Health and Medicine ︱ Gert Jan van der Wilt
Values and
evidence meet:
Appropriate healthcare assessment for vulnerable patients.
Healthcare technology
assessment is about discovering
how healthcare technologies
enable us to create value. A
key factor is clinical ethics,
yet historically this has been
overlooked. Researchers Gert
Jan van der Wilt, Herbert
Rolden, Janneke Grutters
and Angela Maas at Radboud
University Medical Centre
explore the ethical and social
implications of health care
technologies. Their research
aims to develop concepts
and methods that enable a
patient-centred, comprehensive
approach to help inform
decision-making, both in the
introduction of new technologies
and for the appropriate use
of existing technologies.  well as the likely effects on mortality.
78 www.researchoutreach.org
I
n recent years, the number and variety
of health technologies developed
have increased at a rapid rate. These
include new medications, diagnostic
tests, devices, surgical methods,
medical procedures and systems: all are
developed to solve a health problem and
improve our quality of life. We often take
it for granted that these technologies
are effective and that they show benefits
to the patient, but to be adopted they
also need to represent value for money.
The effectiveness and cost of health
technologies are assessed by a rigorous
process. Clinical evidence is obtained
to show how well the technology works
– the health benefits. The evidence
includes the impact on quality of life
(for example, pain or disability), as
Economic evidence shows how well
the technology works in relation to
how much it costs and whether it
represents value for money. Health
technology assessment (HTA) is a
comprehensive evaluation framework
that generates evidence of the value
of health technologies. In a nutshell,
HTA is about discovering how healthcare
technologies enable us to create value.
It is a systematic, evidence-based
mechanism that evaluates and prioritises
new technologies from economic, social
and ethical perspectives.
VALUE OF INFORMATION ANALYSIS
Economic evaluations are increasingly
used to inform decisions in healthcare;
however, decisions remain uncertain
when they are not based on adequate
evidence. Value of Information analysis
is a systematic approach to measure
decision uncertainty and assess whether
there is sufficient evidence to support
new health technologies. Essentially, it is
a decision support tool for the allocation
of resources to scientific research.
ADDRESSING CLINICAL ETHICS
Ethics concerns what is right and wrong
and the reasons that we give for our
choices and actions. Clinical ethics
refers to the study of ethical issues and
promotes making the ‘right’ choices and
decisions in the delivery of healthcare.
It concerns basic ethical principles such
as autonomy (the right for individuals
to make choices about what happens
to them), beneficence (the desire to
do good), non-maleficence (the duty
to prevent harm), and justice (fairness).
ETHICAL DILEMMAS
IN CLINICAL RESEARCH
Given the tremendous rate of
development of health innovations,
it’s important to carefully consider
the research questions that will
be addressed: how, where, when
and by whom? These questions
pose a challenge when the patients
participating in those studies
are vulnerable.
Patients may be vulnerable for a
variety of reasons. Firstly, because
they are unable to fully appreciate the
implications of their participation (or
non-participation) in a clinical study
(e.g., children and
elderly people
with compromised
These questions pose a particular
cognitive abilities). challenge when the patients participating
in those studies are vulnerable.
Secondly, patients
may be vulnerable
because they
are more likely to sustain adverse
outcomes, for instance, because of co-
morbidities, such as diabetes or heart
failure. Thirdly, their participation may
be considered as exploiting some sort
of disadvantage (e.g., they being poor
or dependent). Conversely, despite the
importance of these considerations,
not providing vulnerable patients with
the possibility to participate in clinical
research results in the uncertainty of
treatments being safe and beneficial
for them. The participation of vulnerable
patients in clinical research presents
ethical dilemmas.
This is where the work of researchers
Gert Jan van der Wilt, Janneke Grutters,
Angela Maasand Herbert Rolden comes
in. This dedicated team of researchers
have worked together to investigate
methods for exploring the ethical
and social implications of health care
technologies.
SPECIFYING NORMS
Henry Richardson of Georgetown
University, Washington DC (1)
established the method of specifying
norms as a method of moral
argumentation – as a way of resolving
ethical dilemmas in a transparent
and systematic way. Richardson’s unique
framework recognises that generic moral
principles can be specified in multiple
ways, also that it offers several rules
for preserving the moral import of the
original, unspecified principle. Giving
the example of a severely malformed
newborn child, whose parents wish that
their child should be allowed to die,
Richardson proposes three moral norms
facing the healthcare provider:
Norm 1. It is wrong to kill
innocent people.
Norm 2. We should respect the
reasonable choices of parents regarding
their children (i.e. respecting autonomy).
Norm 3. We should act in the best
interest of persons who have been
entrusted to our care.
Richardson points out that there is
always a gap between general moral
norms (such
as respecting
autonomy) and
judgments as to
what follows from
our commitment
to such norm
in concrete situations.
One way to bridge this gap is by
making the norm more specific. For
example, norm 1 can be conceived as
a specification of a still more general
norm, expressing respect for persons:
Norm 1: It is wrong to kill innocent
people who have attained self-
consciousness or who have the
potential to develop self-consciousness
over time.
www.researchoutreach.org 79
 Behind the Research

Gert Jan van der Wilt Herbert Rolden Janneke Grutters Angela Maas
E: Gertjan.vanderwilt@radboudumc.nl T: +31 24 361 3126 W: www.radboudumc.nl/en/people/gert-jan-van-der-wilt/health-
technology-assessment W: www.validatehta.eu W: www.narcis.nl/person/RecordID/PRS1272404/Language/en
W: www.researcherid.com/rid/H-8120-2014 W: www.integrate-hta.eu W: www.htaplus.nl/what-is-hta-/
As Prof van der Wilt explains: “According
to this framework when we find ourselves E: hj.rolden@raadrvs.nl T: +31 6 1503 5377 www.linkedin.com/in/herbert-rolden/
in a dilemma, the key task is to develop W: www.raadrvs.nl/over-de-rvs/medewerkers/medewerkers/dr.-h.j.-herbert-rolden
alternative specifications of the various
moral principles. In other words, we E: janneke.grutters@radboudumc.nl T: +31 (0)24 361 69 22 W: www.radboudumc.nl/en/people/janneke-grutters W: www.
need to find out what follows from radboudumc.nl/en/people/janneke-grutters @JannekeGrutters https://nl.linkedin.com/in/janneke-grutters-60a1a29
our commitment to a particular moral
E: angela.maas@radboudumc.nl T: +31 6 51585435 W: www.hartvoorvrouwen.nl
principle in a specific situation, taking into
@maasangela www.linkedin.com/in/angela-maas-54984413/
account that one or more other moral

In addition to assessing safety, clinical

principles should be observed, too.”

Research Objectives References

Building on Richardson’s work, the team
present a framework that makes explicit
the moral principles that guide decisions
in a concrete situation and that are the
cause of the ethical dilemma in hand.
Professor van der Wilt says: “These could
include, for example, our desire to respect
patients’ autonomy, our desire to be
able to act truthfully, our desire to treat
all people fairly, and our desire to spend
resources wisely. We then need to realise
that such principles are quite abstract
and generic and that in order to decide
what follows from our commitment
to these norms in concrete situations,
we need to specify them.”
A NEW FRAMEWORK
The team at Radboud University neatly
illustrate the application of the framework
in a recent publication. The team used
the case study of pre-menopausal women
with atrial fibrillation, posing the question
whether these women should be invited
to participate in clinical studies of a
new type of blood thinners, novel oral
benefits and cost-effectiveness, it is
important to consider the social and
ethical factors to guide decision-making.
anticoagulants (NOAC). These women
could be considered vulnerable since
they are at increased risk of substantial
bleedings that are difficult to control and
that may have serious consequences.
Due to their non-participation in key trials,
there is uncertainty for this cohort whether
the risks that are associated with these
drugs are outweighed by the advantages,
compared with conventional treatment.
They addressed the question of whether
research of this new class of drugs for
these women would be appropriate, both
from an ethical and economic perspective.
SHOULD PREMENOPAUSAL WOMEN
WITH AF HAVE BEEN INCLUDED IN
TRIALS OF ANTICOAGULANTS IN
THE FIRST PLACE?
Using Richardson’s method of specifying
norms as a wider framework the team
proposed how the apparent ethical
dilemma may be resolved, considering
patients’ considerations
and the need to spend
resources for clinical
research wisely. The
team concluded
that in fact inclusion
of premenopausal women with AF
in trials of NOACs would have been
the ideal option.
Incorporating the question whether
research of NOACs in pre-menopausal
women with atrial fibrillation can be
justified on economic grounds was
determined using the value of information
analysis. The research team concluded
that further clinical research on NOACs
in premenopausal women with atrial
fibrillation is justified – both on ethical
and economic grounds.
The team elegantly exemplify that
addressing apparent ethical dilemmas
by employing the use of a method such
as specifying norms can improve the
quality of public practical reasoning. Their
work demonstrates that the method
has substantial value to inform health
policymakers by using solid scientific
evidence on the medical, social, economic
and ethical implications of investments in
health care. In addition to assessing safety,
clinical benefits and cost-effectiveness,
it is important to consider the social and
ethical factors to guide decision-making.
A team of researchers at Radboud University Medical
Centre explore the ethical and social implications of health
care technologies. Their research aims to develop concepts
and methods that enable a patient-centred, comprehensive
approach to help inform decision-making, both in the
introduction of new technologies and for the appropriate
use of existing technologies.
Detail
Bio
Gert Jan van der Wilt (Researcher ID: H-8120-2014) is
professor and head of Health Technology Assessment (HTA)
at Radboud University Nijmegen Medical Centre.
Herbert Rolden is currently a policy advisor for The Council
for Health and Society in The Netherlands.
Janneke Grutters works as associate professor and junior
principle investigator at Radboudumc.
Angela Maas is a clinical cardiologist and is currently one
of the most influential female doctors in Dutch healthcare.
Funding
The Netherlands Organisation for Health Research
and Development (ZonMw)
Richardson, HS (1990). ‘Specifying Norms as a Way to Resolve
Concrete Ethical Problems’. Philosophy & Public Affairs. 19;
4:279-310.
van der Wilt, G., et al. (2018). ‘Combining value of information
analysis and ethical argumentation in decisions on
participation of vulnerable patients in clinical research’. Bmc
Medical Ethics; 19:5 https://doi.org/10.1186/s12910-018-
0245-x  
Rolden et al. (2017). ‘Uncertainty on the effectiveness and
safety of rivaroxaban in premenopausal women with atrial
fibrillation: empirical evidence needed’. BMC Cardiovascular
Disorders; 17:260. DOI 10.1186/s12872-017-0692-1.
Personal Response
In your view, how much importance should the
perspective of the patient have in the evaluation
of healthcare technology?
The patient perspective plays a key role. HTA is about
collaboratively exploring how health technologies enable
us to better realise particular social and ethical values.
This requires carefully integrating empirical analysis and
normative inquiry. All stakeholders, and notably patients,
should be able to recognise and endorse the choices that
are made in the context of an HTA and agree with the
interpretation of its findings.

80 www.researchoutreach.org www.researchoutreach.org 81
Health & Medicine ︱Dr Jessica Walsh, Dr Xue Song, Dr Gilwan Kim and Dr Yujin Park
Counting the costs of
ankylosing spondylitis
Ankylosing spondylitis (AS)
is a chronic rheumatic disease.
A debilitating condition, it
has large patient and societal
burdens. However, the financial
impact of the disease is not
fully understood. Aiming to
change this are Dr Jessica
Walsh from the University of
Utah School of Medicine, Drs
Xue Song and Gilwan Kim
from IBM Watson Health, and
Dr Yujin Park from Novartis
Pharmaceuticals Corporation.
Through retrospective analysis
of recent administrative claims
data, the team comprehensively
reviewed all-cause and AS-
specific costs of disease for US
patients. Their findings provide
insight into the direct medical
costs associated with healthcare
utilisation of patients with AS.
82 www.researchoutreach.org
A
nkylosing spondylitis (AS) is a
painful and progressive form of
inflammatory arthritis that affects
0.1–1% of the US population. A chronic
condition, AS mainly affects the spine
(‘spondylo’), which becomes inflamed,
causing chronic and often severe pain
and stiffness, and can result in extreme
tiredness. Over time, the inflammation
can lead to ankylosis, where new bone
formation in the spine causes sections
of the spine to fuse in a fixed, immobile
position. In extreme cases, patients
become severely disabled and functional
disabilities have a large impact on
the ability to carry out everyday tasks
and may result in the inability to work.
AS can also cause inflammation, pain,
swelling and stiffness in other areas
of the body. Inflammation that occurs
at the site where ligaments or tendons
Their study is the first comprehensive
analysis comparing healthcare utilisation
and direct costs in AS patients, compared
to matched controls.
attach to the bone is known as
entheses. Other areas such
as the hips, ribs, heels,
and other joints can
also be affected.
Symptoms tend
to develop gradually,
usually over several months or
years, and patients may have periods
of remission followed by relapse.
Unfortunately, there is no cure for AS.
However, treatment regimens can
relieve pain and halt worsening of the
condition. Common treatments include
a combination of medication, exercise,
and physical therapy. Consequently,
the impact of AS is substantial; particularly
since it develops relatively early in life,
tending to first develop in late teens
through to 40 years of age. Although
AS onset after 50 years of age is unusual,
because of the often invisible nature
of the disease, AS may go undiagnosed
for many years, and in some cases more
than 10 years, leading to diagnosis
at an older age.
COMMON COMORBIDITIES
Along with inflammation of the spine,
joints, and entheses, patients with AS
often present with peripheral arthritis,
psoriasis, and inflammatory bowel
diseases. Studies also show that
patients with AS have significantly more
comorbidities than matched controls
in the general population, including
cardiovascular disease, diabetes,
malignancies, and depression [1-3].
In addition to the considerable burden
faced by AS patients due to chronic
pain and disability, financial burdens
associated with AS are also substantial.
Despite this, there are limited data about
the direct costs of AS.
A team of researchers is determined
to gain a better understanding of the
financial burden of AS: rheumatology
specialist Jessica Walsh, MD, University of
Utah School of Medicine; Xue Song, PhD,
an Outcomes Research Practice Leader at
IBM Watson Health; Gilwan Kim, PharmD,
MS, Analyst Manager at IBM Watson
The gaps between vertebrae provide a lot of our
ability to move. When sections of the spine fuse
together, this mobility is lost.
Health; and Yujin Park, PharmD, Associate The study included 6,679 patients aged
Director in Health Economics and 18 years and older with at least one or
Outcomes Research and Medical Access more inpatient or at least two or more
at Novartis Pharmaceuticals Corporation. outpatient medical claims for AS between Physical therapy can help alleviate symptoms of AS.
Their research, supported by Novartis January 1, 2012, and December 31,
Pharmaceuticals Corporation, provides 2014. Patients were matched (by age, healthcare utilisations and direct
insight into the direct medical costs geographic location, index calendar costs than matched controls with
associated with AS. The team noted that year, and sex) with controls without AS significantly higher rates of total all-
the majority of research into AS-related at a ratio up to 1:5 (19,951 patients). cause inpatient admission (12% vs 6%),
costs has been undertaken outside the All-cause and AS-specific healthcare emergency department visits (23% vs
United States. Recognising a gap in the utilisations and associated direct costs 15%), nonhospital-based outpatient
literature, the team investigated all-cause were compared between the two patient visits (100% vs 84%), hospital-based
and AS-specific direct costs in US patients groups over the course of 12 months. outpatient visits (68% vs 46%), other
with AS to better understand the financial outpatient services (97% vs 81%),
impact of the disease. Their study is the Their results were striking. Patients and medication use (97% vs 82%) than
first comprehensive analysis evaluating
healthcare utilisation and direct costs
with AS had substantially higher the matched control group.
in US patients with AS compared with
matched controls.
COUNTING THE COSTS OF AS
The research team undertook
retrospective analysis of recent
administrative healthcare claims data
from US patients. The team used the
IBM Watson Health MarketScan®
Commercial Claims and Encounters
(Commercial) database and Medicare
Supplemental (Medicare) database. Both
large databases provided longitudinal
information on healthcare services
(including inpatient and outpatient
services, long-term care, and prescription
drug claims) for patients insured under
various health plans. Their study was
recently published in Rheumatology Over time, inflammation can lead to ankylosis, where new bone formation in the spine causes sections
and Therapy. of the spine to fuse in a fixed, immobile position.
www.researchoutreach.org 83
Notably, patients with AS had a tenfold-
higher median total all-cause healthcare
A $35,000

$30,000
$33,285
Patients with AS

Matched controls
Behind the Research

Mean costs (USD 2015)

$25,000
cost than matched controls ($24,978 vs
$2,139 per patient per year). Higher costs $20,000
associated with AS were largely a result
$15,000 $14,074
of increased medical outpatient services $13,220

(mean cost $13,220 vs $4,602, per patient $10,000 $8,310

per year) and outpatient pharmacy $4,990 $4,602 $5161

$6,419

$5,000
costs (mean cost $14,074 vs $1,737, per $1,971
$385 $222
$1,255 $519
$2,053 $1,812 $1,737
Dr Jessica A. Walsh Dr Xue Song Dr Gilwan Kim Dr Yujin Park
patient per year), as illustrated in the
E: Jessica.walsh@hsc.utah.edu E: songx@us.ibm.com E: kimgi@us.ibm.com E: Jina.park@novartis.com
$-
Total Inpatient Total medical Emergency Outpatient visit Outpatient visit Other outpatient Outpatient
figure opposite. Outpatient pharmacy healthcare outpatient service department (non hospital- (hospital-based) service pharmacy
based)
costs associated with AS included use
B
Total medical outpatient service
$18,000
of biologic therapies, other AS-related
medications (e.g. anti-inflammatory drugs,
$16,000
$16,337

$14,595
Research Objectives
Mean costs (USD 2015)

$14,000
antirheumatic drugs), antihypertensives, The team’s work has unveiled the direct costs of healthcare for patients with ankylosing spondylitis.
and antidepressants. $12,000

$10,000

The research team suggests that the

presence of common comorbidities
$8,000
Detail References
$6,000
contributes to the increased utilisations $4,000 Jessica A. Walsh
and costs observed in patients with AS $1572 University of Utah School of Medicine and Salt Lake City 1 W
 alsh JA, Song X, Kim G, Park Y. (2018). Healthcare
$2,000
compared to matched controls. Their $170 $21
$402 $672 $477
Veterans Affairs Medical Center, Salt Lake City, UT utilization and direct costs in patients with ankylosing
$-
analysis showed that patients with AS had Total Inpatient Total medical Emergency Outpatient visit Outpatient visit Other outpatient Medicatione spondylitis using a large US administrative claims
healthcare outpatient department (non hospital- (hospital-based) service
significantly higher rates of cardiovascular based)
Xue Song database. Rheumatol Ther. 5(2):463-474. doi: 10.1007/
Total medical outpatient service
disease, depression, malignancies, IBM Watson Health, Cambridge, MA s40744-018-0124-4.
osteoporosis, sleep apnoea, and spinal A (top): Mean direct healthcare costs per patient per year over a 12-month follow-up period. All-cause
healthcare costs for patients with AS and matched controls. Note how the cost for patients with AS
fracture, as well as inflammatory bowel is consistently higher than for the matched controls. Gilwan Kim 2 W
 alsh JA, Song X, Kim G, Park Y. (2018). Evaluation
disease and psoriasis than matched B (bottom): AS-related healthcare costs for patients with AS. IBM Watson Health, Cambridge, MA of the comorbidity burden in patients with ankylosing
controls. These comorbidities require spondylitis using a large US administrative claims data
additional medications, treatments AS and comorbidities and the role and costs could not be determined in the Yujin Park set. Clin Rheumatol. 37(7):1869-1878. doi: 10.1007/
and complicate AS management, of inflammation in the development current study, since this information is not Novartis Pharmaceuticals Corporation, East Hanover, NJ s10067-018-4086-2.
leading to increased costs. However, of comorbidities in patients with AS.” The available from administrative claims data.
as the authors note: “Further research team also noted that effects of severity of Bio 3 W
 alsh JA, Song X, Kim G, Park Y. (2018). Evaluation
is needed to fully determine the potential disease and other risk factors (e.g. obesity CONCLUSION Jessica Walsh, MD, is an Instructor at the University of Utah of the comorbidity burden in patients with ankylosing
cause and effect relationships between and smoking) on healthcare utilisation The research of this team of colleagues School of Medicine and George E. Wahlen Veteran Affairs spondylitis treated with tumour necrosis factor inhibitors
fills a gap in the body of knowledge on Medical Center. As a rheumatologist, her clinical interests using a large administrative claims data set. J Pharm
The research of this team of colleagues
include spondyloarthritis and psoriatic diseases.
AS comorbidities and costs of care for US Health Serv Res. 9(2):115-121. doi: 10.1111/jphs.12212.

fills a gap in the body of knowledge

patients with AS. Their work helps better
Xue Song, PhD, is an Outcomes Research Practice Leader
represent the overall costs associated
at IBM Watson Health.
on AS comorbidities and costs of care with AS: in addition to its physical,
psychological and social burden, the Personal Response
for AS patients in the USA. current study highlights the high economic
Gilwan Kim, PharmD, MS, is an Analyst Manager at IBM
Watson Health.
burden of the healthcare needs of AS Your research provides insight into the cost of the
patients. Findings from their descriptive healthcare needs of patients with AS. What’s next
Yujin Park, PharmD, is an Associate Director in Health
analysis using large administrative claims for your work?
Economics and Outcomes Research and Medical Access
databases provide key insights into the at Novartis Pharmaceuticals Corporation. This study looked at direct costs associated with
direct medical costs associated with AS, but studies that evaluate societal and indirect costs,
healthcare utilisation in patients with AS Funding such as work productivity, disability, and caregiver costs,
across the United States. The total financial This study was sponsored by Novartis Pharmaceuticals will provide a more complete picture of the economic
burden. This is especially important for patients in the
burden of AS could not be determined Corporation, East Hanover, NJ.
US healthcare system because previous studies have
in the current study because indirect costs
shown indirect costs associated with AS to be higher
related to AS – such as disability, loss Dr Walsh is a consultant for Novartis Pharmaceuticals than direct costs. In addition, as the diagnostic delay
of work productivity, and caregiver costs Corporation. of AS is one of the biggest challenges in optimising
– were not measured. Further research care, further research quantifying the cost of delayed AS
aimed at quantifying the total financial Dr Song and Dr Kim are employees of IBM Watson Health. diagnosis from payer and patient perspectives would
burden of AS from the individual patient help to raise the importance of this issue. 
standpoint and society perspective would Dr Park is an employee of Novartis
Symptoms, such as inflammation and chronic pain, increase over time for many patients. be beneficial. Pharmaceuticals Corporation.

