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CONTENTS
06 NEW HOPE FOR MUSCULAR
DYSTROPHY TREATMENT
Dr Ahlke Heydemann
Developing new and more
effective treatments based
on existing drug FTY720.

10 EXTENDING THE HALF‑LIFE

OF THERAPEUTIC PEPTIDES
Dr Mamoun Alhamadsheh
Developing new treatments
for diseases caused by protein
aggregation, including
Alzheimer’s disease

14 ECCO: IMPROVING

42
OUTCOMES FOR ALL
CANCER PATIENTS IN
EUROPE THROUGH

38
MULTIDISCIPLINARITY
Birgit Beger
Connecting the European
cancer community by
leveraging knowledge.

18 COMPUTATIONAL METHODS 30 HELPING PATIENTS PUT 42 A SHINING LIGHT IN THE

OF RESEARCHING CANCER
TREATMENTS
Dr Benjamin Haibe-Kains
Developing machine learning
tools and databases to help
understand cancer.
22 SWIMMING AGAINST THE
STREAM: MODERN-DAY
CHALLENGES TO MALE
REPRODUCTIVE HEALTH
Dr Bernard Robaire
Exposing the impact of
age, health and exposure to
chemicals on male fertility.
26 A CAREER IN CANCER
Dr Bruce Zetter
Seeking treatments for highly
aggressive, metastatic cancers
and mentoring students.
THEIR BEST FOOT FORWARD
Dr Gillian Hawker
Developing standardised
patient assessment criteria for
knee surgery.
34 LET’S HEAR IT FOR THE
PROTEOME
Dr Jeffrey Savas
Understanding the effects of
loud noise upon the molecular
workings of the inner ear.
38 UNRAVELLING THE
CELLULAR MECHANISM
OF SPINAL MUSCULAR
ATROPHY: FROM GENE AND
MODIFIERS TO THERAPY
Dr Brunhilde Wirth
Using advanced genetics
to better understand spinal
muscular atrophy.
FIGHT AGAINST CHILDHOOD
LEUKAEMIA?
Dr C. James Lim
Unravelling the mechanisms
of acquired chemotherapy
resistance in childhood cancer.
46 FLUOXETINE (PROZAC) USE
IN CHILDREN: WORKING
TOWARDS A CUSTOMISED
APPROACH
Dr Mari Golub
Looking at the behavioural
effects of fluoxetine (Prozac) on
brain development.
50 HIGH PRESSURE TALK WITH
PROFESSOR RHIAN TOUYZ
Professor Rhian Touyz
Discovering mechanisms of
cardiovascular disease at the
Institute of Cardiovascular and
Medical Science.
50
54 HOW TO PROMOTE GENDER
EQUITY IN THE GREEN
ECONOMY
Dr Bipasha Baruah
Examining the reasons for
inequality in the emerging green
economy.
58 GLOBALISATION THROUGH
A POST-COLONIALIST LENS:
UNDERSTANDING OUR PAST
IS KEY TO OUR PRESENT
Professor Diana Brydon
We must learn from the past in
order to ask better questions in
the future.
62 A FASCINATION WITH
VIOLENCE: APPETITIVE
66
66 EMERGING FORMS
OF METROPOLITAN
GOVERNANCE IN LATIN
AMERICA
Dr Raul Acosta Garcia
Investigating the efforts
of grassroots activists in
Guadalajara, Mexico
70 A SUSTAINABLE APPROACH
TO ENVIRONMENTAL
MANAGEMENT
Dr Meghann Jarchow
Varied factors affect the current
functioning and management of
the Upper Missouri River.
74 FROM BEER TO BRAINS
HOW YEAST MOLECULAR
78
78 INTO THE DEEP
UNDERSTANDING
SWORDFISH ECO-
PHYSIOLOGY
Dr Diego Bernal
Explaining how swordfish can
move from warm to cool water
without negative effects.
82 OPEN-SOURCE
BIOINFORMATIC SOLUTIONS
FOR ‘BIG DATA’ ANALYSIS
Drs Tim Griffin and Pratik
Jagtap
Developing workflows on an
open source platform for the
analysis of multi-omic data.
86 COMMUNICATION

I am proud of the trans-national,

AGGRESSION IN MALES AND GENETICS PROVE THE The changing perception of
FEMALES IMPORTANCE OF INTRONS climate change.

transgenerational,
Dr Danie Meyer-Parlapanis & Dr Tracy Johnson
Dr Mareike Augsburger Investigating the way in which

trans-disciplinary research
Studying the effects of violence- cells synthesise, splice, and
related trauma on appetitive process RNA.

team building I have been involved in.

aggression.