84 www.researchoutreach.org www.researchoutreach.org 85
Health and Medicine ︱ Dr Laura Bonnett
How data is improving
driving policies
for epilepsy patients
Until recently, UK epilepsy
patients’ quality of life and
the public’s safety rested on
driving policies informed by
neurologists’ ‘expert opinions’.
However, Dr Laura Bonnett
of the University of Liverpool
and her team have found
hard evidence to back up and
improve these policies. By
determining the risk of recurring
seizures in first-time seizure
patients, those on antiepileptic
drug withdrawal programs
and patients suffering from
breakthrough seizures, Dr
Bonnett and her team have
helped epilepsy patients regain
their licences (and their freedom)
sooner while ensuring that their
risk of seizure falls under the
Driver and Vehicle Licensing
Agency’s threshold of 20%.
86 www.researchoutreach.org
S
eizures are sudden surges of
electrical activity in the brain.
Often, they are accompanied by
muscle spasms, lapses in consciousness
or awareness, staring spells, or cognitive
or emotional symptoms, such as fear,
anxiety or deja vu and can last anywhere
from a couple of seconds to several
minutes. According to Dr Bonnett, one in
20 people will experience one-off seizures
in their lifetime while one in 120 people
in the United Kingdom (UK) will have
epilepsy – a neurological and physical
condition marked by recurring seizures.
Although some people are prevented
from driving due to their medical
condition, road users – such as drivers,
cyclists and pedestrians – may still
encounter drivers with epilepsy or one-off
seizures. Importantly, the UK Driver and
Vehicle Licensing Agency (DVLA) only
reinstates patients’ car licences after
their risk of having a seizure in the next
year falls to 20% – the same as the risk
of a newly qualified driver having an
accident in their first year behind
the wheel. However, until recently,
patients relied on the ‘expert
opinions’ of neurologists
to determine when they’d
reached this threshold – often
forcing them to wait a year
before they could regain their
licence as long as they didn’t
have another seizure
in the meantime.
Now, research by Dr Laura Bonnett
of the University of Liverpool
and her team is helping to
pinpoint the time that their
risk of seizure is reduced to
20% or below, getting patients
back on the road sooner and ensuring
the safety of all road users.
RISK OF SEIZURE RECURRENCE:
First-time seizure patients
In her 2010 study, Dr Bonnett found that
people with a first-ever seizure were more
likely to have a second seizure if they:
have a known cause for the first seizure,
such as a head injury or brain infection;
have a parent with epilepsy; were asleep
when the first seizure occurred or weren’t
treated straight after the first seizure.
Patients were also at higher risk if they
displayed abnormal results from a head
scan or electroencephologram (EEG).
In her Award Lecture for the British
Science Festival, Dr Bonnett likened
an EEG to getting hair dyed at a salon.
However, instead of covering their hair
in foil and ending up with a bold new
colour, patients have receivers stuck
to their head and obtain a chart showing
their brain activity.
During this study, Dr Bonnett and her
team used data from a randomised
clinical trial with 637 patients, aged 16
years and over, that had had a first-time
seizure. Of these, 317 received treatment
immediately after the first seizure while
320 did not.
Fortunately for the experts and road users,
statistical analysis showed that if patients
were to regain their licence a year after
the initial seizure the risk of them having
a seizure in the next 12 months was 7% if
they had treatment and 10% if they didn’t.
Moreover, if Dr Bonnett and her team
were to account for patient variability,
such as age and sex – by calculating 95%
confidence intervals – the figures fell to
An electroencephalogram (EEG) allows doctors
to study a patient’s brain waves.
between four and 11% and six and 15%
for the groups with and without treatment
respectively. (A confidence interval is a
range of numbers in which researchers
According to Dr Bonnett, one in 20 who had a seizure recurrence during or
following AED withdrawal, recommenced
people will experience one-off seizures treatment, and were seizure-free for six
in their lifetime.
months after treatment was restarted
had an 18% chance of having a seizure
in the next 12 months. However, the
can be 95% certain the true statistic would be allowed to drive again. And, small sample size prevented the team
lies.) All well below the 20% threshold. the European Union (EU) standard stated from achieving a risk definitively below
However, when the researchers looked that patients experiencing seizures during 20% (with the confidence interval being
at the risk of seizure in the year following a physician-advised change or withdrawal 10% to 27%). Conversely, if patients
the six months after the first seizure, they of medication needed three months were seizure free for twelve months after
found it to be 14% for the treated group off driving, if the previously effective restarting treatment, the risk was 17%
and 18% for the untreated group. Still treatment was reinstated. (8% to 27%) and at three months, the risk
below the 20% threshold! was 26% (17% to 35%).
To determine the suitability of these
These results led the DVLA to reduce recommendations, Dr Bonnett and In her paper, Dr Bonnett expressed
the licence penalty from 12 months to her team reviewed data from the Medical concerns that – based on the discrete
six months, even though the upper limit Research Council’s AED withdrawal estimates – UK legislation was too
of the untreated group’s confidence study. Here, they found that patients conservative and that the EU standard
interval was 23%. Here, the DVLA chose
to focus on the discrete figures, rather
than confidence intervals, as the high
volume of applications prevents them
from calculating the risk on a case-by-
case basis.
After antiepileptic drug withdrawal
Understanding the importance of her
work, Dr Bonnett extended her research
to explore the risk of seizure recurrence
after antiepileptic drug (AED) withdrawal.
When her study was published in
2011, the DVLA advised that patients
undergoing AED withdrawal should
not drive for six months after the last
dose had been taken. Furthermore,
under the Road Traffic Act, if patients
were to restart treatment, they had to A patient undergoing electroencephalography.
be seizure free for a year before they
www.researchoutreach.org 87

Newly qualified drivers have a 20% risk of having
an accident in their first year behind the wheel.
was too liberal and she has conveyed
these concerns to policy makers.
After a breakthrough seizure:
According to Dr Bonnett, a breakthrough
seizure is the first seizure after at least
12 months’ seizure freedom while on
treatment. Under the DVLA regulations,
patients who have had a breakthrough
seizure cannot drive for a year.
To ensure the risk of recurring seizures
following a breakthrough seizure falls
under the 20% threshold by this time,
Dr Bonnett and her team chose to
reanalyse data from the standard versus
new antiepileptic drugs (SANAD) study.
Epilepsy is not the only
condition that increases
the likelihood of having
an accident.
88 www.researchoutreach.org
Many of these policies are informed
by ‘expert opinions’ rather than hard
evidence...
This involved taking data from a
randomised clinical trial where they
observed 339 eligible patients aged
16 years and over. While the initial study
separated these patients into ‘Arm A’
and ‘Arm B’ based on the medications
they received, Dr Bonnett and her
team pooled the data to explore risk of
recurring seizures regardless of treatment.
Overall, the team found the risk of
recurring seizures at one year to be 17%
(15% to 19%), while the risk at six months
was 32% (28% to 36%), supporting the
DVLA’s decision to have patients
wait a year to retrieve their
licence. However, the study
found that some subgroups
needed at least 15 months
off before they reached
the 20% threshold.
THE NEED
FOR EVIDENCE-
BASED POLICY
According to Dr Bonnett,
the number of people killed
or seriously injured in UK road
accidents is relatively low compared
to international standards. She believes
this is partly due to policies preventing
people with certain medical conditions
from driving. However, many of these
policies are informed by ‘expert opinions’
rather than hard evidence – just as those
around people driving with epilepsy
were prior to Dr Bonnett’s work. This
can significantly impact the public’s safety
and the patients’ quality of life.
This is clearly shown through the three
studies discussed in this article, where
policies were initially too harsh (in
the case of first-time seizure patients)
or too lenient (in the EU’s policies around
AED withdrawal). Furthermore, studies
have shown that people with medical
conditions other than epilepsy are
26 times more likely to have an accident
than those with epilepsy. Thus, there
is a greater need for research into those
medical conditions and their impact
on driving ability in order to inform
policies and improve road safety. As
a result, Dr Bonnett’s next mission is to
explore driving policies around diabetes.
Behind the Research
Dr Laura Bonnett
E: L.J.Bonnett@liverpool.ac.uk T: 0151 795 9686 W: www.liverpool.ac.uk/translational-medicine/
staff/laura-bonnett/ @ljbcmshe
Research Objectives References
Dr Bonnett’s work focuses on prediction modelling within Bonnett L, Shukralia A, Turdur-Smith C, et al. (2011).
chronic conditions such as epilepsy. Her work has been used by Seizure recurrence after antiepileptic drug withdrawal and
the UK-based Driver and Vehicle Licensing Agency to modify the implications for driving: further results from the MRC
Antiepileptic Drug Withdrawal Study and a systematic review.
their driving regulations for people with seizures and epilepsy.
Journal of Neurology, Neurosurgery & Psychiatry, 82(12), 1-6.
Bonnett L, Tudur-Smith C, Williamson P, and Marson A.
Detail (2010). Risk of recurrence after a first seizure and implications
for driving: further analysis of the Multicentre study of early
Department of Biostatistics Epilepsy and Single Seizures. BMJ, [online] 341, 1-8. Available
Waterhouse Building at: www.bmj.com/content/341/bmj.c6477 [Accessed
Block F 04.12.18).
1-5 Brownlow Street
University of Liverpool Bonnett L, Powell G, Tudur-Smith C, Marson, A. (2017). Risk
L69 3GL of a seizure recurrence after a breakthrough seizure and the
implications for driving: further analysis of the standard versus
UK
new antiepileptic drugs (SANAD) randomised controlled trial.
BMJ Open, [online] 7:e015868, 1-6. Available at: https://
Bio
bmjopen.bmj.com/content/bmjopen/7/7/e015868.full.pdf
Dr Bonnett is a medical statistician primarily interested in
[Accessed 04.12.18].
the development and validation of prognostic (prediction)
models. She researches methods to model recurrent events D’Ambrosio R, Miller J. (2010). What Is an Epileptic Seizure?
such as seizures. This work will inform patient counselling Unifying Definitions in Clinical Practice and Animal Research
and improve quality of life for people living with long-term to Develop Novel Treatments. Epilepsy Currents, [online]
conditions such as epilepsy and asthma. 10(3), 61-66. Available at: https://onlinelibrary.wiley.com/doi/
abs/10.1111/j.1535-7511.2010.01358.x [Accessed 04.12.18].
Funding
Mayo Clinic Staff. Seizures. [online] Mayo Clinic. Available at:
National Institute for Health Research www.mayoclinic.org/diseases-conditions/seizure/symptoms-
causes/syc-20365711 [Accessed 04.12.18]
Collaborators
Naik, Puja Appasaheb, et al. “Do drivers with epilepsy have
• L J Bonnett • A Shukralla
higher rates of motor vehicle accidents than those without
• A G Marson • C Turdur Smith
epilepsy?.” Epilepsy & Behavior 47 (2015): 111-114.
• G A Powell • P R Williamson
Schachter, S., Shafer, P., Sirven, J. (2014). What is a seizure?.
Personal Response [online] Epilepsy Foundation. Available at: www.epilepsy.com/
learn/about-epilepsy-basics/what-seizure [Accessed 04.12.18].
What inspired you to explore driving policies
around epilepsy and why have you chosen to focus
on diabetes in your next project?
As an applied statistician my main aim is to make
a difference to people using numbers. My colleague
(Prof Marson) is a member of the DVLA’s Drivers Medical
Group. In 2008 this group discussed the differing driving
guidelines between the EU and the UK and the need
for evidence to support their decision making. As a
statistician (and a PhD student) I was in the perfect
position to provide the much-needed evidence.
The rest, as they say, is history!
Diabetes offers a new but related challenge – driving
guidelines have to consider hypos and other outcomes
such as eye problems and heart complications.
www.researchoutreach.org 89
Health and Medicine ︱ Dr Lynne Ann Barker
New innovations
in traumatic brain
injury research
Lynne Ann Barker is a pioneer
in the field of traumatic brain
injury (TBI). Her work aims
to understand how trauma
to the brain leads to changes
in behaviour and cognitive
ability in those affected.
She has also worked to develop
new experimental methods
for assessing cognitive ability,
including computerised
simulations that incorporate
real-world tasks such as cooking,
with the aim of increasing
the speed and efficiency
of diagnoses of these life-
changing injuries.
90 www.researchoutreach.org
T
he brain is an organ of incredible
complexity. Contained in a space
no larger than a football is 100
billion cells that connect in unimaginably
complex ways. From this complexity arises
all the behaviours that make us human.
From tacit (non-conscious) processes
that occur without us even being aware,
to executive functions: higher-order
processes that are associated with goal-
directed behaviours such as planning
and target-seeking.
The brain might be the most intricate and
complicated organ in the body, but it is
also the most precious and vulnerable.
Damage to the brain can be disastrous
to an organism, leading to cognitive
impairments that can result in a lifetime
of debilitating symptoms. Lynne Ann
Barker and her colleagues are working
to understand how damage to the brain
results in cognitive impairment and to
develop new techniques to diagnose
and treat those with traumatic brain injury.
YOUNG AT HEART,
DELICATE OF MIND
One of the questions Barker has been
keen to address is whether age plays a
role in the response of the brain to injury.
The so-called ‘latent deficit hypothesis’
suggests that injury sustained earlier in
life (from 17-25 years old) may produce
greater lasting cognitive impairments than
those sustained later (28 years and older).
In 2006, Barker and colleagues tackled
this question by performing a study with
people who had sustained head injuries
that resulted in lesions to the frontal brain
regions. They compared groups of young
and older participants using a range
of tests aimed at assessing their executive
and implicit (unconscious) cognitive
ability. Interestingly, although there were
no differences in executive function,
the young cohort showed greater deficits
in implicit cognitive function than those
that sustained their injuries later in life.
Dr Barker thinks the differences in
response to TBI between young and
old might be due to the crucial period
of brain development that occurs in
early adulthood. She writes:“We are only
now beginning to fully appreciate that
swift morphological change to the brain
between ages 17-25 confers vulnerability
to greater effects of traumatic brain injury
on cognition and an increased likelihood
of the first incidence of mood disorder,
Brain in coronal plane showing lacuna infarcts
to mid-brain structures resulting in constant pain
for the patient.
psychosis and eating disorder during this
age range”
The exact nature of the morphological
changes that occur during this period of
adolescent neurodevelopment and how
they lead to the vulnerability to brain
injury is still under investigation, but it is
hoped that continued work in this area will
continue to yield further insight.
THE SUBCONSCIOUS MIND
It was interesting for Dr Baker and her
group to note that the adolescents
showed deficits in implicit as well as
executive functions. In neuropsychology,
implicit, also referred to as tacit or
unconscious, brain functions describe
a response to stimuli that are subliminal
or go unnoticed. It had been previously
thought that these types of cognition
were less affected than their executive
counterparts by brain injury. In fact,
Dr Barker’s work has been instrumental
in highlighting the importance of changes
to implicit cognition following TBI.
Her 2006 study in Neuropsychologia
was the first to show through an
empirically rigorous group study that tacit
cognition is impaired in cases of head
injury. Her group compared 20 patients
with head injuries and a cohort of I.Q.
and age-matched controls. The two
groups underwent MRI scans and a battery
of four tests to determine their implicit
cognitive abilities. These tests included
a serial reaction time task (SRT), a mere
exposure effect task, automatic stereotype
activation and hidden co-variation
detection. The impact of the injuries was
clear – those with brain trauma performed
Partial screenshot of item cooking in Cog-LAB task .
The brain might be the most intricate and
complicated organ in the body, but it is
also the most precious and vulnerable.
worse in three out of four tests of implicit
cognition. Interestingly, performance on
the SRT task correlated with a composite
measure of executive function, suggesting
a relationship between these two aspects
of cognition. Indeed, the authors suggest
that implicit and explicit cognition may
interact to produce the dysfunctional
behaviour that is observed after TBI.
And the field seems to be taking note of
this – following the publication of this work
there has been a renewed focus on the
role subconscious impairments can play in
the behavioural deficits of people with TBI.
Dr Barker recognises that given the
greater emphasis on the impact of implicit
impairments in TBI comes a need for
better ways to test for these deficits.
To this end, she has programmed a
number of variants of the SRT task which
are run using PSYSCOPE, a computer
programme that allows researchers to
design and run psychology experiments.
According to Dr Barker, the importance
of implicit deficits is often overlooked:
“We toiled over the SRT task, trialling
and refining it, to ensure that it reliably
captured tacit processes”. This hard work
seems to have paid off; almost every
single one of the 150 people with brain
injury tested using the improved SRT test
demonstrated impairment compared
to healthy controls. These studies were
included in the Brain Sciences special
issue The Brain Knows More than It
Admits: The Control of Cognition and
Emotion by Non-Conscious Processes.
This collection highlights the best
experimental methods for capturing tacit
cognitive processes.
However, one shouldn’t think Dr Barker is
interested only in the subconscious; she
has been a leading voice in a discussion
going on in cognitive neuroscience
surrounding the study of executive
function. She thinks that there needs to be
a unification approach across disciplines,
a refinement of techniques and a broader
consensus about how to close the gap
between theory and therapy, to ensure
sufferers of brain injury receive the
best possible treatment. Readers may
be interested to seek out an editorial
piece she has written on this subject for
Frontiers in Behavioural Neuroscience,
titled: ‘Executive Function(s): Conductor,
Orchestra or Symphony? Towards a Trans-
Disciplinary Unification of Theory and
Practice Across Development, in Normal
and Atypical Groups’.
www.researchoutreach.org 91

COOKING UP SOMETHING GREAT
In addition to her pioneering work
on the underlying biology of brain
injury, Dr Barker has been leading the
development of innovative new ways
of diagnosing cognitive impairment.
She was one of the first to recognise that
modern technological advances could
Cog-LAB could be used as a novel approach
for determining cognitive impairment
in head injury patients.
be used to design more sophisticated
neurocognitive tests. Currently, diagnosis
of cognitive deficits is expensive and
time-consuming. However, she realised
that modern computing offered the
chance to design automated tests that
could speed up this process.
Dr Barker wanted to use the opportunity
of the emerging technology to design
tests that incorporate simulations of
real-world tasks. She notes: “In real life,
complex tasks such as cooking are often
significantly affected when a person
92 www.researchoutreach.org
sustains a brain injury or early on in the
course of a neurodegenerative disorder
because they require the coordination
of multiple cognitive functions.” With this
in mind, she has designed a task-based
test for cognitive impairment that centres
around a cooking simulation. This cooking
task (CT) prototype named Cog-LAB has
the ability to measure multiple different
aspects of cognitive function at once.
In a 2015 study in Frontiers in Behavioural
Neuroscience, Dr Barker and colleagues
generated some preliminary data on
the efficacy of Cog-LAB. The aim was
to see how the CT stacks up to more
conventional cognitive tests. To this end,
forty-six non-impaired participants took
part in the CT as well as various sub-tests
from standardised neuropsychological
tasks. The result of this comparison was
that the CT performed well, providing
a proof-of-principle that Cog-LAB
could be used as a novel approach for
determining cognitive impairment in head
injury patients. Following the publication
of the preliminary study, Dr Barker’s work
was awarded the MEDIPEX award for
NHS innovation in 2016 and a subsequent
MRC Confidence in Concept grant
to develop Cog-LAB.
Brain injury is in the eye of the beholder
Another innovative approach that
shows great promise involves using
scanning techniques to look for changes
in the eye which could represent an
early warning sign of brain injury. In a
recently published study https://www.
dovepress.com/investigating-possible-
retinal-boilermakers-of-head-trauma-in-
Olympic-bo-peer-reviewed-article-EB,
Dr Barker and colleagues compared
Olympic boxers to control patients to
see if they could detect alterations to
different structures within the eye. Using
a technique known as optical coherence
tomography (OCT), the group found that
the boxers had a thinning of their maculas
and retinal nerve fibre layers (RNFL). This
is an exciting proof-of-principle for a
technique which could provide a much
more efficient way to diagnose brain
trauma, as well as potentially providing an
early warning sign for damage that might
not yet reach the threshold to produce a
noticeable cognitive impairment capable
of being detected with current methods.
THE FUTURE
Readers can now find out more about the
eye-scanning study as it has been recently
published in the journal Eye and Brain.
As for Cog-LAB, its future lies in a planned
clinical trial which aims to assess how well
it can perform in patients with various
neurological impairments, namely TBI,
stroke and early dementia. The goal of the
study is to assess the use-ability, reliability
and sensitivity of the test compared
to conventional diagnostic approaches,
and with the promise shown by the work
so far, the results are eagerly awaited.
Behind the Research
Dr Lynne Ann Barker
E: l.barker@shu.ac.uk T: +44 0114 225 5379 W: www.frontiersin.org/research-topics/1270/executive-functions-conductor-
orchestra-or-symphony-towards-a-trans-disciplinary-unification-of-theo W: www.lidsen.com/journals/neurobiology/neurobiology-
special-issues/new-develop-brain-injury W: www.shu.ac.uk/about-us/our-people/staff-profiles/lynne-barker www.linkedin.com/
in/lynne-barker-19521a53/?originalSubdomain=uk W: www.shu.ac.uk/research/specialisms/centre-for-behavioural-science-and-
applied-psychology
Research Objectives References
Dr Barker’s work focuses on the effects of brain injury on Barker LA, Andrade J, Morton N, Romanowski CA, Bowles DP.
neural structures and cognition and behaviour, brain and (2010). ‘Investigating the ‘latent’ deficit hypothesis: age at time
cognitive maturation in young adults, and effects of diet of head injury, implicit and executive functions and behavioural
on brain injury recovery insight’. Neuropsychologia, 48(9):2550-63.
Barker LA, Andrade J, Romanowski CA, Morton N, Wasti A.
Detail (2006). ‘Implicit cognition is impaired and dissociable in a
head-injured group with executive deficits’. Neuropsychologia,
Bio 44(8):1413-24.
Dr Lynne Ann Barker is a Reader in Cognitive Neuroscience
and conducts research on the functional effects of brain Barker LA and Morton N. (2018). ‘Editorial: Executive
Function(s): Conductor, Orchestra or Symphony? Towards a
trauma, clinical functional measurement, biomarkers of
injury and developmental brain morphology. She is currently Trans-Disciplinary Unification of Theory and Practice Across
writing a neuroscience textbook and teaches postgraduate Development, in Normal and Atypical Groups’. Front Behav
students on the Applied Clinical Cognitive Neuroscience Neurosci, 12: 85.
course. She supervises several PhD students and is the
Postgraduate Research Tutor for all PhD students in the Barker LA. (2012). ‘Defining the Parameters of Incidental
department. She is a founder member of the Cognition Learning on a Serial Reaction Time (SRT) Task: Do Conscious
and Neuroscience (CaN)Research Group. She was recently Rules Apply?’ Brain Sci, 17;2(4):769-89.
awarded the Medipex NHS Innovation Prize.
Childs C, Barker LA, Gage A, Loosemore M. (2018).
Funding ‘Investigating possible retinal biomarkers of head trauma
Cog-LAB study funded by MRC Confidence in Concept in Olympic boxers using optical coherence tomography.’
competitive round 5. Eye and Brain:10,1–10.
Doherty TA, Barker LA, Denniss R, Jalil A, and Beer MD. (2015).
Collaborators HIVE Information ‘The cooking task: making a meal of executive functions’. Front
• Dr Nick Morton Technology, Sheffield, UK Behav Neurosci; 9: 22.
• Prof Charmaine Childs – specifically (Sooze, Jamie
• Prof Annalena Venneri and Allen)
• Dr Sophie Taylor
• Leanne Greene
• Dr Richard Grunewald
• Professor David Sanders
Personal Response
• Professor John Reidy • Carolyn Taylor
• Professor Brian McGuire • Dr Caroline Jordan How does your range of experimental versions of the
• Rebecca Dennis • Dr Bernard Corfe Serial Reaction Time Task help in the elucidation of the
• Dr Catherine Day • Dr Caroline Dalton role of tacit cognition in deficits following TBI?
• Dr Paul Richardson • Dr Mike Loosemore MBE
Tacit processes are what happens whilst we are thinking
• Professor Jackie Andrade • Alex Gage
about other things. Often overlooked, they play a vital
• Dr Charles Romanowski • Dr Lambros Lazuras
role in reading and responding to others’ intentions and
• Dr Jenny Drabble • Dr Martin Thirkettle
gestures, facilitating many aspects of social cognition. Social
• Dr David Bowles • Dr Caroline Jordan
functions are disrupted by brain trauma. We toiled over
• Dr James Taylor • Dr Bernard Corfe
the SRT task, trialling and refining it, to ensure that it reliably
• Dr Lisa Reidy
captured tacit processes. Almost every single person tested
• Dr Sue McHale
on this task with a brain injury (> 150) showed impairment
• Holly Ashton
compared to non-brain injured people: A fundamental
• Dr Alistair Atherton
function is lost. Presently, one of my PhD students (Leanne
Greene) is investigating how this loss contributes
to social deficits. 
www.researchoutreach.org 93
Health and Medicine ︱ Drs Lynn Selemon and Alvaro Duque
MacBrainResource:
Virtual access to decades-old primate brains
MacBrainResource is a vast
collection of macaque brain
slides and electron microscope
(EM) blocks generated in
the laboratories of Dr Pasko
Rakic and the late Dr Patricia
Goldman-Rakic. Drs Lynn
Selemon and Alvaro Duque
at Yale University School of
Medicine are committed to
making these valuable brains
available to researchers both
on-site and remotely via website
access (macbrainresource.org).
MacBrainResource represents
a 21st century solution for
researchers faced with
mounting obstacles to primate
research and one that does
not require the sacrifice of any
additional animals.
94 www.researchoutreach.org
T
he human brain is incredibly
complicated. Decades of research
have been devoted to elucidating
the structure, function and development
of the human brain and to identifying
abnormalities associated with neurologic
and neuropsychiatric disorders, such as
stroke, epilepsy, Alzheimer’s, Huntington’s,
and Parkinson’s diseases, to name only a
few. Moreover, recent evidence suggesting
that diseases like schizophrenia and
autism are linked to prenatal disturbances
highlights the importance of gaining a full
grasp of early human brain development.
Direct study of the human brain has
unquestionably provided the basic
foundation for our knowledge of human
neuroanatomy and neural development.
However, human studies are necessarily
limited to non-invasive examination of
normal architecture. Animal models
provide a means of circumventing this
limitation. Systemic and intracranial
injections allow researchers to explore
developmental mechanisms in greater
depth and to elucidate brain connectivity.
Experimental manipulations enable
greater understanding of the impact
of lesions on connected brain areas
and of prenatal perturbation on
brain development. Non-human
primates, including prominently
macaques (Macaca mulatta),
have been used extensively
in neuroscience research as
their brains are very similar
to humans and their brain
development is protracted
much like that in humans.
Over the past few decades,
the enormous cost of primate
housing and care, tightened
regulations on primate
research and changing
attitudes towards primate
use in medical research
has led to a reduction
in primate research across the globe.
These challenges are major deterrents
to primate brain research. Drs Lynn
Selemon and Alvaro Duque in the
School of Medicine at Yale University
have created a unique online resource
known as Macaque Brain Resource
(MacBrainResource) containing five
distinct collections of macaque brain
tissue. The mission of MacBrainResource
is to foster new primate brain research
using brain tissues generated over
the past 50 years.
MacBrainResource is derived from years
of experimental research in Dr Pasko
Rakic’s and the late Dr Patricia Goldman-
Rakic’s laboratories. Drs Selemon and
Duque, who have worked with Drs Rakic
and Goldman-Rakic, are now at the
center of the pioneering effort to provide
worldwide access to these collections.
With funding from the National Institute
of Mental Health, histologic slides
and EM images will be digitised as
requested: these materials will be freely
available to researchers for remote access
and analysis so they can be used to make
new discoveries – with no animals being
harmed in the process.
NOSE TO THE GRINDSTONE
Unravelling the mysteries of brain
development, its structure and function
was the passion of the late Dr Patricia
Goldman-Rakic and continues to be a
life-long endeavour for Dr Rakic. Early
in their careers they chose the non-
human primate brain as a model due
to its similarity with the human brain.
Developmental studies in the non-human
primate are particularly challenging as
these require a breeding colony with
specialised facilities for pregnant, infant
and juvenile non-human primates. Whilst
in the Department of Neuroscience
at Yale, the Rakic/Goldman-Rakic
laboratories overcame these challenges
and in doing so established one of the
few non-human primate breeding
colonies in the world.
Decades of research from many
scientists in the Rakic/Goldman-Rakic
laboratories generated an immense
collection of over 7000 brain slides
and EM blocks, that now comprise the
five collections of MacBrainResource.
Duplicating the scale of this collection
today would be extremely difficult,
making MacBrainResource an incredibly
important resource for scientists.
UNIQUE COLLECTIONS
As a young scientist, Dr Rakic asked
the question ‘where and when
are neurons made during brain
development?’ To answer this conundrum
the Rakic laboratory used a technique
that was novel at the time, injection of a
compound called tritiated thymidine into
pregnant monkeys. Radioactive tritiated
thymidine gets incorporated into the
DNA of cells that are undergoing cell
division. Those cells that are undergoing
their final cell division, that is the division
Figure 1. Slides available on the MacBrainResource website appear as low magnification thumbnails.
that gives rise to newly generated
Approved investigators will be granted access to a database of slides that can be zoomed to high
neurons, will be most densely labelled. magnification that enables viewing of labelling in single cells. Top row: sagittal views of the brain stem
and cerebellum in a macaque brain harvested at postnatal day 76 (P76) following thymidine injection
Quantitation of the number of densely
at embryonic day 30 (E30). Middle row: coronal sections through an embryonic day 60 (E60) brain
radioactive neurons present in a specific following thymidine injection one week earlier (E53). Bottom row: coronal sections through P75 brain
brain structure following injections at that has been immunocytochemically processed for neuropeptide Y.
various foetal ages allows determination
of when neurons in that structure were in the formation of memories. After Dr only places in the world where these
born. The samples of brain tissue from Goldman-Rakic joined Dr Rakic at Yale surgeries were conducted largely due
these experiments were collected she continued to study brain connectivity to Dr Rakic and Dr Goldman-Rakic’s
throughout the 70s and 80s and make up and accumulated a large collection expertise. Postnatal lesioned cases are
Collection 1. This collection is currently of brain material revealing different also included in Collection 3.
being used to investigate contemporary connecting networks across the brain,
questions in brain development. constituting Collection 2. Drs Rakic and Goldman-Rakic turned
their attention towards schizophrenia
For Collection 2 we introduce one Collection 3 represents the culmination for Collection 4. This complex disorder
of the most influential women in of collaboration of Drs Rakic and affects thoughts, emotions and behaviour
neuroscience, Dr Goldman-Rakic. Goldman-Rakic at Yale. With their and it can lead to inappropriate actions,
Her research focused on understanding combined prowess as accomplished false perceptions, fantasy and delusion.
the prefrontal cortex – the part of the surgeons, they conducted surgery Dr Selemon’s studies in cortical brain
brain that resides under your forehead. in prenatal animals either to resect samples from patients with schizophrenia
Her research group mastered a technique or to inject brain areas at various had indicated that the prefrontal cortex
that was relatively new in the 70s, known developmental stages. To do this, they lacks connectivity to the rest of the
as tracer autoradiography. By labelling removed the foetus from the mother brain. With this in mind, researchers in
amino acids, the building blocks of to perform the experimental procedure the Rakic/Goldman-Rakic labs set out
proteins, the Goldman-Rakic lab was able and then replaced the foetus back to create a non-human primate model
to visualise neurons connecting different in the mother’s womb. Yale is one of the to test the role of brain development
regions of the brain. Dr Goldman Rakic,
her postdoctoral associate Dr Selemon Duplicating the scale of this collection
today would be extremely difficult, making
and others in the group found multiple
channels of communication across brain
regions, including identifying connections
between the prefrontal cortex and
MacBrainResource an incredibly important
the hippocampus, a region involved resource for scientists.
www.researchoutreach.org 95
in schizophrenia. They used prenatal
exposure to X-irradiation to curtail
generation of neurons during foetal
development. Many of the animals were
raised to adulthood at which time their
brain tissue was collected and processed
in a manner compatible with stereologic
analysis. These celloidin-embedded, thick
brain sections comprise Collection 4. This
collection provides a unique opportunity
to study the effects of disturbing foetal
brain development in the adult brain.
Collection 5 takes a closer look at the
connections between different neurons,
known as synapses. Researchers from
the Rakic/Goldman-Rakic groups
studied synaptogenesis, the formation
of synapses, in multiple regions of the
non-human primate brain. High resolution
electron microscopy was used to reveal
structures of neurons that cannot be
seen with a light microscope. In one
prominent study, Drs Rakic, Goldman-
Rakic and collaborators analysed 25
non-human primates from foetal brains
up to adults of 20 years. They found that
in the non-human primate cortex synapses
are overproduced during development
and are subsequently reduced during
adulthood, concurring with the patterning
described in the human cortex.
GOLD MINE
Decades later, these five collections are still
being used to generate data. Researchers
from universities around the world,
including Illinois, California and Sydney,
have visited the School of Medicine at
Yale to analyse regions of the brains
that had not been examined by Rakic/
Goldman-Rakic labs. Drs Lynn Selemon
and Alvaro Duque hope that through
digitisation, MacBrainResource will make
all five collections more widely accessible
to researchers not affiliated with Yale.
Drs Selemon and Duque have utilised
the collections in some of their
studies and are passionate that other
neuroscience researchers get the
opportunity to do the same. Collection
1 has been utilised by Dr Duque
Making MacBrainResource available to
the larger neuroscience community will
facilitate primate brain research for a new
generation of researchers.
96 www.researchoutreach.org
Figure 2. Collection 4 is comprised of fetally irradiated and control brains that were processed
for stereologic analysis. This figure illustrates that images suitable for stereologic analysis can
be generated for remote access. A low-magnification view of the striatum of an adult animal exposed
to fetal irradiation is shown (top inset); the box indicates the location of high-magnification views
spanning the 15 µm, z-axis focal plane. Arrows indicate cells in focus at focal plane 0 µm (top), -7.5 µm
(middle), and -15 µm (bottom).
who compared a more contemporary
method of identifying new neurons, called
BrdU, to the tritiated thymine injected
non-primates in Collection 1. He found
that neurons taking up BrdU weren’t
as healthy. This has important implications
for researchers using BrdU as a marker of
new neurons. So important in fact that Dr
Duque was asked to contribute a chapter
to a technical book series. Collections
2-5 haven’t been utilised as extensively.
In one recent publication, Dr Selemon
and her colleagues compared a new
tracing method, dynamic programming
in conjunction with diffusion tensor
imaging, to the tracer autoradiography
method found in Collection 2 to
corroborate findings. Dr Selemon, Dr
Duque and other researchers at Yale
believe that making MacBrainResource
available to the larger neuroscience
community will facilitate primate brain
research going forward.
Behind the Research
Dr Lynn Selemon
E: macbrainresource@yale.edu T: +1 203 785 4323 W: macbrainresource.org
Detail
Department of Neuroscience
Yale University School of Medicine
New Haven, CT 06510
Bio
Dr Lynn Selemon, a Research Scientist
in the Department of Neuroscience,
earned a doctorate in neuroscience from
the University of Rochester. As a postdoctoral associate
of Dr Goldman-Rakic at Yale, she conducted tract tracing
experiments to elucidate cortical pathways in the brain.
Her more recent research has focused on neuroanatomic
abnormalities associated with schizophrenia and PTSD.
Dr Alvaro Duque, a Research Scientist in the Department
of Neuroscience, earned his doctoral degree in neuroscience
from Rutgers University in Dr Laszlo Zaborszky’s lab. He was
a postdoctoral associate at Yale in the labs of Drs Patricia
Goldman-Rakic and David McCormick. Currently, he is working
with Dr Pasko Rakic on studies of primate development.
Funding
NIMH (1RO1MH113257)
Collaborators
Dr Alvaro Duque and Dr Lynn Selemon are co-PIs
on this project. They would like to acknowledge the
following collaborators:
• Dr Pasko Rakic, consultant
• Philip Barello, computer systems manager
• Mary Pappy, histology technician
• Yuri Morozov, EM technician
• Tayor Spadory, current undergraduate intern
• Aviva Rabin-Court, past undergraduate intern
Personal Response
Using animal models for research is presenting more
challenges now than it has done in the past. How do you
see neuroscientists conducting research in the future?
Today neuroscientists who wish to address scientific
questions in the non-human primate face enormous hurdles
in terms of cost, regulation and an increasingly unfavourable
public attitude towards animal research. MacBrainResource
provides a 21st century solution that circumvents these
obstacles by allowing researchers worldwide to conduct
new research without having to bear the exorbitant costs of
primate research or sacrifice any animals. It is our mission to
maximise usage of these valuable primate brain materials and
by doing so promote primate research for the benefit and
advancement of science. 
Dr Alvaro Duque
Research Objectives
MacBrainResource is an online repository of macaque brain
material available for the use of researchers.
References
MacBrainResource, Yale School of Medicine, available at URL:
macbrainresource.org
https://medicine.yale.edu/neuroscience/macbrain/
SFN 2018 abstract and poster: MacBrainResource: archived
macaque brains available for neuroanatomical and
neurodevelopmental studies
Selemon LD, Rajkowska G, Goldman-Rakic PS (1995)
Abnormally high neuronal density in the schizophrenic cortex.
A morphometric analysis of prefrontal area 9 and occipital
area 17. Arch Gen Psychiatry, 52(10), 805-818.
Selemon LD, Zecevic N (2015) Schizophrenia: a tale of two
critical periods for prefrontal cortical development. Transl
Psychiatry, 5, e623.
Ratnanather JT, Lal RM, An M, Poynton CB, Li M, Jiang H,
Oishi K, Selemon LD, Mori S, Miller MI (2013) Cortico-cortical,
cortico-striatal and cortico-thalamic white matter fiber tracts
generated in the macaque brain via dynamic programming.
Brain Connect, 3(5) 475-490.
Duque A, Rakic P. (2011). Different effects of BrdU and
3H-Thymidine incorporation into DNA on cell proliferation,
position and fate. J Neurosci. 31(42):15205-15217.
Duque A, and Rakic P. Identification of proliferating and
migrating cells by BrdU and other thymidine analogues.
Benefits and limitations. In: Immunocytochemistry and
Related Techniques. Neuromethods Vol 101 p.123-139.
A. Merighi and L. Lossi, Ed. Springer Science and Business
Media. 2015
Duque A, Krsnik Z, Kostovic I, Rakic P. (2016) Secondary
expansion of the transient subplate zone in the developing
cerebrum of human and nonhuman primates. PNAS
113:9892-9897.
Duque A, Selemon L. MacBrainResource: sharing primate
specimens around the world. (2018). Research Features
Magazine. Health and Medicine. May 1st, 2018 Issue.
England. https://researchfeatures.com/2018/05/01/
macbrainresource-sharing-primate-specimens/
Rash BG, Duque A, Morozov YM, Arellano J, Micali N, Rakic
P. (2019). Origins and dynamics of gliogenesis in the outer
subventricular zone of the developing primate cerebrum.
PNAS in print.
www.researchoutreach.org 97
Health & Medicine ︱ Professor Silvia Conde
The carotid body
A candidate for regaining glucose tolerance
in Type 2 diabetes
Professor Silvia Conde and her
team from the NOVA Medical
School, NOVA University of
Lisbon, have proposed a new
strategy for treating metabolic
diseases. Previously, they
showed that an over-active
homeostasis sensor called the
carotid body could cause insulin
resistance and disrupt glucose
tolerance, common in Type 2
diabetes. In their new study, Prof
Conde’s team applied a kilohertz
frequency alternating current
into the carotid sinus nerve of
diabetic animal models, which
resulted in a significant recovery.
This type of bioelectric
neuromodulation could be
developed into an alternative
therapy and clinical diagnostic
tool for a range of metabolic
disorders in the future.
The carotid body is located by the fork
in the carotid artery – shown here in red.
98 www.researchoutreach.org
T
here’s no sugar coating it – how
and what we eat has a huge impact
on our bodies. A high fat, high
sugar diet can upset a body’s mechanism
to deal with the excess. This upset can
cause resistance to the sugar-regulating
hormone insulin and failure of insulin-
secreting pancreatic beta cells. These
result in deterioration of overall glucose
metabolism. Once diet and exercise can
no longer contain the condition, patients
need external glucose-lowering agents
to control their blood sugar levels.
Despite a number of treatment options,
Type 2 diabetes is one of the fastest
growing health threats in the world, with
a predicted 500 million global patients
by 2040. Many patients maintain poor
glucose control despite insulin treatment
and combination therapy, which suggests
these strategies may not treat the prime
sources for the disease onset.
In fact, obstructive sleep apnoea
and ovarian syndrome patients have
also shown resistance to insulin.
If distorted glucose tolerance can
occur independently from obesity,
some unknown biological triggers
could be at the root of these
metabolic disorders.
CAROTID BODIES
One possible trigger candidate
for Type 2 diabetes is the carotid body.
Carotid bodies are chemoreceptors
located in the bifurcation of carotid
arteries, which run along both sides
of the throat. Their main purpose is to
detect changes in oxygen, carbon dioxide
and pH levels in the blood. When faced
with dangerous levels, carotid bodies
increase the frequency of impulses,
known as ‘action potentials’, in their
sensor nerve, the carotid sinus nerve.
This nerve signals the central nervous
system to turn on a range of responses
to calm the situation. These responses
induce homeostasis – balance of the
internal environment.
In addition, carotid bodies can sense
insulin and may even be able to detect
blood sugar levels. Due to their sensing
abilities, carotid bodies are likely to
be important metabolic sensors for
controlling energy homeostasis. Yet
how carotid bodies are linked to insulin
resistance and rising metabolic disorders
has been critically unclear.
A NEW THERAPEUTIC TARGET
Professor Silvia Conde and her team
thus began to investigate the link
between carotid bodies and diabetes. In
2013, they showed that carotid bodies
were over-active in insulin-resistant,
glucose-intolerant and hypertensive
animal models. Over-stimulated carotid
bodies were shown to flood downstream
neural signalling, causing symptoms
present in Type 2 diabetes, metabolic
syndrome and obstructive sleep apnoea.
Prof Conde’s research team saw
the carotid body as a new therapeutic
target for treating metabolic diseases.
In 2017, they performed a chronic
bilateral surgical resection (partial
removal) of the carotid sinus nerve,
which disconnected its signalling
to the brain in diabetic rat animal
models. Astonishingly, they found
that resection of the sinus nerve
restored normal insulin sensitivity
and glucose homeostasis for up to
11 weeks. Prof Conde’s study proved
that an over-active carotid body could
therefore be key to understanding
the pathophysiology of Type 2 diabetes
and other metabolic diseases.
Monitoring blood sugar levels can help
to manage diabetes.
However, Prof Conde suggests that
the surgical procedure is an unlikely
therapy for diabetic patients. Resection
of the carotid body is not only irreversible
and invasive, but could have lasting
side effects, such as impaired responses
to oxygen and carbon dioxide levels,
and loss of adaptation to exercise
and blood pressure regulation. A safer
way of decreasing carotid body function
was therefore still missing.
BIOELECTRIC NEUROMODULATION
Prof Conde’s team embarked on the hunt
for an alternative solution. In partnership
with Galvani Bioelectronics (formerly
GlaxoSmithKline Bioelectronics), her
2018 study proposes a new strategy
for rebooting over-active carotid bodies –
energy itself, or in this case, electricity.
The team hoped to find out whether
bioelectric modulation of the carotid
sinus nerve could restore insulin sensitivity
Due to their insulin-sensing ability, carotid
bodies are likely to be important metabolic
sensors for controlling energy homeostasis.
lifestyle are both risk factors for Type 2 diabetes.
and glucose tolerance in Type 2 diabetic
animal models. A group of rats were fed
a high fat and sugar diet for 14 weeks,
after which cuff electrodes were implanted
bilaterally into the carotid sinus nerve
of the diabetic group. Similar electrodes
were also planted onto control group
rats, fed with a normal diet. Additional
sensors were placed in the rat diaphragm
to record electrical activity of the skeletal
and heart muscles.
A 50 kilohertz (kHz) frequency alternating
current (KHFAC) was then run through the
electrons into the carotid sinus nerve. After
nine weeks of bioelectrical treatment, the
rats were examined for insulin sensitivity
and glucose tolerance by measuring
biomarkers such as plasma insulin,
glucagon, c-peptide and lipid profiles.
The results were remarkable. The team
found that the bioelectric treatment
significantly increased insulin sensitivity
and glucose tolerance after one week.
These effects continued throughout
the rest of the treatment period but
reversed back to diabetic levels after the
KHFAC was ceased. Bioelectric treatment
Being overweight and leading a sedentary
showed similar efficiency as did resection
of the carotid sinus nerve. However,
bioelectric modulation was fully reversible,
and had no significant side effects.
FUNCTIONAL DIAGNOSIS
Knowing that the carotid body
chemoreceptors are involved in
metabolic disease progression has vast
clinical relevance. Since the carotid body
function and glucose homeostasis are
connected, evaluating the organ’s activity
could act as a promising door to unravel
the disease phenotypes of a range
of metabolic diseases.
Prof Conde highlights that currently no
medical device links carotid body function
to neuroendocrine status, nor are there
Sugar in the diet becomes sugar in the
bloodstream. The carotid body can become
tolerant to blood glucose levels.
www.researchoutreach.org 99