PROFESSOR DIANA BRYDON RESEARCH AREAS

Page 58
Health & Medicine Behavioural Sciences Biology

www.researchoutreach.org 5
Health & Medicine ︱ Dr Ahlke Heydemann
Sarcoglycans

New hope for muscular α β

α
Dystroglycans

dystrophy treatment
Sarcolemma

δ γ β

Muscular dystrophy (MD) is
a family of genetic diseases
which cause muscular weakness.
Their severity varies but all
are progressive and many are
ultimately terminal. Until now,
therapy options have been
purely palliative, treating only
the symptoms of MD. Dr Ahlke
Heydemann of the University of
Illinois at Chicago is developing
new and more effective
treatments. Her current work
focuses on a drug – FTY720 –
which has shown great potential
in animal models and is already
licensed for use in the treatment
of other human diseases.
A
ffecting just over one in a
thousand people, muscular
dystrophy (MD) is the most
widespread lethal genetic disease of
humans. Causing muscle weakness and
wasting, sufferers become increasingly
disabled as the disease progresses. If the
heart or respiratory system is affected,
the condition may be terminal. There
are about 60 different forms of muscular
dystrophy, ranging from the most common
Duchenne MD, which often causes death
by the age of thirty, to rarer, more slowly-
progressing or later-onset forms.
All types of MD are caused by mutations
in genes implicated in muscle structure
and function. For instance, Duchenne
MD is caused by a mutation in the gene Dystrophin
encoding the protein dystrophin, which
helps hold muscle cells together, giving nNOS
them strength. Errors in such genes
result in muscle weakness, damage and
inflammation, although the severity
and speed of disease progression can Actin
vary considerably between different
mutations.
Dystrophin is actually part of a complex
of molecules situated in the membrane
encircling muscle cells. Other members
of the complex include proteins
called sarcoglycans, and mutations in
Figure 1. The dystrophin glycoprotein complex at the muscle cell membrane – also known as the sarcolemma. Many muscular dystrophy causing mutations
sarcoglycan genes cause another type of
occur in the proteins depicted here. In this article mutations in dystrophin and γ-sarcoglycan are discussed. When mutations occur in these two proteins
MD, limb-girdle MD, which begins in the disease progression is similar. This disease progression is diagramed in Figure 2. Redrawn from Roberts et al, Biochemical and Functional comparisons of mdx
muscles of the shoulder and pelvis. and Sgcg (-/-) muscular dystrophy mouse models. Biomed Res Int 2015; 1314362.

DYING FOR A TREATMENT
One thing all forms of MD have in
common is a lack of effective treatment.
Current therapies, often reliant upon
steroids, can lessen the symptoms but
are unable to slow disease progression.
They also come with many unwanted
side effects. Dr Heydemann is one of a
number of researchers looking at new
methods of treating the causes of MD.
One promising
inflammation in the debilitating
autoimmune disease, multiple sclerosis
(MS). Fingolimod – which is marketed
under the trade name Gilenya – appears
to interact with membrane-bound
receptors called the sphingosine-
1-phosphate receptors, which are
involved in many crucial biological
processes, including immune responses.
Fingolimod binds to the receptors by
mimicking its substrate, sphingosine-
– and has already found significant
effects upon disease progression in
three different types of muscle: skeletal
muscle, which controls limb movements;
heart muscle; and the diaphragm, which
facilitates breathing.
A MULTI-FUNCTIONAL MOLECULE
Dr Heydemann has documented that
fingolimod has at least three separate
mechanisms of action against MD.
Firstly, it initiates