Bioelectric treatment of the carotid body could
help modulate the body’s response to glucose.
any clinical guidelines focusing on how
the organ balances glucose and lipid
homeostasis. She highlights that functional
diagnosis of the carotid body would
also have disease predictive value, as it
could screen for patients with developing
respiratory and metabolic disorders.
OVERCOMING SIDE EFFECTS
Despite these predictions,
neuromodulation of the carotid sinus
nerve is still far from a viable therapy.
Bioelectric modulation can result in similar
side effects as surgical resection, since
KHFAC treatment could affect other
functions of the carotid sinus nerve, such
as accurately adjusting blood pressure.
Although these effects did not appear
in Conde’s 2018 study, the continuous
electrical current into the nerve could
impair blood pressure fine tuning,
exercise intolerance and carbon dioxide
sensitivity in humans.
Prof Conde’s group use a diabetic rat model
to study the impact of modulation of the carotid
sinus nerve in this disease.
100 www.researchoutreach.org
A healthy lifestyle can reverse prediabetes.
Prof Conde proposes bioelectric
modulation of the carotid sinus nerve
for controlling carotid body activity
in metabolic diseases.
Prof Conde’s team currently focuses
on minimising the off-target effects of
bioelectric neuromodulation. One way
to do this is to identify and characterise
specific neural circuits related to over-
activity in metabolic diseases. The team
hypothesises that different fibres within
the nerve link to different stimuli and
mapping out these neural pathways can
develop selective therapeutic modulation.
Prof Conde states that promising
uses for continuous high frequency
blocking of the sinus nerve would be
“to resynchronize action potential firing
disease patterns in specific fibres” or
perform an “intermittent block of the
carotid sinus nerve”. These approaches
could lead to bioelectric treatments that
discriminate between glucose and insulin
mediating pathways without affecting
others, such as oxygen and carbon
dioxide chemo-sensitivity.
THOUGHTS FOR THE FUTURE
Overall, Prof Conde’s research shows
how little we still understand our basic
energy metabolism. Her research takes
us a step closer to the root causes of
common disorders like Type 2 diabetes.
The proposed bioelectric treatment
of the carotid body is a tuneable and
reversible strategy, which could have
minimal interference with a patient’s daily
activities. However, as Prof Conde points
out, the next step is to find a bioelectric
method for selective modulation and with
no off-target effects.
Behind the Research
Professor Silvia Conde
E: silvia.conde@nms.unl.pt T: +351 918974400 W: http://cedoc.unl.pt/neuronal-control-
metabolic-disturbances/ W: www.facebook.com/groups/1118454071556934/
Research Objectives References
Conde, S., & Guarino, M. (2018). Targeting bioelectronically
Prof Conde’s work focuses on the carotid body and its role
in metabolic diseases. the carotid sinus nerve in Type 2 diabetes: strengths,
drawbacks and challenges for the future. Bioelectronics
In Medicine,1(3), 167-170.
Detail Ribeiro, M., Sacramento, J., Gonzalez, C., Guarino, M.,
CEDOC, NOVA Medical School, Monteiro, E., & Conde, S. (2013). Carotid Body Denervation
Rua Câmara Pestana, Prevents the Development of Insulin Resistance and
nº6, Edificio 2, Hypertension Induced by Hypercaloric Diets. Diabetes, 62(8),
piso 3 2905-2916.
Lisbon
Portugal Sacramento, J., Ribeiro, M., Rodrigues, T., Olea, E., Melo,
B., & Guarino, M. et al. (2016). Functional abolition of
Bio carotid body activity restores insulin action and glucose
Silvia Conde graduated in Biochemistry in 2000 and homeostasis in rats: key roles for visceral adipose tissue and
pursued her PhD in 2007 from both NOVA University of the liver. Diabetologia, 60(1), 158-168.
Lisbon and the University of Valladolid. She is Principal
Investigator at CEDOC and assistant professor at NOVA Sacramento, J., Chew, D., Melo, B., Donegá, M., Dopson,
Medical School. In 2009 she was awarded the Portuguese W., & Guarino, M. et al. (2018). Bioelectronic modulation of
L’Oréal Medals Honor for Women in Science. carotid sinus nerve activity in the rat: a potential therapeutic
approach for type 2 diabetes. Diabetologia, 61(3), 700-710.
Funding
•G
 alvani Bioelectronics
•P
 ortuguese Foundation for Science and Technology
Personal Response
Collaborators
•T
 he CEDOC team: Maria P. Guarino, Joana F. Sacramento,
Maria J Ribeiro, Bernardete Melo How did you first get interested in the possibility of
•T
 he Galvani team: Daniel Chew, Sonal Patel, Nishan bioelectric neuromodulation of the carotid body?
Ramnarain, Victor Pikov, Kristoffer Famm After our publication in 2013 in Diabetes (Ribeiro et al.,
Diabetes, 2013) where we described how the carotid body
is involved in the genesis of peripheral insulin resistance and 
that carotid body dysfunction is present in animal models of
metabolic dysfunction, we were contacted by the recently
(at that moment) formed GSK bioelectronic unit. They
were searching for diseases controlled by the peripheral
nervous system that could be targeted bioelectronically.
We started a collaboration with them that resulted in the
present findings – that carotid sinus nerve bioelectronics
modulation can restore insulin sensitivity and glucose
homeostasis in animals with Type 2 diabetes.
www.researchoutreach.org 101
Health & Medicine ︱ Dr Daniel Linseman

A potential
BDNF Aβ/p-Tau IL-10/TNFα

CONCUSSED
BRAIN

new treatment
mTBI (multiple)

AD

for brain injury

Tauopathy

HEALTHY BRAIN

Aβ/p-Tau IL-10/TNFα BDNF

THERAPEUTIC

T
he brain is an incredibly complex
Injuries to the brain can have dire consequences, leading to debilitating
symptoms and an increased risk of long-term degenerative diseases such organ. From that complexity
as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). Despite comes the ability to think,
the impact these injuries have on the lives of millions, there are no imagine, and perform equally complex
good treatments or preventative therapies. Associate Professor Daniel tasks. The brain is our species’ most
Linseman, of the Department of Biological Sciences and the Knoebel precious commodity, responsible for
Institute for Healthy Aging at the University of Denver, is working to making us the most successful animal
remedy that. His research focuses on understanding the mechanisms on the planet. It is also our most
that underlie brain injury and dysfunction. Interestingly, his recent work precious asset, making us who we
on the dietary supplement Immunocal ®, shows it to be a potential option are as humans. Unfortunately for us,
for mitigating the deleterious effects of traumatic brain injuries (TBIs), it is particularly susceptible to injury.
such as concussion, and diseases like ALS.
There are 1.7 million incidents of
traumatic brain injury (TBI) in the USA
alone, each year. The consequences can
be severe; one in three of every injury-
IMMUNOCAL®, AN OXIDATIVE
STRESS RELIEVER IN TBI
To generate energy, our cells take
oxygen from the air we breathe and
use it to release energy stored in the
food we eat. This process is essential to
our survival. By-products of this process
are potentially harmful molecules known
as reactive oxygen species (ROS). These
INTERVENTION
Immunocal®
(GSH precursor)
mitochondria. This damage can result
in cell death, producing a worsening
of symptoms.
Dr Linseman’s approach is to minimise
the damage caused by ROS in the
injured brain. To do this, he is looking
into methods to increase the ability
of the brain to neutralise ROS,
How Immunocal® can relieve oxidative stress
in traumatic brain injury.
such as boosting levels of the ROS
scavenger glutathione.
To that end, his group has been testing
a dietary supplement derived from whey
protein called Immunocal®. Immunocal®
contains high levels of a molecule called
cysteine, an important precursor from
which glutathione can be produced.
The hope is that by providing precursors

The brain is our species’ most precious

related death is due to a TBI. Those
who survive can be burdened with motor
or cognitive impairments that severely
reduce their quality of life. There can
also be long-term implications; people
who have suffered TBI have an increased
risk of developing neurodegenerative
diseases such as Alzheimer’s disease
and amyotrophic lateral sclerosis (ALS).
Despite the severe impact on individuals
and society, there are no approved
treatment options. That is not to say that
researchers are not actively pursuing
their development; Dr Linseman is
one such researcher interested in
understanding the mechanisms that
could explain what happens in the
brain when it is diseased or injured.
He sees one aspect as being particularly
important: oxidative stress. His work on
reducing the effects of oxidative stress
has shown that the dietary supplement
Immunocal® could be useful for reducing
the severity of symptoms in disorders
where oxidative stress causes problems,
such as TBI or ALS.
such as cysteine, the amount of
glutathione will increase, and cells will
commodity, responsible for making build up a more robust defense against
harmful ROS following injury.
us the most successful animal on the
A 2018 study by Dr Linseman’s team
planet. It is also our most precious asset. demonstrated that this is indeed the case.
molecules are harmful because, if left
unchecked, they can lead to damage
of important cellular components such
as DNA and mitochondria (the energy
producing parts of a cell). However,
some production of ROS is normal, and
cells come equipped to deal with them.
Cells contain scavengers – antioxidant
molecules such as glutathione that can
react with the ROS and convert them
to harmless waste products.
However, research has shown that this
process is disrupted during injury and
disease. Injuries such as TBI can result
in an increase in the generation of
ROS. The scavenging system becomes
over-burdened and ROS start to
damage parts of the cell such as the Dr Linseman’s team used a mouse model to test the effects of Immunocal®.