One thing all forms of MD have in

avenue lies in
reinforcing the
muscle cell
membrane in
common is a lack of effective treatment
the absence of
dystrophin or one of the sarcoglycans.
“If we can restore as little as twenty
percent of the function of dystrophin,
for instance, others have seen real
functional benefits for patients,” says Dr
Heydemann.
Her current work focuses on a drug
called FTY720 or ‘fingolimod’, already
licensed for treatment of chronic
1-phosphate. In doing so, it triggers a
reduction in the permeability of the cell
membrane and strengthens it against
damage.
Dr Heydemann is testing fingolimod
in genetically engineered strains of
laboratory mice bred to have and exhibit
the symptoms of limb-girdle MD type
2C – a fully lethal disease in humans
molecular changes
which support
the membrane
surrounding
muscle cells. This
strengthens the muscles. Secondly, as
in MS, fingolimod reduces the chronic
inflammation caused by infiltration of the
body’s own immune response. Thirdly, it
prevents fibrosis, a build-up of inflexible
connective tissue which impedes muscle
function by preventing the tissue from
contracting. Crucially, fibrosis also
hinders muscle relaxation, which is vital
for the correct functioning of muscles,

6 www.researchoutreach.org www.researchoutreach.org 7
including the heart and diaphragm.
Fibrosis also hinders damaged muscle
tissue from regenerating, and impedes
the delivery of treatments to affected
muscles.
Dr Heydemann’s mouse studies have
shown that just a three-week treatment
with fingolimod dramatically inhibits
fibrosis in all three muscle types studied.
Ultimately, these changes produce
measurable and potentially life-
changing improvements in the function
of the heart and diaphragm. However,
treatment must be initiated early: it
does not yet appear possible to reverse
the changes caused by MD, but only to
prevent progression from occurring.
Fingolimod is a promising new option
for MD treatment: it has few side effects
and, being already approved in many
countries for MS treatment, it should
be possible to move quickly to the
stage of clinical trials. Furthermore,
the mechanisms by which it fights MD
are entirely separate from that of the
steroid drugs usually used to treat the
disease’s symptoms. This means that the
two therapies can be used together in a
coordinated approach to produce highly
beneficial outcomes for patients. In
fact, as Dr Heydemann puts it: “The real
advantage of the long list of therapies
that are now being developed for MD
is that patient-specific co-therapies can
be formulated.” These target multiple
points in the disease progression and
limit side effects by minimising the
dosage of any one treatment.
MORE QUESTIONS THAN ANSWERS
Dr Heydemann’s work into fingolimod
continues: so far it has raised almost
more questions than it has answered!
She now aims to fine-tune the dosage
and treatment regime to maximise
benefits in her MD mice, as well as
investigating any other potential
benefits it might have beyond reducing
fibrosis and strengthening the muscle
membrane. Crucially, she intends to
There are many reasons to be optimistic
regarding the imminently available
therapies for muscular dystrophy
8 www.researchoutreach.org
Figure 2. Disease progression follows a well-documented path for dystrophin and γ-sarcoglycan
mutations, although faster in the dystrophin mutant mice and humans than in the γ-sarcoglycan
mutant mice and humans. Normal muscle progresses through the stages until non-remodelling
fibrotic scar tissue is formed within the muscles.
Normal, healthy muscle
Membrane damage,
immune infiltrate
DISEASE PROGRESSION
Degeneration/regeneration
Necrosis/apoptosis
Myocytes replaced
by fibroblasts
Fibrosis/scar
investigate exactly how fingolimod complex. She is also investigating
works, including the highly complex how fingolimod interacts with existing
cascade of cellular and molecular signals steroid treatments to produce further
that are brought to play downstream of improvements in patient health. And
the sphingosine-1-phosphate receptors. she is studying a new ‘super-healing’
strain of mouse in which MD symptoms,
Intriguingly, initial studies have shown particularly fibrosis, are diminished.
that fingolimod can cause cells
to increase production of certain MD research is an exciting field to work
sarcoglycans, suggesting it may be able in, with so many potential treatments
to re-establish parts of the dystrophin coming to light that it is difficult to attract
enough patients to take part in clinical
trials for all of them. As Dr Heydemann
herself concludes: “There are many
good reasons … to be very optimistic
regarding the imminently available
therapies for muscular dystrophy.”
Behind the Bench
Dr Ahlke Heydemann
E: ahlkeh@uic.edu T: +1 312 355 0259
W: http://physiology.uic.edu/faculty/index.html?fac=ahlkeheydemann&cat=active
MORE INFO: musculardystrophyuk.org mdaeurope.org
Research Objectives
Dr Heydemann’s research focuses on
identifying new and more effective
treatments for Muscular Dystrophy. In
particular, she and her research team
have identified an immune inhibitor
that significantly decreases pathology
in mouse models of Muscular
Dystrophy.
Funding
National Institutes of Health (NIH)
National Institute of Arthritis and
Musculoskeletal and Skin Diseases
(NIAMS)
Q&A
How did you get involved in
muscular dystrophy research?
After my very basic science PhD, I was
determined to work on something
more clinically applicable. I had met
Dr McNally years earlier and found
her work highly intriguing and I could
easily see how her lab’s work would
benefit patients. After discussing a few
potential projects, we agreed upon
my doing a post-doc in her lab. The
passion to help the patients quickly
became instilled in me.
What is fibrosis and what is its
significance in muscular dystrophy?
Fibrosis is an internal scar. The scar
behaves differently in different
tissues and organs. In muscle, the
key detrimental facts regarding scars
are that: scars do not contract; scars
impede natural healing; scars do not
let therapies through to the diseased
cells; and in cardiac muscles scars
do not propagate the contraction
impulse. In healthy damaged muscles,
Collaborators
Dr Maria Siemionow, professor in
UIC’s Department of Orthopaedic
surgery. Together Drs Heydemann and
Siemionow are analysing genetically
corrected muscle stem cell transplants
into mdx mice.
Bio
Dr Heydemann received her
undergraduate degree from the
University of Maryland and her PhD
from the University of Chicago. She
later went on to work as a post-doc
with Elizabeth M McNally at the
scars remodel, break down, and the
muscle heals itself. Muscles in a muscular
dystrophy patient lose this ability to
remodel and heal themselves.
Why would a drug used to treat
multiple sclerosis also be beneficial in
the treatment of muscular dystrophy?
After the initial muscle damage caused
by muscular dystrophy, the immune
system enters the muscles to clean up the
dead tissue debris. After repeated cycles
of cleaning up debris the immune system
actually creates more muscle damage.
This chronic inflammation is pathogenic.
In multiple sclerosis FTY720 helps the
patients by keeping the immune cells
away from the damaged tissues. We
initially tested if FTY720 would do the
same – reduce chronic inflammation – for
the MD mice. We found that FTY720 did
this and, thankfully, so much more.
I feel once these last hurdles are surpassed
a large number of young muscular
dystrophy patients can begin to have
healthier longer lives
University of Chicago until 2011, when
she became an Assistant Professor at
the University of Illinois at Chicago.
Contact
Ahlke Heydemann, PhD
Associate Professor
University of Illinois, Chicago
COMRB 2035, MC 901
835 South Wolcott Ave.
Chicago, IL 60612-7352
USA
How important are animal models in
your research?
Animal models, in particular the
mouse model, are critically important
for the MD research community. The
tremendous advances we are currently
making are only possible because of
the mouse models of the diseases.
What do your results mean for
sufferers of muscular dystrophy?
FTY720 will require additional
preclinical testing. We still have to
establish the optimum dose and
delivery timings for mice and then
extrapolate that to the patients. Luckily,
we can utilise the known safe dose
from the multiple sclerosis patients to
inform our decision. I feel once these
last hurdles are surpassed a large
number of young muscular dystrophy
patients can begin to have healthier
longer lives.
www.researchoutreach.org 9
Health & Medicine ︱ Dr Mamoun Alhamadsheh