102 www.researchoutreach.org www.researchoutreach.org 103

His group used a mouse model of TBI
to determine if supplementation with
Immunocal® could improve symptoms.
They gave mice the supplement twice
daily for 28 days prior to administration
of a moderate TBI. The first question
the group had was whether feeding
the mice Immunocal® would increase
glutathione levels. They were pleased
to see that the Immunocal®-treated group
showed a significant increase in the levels
of glutathione in the brain compared
to untreated mice subjected to TBI.
Next, they looked to see if symptoms of
the injury were improved. Excitingly, mice
that received Immunocal® showed less
impairment in their motor and cognitive
abilities than controls, demonstrating that
Immunocal® has the potential to improve
the outcome of serious injury to the brain.
Next, the group looked in more detail
at the mouse brains to try and understand
how they changed in response to injury.
Although the initial damage to the
brain seemed to be similar between
treatment and control groups, the
researchers noticed differences in
how the brain degenerated over time.
The supplemented mice had less
degeneration of their neurons (the cells
responsible for transmitting information
in the brain), and the connections
between neurons in different parts of the
brain remained more intact. Interestingly,
the supplemented mice had reduced lipid
peroxidation in the brain, a sign that they
suffered reduced levels of oxidative stress
compared to controls.
NEURODEGENERATION
There is ample evidence that oxidative
stress plays a key role in the pathology
of various neurodegenerative diseases
such as Alzheimer’s disease and ALS.
The effects of oxidative stress
Reactive oxygen species or ‘free radicals’ can damage cells, even causing cell death.
104 www.researchoutreach.org
In ALS, motor neuron function is impaired
leading to a loss of control over movement.
Excitingly, mice that received Immunocal
showed less impairment in their motor
and cognitive abilities than controls.
In ALS, motor neurons that carry signals
from the brain to various parts of the body
begin to die. As the cell death worsens,
people with the condition progressively
lose control over their movement. It
is a devastating disease with a lack of
effective treatments and although the
cause of the neuronal death in ALS is
not known, it is suspected that oxidative
damage plays a key role. Dr Linseman
therefore wanted to know if Immunocal®
could improve the symptoms of ALS as it
had done in their TBI model.
In the 2014 paper in the journal
Antioxidants, his group used a mouse
model of ALS. The mice they used have
a mutation in the gene superoxide
dismutase 1 (SOD1) which causes them
to develop a condition which is similar
to that of human ALS. They wanted
®
to know if supplementing these mice
with Immunocal® could improve their ALS
symptoms compared to mice that did
not receive supplementation. They were
pleased to see that mice supplemented
with Immunocal® had a modest delay
in the age at which their symptoms
presented, 98.5 ± 1.1 days compared
to 91.6 ± 0.9 days for the untreated ALS
mice. What is more, their symptoms also
improved; mice that received Immunocal®
showed less decline in grip strength (a
measure of the loss of muscle control
that occurs as the disease progresses).
Finally, looking at the levels of glutathione
confirmed that, as in the TBI model,
Immunocal® supplementation of the ALS
mice had a bolstering effect on levels,
both in the blood and in spinal cord tissue.
THE FUTURE
A wealth of research suggests that
oxidative stress leads to increased
damage and a worsening of symptoms
in a number of brain disorders including
TBI and ALS, and yet a good means of
combating these diseases is yet to be
found. From Dr Linseman’s preclinical
work in mice, Immunocal® shows great
promise. The next step will be testing
the effects of Immunocal® in humans and,
although the road from animal studies
to a treatment for humans can be a long
one, we wish him great success.
Behind the Research
Dr Daniel Linseman
E: daniel.linseman@du.edu T: +1 (303) 359 5905 T: +1 (303) 871 4663
Research Objectives
Dr Linseman and his lab explore a prospective
nutritional supplement, Immunocal®, for enhancing
resilience and improving recovery following traumatic
brain injury which could be taken as a preventative
measure by high-risk populations.
Detail
Daniel Linseman
Knoebel Institute for Healthy Aging
University of Denver
2155 E. Wesley Ave.
Denver, CO 80208, USA
Bio
Dr Linseman’s research is focused on mechanisms
of neuronal death in degenerative disorders and episodes
of neurotrauma, with a particular emphasis on ALS,
Alzheimer’s, and traumatic brain injury. Dr Linseman
is an Associate Professor in the Department of Biological
Sciences and the Knoebel Institute for Healthy Aging
at the University of Denver.
Funding
Immunotec, Inc. (Quebec, Canada)
Collaborators
• Natalie Serkova, PhD
University of Colorado Anschutz Medical Campus
References
Ignowski, E., Winter, A. N., Duval, N., Fleming, H., Wallace,
T., Manning, E., Koza, L., Huber, K., Serkova, N. J., &
Linseman, D. A. (2018). The cysteine-rich whey protein
supplement, Immunocal®, preserves brain glutathione and
improves cognitive, motor, and histopathological indices
of traumatic brain injury in a mouse model of controlled
cortical impact. Free radical biology & medicine, 124, 328-
341.
Ross, E. K., Gray, J. J., Winter, A. N., & Linseman, D. A.
(2012). Immunocal® and preservation of glutathione as a
novel neuroprotective strategy for degenerative disorders
of the nervous system. Recent patents on CNS drug
discovery, 7(3), 230-5.
Ross, E. K., Winter, A. N., Wilkins, H. M., Sumner, W. A.,
Duval, N., Patterson, D., & Linseman, D. A. (2014). A
Cystine-Rich Whey Supplement (Immunocal(®)) Delays
Disease Onset and Prevents Spinal Cord Glutathione
Depletion in the hSOD1(G93A) Mouse Model of
Amyotrophic Lateral Sclerosis. Antioxidants (Basel,
Switzerland), 3(4), 843-65.
Winter, A. N., Ross, E. K., Daliparthi, V., Sumner, W.
A., Kirchhof, D. M., Manning, E., Wilkins, H. M., &
Linseman, D. A. (2017). A Cystine-Rich Whey Supplement
(Immunocal®) Provides Neuroprotection from Diverse
Oxidative Stress-Inducing Agents in Vitro by Preserving
Cellular Glutathione. Oxidative medicine and cellular
longevity, 2017, 3103272.
Personal Response
Could you tell us about any planned or current studies
with Immunocal® in humans?
Immunotec, Inc. (Quebec, CA) is currently performing
a pilot clinical study in patients with mild cognitive
impairment (MCI): “Nutritional Intervention With the Dietary
Supplement, Immunocal® in MCI Patients: Promotion of
Brain Health”. The Principal Investigator for this study is
Dr Hyman Schipper at the Memory Clinic/Jewish General
Hospital located in Montréal, Quebec, Canada.
www.researchoutreach.org 105
Health & Medicine ︱ Dr Sanjay Gupta
Plant phytochemicals
A new cancer chemopreventative?
Dr Sanjay Gupta from
Case Western Reserve
University is exploring the
chemopreventative properties
of phytochemicals such as
polyphenols and flavonoids,
found in plants. The team aim
to enhance our understanding
of the epigenetic mechanisms
that are influenced by
phytochemicals resulting
in cancer prevention. By
manipulating gene expression,
without changing the genetic
code, phytochemicals can
inhibit both oxidative stress and
the effects of cancer-inducing
proteins. Using dietary agents
could be a cost-effective, non-
toxic therapeutic tool to prevent
cancer and improve the quality
of life of patients.
Phytochemicals are derived from plants that
we eat as part of a healthy diet.
106 www.researchoutreach.org
C
ancer is a leading cause of death
worldwide and is responsible
for one in six mortalities.
Furthermore, around 70% of cancer
deaths in 2008 occurred in developing
countries. Cancer treatments are
extremely expensive and the effectiveness
of these drugs is limited. Consequently,
many people cannot afford treatment,
especially patients from low-income
countries, resulting in suffering and
increased mortality. However, around 30%
of all cancer deaths could be prevented
by a change in lifestyle and diet. It is well
known that phytochemicals, derived
from plants eaten as part of our diet, are
powerful bioactive compounds and have
an important role in antioxidation and
cancer chemoprevention. This inspired
Dr Gupta and his team to conduct
extensive research that explores natural
cancer prevention using dietary agents.
In particular, Dr Gupta is focussed on
the role of phytochemicals as epigenetic
modifiers in cancer.
WHAT IS EPIGENETICS?
Epigenetics is the study of chemical
changes to the genome that are heritable,
reversible and affect gene expression
without alteration of the genetic
code itself. One essential epigenetic
mechanism is DNA methylation. This
is where methyl groups are added to
the DNA molecule, most commonly
at the 5-carbon of the cytosine ring.
The addition of the methyl group inhibits
a process known as transcription, resulting
in reduced gene expression. The removal
of these methyl groups, or ‘DNA
demethylation’, can therefore enhance
gene expression. Another important
epigenetic mechanism is histone
modification. Histones are proteins which
have a role in DNA packaging. DNA
wraps itself around eight histone proteins
to form chromosomes. Modification of
histones by processes such as acetylation
can affect gene expression. Addition
of acetyl groups to the histone proteins
decreases the strength of the interaction
of the histone protein with the DNA
resulting in a more relaxed chromatin
structure. This is associated with increased
levels of gene transcription. Conversely,
the removal of acetyl groups from the
histone protein (deacetylation) results
in reduced levels of gene expression.
By investigating the impacts of
phytochemicals on epigenetics, Dr Gupta
aims to use cost-effective, minimally toxic
dietary agents as a cancer preventative
or to improve the quality of life
of suffering patients.
GREEN TEA POLYPHENOLS
In a recent study, Dr Gupta and his
colleagues showed that polyphenols,
found in green tea, can be used to delay
breast cancer progression and invasion.
The molecular pathway regulating
tumour development is extremely
complex. One of the earliest steps in
the pathway is extracellular matrix (ECM)
remodelling. The ECM is a network of
macromolecules such as glycoproteins
and enzymes that provide support
to the surrounding cells. In
tumour progression, matrix
metalloproteinases (MMPs)
degrade parts of the ECM,
generating matrikines.
These are active molecules
Many people, particularly in low-income countries,
cannot afford expensive cancer treatment. Dr Gupta has shown that polyphenols, found in
green tea, can be used to delay breast cancer
progression and invasion.
GTP has the potential to alter both DNA
methylation and chromatin remodelling –
two essential epigenetic mechanisms.
that enhance tumour progression CHEMOPREVENTION
and tumour cell invasion. MMP activity OF PROSTATE CANCER
is regulated by ‘tissue inhibitors of matrix Prostate cancer is the second leading impacts of GTP exposure. Epigenetic
metalloproteinases’ (TIMPs). These are cause of cancer-associated mortality silencing of gluthathione-S-transferase
natural inhibitors of MMPs and it has and is the most common cancer in men. pi (GSTP1) is a key feature of prostate
been hypothesised that upregulation of In the UK, 129 men are diagnosed with cancer. GSTP1 is an enzyme that has an
TIMPs in cancer cells could inhibit invasion prostate cancer every day. Clearly, there important role in detoxification of potent
and metastasis. Interestingly, studies is an urgent need to develop novel compounds such as carcinogens. In
have shown that green tea polyphenols therapies to combat prostate cancer. Dr prostate cancer, GSTP1 gene expression
(GTPs) such as epigallocatechin-3-gallate Gupta and his colleagues explored the is repressed due to the epigenetic
(EGCG) suppress the activity of MMPs molecular pathway underpinning prostate mechanism of DNA methylation at
in breast and prostate cancer lines. Dr cancer and investigated the epigenetic the promoter site. The team performed
Gupta and his team decided to explore
this further by investigating the effect PROSTATE CANCER
of EGCG on TIMP regulation and
the potential epigenetic mechanisms
underpinning this interaction. The team
treated two different lines of breast
and prostate cancer cells with EGCG
for 72 hours and found that TIMP-3
mRNA and protein levels increased
significantly. Additional investigation
revealed that this was due to epigenetic
regulation. EGCG treatment increases
histone protein acetylation, resulting in
increased levels of TIMP. Furthermore,
the team discovered increased H3K27
trimethylation at the TIMP-3 promoter
site, which enhanced gene expression. Tumours in the prostate compress the urethra making urination difficult and uncomfortable.
www.researchoutreach.org 107

a study in which human prostate cancer
cells were exposed to GTP for 1–7 days.
Results revealed that GSTP1 was re-
expressed and DNA methyltransferase
(the enzyme responsible for DNA
methylation) was inhibited, reducing
the inhibiting effects of DNA methylation
at the GSTP1 promoter site. Furthermore,
chromatin immunoprecipitation assays
revealed that prostate cancer cells treated
with GTP have remodelled chromatin,
resulting in increased transcriptional
activation of the GSTP1 gene, leading
to increased gene expression. Overall,
these ground-breaking results show
that GTP has the potential to alter
both DNA methylation and chromatin
remodelling – two essential epigenetic
mechanisms, highlighting the value
of GTP as a chemopreventative tool
for prostate cancer.
ANTIOXIDANT PROPERTIES
OF APIGENIN
Apigenin is a flavone subclass of flavonoid,
found in many herbs, fruits and vegetables
such as parsley, onions, oranges and
chamomile and is an essential component
of our diet. Studies have shown that
Apigenin is found in oranges, as well as many
other fruits, vegetables and herbs.
108 www.researchoutreach.org
Current treatment options for prostate
cancer include radiation therapy.
Apigenin accumulates in the nuclear
matrix and binds to DNA, reducing DNA
damage via oxidative stress.
apigenin possesses a variety of beneficial
properties such as tumour growth
inhibition and antioxidant activity. Dr
Gupta and his team aimed to research
the effect of apigenin on prostate cancer
cells. Human prostate cancer is extremely
vulnerable to oxidative stress in which
free radicals react with proteins and DNA,
often causing extensive damage. DNA
mutations caused by oxidative stress can
result in malignant changes, enhancing
the risk of prostate cancer development.
The team performed an in-depth study,
exploring the cellular uptake of apigenin
in prostate cancer cells. Results revealed,
for the first time, that apigenin
accumulates in the nuclear
matrix and binds to
DNA, reducing DNA
damage via oxidative
stress. Interestingly,
apigenin preferentially
accumulates in cells
which have androgen
receptors. Apigenin
binds to androgen
receptors and inhibits
its expression in prostate
cancer cells. Dr Gupta suggests that
apigenin could possess androgen receptor
inhibition properties, interfering with
androgen signalling, reducing oxidative
stress. However, more research is needed
to clarify this hypothesis.
FUTURE RESEARCH
Dr Gupta’s ground-breaking research
has shown the value of dietary
phytochemicals as cancer preventative
agents. The role of phytochemicals as
epigenetic modifiers has been supported
by the studies of Dr Gupta and his team.
However, our knowledge about the exact
molecular mechanisms underpinning
epigenetic alterations is still limited.
Furthermore, more clinical research
must be performed. For example, an
important next step is determining the
most effective dose of phytochemicals
required for optimal beneficial effects
in humans. Overall, these cost-effective,
low toxic dietary agents have the
potential to be used as preventatives
for people at risk of developing cancer
or as treatments to improve the quality
of life of those suffering.
Behind the Research
Dr Sanjay Gupta
E: sanjay.gupta@case.edu T: +1 216 368 6162 W: http://casemed.case.edu/dept/urology/biogupta.cfm W: https://cwru.
pure.elsevier.com/en/persons/sanjay-gupta/network/ W: www.youtube.com/watch?v=KKlfg8XvXac W: www.epibeat.com/
aging-environment-disease/diet-cancer-phytochemicals-epigenetic-modifiers/5329/ W: www.youtube.com/watch?time_
continue=4&v=21fFd1JnZHY
Research Objectives References
Dr Gupta’s mission is to identify and develop cost-effective, Deb, G., Thakur, V.S., Limaye, A.M. and Gupta, S.,
minimally toxic bioactive agents as cancer preventative 2015. Epigenetic induction of tissue inhibitor of matrix
agents for long-term use and as adjuvants in various metalloproteinase-3 by green tea polyphenols in breast cancer
therapies with a focus on epigenetic research. cells. Molecular carcinogenesis, 54(6), pp.485-499.
Kanwal, R., Datt, M., Liu, X. and Gupta, S., 2016. Dietary
flavones as dual inhibitors of DNA methyltransferases and
Detail histone methyltransferases. PloS one, 11(9), p.e0162956.
Dr Sanjay Gupta Pandey, M., Shukla, S. and Gupta, S., 2010. Promoter
demethylation and chromatin remodeling by green tea
Case Western Reserve University
polyphenols leads to re-expression of GSTP1 in human
Department of Urology
prostate cancer cells. International Journal of Cancer, 126(11),
2109 Adelbert Road
Wood Research Tower, RTG01 pp.2520-2533.
Cleveland, Ohio 44106
Shankar, E., Kanwal, R., Candamo, M. and Gupta, S., 2016,
USA October. Dietary phytochemicals as epigenetic modifiers in
cancer: promise and challenges. In Seminars in cancer biology
Bio (Vol. 40, pp. 82-99). Academic Press.
Dr Gupta was awarded his PhD by Avadh University in 1992
Sharma, H., Kanwal, R., Bhaskaran, N. and Gupta, S., 2014.
and his research was conducted at the Industrial Toxicology
Plant flavone apigenin binds to nucleic acid bases and reduces
Research Center and King George’s Medical College,
oxidative DNA damage in prostate epithelial cells. PLoS One,
Lucknow, India. He completed his postdoctoral fellowship
9(3), p.e91588.
in the Department of Dermatology at Case Western
Reserve University. Cancer: Key Statistics. The World Health Organization.
Available at: www.who.int/cancer/resources/keyfacts/en/
Funding [Accessed 05/01/2018]
• National Cancer Institute (NCI)
About Prostate Cancer. Prostate Cancer UK. Available at
• National Center for Complementary and Integrative https://prostatecanceruk.org/prostate-information/about-
Health (NCCIH) prostate-cancer [Accessed 05/01/2019]
• National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK)
• Cancer Research Foundation
• Department of Defense (DoD)
• Ohio Board of Regents-Presidential Research Initiative
Personal Response
• Gateway for Cancer Research
Where do you see your research focus in five
• United States Department of Veterans Affairs (VA)
years’ time?
Collaborators In the next five years, our plan is to move our research
• Cleveland State University, USA from the bench to the clinic in testing the promising agents
• Cleveland Clinic Foundation, USA through clinical trials.
• Purdue University, USA
• University of Louisville, USA
• University of Oslo, Norway
• University of Ioannina, Greece
• Central University of Punjab, India
• Indian Institute of Technology, India
• Institute of Life Sciences, India
• North-Eastern Hill University, India
• Second Hospital of Lanzhou University, China
www.researchoutreach.org 109
Health and Medicine ︱ Dr Robert Katona
Adipose stem cells
may promote cancer
progression
Adipose stem cells have
been considered ideal for
use in regenerative medicine
due to their ‘safe and reliable’
qualities and ability to be easily
and repeatedly harvested from
humans. However, new research
led by Dr Robert Katona of
the Biological Research Centre
of the Hungarian Academy
of Sciences’ Institute of Genetics
calls their safety into question,
suggesting that the stem
cells may promote cancer
development.
S
tem cell-based therapies have
carried the hopes of researchers,
physicians and patients for over
thirty years, showing great promise in their
ability to restore damaged and diseased
organs and tissue. Most stem cell
therapies rely on adult stem cells called
mesenchymal stem cells (MSCs), which
can differentiate into cartilage, bone,
connective tissue, muscle or adipose (fat)
tissue. MSCs can be obtained from almost
any organs or tissues (bone marrow, lung,
spleen, liver, fat etc.). The MSCs derived
from fat tissue are called adipose stem
cells (ASCs) and these can be isolated
with minimal ethical conflict.
Until recently, bone marrow served as
the main source of MSCs. However,
adipose tissue became much more
attractive as researchers realised that
ASCs were abundantly available and
could be easily and repeatedly sampled
with minimally invasive procedures.
Furthermore, adipose stem cells have
demonstrated low immunogenicity (i.e.,
they are unlikely to react with the immune
system) and some immunosuppressive
properties which prevent the body from
rejecting them – making them safe for
therapeutic use. As a result, ASCs have
been used in several
clinical trials to treat
conditions such
as diabetes
mellitus, liver
disease,
traumatic
injuries and
corneal
lesions,
worldwide.
However, further
research into human
NUMBER OF CELLS
and mouse ASCs has revealed that they
are prone to chromosomal instability –
they may lose or gain chromosomes.
These kinds of mutations have been
associated with cancer and, while no
cancerous transformations of ASCs have
been observed yet, ASCs have been
shown to incorporate into tumours and
promote their growth, raising concerns
about the true safety of ASC therapies.
Now, research led by Dr Robert Katona
of the Biological Research Centre of
the Hungarian Academy of Sciences’
Institute of Genetics has shown that
ASCs with an abnormal number of
chromosomes may promote cancer
development and act as tumour support
structures, known as stroma.
INVESTIGATING ASC
BEHAVIOUR IN MICE
In order to get a better understanding
of ASC behaviour, Dr Katona and his
team extracted the visceral fat – the deep
abdominal fat that surrounds organs
– from mice and cultured the visceral
adipose stem cells (vASCs) in vitro
for several months.
The changes were almost immediate
and cell growth and division slowed
down, with cell numbers decreasing in
the first few weeks. Soon after, the cells
began to deteriorate, becoming enlarged
and flattened, with most stopping
growth and proliferation altogether.
Surprisingly, however, some continued to
divide and after 50 days, the cell culture
had grown beyond the initial sample size.
By now, the cells were showing signs
of increased DNA content, with most
cells having four or more copies of
at least one chromosome, rather than
30 00 00
25 00 00
20 00 00
15 00 00
p3
p2 p4
10 00 00
p5 p7
p1 p6 p8
5 00 00
0 0
0 50
NUMBER OF DAYS
Fifty thousand vASCs were plated and cultured in triplicate samples. Cells were passaged when the
culture reached confluency and the living cell number of vASCs was determined with trypan blue staining
and counting with BioRad TC10 counter device. The graph shows the average ± SD of living cell numbers
in three parallel samples. The x-axis indicates days in culture from the initial plating, and the measuring
points are referred as p1 to p13. A representative of three independent experiments is shown.
the usual two, causing cells to have even
up to 163 chromosomes in total, rather
than the usual 40. This was confirmed
using flow cytometry – where a liquid
cell culture is poured down a tube
and passed through one or more lasers
to determine the physical and chemical
properties of the cells – and microscopy.
In both cases, DNA within the cells was
stained so that it would fluoresce when
hit with a laser and become visible
to the researchers.
This result is significant as multiple DNA
copies can lead to altered gene expression
and change the cells’ behaviour.
To see how the cells’ gene expression
and behaviour had changed, the
researchers developed an immortalised
ASC cell line, containing the abnormal
DNA configuration which they called
ASC.B6 and compared its activity to
original vASCs. While the ASC.B6
cells were still able to differentiate into
mature cells as normal, transcriptome
analysis – study of the total sum of
messenger RNA (an intermediary
between DNA and proteins) present
in the cell – showed that 2395 genes
were being expressed at least twice
as much or as low as normal.
In particular, genes and gene products
responsible for cell growth, division
and movement were overrepresented
in ASC.B6, showing that these
cells might be involved in cancer
development. This was backed by
p13
p12
COUNTS
p11
p10
p9
100
increased expression of cancer stem cell
markers Sca-1, CD29, and Krüppel-like
factor 4 (Klf4). Interestingly, expression
New research lead by Dr Robert Katona
has shown that ASCs ... may promote
cancer development and act as tumour
support structures.
of another cancer stem cell marker,
Nestin, actually decreased.
ASCs CAN PROMOTE TUMOUR
CELL GROWTH
To demonstrate this, Dr Katona and his
team co-cultured the 4T1 murine breast
cancer cell line with vASCs or ASC.B6.
Both ASC cultures enhanced proliferation
of 4T1, although ASC.B6 did so far more
than the vASCs. Surprisingly, most of the
tumour-promoting growth factors were
expressed at similar levels in both vASCs
and ASC.B6. However, expression of one
tumour-promoting growth factor, insulin-
Metaphase chromosome spreads were made from colchicine-blocked vASCs at passage numbers 4
and 7, and ASC.B6. Chromosomes were DAPI stained and counted using a fluorescent microscope.
350
vASC P3
vASC P6
280
vASC P20
ASC B6
210
140
70
0 200 400 600 800 1000
DNA-CONTENT
The DNA content of vASCs at passage
numbers 3, 6 and 10 and of ASC.B6 cell line
was determined by propidium-iodide staining
and flow cytometric analysis.
like growth factor 1 (IGF1), increased
in ASC.B6 compared to vASCs (IGF1
production of vASCs was only initiated
when they started to show increased
DNA content) and was found in the broth
surrounding both cultures. Moreover,
treatment with an IGF1 antibody
significantly decreased tumour growth,
suggesting that IGF1 production was
at least partly responsible for ASC.B6’s
tumour growth promoting effect.
WHY IGF1?
IGF1 is responsible for promoting
mammary terminal end bud, ductal and
gland formation in healthy mammals.
While it’s mostly produced in the liver, it
is also expressed in mammary stromal
www.researchoutreach.org 111