Extending the half‑life

of therapeutic peptides
Dr Mamoun Alhamadsheh is Associate Professor at
the University of the Pacific, Thomas J. Long School of
Pharmacy and Health Sciences, California. He heads a
multi-disciplinary team working in the field of protein-
protein interactions. Their research is focused on the
development of new treatments for diseases caused
by protein aggregation, including Alzheimer’s disease
and transthyretin amyloidosis. Their current work in
peptide conjugation is showing great promise. After
publishing their work in the prestigious journals PNAS
and Nature Chemical Biology, the team are now about
to embark on exciting new clinical trials to evaluate
the efficacy of a new therapy for a form of heart
disease caused by transthyretin amyloidosis.
A
myloidosis is a group of rare but serious conditions
caused when deposits of damaged proteins known as
amyloid fibrils, accumulate around tissues and organs.
Over time these accumulations interrupt the normal function of
the organ and in advanced cases can cause organ failure.
Cardiac amyloidosis, which is commonly caused by
aggregation of immunoglobulin light chain (AL) or
transthyretin (TTR), is a main contributor of morbidity and
mortality in patients with amyloidosis. TTR amyloidosis (ATTR)
is a progressive, fatal disease in which deposition of amyloid
derived from either mutant or wild-type TTR causes severe Above: The AG10 analogue-peptide conjugate can bind reversibly to the thyroxine binding sites
organ damage and dysfunction. Clinically, ATTR presents of endogenous human TTR (shown as ribbon diagram with transparent surface). This will increase
as: (i) a cardiomyopathy (ATTR-CM) which is an infiltrative,
the in vivo half-life of peptides by protecting against proteases and by decreasing glomerular
filtration. Importantly, due to its reversible binding to TTR, the binding affinity of the peptide
restrictive cardiomyopathy characterised by progressive conjugate to its target receptor would not be adversely affected.

This ability to extend the life of peptides

will have future applications in the
imaging and treatment of tumours
left and right heart failure, or (ii) a
peripheral polyneuropathy (ATTR-PN),
a neurodegenerative disease affecting
sensorimotor and autonomic functions.
TTR is a transport protein secreted by
the liver. It is found in the serum and
the cerebrospinal fluid and named after
its function in transporting thyroxine
and retinol (vitamin A). TTR is coded
for by the TTR gene, and a faulty copy
of this gene can lead to misfolding of
the TTR protein. This structural change
leads to the protein aggregation and
the creation of the amyloid fibrils. The
build-up of these TTR amyloid fibrils
in the heart leads to ATTR-CM. There
is currently no cure for ATTR-CM.
Alhamadsheh’s team (in collaboration
with Stanford University) developed
a small molecule, called AG10, that
stabilises TTR against amyloidoisis.
AG10 is currently being developed by
as a therapeutic agent for ATTR-CM.
THERAPEUTIC PEPTIDES
Peptides are essential for carrying out
vital biological functions. A peptide
is smaller than a protein – peptides
are made of up to 50 amino acids
(over 50 amino acids gives you a
protein). It has long been known that
peptides (e.g. insulin) have great
utility in therapeutics. Some of their
advantages include binding with high
selectivity – making them effective
and reliable. Many peptides are made
inside the body, so the immune system
does not attack them and there is little
chance of rejection. They are easy to
synthesise in the lab and, compared to
large proteins, are capable of crossing
the cell membrane, meaning they can
deliver treatments straight into the cell.
One of the downfalls of peptides is
that they have a poor pharmacokinetic
profile – that means that do not
circulate in the body for a long time.
The half-life of a peptide is usually
Above: TTR acts as a “Rock” that protects
the peptide “Paper” from degradation by the
protease “Scissors”.
between two and 30 minutes, after
which they are quickly filtered out
by the kidneys. This means that any
treatment they carry only has a very
short time to reach the part of the body
where it is required. To compensate for
this short window of activity, peptide
treatments are often administered
in high and frequent doses. This
obviously has an impact on the patient
experience and increases the cost of
treatment.
A NOVEL APPROACH TO INCREASE
THE THERAPEUTIC POTENTIAL
OF PEPTIDES
The in vivo half-life of holo-RBP (a
protein that carries vitamin A in the
blood) is around three hours. However,
when holo-RBP is bound to TTR (our