120
PERCENTAGE OF POSITIVE CELLS (%)
*
100
80
60 **
40
20
0 0
CD29 CD44 Sca1
Cell surface markers of vASCs at passage 3 and ASC.B6 cells were
detected by flow cytometry and the percentage of positive cells was
determined. The bars show the mean ± SD from three independent
experiments, the statistical analysis was t-test with P-values set at:
*P < 0.05, **P < 0.01.
cells. As a result, overexpression of IGF1
can lead to breast cancer development,
progression and metastasis. This is
reflected in Dr Katona’s results where
he exposed vASCs and ASC.B6 to 4T1
murine breast cancer cells.
The tumour-promoting effect of IGF1
is often heightened when it binds to
its receptor – IGF1R. This makes it a
promising target for human breast cancer
therapies and several researchers have
already attempted clinical trials that treat
breast cancer with IGF1R or receptor
tyrosine kinase inhibitors. Unfortunately,
these clinical trials were stopped as IGF1R
antibody therapy caused hyperglycaemia
vASCs at passage numbers 3, 6 and 10 and ASC.B6 cell line were stained for SA-βgal activity
for 16 h and then the blue staining (senescence) was detected with an inverted light microscope.
Mammalian stem cells dividing.
112 www.researchoutreach.org
40
vASC
ASC.B6
30
20
10
CD106 CD11b CD45 Cancer
growth and movement
proliferation
Functional enrichment analysis done by IPA for the identification of biological
functions and diseases that were most profoundly represented by the
differentially expressed genes. Only carcinogenesis associated categories are
presented, all of which are highly affected. Right-tailed Fisher’s exact test was
used to calculate a p-value. False discovery rates (FDR) were generated based
on the Benjamini-Hochberg corrected p-values.
By now, the cells were showing signs
of increased DNA content, with... cells
having up to 163 chromosomes in total,
rather than the usual 40.
– increased blood sugar – and metabolic
syndrome in patients while receptor
tyrosine kinase inhibitors led to patients
developing metabolic toxicities.
Currently, researchers are exploring
alternative anti-IGF1 antibodies, with
some successfully slowing or even
inhibiting cancer proliferation in late-
stage cancer patients. While this sounds
Threshold
Cellular Cellular Death and Cell cycle
survival
like a lot of effort, finding effective
therapeutic targets against tumour
stroma, such as ASCs, is critical, as their
secretion of IGF1 can lead to cancer drug
resistance, minimising the effectiveness
of treatments and leading to poorer
patient prognosis.
CAN THE MOUSE MODEL
BE APPLIED TO PEOPLE?
Dr Katona believes it can. Mouse models
are used due to their high similarity with
humans, (we share 85% of our protein-
coding DNA). As a result, cancerous
activities observed in mice would most
likely reflect those in humans. Just as
in mice ASCs, ageing and deteriorating
human ASC cultures have had altered
chromosome numbers. Dr Katona
expects this would also be the case
in the body and could be due to higher
concentrations of reactive oxygen
species or inflammatory mediators
which promote chronic inflammation
in the tumour microenvironment.
While Dr Katona hopes that his mouse
ASC model could be used for further
research into the genes responsible
for cancer development and potential
treatments targeting tumour stroma,
his findings could also influence future
use of therapeutic ASCs.
Behind the Research
Dr Robert Katona
E: katona.robert@brc.mta.hu T: +3662433397 W: www.brc.hu/gen_acstem.php
Research Objectives References
Dr Katona’s work uses a mouse adipose stem cell model Fajka-Boja, R., Marton, A., Tóth, A., Blazso, P., et al. (2018).
system to study cancer and cancer stem cell development. Increased insulin-like growth factor 1 production by
polyploid adipose stem cells promotes growth of breast
cancer cells. BMC Cancer, [online], 18, 872-884. Available
at: https://bmccancer.biomedcentral.com/articles/10.1186/
Detail s12885-018-4781-z [Accessed 22/01/2019].
Institute of Genetics Frese, L., Dijkman, P. and Hoerstrup, S. (2016). Adipose
Biological Research Centre Tissue-Derived Stem Cells in Regenerative Medicine.
Hungarian Academy of Sciences Transfusion Medicine and Hemotherapy, [online], 43(4),
268-274. Available at: https://www.ncbi.nlm.nih.gov/pmc/
6726. Szeged, Temesvari krt. 62.
Hungary
articles/PMC5040903/ [Accessed 22/01/2019].
Karanes, C., Nelson, G., Chitphakdithai, P., Agura, E., et al.
Bio (2008). Twenty Years of Unrelated Donor Hematopoietic
Dr Katona is Principal Investigator at the Artificial Cell Transplantation for Adult Recipients Facilitated by the
National Marrow Donor Program. Biology of Blood and
Chromosome and Stem Cell Research Laboratory. He has
Marrow Transplantation, [online], 14(9), 8-15. Available at:
28 years’ experience in basic research and R&D research. https://www.bbmt.org/article/S1083-8791(08)00249-8/
His fields of expertise are molecular biology, biochemistry, fulltext [Accessed 22/01/2019].
cell biology, transgenics, stem cell biology, nanotechnology,
Miana, V. and González, E. (2018). Adipose tissue stem
cytology and industrial protein production.
cells in regenerative medicine. ecancermedicalscience,
[online], 12, 822-836. Available at: https://www.ncbi.
Funding nlm.nih.gov/pmc/articles/PMC5880231/ [Accessed
This work was funded by the GINOP-2.3.2-15-2016-00001 22/01/2019].
and GINOP-2.3.2-15-2016-00039 grant of the National
Robertson, S. (2018). What is flow cytometry? [online]
Research, Development and Innovation Office.
News Medical Life Sciences. Available at: https://www.
news-medical.net/life-sciences/What-is-Flow-Cytometry.
Collaborators aspx [Accessed 22/01/2019].
• Roberta Fajka-Boja
(2010). Why mouse matters. [online] National Human
• Annamaria Marton
Genome Research Institute. Available at: https://www.
• Anna Toth genome.gov/10001345/importance-of-mouse-genome/
• Peter Blazso [Accessed 22/01/2019]
• Vilmos Tubak
• Balazs Balint
• Istvan Nagy
• Zoltan Hegedus
• Csaba Vizler
Personal Response
Given your results, would you suggest people
reconsider the use of therapeutic ASCs and if so, under
what circumstances?
Yes, but people should receive ASC therapy only
if all the safety issues have been addressed by double
blind, regulated and controlled clinical trials. Any clinically
unproven procedures should be strongly avoided.
www.researchoutreach.org 113
Biology ︱ Dr Nan-ping Weng
The biology of ageing
What causes ageing? Is it
inevitable? Could it be slowed
or even reversed? Humans
have wanted to know the
answer to these questions
ever since we became aware
of our own mortality. Despite
the tremendous advances that
have been made in our scientific
understanding over the past
century, ageing remains one
of the greatest mysteries in
biological science. But scientists,
like Dr Nan-ping Weng of the
National Institutes of Health,
are slowly uncovering its secrets.
114 www.researchoutreach.org
D
r Nan-ping Weng thinks the
best experimental approach to
study human ageing is through a
longitudinal approach. A ‘cross-sectional’
approach comparing groups of young
individuals to older groups is commonly
used and yielded rich information
regarding the difference between
the young and old groups. But this
approach has issues, according to Weng:
“Substantial differences in environmental
experiences exist between young and
old subjects, it is sometimes difficult to
distinguish those true biological changes
with age, from different life experiences”.
With this in mind, he utilises an approach
that tracks the changes that occur to
Humans have wanted to know the answer
to these questions ever since we became
aware of our own mortality.
people over time. These follow-ups can
come after 5 years, 10 years, 20 years, or
even lifetime long. Although more time-
consuming and expensive than the cross-
sectional approach, so-called longitudinal
studies allow researchers to minimise the
variables that might otherwise confuse
their conclusions.
IMMUNE SYSTEM DECLINE
It is well known that as people age, they
become more susceptible to infection and
other diseases as well, it is one of the
reasons we vaccinate the elderly
to influenza. In his longitudinal
studies of ageing, Dr Weng
is trying to understand what
changes in the immune
system as people
age, and how this
impacts their susceptibility to disease.
In Dr Weng’s group’s 2016 study
published in Immunity & Ageing, Dr
Weng wanted to understand two things.
Firstly, was there a change in the different
types of immune cells in individuals as
they age and, secondly, could a pattern
be determined by comparing individuals?
To do this, they looked at four different
types of immune cells: B cells (cells that
produce antibodies to fight infection,
Natural killer (NK) cells (part of the inbuilt
or ‘innate’ system which seek out and kill
infected cells and two types of T cells (part
of the immune system that can adapt
following infection. T cells come in two
flavours, CD4+ cells secrete signals to
aid other immune cells in the fight, and
CD8+, which, like NK cells, seek out and
kill infected cells specifically. These cells
are known collectively as lymphocytes.
Dr Weng and colleagues tracked the
changes to immune cell numbers in 165
subjects aged from 24 to 90 years old.
The results showed that a large degree
of variability from person to person.
Some showed a decline, some no change
and some had an increase.
To try and understand this further, the
group looked to see if the rate of change
varied as people got older. They were
interested to see that the rate of change
stayed quite consistent over time.
This means that although two people
could display very different changes to
their immune system as they age, their
individual pattern of change did not seem
to vary over time.
Interestingly, different immune cells seem
to vary to different extents. Most variable
WHAT WE LOSE WITH AGE
Chromosome
As cells divide
Telomeres
End caps that protect
the chromosome
were CD4+ T cells, followed by: NK cells,
CD8+ T cells and B cells. The group
wondered if these differences might
be due to infection with viruses such as
cytomegalovirus (CMV), but this proved
not to be the case. However, they did
find that levels of T cells correlated with
levels of the cytokine (a soluble signal that
controls immune function) IL-15, which is
known to cause these cells to expand in
number. Similarly, the number of B cells
was found to correlate with signal TNF-RI,
which causes a similar expansion in these
cells. Therefore, differences in the levels
of these soluble signals may have
produced this variability.
TELOMERES AND AGEING
But what might cause the levels of
immune cells to change? An explanation
for why the levels of certain immune cells
drop in some people as they age may
lay in something called a telomere.
Each time a cell divides in two, the cell
needs to make an identical duplicate
of its DNA (the template that instructs
a cell how to function) so that each
daughter cell receives a copy. On the
end of each DNA strand is a sequence
called a telomere. Each time the cell
divides, the telomere shortens until
eventually, it becomes so short that the
cell can no longer divide. Why the DNA
is capped with these telomere sequences
is not known for sure, but some have put
Cell
Cell
Cell
over time...
...telomeres shorten, and eventually cell division stops
forward the idea that they may act as a in 465 people between 21-88 years over
safety mechanism to prevent cells from a period of 13 years. Examining a pool
dividing out of control, which could lead of immune cells that includes T, B and
to cancer. NK cells, the group found that telomere
length decreased as the participants
In order to fulfil their function, the aged. Interestingly, the rate of change
lymphocytes of the immune system are among T cells, B cells and monocytes
required to divide many times. This has varied, which may be a result of
led scientists to wonder if they could be the different functions they fulfil.
susceptible to telomere shortening. To
address this question Dr Weng published Despite the telomere shortening with
two studies in the journal Clinical Science each division, cells do have a tool they
(2015) and Frontiers of Immunology can use to lengthen their telomeres
(2017) that aimed to track the length once more: an enzyme (protein catalyst)
of immune cell telomeres as people age. known as telomerase. The levels of this
enzyme are usually tightly controlled,
The first study was performed in 216 probably due to the risk of cancer. The
people aged between 20-90 years of study found that a substantial amount
age over a period at 0, 5, and 12 years, of the variation seen in T cell telomere
and the second study was performed length could be accounted for by
Cumulative effectors
of life-long stressors
and diseases
Healthy young Old inflammaging
environment IL-1β, IL-6, TNF-α
Inflammaging refers to the chronic, low-grade inflammation that characterises ageing. In young
adults, tissue microenvironment is healthy whereas cumulative insults by stressors and diseases over
a life-long time, results in damage of microenvironment and increased inflammation-related cytokines
in circulation. This figure is modified based on Franceschi et al Seminar in Immunology 2018.
www.researchoutreach.org 115

different levels of telomerase activity in
cells, in combination with other factors
including the number of immature T cells
and physiological features such as blood
glucose level.
Notable was the fact that, as with the
group’s 2017 study, the differences
observed varied substantially between
participants. Most noticeably, age-related
trajectories of telomere attrition, elevated
circulating inflammatory cytokines, and
anti-CMV IgG are independent, and that
ageing individuals do not show a uniform
pattern of change in these variables
(Figure 3). Highlighting the importance
of studying changes in individuals, rather
than averaging whole groups together.
EXPLAINING IMMUNE
SYSTEM DECLINE
If the telomere length of immune cells
decreases as people age, could there
be a link between the length of a person’s
telomeres and the ability of their immune
system to defend against infection?
To tackle this question Dr Weng and
colleagues performed a study which
was published in 2015 in The Journal
of Infectious Diseases. In the paper,
the group use a group of 22 healthy, older
individuals, that had immune cells with
either particularly short or long telomeres
and determined the strength of their
immune response to an influenza vaccine.
As the body mounts an immune response
to an invading virus such as influenza,
B cells produce large amounts of
antibodies. Antibodies are proteins that
stick to the virus, rendering it unable to
infect cells. Antibodies are highly specific,
so they must be generated for each
new strain of influenza virus that a person
encounters. As the vaccine contains
an inactive influenza virus, the researchers
could measure the levels of influenza
antibodies produced after participants
received the shot and use it to determine
the strength of their immune response.
Dr Weng’s group were interested to
see that those with a strong antibody
response to influenza infection, had
When looking at Dr Weng’s studies, one
thing becomes clear, the way in which
individuals age varies greatly.
116 www.researchoutreach.org
INDIVIDUALIZED AGE-ASSOCIATED CHANGES IN IMMUNE SYSTEM
YOUNG AGEING
TELOMERE
TELOMERE
TELOMERE
TELOMERE
TELOMERE
TELOMERE
Ageing of immune system measured by three independent biomarkers: telomere length, inflammation-
related cytokines (IL-1b, IL-6, and etc.), and anti-CMV IgG titer. In young adults, all three parameters are
good, with advance of age, old adults display different degrees of changes in these three biomarkers.
longer B cell telomeres than those with
a weak response. They also found that
shorter telomeres in influenza-specific
CD8+ T cells also positively correlated
with their ability to undergo cell divisions.
This raises the possibility that shortening
of telomeres in immune cells could
contribute to the decline in a person’s
ability to fight off infection as they age.
THE FUTURE
The changes that occur during ageing
and how these result in declining
health, is an area of interest for society
and scientists alike. By tracking changes
in subjects over time, researchers such
Behind the Research
OLD
TELOMERE SHORTENS
AFTER MULTIPLE
REPLICATIONS TELOMERE LENGTH
TELOMERE Long
TELOMERE SHORTENS
Dr Nan-ping Weng
AFTER MULTIPLE
REPLICATIONS
E: Wengn@mail.nih.gov T: +1 410 558 8341 W: https://irp.nih.gov/pi/nan-ping-weng W: www.
TELOMERE SHORTENS
AFTER MULTIPLE
REPLICATIONS
nia.nih.gov/research/labs/lmbi/lymphocyte-differentiation-section W: www.researchgate.net/
TELOMERE AT
SENESCENCE
profile/Nan-ping_Weng
Short
TELOMERE SHORTENS
AFTER MULTIPLE
Research Objectives References
REPLICATIONS INFLAMMATION-
CYTOKINES
Dr Nan-ping Weng’s research is focused on understanding Lin Y, Damjanovic A, Metter EJ, Nguyen H, Truong T, Najarro
Low
the mechanism of age-related changes in immune K, Morris C, Longo DL, Zhan M, Ferrucci , Hodes RJ6, Weng
function with emphasis on telomere in T cell function, TCR NP. (2015). ‘Age-associated telomere attrition of lymphocytes
repertoires, and naïve and memory T cell maintenance using in vivo is co-ordinated with changes in telomerase activity,
TELOMERE AT human Longitudinal Study (BLSA) and mouse models. composition of lymphocyte subsets and health conditions’.
SENESCENCE
Clin Sci (Lond), 128(6):367-77. doi: 10.1042/CS20140481.
High Detail Lin, Y., Kim, J., Metter, E. J., Nguyen, H., Truong, T., Lustig, A.,
Ferrucci, Weng, N. P. (2016). ‘Changes in blood lymphocyte
251 Bayview Blvd., numbers with age in vivo and their association with the levels
TELOMERE AT
CMV IgG TITER Baltimore, of cytokines/cytokine receptors’. Immunity & Ageing: I & A,
SENESCENCE Low 13, 24.
MD 21224,
USA
Lustig A, Liu HB, Metter EJ, An Y, Swaby MA, Elango P,
Ferrucci L, Hodes RJ, Weng NP. (2017). ‘Telomere Shortening,
Bio
Inflammatory Cytokines, and Anti-Cytomegalovirus Antibody
Dr Weng received his MD from Fudan University Shanghai
TELOMERE AT
High
Follow Distinct Age-Associated Trajectories in Humans’. Front
SENESCENCE Medical College (former Shanghai First Medical College), Immunol, 8:1027.
China and PhD in Immunology from Baylor College of
Medicine. He obtained his postdoctoral training at NCI, Najarro , Nguyen H1, Chen G, Xu M, Alcorta S, Yao X, Zukley
NIH. He joined the National Institute on Aging (NIA) as L, Metter EJ, Truong T, Lin Y, Li H, Oelke M, Xu X, Ling SM,
a tenure-track investigator and now is a tenured senior Longo DL, Schneck J, Leng S, Ferrucci L, Weng NP. (2015).
investigator at the Laboratory of Molecular Biology and ‘Telomere Length as an Indicator of the Robustness of B- and
T-Cell Response to Influenza in Older Adults’. J Infect Dis,
Immunology, NIA.
212(8):1261-9.
Funding
as Dr Weng are helping to shed light
on these questions.
This research was supported entirely by the Intramural
Research Program of the NIH, National Institute on Aging.
Personal Response
When looking at Dr Weng’s studies Collaborators What future studies do you have planned?
one thing becomes clear, the way in • Richard Hodes We are currently focusing on unravelling the underlying
which individuals age varies greatly. This • Luigi Ferrucci mechanisms of lymphocyte ageing from single cell to
heterogeneity highlights the importance cell population to their collective function. We hope we
of his approach; if we simply average will be able to determine cellular ageing at the individual
cell level and to apply the multi-parameters approach to
together groups of participants we may
measure immune system age. Such depth measurements
lose important information in the noise. of an individual allow us to determine general and specific
changes in lymphocytes and to develop new tools for
A proper understanding of the clinical applications in precision medicine. 
processes that underlie ageing is crucial
if we are to improve our health in old
age. This includes bolstering our ability
to fight off infection as we get older and
to enhance the function of the immune
system when it gets “old”, such as in
the case of reduced ability to fight off
influenza infection. We, therefore, await
the results of Dr Weng’s future studies
with great anticipation.
www.researchoutreach.org 117
Health & Medicine ︱ Dr Hanne van Ballegooijen
Dream team:
Improving hearts and bones with vitamins D and K
Vitamins are essential nutrients
our bodies require to perform
important functions. Although
they can be absorbed through
a healthy lifestyle, many people
are deficient in vitamins such
as vitamin D and vitamin K.
Dr Hanne van Ballegooijen
and her team from Amsterdam
UMC, location VUmc, work to
understand the consequences
of such deficiencies on human
health. Future research may
focus on the combination of
specific vitamins and long-term
impact of supplement use,
a popular worldwide trend.
118 www.researchoutreach.org
V
itamins are organic compounds
essential for our bodies to perform
a range of specific functions. As
we cannot produce these ourselves, we
must absorb them through our daily diets
or lifestyles. Two important fat-soluble
vitamins are vitamin D and vitamin K.
WHY DO VITAMINS MATTER?
Vitamin D is responsible for controlling
the amount of calcium and phosphate
in our bodies. Without vitamin D we
cannot absorb calcium, which means
our bones are at risk of becoming soft or
brittle. Vitamin D is often associated with
getting enough sunlight, as the majority
of vitamin D comes from exposing our
bare skin to sunlight. It is very difficult to
get sufficient vitamin D from diet alone.
Less commonly understood than vitamin
D is vitamin K. Unlike vitamin D, vitamin K
is predominantly obtained through diet.
Sources include leafy green vegetables,
fish, fermented dairy and eggs. Vitamin K
is the term used to represent a group of
compounds (vitamin K1, vitamin K2 etc.
based on their chemical structure and
side chain) which contribute towards our
body’s ability to clot blood. Vitamin K can
only be stored in small amounts and
should be consumed daily.
Understandably,
anyone concerned
about vitamin
D deficiency may choose to top up
their levels with artificial forms known as
supplements. The use of supplements
is widespread practice throughout
the world with tablet forms often
available in supermarkets at low prices.
However, the availability of over-the-
counter supplements containing single
vitamins or nutrients may not take into
consideration the unknown long-term
consequences and the importance of the
interaction between different vitamins.
Vitamins D and K may work together
to ensure calcium is correctly distributed
in our bodies. Whilst vitamin D plays
an overarching role in stabilising bodily
calcium levels in our blood, vitamin K
helps to ensure the calcium is distributed
to our bones, as well. Research by Dr
Hanne van Ballegooijen of Amsterdam
UMC, location VUmc, is some of the first
to investigate the health benefits of this
combination of vitamins.
HOW CAN VITAMINS D
AND K AFFECT OUR HEALTH?
Dr van Ballegooijen’s research forms
part of 10 years of study into the
function of vitamin D in our bodies with
a particular focus on cardiovascular
health. Specifically, her latest research
considers the potential mechanism
between the interaction of vitamin D
and K and explores the benefits to both
cardiovascular and bone health.
Cardiovascular health problems
affect many people around the world
and according to the World Health
Organization, account for a
third of deaths worldwide.
The consequences are
devastating. Bone health
problems are less often
directly culpable as a
cause of death, but are
GOOD NUTRITION
PROMOTES VITAMIN K
NATURAL SUNLIGHT HEALTHY HIGHER
PROMOTES VITAMIN D CARDIOVASCULAR SYSTEM BONE DENSITY
When vitamin K and vitamin D are received in the correct amounts, there are benefits to the cardiovascular systema and to bone density. Both of these factors
are important for a healthy, active lifestyle.
particularly common among older adults. the long-term consequences of even in people aged 55 to 65 years. When
Unfortunately, this demographic is also at low-dose vitamin D supplements have the participants were followed up
increased risk of cardiovascular difficulties. not received much research attention. approximately six years later the team
found 62% of the group with insufficient
The specific aim of the research by Dr In the studies conducted on Dutch vitamin D and K had developed
Hanne van Ballegooijen was to discover population cohorts, some groups hypertension. The combination of low
the potential synergy of vitamin D and were found to be particularly at risk. levels of vitamin D and K also showed
K to best understand their combined Older adults who were deficient in participants had increased systolic blood
functionality. That began by unravelling both vitamins were found to have pressure when compared with the group
the complex interaction between the greater risk of high blood pressure with higher levels of both vitamins.
two vitamins to better understand also known as hypertension. The study The team concluded that the combination
their impact on each other. One of the used data from the Longitudinal Aging of low levels of both vitamins D and K led
hypotheses is that vitamin D stimulates
the creation of vitamin K-dependent
proteins within the body. Once created,
The consumption of a well-balanced
these proteins need vitamin K for optimal diet is most important for the prevention
functioning. In this way, our body ensures
that our calcium levels will always be well of chronic diseases.
distributed. Without vitamin K, these
proteins cannot carboxylate to function Study to research the incidence of to increased systolic blood pressure and
properly. But what if these vitamins are high blood pressure and hypertension a greater risk of incident hypertension.
not supplied in optimal amounts due to
supplementation of only one vitamin?
The team suggests that widespread STAGES OF ATHEROSCLEROSIS
vitamin D supplementation may therefore
be part of the reason for the vitamin K
deficiencies identified in humans.
FINDINGS FROM
POPULATION STUDIES
The team hypothesises that vitamins
D and K could only interact correctly
with each other if they were present
in combination and in the right amount.
As previously mentioned, many people Atherosclerosis is the most common type of arteriosclerosis. Fatty plaques build up in the blood vessels
choose to take supplements. However, and eventually restrict and even block the flow of blood.
www.researchoutreach.org 119
A second study conducted among kidney
transplant recipients elucidated the role
of low levels of both vitamin D and vitamin
K and long-term outcomes. Though
transplant recipients are significantly more
likely to survive compared with dialysis
recipients, their chance of graft failure
and eventual associated mortality remains
high. Kidney transplant recipients tended
to demonstrate low levels of a range of
micronutrients, including vitamins D and
K. The kidney transplant recipients were
included in the study between 2002-2003
approximately six years after receiving
their transplants. When followed up
almost 10 years later, more than a quarter
of the cohort had died and a further 10%
had developed death-censored graft
failure. The team concluded that kidney
transplant recipients who demonstrate
deficiencies in both vitamins D and K have
a higher risk of graft failure, and a higher
risk of mortality. A further conclusion
showed that patients who were treated
with vitamin D and who had low vitamin
K levels had a greater risk of death or
transplant failure than those who weren’t.
Nowadays, kidney patients are all given
vitamin D treatment, but the long-term
consequences are poorly understood.
The team originally hypothesised that
members of “at-risk” groups who used
vitamin D supplements and had low
vitamin K levels would be at greater risk
of disease. Their research has shown that
those undertaking vitamin D therapy or
taking supplements with low vitamin K
status had indeed a much higher risk of
In the right proportion, vitamins K and D can
contribute to a healthy cardiovascular system.
120 www.researchoutreach.org
Eating a healthy, balanced diet rich in vitamin K has many health
The long-term consequences of vitamin D
supplementation on clinical outcomes
are poorly understood.
mortality and graft failure. The next step
is to unravel whether vitamin D combined
with vitamin K rich foods or vitamin K
supplementation together could improve
bone and cardiovascular health.
LOWER RISK
OF FRACTURES
LESS
ARTERIOSCLEROSIS
HIGHER BONE
DENSITY
benefits for the bones and cardiovascular system.
RESEARCH IN THE FUTURE
Having already researched vitamin D
and vitamin K extensively, Dr Hanne van
Ballegooijen still has plans to discover
more about the impact and consequences
of vitamin D for human health. Future
research may include considering the
consequences of long-term vitamin D
supplement use. This research would
form an important part of future health
knowledge as the side effects of long-
term vitamin D supplement use remain
poorly understood.
The future will tell us whether successful
vitamin D supplementation, when
used appropriately in combination
with vitamin K, could prove to be an
inexpensive solution to develop new
preventative methods of stimulating
cardiovascular health.
Behind the Research
Dr Hanne van Ballegooijen
E: aj.vanballegooijen@vumc.nl T: +31 20 44 43127 W: www.researchgate.net/profile/Hanne_Van_Ballegooijen2
Research Objectives
Dr Hanne van Ballegooijen has been working on vitamin
D for almost 10 years. Her work suggests that vitamin D
status alone is not strongly related to cardiovascular disease
and that combining vitamin D with vitamin K might improve
its efficacy.
Detail
Dr A.J. (Hanne) van Ballegooijen, PhD
Amsterdam UMC, location VUmc Amsterdam
De Boelelaan 1117
1081 HV Amsterdam
The Netherlands
Bio
Dr van Ballegooijen is an assistant professor at the
Amsterdam UMC, location VUmc, at the department of
Nephrology and Epidemiology & Biostatistics, Amsterdam.
Her research is focused on nutrition and lifestyle
determinants in the etiology of cardiovascular diseases
and chronic kidney disease. A better understanding of
these relationships may help to promote cardiovascular
health. Further, she is involved in teaching and supervision
of students in the field of nutritional epidemiology
and cardiovascular and kidney disease. She enjoys
these teaching activities to encourage critical thinking
and to stimulate others to outperform themselves.
Funding
Niels Stensen Fellowship
Dutch Kidney Foundation
ZonMw
Collaborators
Amsterdam: Prof J.W.J. Beulens and Dr. M.G. Vervloet
Maastricht: Prof. L. Schurgers
Graz, Austria: Dr. S. Pilz, Dr. N. Verheyen
Seattle, USA: Prof B. Kestenbaum, Prof I. de Boer
References
Nair R and Maseeh A, 2012. Vitamin D: The
“sunshine” vitamin. Journal of pharmacology &
pharmacotherapeutics, 3(2), p.118.
US Department of Health and Human Services, 2004. Bone
health and osteoporosis: a report of the Surgeon General.
Rockville, MD: US Department of Health and Human
Services, Office of the Surgeon General, 87.
van Ballegooijen AJ, Cepelis A, Visser M, Brouwer IA,
van Schoor NM and Beulens JW, 2017. Joint association
of low vitamin D and vitamin K status with blood pressure
and hypertension. Hypertension, 69:1165-1172.
van Ballegooijen AJ, Pilz S, Tomaschitz A, Grübler
MR and Verheyen N, 2017. The synergistic interplay
between vitamins D and K for bone and cardiovascular
health: A narrative review. International journal
of endocrinology 2017.
van Ballegooijen, AJ, Beulens, JWJ, Keyzer, CA, Navis
GJ, Berger SP, de Borst MH, Vervloet MG, Bakker SJL,
Joint Association of Vitamin D and K Status with Long-
Term Outcomes in Stable Kidney Transplant Recipients,
Nephrology Dialysis Transplantation, 2019.
Personal Response
Considering modern lifestyles, is it realistic
to expect the majority of the population to obtain
sufficient amounts of vitamin D or vitamin K
without supplements, or do we need to instead
improve supplements?
More clinical data about the potential interplay
between vitamin D and vitamin K metabolism is urgently
needed before broader treatment recommendations
can be given.
The consumption of a well-balanced diet is key for
population-based primary prevention of chronic
diseases. As more is discovered about the powerful
combination of vitamins D and K, it gives a renewed
reason to eat a healthy diet including a variety of foods
such as vegetables and fermented dairy for bone and
cardiovascular health.
www.researchoutreach.org 121
Health & Medicine ︱ Dr Stephen Barr

Evolutionary arms race

A 400 million-year-old battle between HIV and ancient
genes, HERC5 and HERC6

Two human genes, HERC5
and HERC6 have protective
effects against HIV and other
viruses. Dr Stephen D. Barr from
Western University, Canada,
traces the evolution of these
genes throughout human
history and investigates their
protective effects. His work
has shown that these genes
are involved in an evolutionary
arms race, with host defence
mechanisms and the virus ever
trying to outwit one another.
Increased understanding of
the viral mechanisms involved
may present novel therapeutic
targets for antiviral treatments.
T
he immune system is part of the
host’s defence mechanism against
potentially dangerous pathogens,
such as bacteria and viruses. However,
many viruses have evolved ways in which
they can avoid elimination by the cells
of the immune system. These adaptations
include avoiding detection or hiding
from immune cells, interfering with host
processes or preventing recruitment
of immune cells to the site of infection.
HIV is one such virus which evades
the immune response by preventing
antibodies from binding to itself and by
destroying immune cells, amongst other
strategies. Understanding more about
the mechanisms which viruses use to
avoid antiviral activity is vital for the future
candidate for HIV therapy. In contrast,
whilst HERC6 also inhibited HIV
replication, it did so to a much lesser
extent than HERC5.
Based on this work, the Barr lab were
also interested in the origin of the
HERC5 gene and how its antiviral activity
has evolved in vertebrates.
In order to do this, they searched genome
databases to find the earliest emergence
of the small HERC gene members
and tracked their evolution through
vertebrates over time. More recent
versions, or distantly related versions,
of genes can be recognised by matching
similarities in their genetic sequences
to their ancestral genes. In this way a
Three dimensional models of evolutionarily similar HERC5 proteins.
dozens of evolutionarily divergent HERC must be met by an increase in fitness ANTIVIRAL EFFECTS
proteins, looking for similarities and by the competing organism. AGAINST OTHER VIRUSES
differences that might give clues about In order to assess whether the antiviral
how the antiviral function of HERC5 HERC genes originated in marine effects of the genes were effective against
emerged. One example of a program species; however, not all vertebrates related viruses, Dr Barr and his team
which they used for this complex analysis possess HERC genes. This suggests that tested their antiviral activity towards
is the Structural Alignment of Multiple different forms of the genes emerged a non-human virus, the monkey version
Proteins (STAMP), of HIV called simian
which aligns proteins
based on their Since viruses such as HIV have been in immunodeficiency
virus (SIV). SIV is
battle for so long, they have had time
three-dimensional thought to be at least
structures. The 32,000 years older
STAMP analysis to learn ways to get around the host than HIV, so it could

defence shields and become smarter.

The HIV virus. Some human genes
have protective effects against the virus.
development of antiviral drugs.
THE HERC GENE FAMILY AND HIV
Several proteins induced by signalling
molecules, called interferons, have
previously been identified as exhibiting
antiviral activity towards HIV. These
proteins include those encoded by a
family of genes called HERC genes. There
are six HERC members that are classified
into ‘large HERC’ proteins (HERC1
and HERC2) and ‘small HERC’ proteins
(HERC3, HERC4, HERC5 and HERC6).
The small HERC proteins are highly similar
proteins of which only HERC5 and HERC6
are interferon-induced in humans.
Although the functions of the small HERC
family members are not fully understood,
they do have antiviral effects.
Dr Stephen D. Barr and his team
at Western University, Canada,
previously discovered that
the human protein called
HERC5 potently inhibited
the replication of human
immunodeficiency virus
(HIV), identifying it as a new
family tree of genes can be made, which
identifies the original genes and follows
the changes and divergence of these
genes over time and between species.
Dr Barr’s team showed that the oldest
member of the small HERC gene family
is HERC4. HERC4 is present in one of
the few lineages of jawless fish that
survive today, sea lampreys, which
originated almost 600 million years ago.
HERC4 has since duplicated itself three
times at different evolutionary timepoints
in the tree of life. The last expansion
of the HERC family happened after
the divergence of the ray-finned fish, such
as eels, salmon and sturgeon, around
400 million years ago and this probably
resulted in a duplication of the HERC6
gene which gave rise to HERC5. The
earliest vertebrate identified to possess
HERC5 was an ancient marine organism
called the coelacanth, a type of fish that
emerged over 400 million years ago.
To better understand how HERC5
and the other HERC proteins evolved
in vertebrates, Dr Barr’s team compared
showed that a
particular region of
the HERC5 protein
that is key for antiviral activity, the RCC1-
like domain, was highly similar in other
HERC proteins and in HERC proteins
from evolutionarily distant species, such
as coelacanth and human. This highlighted
the potential that HERC5 in other
vertebrates, and perhaps other HERC
proteins, may possess antiviral activity
and that this activity has an ancient origin.
AN EVOLUTIONARY ARMS RACE
In order to avoid detection and
destruction by the host immune
defences, viruses continually evolve
mechanisms to escape detection. To
combat this, host defences must also
evolve to keep pace with the viral
adaptations. This evolutionary arms
race, sometimes called the Red Queen
hypothesis, is the driving force behind
the battle to simply survive in a constantly
evolving environment. This dynamic
coevolution process is caused by a
positive feedback loop; gain of fitness,
or the ability to survive, in one organism
be hypothesised
that primate immune
responses may
at different points during evolution, be more evolved to target SIV compared
when they would confer a survival to HIV. They tested HERC5 and HERC6
advantage to the host. Two of the more as these exhibited both the strongest and
recent HERC genes, HERC5 and HERC6, the weakest antiviral effects in human cells.
were observed to have been involved
in an evolutionary arms race with Human cells expressing increasing
viruses for hundreds of millions of years. concentrations of coelacanth HERC5,
Because of this battle, these genes have human HERC5 or human HERC6 were
developed sophisticated ways to put infected with either SIV or HIV. As the
up a shield in cells to block viruses. team predicted, human HERC5 showed
the greatest protective effect against
Using sequence analysis, the Barr lab
showed that positive selection pressure
is causing both HERC5 and HERC6
to evolve. For example, they have
previously demonstrated that part of
the RCC1-like domain in HERC5 has been
evolving for over 100 million years in
this way, providing further evidence that
these genes are inextricably linked with
viral evolution. Interestingly, HERC3 and
HERC4, which also possess the RCC1-
like domain, do not seem to be evolving
under selective pressure despite being A coelecanth, the earliest vertebrate identified to
much older than HERC5 and HERC6. possess HERC5.

www.researchoutreach.org 123

Salmon (large image), sea lamprey (top
inset) and sturgeon (bottom inset) all
carry versions of the HERC genes.
HIV, with coelacanth HERC5 and human
HERC6 showing little inhibition of HIV.
Surprisingly, all HERCs potently inhibited
SIV virus replication. This suggests that
the protective responses of HERC5
and HERC6 exhibit species- and virus-
specific activity.
Given the knowledge that the RCC1-
like domain is important in the immune
response against viral infection, Dr Barr
asked why HERC5 and HERC6 varied in
their antiviral activities, with particular focus
on this domain. Indeed, his team showed
that if part of the RCC1-like domain from
HERC5 was transferred into HERC6, then
HIV particle production was inhibited to
a level similar to HERC5. Dr Barr mentions
that, “additional structure-function studies
are needed to understand exactly how
Photo Credit: Crystal Mackay, Schulich School of Medicine & Dentistry, Western University
124 www.researchoutreach.org
Two of the more recent HERC genes,
HERC5 and HERC6, were observed
to have been involved in an evolutionary
arms race with viruses for hundreds
of millions of years.
this part of the RCC1-like domain exerts
its antiviral activity.”
Since viruses such as HIV have been
in battle for so long, they have
had time to learn ways to get around
the host defence shields and become
smarter. Consequently, this new level
of sophistication can allow these
viruses to jump the species barrier
Dr Barr with Ms Ermela Paparisto, the
first author of the 2018 study and a
PhD student in Dr Barr’s laboratory.
to establish new infections in humans,
a process called zoonosis. An interesting
comparison would be to infect monkey
cells with the viruses to see whether
the observations from human cells
are also seen in another species.
DEVELOPMENT
OF NOVEL THERAPIES
Dr Barr’s work investigating the arms race
between genes and viruses has provided
new insights into how both the immune
system and viruses have evolved. The
work by the Barr lab has highlighted
that the HERC family are likely to have
an important role in intrinsic immunity.
Dr Barr’s ultimate goal is to discover
more about the mechanisms which
viruses use to inactivate HERCs and other
similar antiviral proteins. In doing so,
he provides a window of opportunity by
which this knowledge can be exploited
for the development of novel antiviral
drugs. If these mechanisms can be
specifically targeted, antiviral genes
such as HERCs will remain active during
infection and will increase viral clearance
and therefore improve the outcome
for the patient.
Behind the Research
Dr Stephen Barr
E: stephen.barr@uwo.ca T: +1 519 661 3438 W: http://publish.uwo.ca/~sbarr9/
www.youtube.com/watch?list=PLA0E847DD01B0FA01&v=3PcfQhaQNK8
Research Objectives
Dr Stephen Barr’s work aims to illuminate the evolution of
the HIV virus and the family of HERC genes that inhibit HIV.
Detail
Western University
Schulich School of Medicine & Dentistry
Department of Microbiology & Immunology
Dental Sciences Building Room 3007
London, Ontario
N6A 5C1
Canada
Bio
Dr Barr obtained his PhD in Molecular Biology from the
University of Calgary under the supervision of Dr Lashitew
Gedamu, studying a family of antioxidant proteins called
Peroxiredoxins and how they protected cells from infection
by Leishmania. He then studied various aspects of HIV
biology as a Postdoctoral Fellow with Dr Rick Bushman at
the University of Pennsylvania. He continued his Fellowship
with Dr James Smiley at the University of Alberta where he
studied the host interferon response towards HIV. In 2008,
Dr Barr became an independent investigator where his
laboratory continues to study the host interferon response
towards viruses such as HIV and Ebola virus.
Funding
• Natural Sciences and Engineering Research Council
of Canada (NSERC)
• Canadian Institutes of Health Research (CIHR)
• CWRU/UH Center for AIDS Research (CFAR)
• National Institute of Allergy and Infectious Diseases
(NIAID)
Collaborators
• Dr Eric Arts
• Dr Yong Gao
@BarrLab
References
Paparisto E, Woods MW, Coleman MD, Moghadasi SA,
Kochar DS, Tom SK, Kohio HP, Gibson RM, Rohringer TJ,
Hunt NR, Di Gravio EJ, Zhang JY, Tian M, Gao Y, Arts EJ,
Barr SD. (2018). Evolution-guided structural and functional
analyses of the HERC family reveal an ancient marine origin
and determinants of antiviral activity. J Virol, 92:e00528-18.
Available at: https://doi.org/10.1128/JVI.00528-18 [Accessed
6 February 2019].
Woods MW, Tong JG, Tom SK, Szabo PA, Cavanagh C,
Dikeakos JD, Haeryfar SMM, Barr SD. (2014). Interferon-
induced HERC5 is evolving under positive selection and
inhibits HIV-1 particle production by a novel mechanism
targeting Rev/RRE-dependent RNA nuclear export.
Retrovirology 11:27. Available at: http://www.retrovirology.
com/content/11/1/27 [Accessed 6 February 2019].
Woods MW, Kelly JN, Hattlmann CJ, Tong JGK, Xu LS,
Coleman MD, Quest GR, Smiley JR, Barr SD. (2011).
Human HERC5 restricts an early stage of HIV-1 assembly
by a mechanism correlating with the ISGylation of Gag.
Retrovirology 8:95. Available at: http://www.retrovirology.com/
content/8/1/95 [Accessed 6 February 2019].
Personal Response
How do you plan to further develop your understanding
of the antiviral effects of the HERC proteins?
We are currently comparing the antiviral activities of
evolutionarily diverse HERC proteins towards HIV and other
viruses such as Ebola virus to better understand how broad
the antiviral activity of HERCs are, and to discover how
viruses evade these HERC proteins for survival. We also
hope to test these effects in animal models that are more
biologically relevant to the human immune system.
www.researchoutreach.org 125
Thought Leader
Iridescent:
Disrupting the classroom for the better
The education system has struggled to keep up with the constant evolution of technology. Iridescent, a global non-
profit organisation, is revolutionising education by providing programmes that empower underserved children through
technology and engineering. With a special focus on underrepresented young girls, Iridescent challenges the negative
myths surrounding AI and uses technology to inspire children to become innovators. Research Outreach spoke with founder
and CEO Tara Chklovski of global non-profit Iridescent, discussing how Iridescent’s goals have become a reality.
I
t is crucial that children have the
technological knowledge and
understanding to succeed in today’s
digital world. Unfortunately, many
education systems are insufficient in
preparing children for the workforce,
especially those from underprivileged
upbringings. Iridescent has identified
the necessity to incorporate STEM
education, technology and AI into
children’s lives at an early stage
through cutting-edge programmes and
technology. Through these methods,
Iridescent hopes to inspire the next
generation to become innovators.
Iridescent has experienced incredible
growth since its inception in 2006; the
non-profit now has a global reach.
Iridescent’s success is attributable to
its clear strategy, its collaboration with
industry experts and its ability to stay
abreast of technological evolution.
126 www.researchoutreach.org
Hi Tara! Can you tell us more about
Iridescent in terms of its background,
history and core mission?
Iridescent is a global non-profit
organisation that provides cutting-
edge STEM education to underserved
children, and their families through two
programmes; Technovation and Curiosity
Machine. We use technology-based
and engineering-based programmes
to achieve the aim of empowering the
world’s underrepresented young people
(especially girls) to become innovators
and leaders.
Our organisation was founded in 2006
from a desire to help the education
system, a system that is often slower to
evolve in the rapidly changing technology
industry. Since Iridescent’s founding, the
non-profit has grown tremendously; we
now operate in more than 115 countries
and deliver STEM curriculum to more
A group of mothers and daughters work together
than 100,000 children and their families
worldwide. Iridescent is proud to be
the first organisation to assist young
girls in underserved communities learn
coding and app development skills
through our Technovation Challenge.
The Technovation Challenge programme
introduces the girls to technological
concepts in an engaging way. We recently
introduced the Artificial Intelligence (AI)
Family Challenge as a new part of our
popular Curiosity Machine programme.
Tell us about your journey into Artificial
Intelligence? What led you to launch
an AI-focused programme?
For 12 years, we have been introducing
children worldwide to cool new
technologies and scientific advances
including nanotechnology, mobile
computing and robotics. We are attuned
to technological trends as well as being
skilled at identifying new skillsets which
on a robotic arm at a Phoenix area school.
children, and their parents, will need
in order to compete and succeed
in today’s evolving workforce. The
renowned fear surrounding Artificial
Intelligence (AI) made AI a natural next
step for our programmes and curriculum.
AI is rapidly changing our world and the
Our two primary programmes, Technovation and Curiosity
Machine, introduce underserved communities to cutting-
edge technologies.
nature of people’s work. The primary
and secondary education systems
are not equipped with the knowledge,
information or resources to respond
quickly enough to prepare children,
or even adults, for the workforce. It is
this problem that Iridescent is working
to solve.
We established the AI Family Challenge
with the goal to empower and equip
children from underserved communities
with the necessary knowledge to play
Left: A father and daughter in New Orleans build circuits as a part of their self-driving car game,
learning basic artificial intelligence concepts.
Right: Children in Somalia get familiar with materials they’ll use as a part of Iridescent’s AI
Family Challenge.
a key role in innovation. Our goal
is to show children that this field is
accessible and that they can play a
pivotal role in the industry from the
onset. Another of our aims is to show
these children that the innovation field
is a viable and fulfilling career path.
What was Iridescent’s impact in 2017
and goals for this year? Is Iridescent
on the right track to completing the
goals set in the 2015-2019 strategic
plan and Theory of Change?
In 2017 alone we reached five of the
six goals outlined in our 2015-2019
strategic plan. Notably, we increased
participant reach nearly 40% to 35,000
annual programme participants, and
we partnered with 7,000+ organisations
worldwide. We were very proud of
effectively scaling for participant and
partner growth whilst simultaneously
decreasing our average costs to $10/
contact hour.
Our organisational growth and increased
global reach in 2017 demonstrate that
families, community partners, and
corporate funders continue to turn
to Iridescent as both a provider and
partner. Stakeholders such as these
trust Iridescent in delivering high-
quality STEM education programmes
that not only teach but also excite
underserved youth.
In 2018 we are making greater strides
towards our 2015-2019 strategic plan.
We are taking steps that will help us
measure, as well as share, the impact
of our programmes on participants,
mentors, partners, and educators
more effectively. Furthermore, we have
committed to increasing our transparency
in our impact reporting.
Our proudest achievement in 2018
was the launch of the AI Family Challenge.
The programme received a wonderful
response from families, educators,
professionals, and funders.
Can you tell us more about the two
programmes Curiosity Machine and
Technovation? What impact have they
had so far?
Our two primary programmes,
Technovation and Curiosity Machine,
introduce underserved communities
to cutting-edge technologies. Through
our detailed, yet accessible curriculum,
we equip and empower kids, their
families, and those mentoring or coaching
them to apply the knowledge they have
learned to solve real-world problems.
This year we launched our a new
initiative, the AI Family Challenge. The
curriculum teaches children ages 8-15,
and their parents about AI technologies.
Families are guided through the process
www.researchoutreach.org 127

A mentor works with Technovation students at
the annual Technovation World Pitch, where girls
from around the world pitch apps they develop
to solve community problems.
of creating an AI-based product that
solves problems that face society
including transportation, health,
the environment and education.
Engineering and AI-knowledgeable
mentors support participating families.
These mentors are rigorously trained
to ensure participants have a positive
experience that is both informative
and engaging.
Technovation Challenge encourages
entrepreneurship in girls (aged 13-18)
Our aim is to ensure that we consistently deliver interesting
and relevant information that is both educational and engaging.
by challenging them to identify a
problem in their community. The girls
are then tasked with developing a
mobile app and a start-up business that
solves the identified problem. The girls
collaborate with mentors to learn
the skills necessary to bring their idea
to life.
Our cutting-edge curricula, teaching
strategies, lesson plans, and mentor
training materials for both programmes
are freely available to educators, parents
and mentors worldwide.
What has your research shown
on how have these programmes
failed and succeeded?
We have found that gathering
128 www.researchoutreach.org
and evaluating insights from our
programme participants, mentors and
educators are critical to understanding
our programmes’ effectiveness. The
evaluation process has also helped
us to identify ways to improve and
enhance our programmes. We
have learned many things across
our programmes, most notably
we’ve discovered:
• Children report having a better
understanding of science and
engineering (74.8%) and are more
interested in science at school (74.8%);
• Parents report having a better
understanding of science and
engineering (77.8%) and that they will
read more science books with their
children (88.9%); and
• College-level student instructors
reported learning practical skills like
critical thinking, creativity, public
speaking, and collaboration.
We are excited about the impact our
programmes have on our audiences.
We are committed to applying a data-
driven approach to continually improve
our operations. Our aim is to ensure
that we consistently deliver interesting
and relevant information that is both
educational and engaging.
Iridescent has some very well-known
supporters and partners – why are they
so important to Iridescent’s success?
We are incredibly fortunate to have
a wide variety of partners who are
as passionate about our mission to
bring STEM education to underserved
children and families through Iridescent.
While our corporate partnerships take
many forms, we have found some of
the best relationships are designed
around skills-based volunteering
opportunities. Through these types of
partnerships, corporations encourage
tech-savvy employees to share their
knowledge by educating youth about
topics ranging from self-driving cars,
to robotics and biomechanics. These
mentors play a crucial role in helping
families learn about complex technology
concepts in engaging and accessible
ways. We’ve also found that this method
of volunteering is a powerful tool
to help engineering companies retain
employees, particularly women.
What are the major challenges in
making AI more accessible to local
communities? How do you overcome
these challenges?
There are multiple factors that impact
people’s acceptance of AI. People’s
perceptions differ and views can range
Families in Ethiopia gather to learn about artificial
intelligence through Iridescent’s AI Family Challenge.
from confusion about what AI is, how AI
can fit into our daily lives and how AI will
disrupt the workforce. There is fear that
AI will take away many jobs, especially
in underserved communities. We often
talk to parents who are concerned about
how they can provide their children with
the necessary tools and skills to succeed
in today’s digital world.
For underserved families, in particular,
there is often limited access to STEM
education beyond what they find in the
classroom. In fact, according to a recent
study we commissioned, only 36% of
children receive technology education
outside of their schooling. We want
to help children and their parents feel
confident and optimistic about their
family’s future in a world filled with
new technologies. We aim to build their
confidence by giving families a hands-
on experience with AI to demystify
the technology and remove the negative
perceptions around it.
How can scientists and engineers
get involved with your programs
and outreach?
There are many ways scientists
and engineers can involve themselves
in our programmes either individually,
or through their employer. We regularly
work with technology professionals
to invent challenges for students based
on the professional’s line of work. This
could include anything from driverless cars
to robotics.
Another method we use is encouraging
professionals to share their story via video
Thought Leader
such as teaching families about a topic many other industries in multiple ways.
within their area of expertise or to inspire We are curious about how Virtual Reality
children and families to tackle challenges combined with AI will result in unique
within our programs. learning journeys for students. Iridescent
has the potential to completely disrupt
Professionals can also make a difference learning as we know it.
by acting as mentors, either online or
within the community. Mentors often In five years, I hope Iridescent will be the
express to us that their mentoring not only leader in AI-education for both children
changes a child’s life but also can have and parents. Iridescent will continue
a transformative effect on their own life. to introduce collaborative platforms to
For example, the experience can teach families worldwide. Through our platform,
the mentor how to communicate complex families can create disruptive products
concepts more effectively whilst working while embarking on exciting learning
in their own professional capacity. journeys in technology.
Iridescent is a 501(c)3 registered non- To find out more about Iridescent’s
profit organisation, and you clearly value mission and their programmes to help
transparency by openly publishing your young people develop, please visit their
financial documents on your website – website at http://iridescentlearning.org.
has this received a positive reaction?
We believe transparency is very important
and we consistently receive positive
reactions across all our stakeholders
for our openness. In fact, for 2018,
we changed our reporting policies so that
we are now analysing and sharing our
key learnings and programmes impact
data on a quarterly basis.
What does the future hold for
Iridescent? Where do you see Iridescent
in the next five years?
We are always evaluating new technology
trends and identifying ways to connect
underserved families with industry experts
who are changing the ways we live, work For more information about
and play. One of the fields we observe Iridescent and its programs, contact
very closely is the world of gaming. info@iridescentlearning.org
The gaming world is usually ahead of
www.researchoutreach.org 129
COMMUNICATION

Accidental Science!
Many of the world’s most incredible discoveries came about by someone finding something they weren’t actually looking
for. Not quite true accidents - each finding was made by a discerning individual following through on their observations,
turning the unexpected into something useful. But chance certainly helped to play a role. Let’s take a look at some
examples of these serendipitous innovations.

I
n 1879, the artificial sweetener
saccharin was discovered by a Russian
chemist who forgot to wash his hands.
Constantin Fahlberg of Johns Hopkins
University was trying to discover new uses
for coal tar. After a long day in the lab,
Fahlberg sat down to eat his sandwiches.
Forgetting to wash his hands he noticed
that they tasted incredibly sweet. Heading
back to the lab, he (bravely) tasted some
of the chemicals he’d been working with.
The results of an experiment combining
o-sulfobenzoic acid with phosphorus
chloride and ammonia produced the
sweet substance. Naming it saccharin,
he patented it five years later, and
mass production began. Around 400
times sweeter than sugar, the artificial
years later when Silver’s colleague, Arthur
Fry, used it as a way of holding bookmarks
to his hymn book while singing in his
church choir. Partnering with Silver, the
pair developed the product. Launched
in 1980, it was an immediate success.
Today, more than 50 billion Post-it Note
products are sold every year.  Percy Spencer was experimenting with
CHANGING MEDICINE FOREVER
Arguably the most famous accidental
finding of all, Sir Alexander Fleming’s
discovery of penicillin changed medicine
forever. Experimenting with the influenza
virus in 1928, Fleming left his laboratory
at St Mary’s Hospital London for a two-
week vacation. He returned to find that
a mould had developed on an accidentally
Howard Florey and Ernst Boris Chain
were jointly awarded the Nobel Prize for
medicine in 1945 for the development
of penicillin.
MAGNIFICENT MAGNETRON
In 1945, Raytheon Corporation engineer
a new vacuum tube called a magnetron.
During his experiments, he discovered
that the chocolate bar in his pocket was
melting. Intrigued, Spencer investigated
further - aiming the magnetron at other
items including popcorn kernels. When
they began to pop, he immediately
clocked its potential. He concluded that
the heat generated was due to microwave
energy and the microwave oven was born.

In 1879, the artificial sweetener saccharin Of course, none of these ‘accidents’ would

was discovered by a Russian chemist who

forgot to wash his hands.
sweetener became widespread when
sugar was rationed during World War I.
Research later showed that the body can’t
metabolise saccharin. The ultimate low-
calorie sweetener, today it’s also a popular
sugar substitute for diabetics.
THE MIGHTY POST-IT NOTE
The wonder that is the handy sticky note
exists because 3M research engineer,
Dr Spencer Silver, failed to make a
strong, tough adhesive. What he actually
discovered were sticky microspheres –
strong enough to hold papers together,
but weak enough to peel apart easily.
Recounting his finding, Silver said: ‘At
that time we wanted to develop bigger,
stronger, tougher adhesives. This was
none of those.’ No application for this
light adhesive was apparent until several
have been the world-changing discoveries
they are without the right person there
to recognise their value. But what they
do show is that innovations can be born
contaminated Staphylococcus bacterial out of the unexpected.
culture plate. On closer inspection, he
noticed that the mould prevented the Rachel Perrin, PhD, is a science
growth of the Staphylococcus. The communication writer based in Bristol, UK.
result? The discovery of the first naturally
occurring antibiotic. Severe and life-
threatening illnesses like meningitis
and pneumonia became treatable.
Fleming later said: ’One
sometimes finds what
one is not looking
for. When I woke
up just after dawn
on Sept. 28, 1928,
CROWDFUNDING FOR GIRLS’ & WOMEN’S EMPOWERMENT
I certainly didn’t plan
to revolutionise all medicine
by discovering the world’s first
antibiotic, or bacteria killer.
But I guess that was exactly
what I did.’ Alexander Fleming,

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