10 www.researchoutreach.org www.researchoutreach.org 11

Dr Mamoun Alhamadsheh and his team at the University of the Pacific,
Thomas J. Long School of Pharmacy and Health Sciences, California.
transport protein that we discussed
previously), the in vivo half-life of holo-
RBP is increased threefold. Inspired
by this, Dr Alhamadsheh and his
team have focused their efforts on an
analogue of the TTR binder described
above, AG10. The team repurposed
this AG10 analogue and conjugated
it to a number of peptides, which
allows the peptides to be carried by
TTR in blood. The binding to TTR is
what provides potent and reliable
stability for the peptides against
degradation and clearance by the
kidneys. By improving the half-life of
these peptides, the effectiveness and
its ability to be active in the body is also
improved. By optimising the harnessing
and protection provided by TTR for
these peptide conjugates, the team
aim to enhance the pharmacokinetic
properties of therapeutic peptides.
As this technique involves a simple
conjugation reaction, it is reliable,
12 www.researchoutreach.org
The team aim to have a safe, effective
treatment available to TTR cardiomyopathy
patients in the near future
predictable, and reversible. There is
hope that this ability to extend the life
of peptides will have future applications
as therapy for metabolic diseases and
as well as in the imaging and treatment
of tumours. The team envision that their
findings will be able to help extend
the in vivo half-life of other molecules
including proteins, oligonucleotides,
oligosaccharides and liposomes,
and will also have applications in the
development and delivery of imaging
agents and other small molecule drugs.
THE FUTURE
AG10 is more effective in stabilising TTR
in human serum than other molecules
in clinical trials. AG10 passed a number
of toxicity studies in animals and can
Behind the Bench
Dr Alhamadsheh
E: malhamadsheh@PACIFIC.EDU T: + 1 209 946 3164 W: http://alhamadshehlab.org/
Research Objectives
Dr Alhamadsheh’s research combines
synthetic organic chemistry with
biochemistry and molecular biology to
study protein-protein interactions.
The team are particularly interested
in developing chemical tools and
therapeutic agents for protein
aggregation diseases such as
Alzheimer’s disease and Transthyretin
Amyloidosis.
Funding
National Institutes of Health (NIH)
Collaborators
• Dr Miki Park, University of the Pacific
Q&A
What have been the most significant
challenges you have faced in
conducting this research so far?
In addition to TTR, there are more
than 4,000 proteins in human serum.
Finding a molecule that has high
binding affinity and selectivity for TTR
be given orally. Clinical trials for this in serum was not an easy task. We
game-changing new molecule (AG10) started working on TTR in 2008 and we
has just started, focusing on patients were the first group to perform a high-
with cardiomyopathy (ATTR-CM) a throughput screening (we screened the
disease of the heart muscle. The trials binding of 120,000 molecules) for TTR
will be run by Dr Alhamadsheh’s new binders. The information and insights
company Eidos Therapeutics, which we gained from the best hits from the
was established in 2016, along with screen were used to develop AG10.
co-founder Dr Isabella Graef. By starting
a company that focuses purely on their Your new technique has tremendous
new-found molecule, the Eidos team therapeutic potential. Could you
aim to have a safe, effective treatment talk us through its advantages?
available to patients in the near future. Besides maintaining the potency of
Alhamadsheh’s team is also using their peptides, our strategy has several
newly developed technology to extend advantages over traditional half-
the in vivo half-life of a number of
peptides.
life extension approaches. (i) Our
approach involves a simple chemical
conjugation of peptides, and the
Dr Wabel Albusairi
• Dr William Chan, University of the
Pacific
Bio
Dr Alhamadsheh is Professor of
Pharmaceutical Chemistry at University
of the Pacific. He received his BS in
pharmacy from JUST in Jordan and
his PhD in organic chemistry from
University of Toledo. He completed
his postdoctoral studies in chemical
biology at Stanford University. He is co-
founder of Eidos Therapeutics.
Dr Wabel Albusairi is Assistant
Professor of Pharmaceutics at
Kuwait University. She received her
products are homogeneous and can
be easily characterised and purified.
(ii) Our peptide conjugates would be
stable products that do not require
refrigeration. This would decrease
the cost of production and storage of
peptide conjugates. (iii) Because of the
smaller size of our peptide conjugates,
we anticipate it to be able to penetrate
solid tumours efficiently and they also
would unlikely cause an immunogenic
response.
What other potential applications are
there for AG10?
Treatment for TTR polyneuropathy and
conjugating AG10 analogues to peptides
to increases the half-life of peptides.
We envision that our approach could
potentially be applicable for enhancing in
vivo half-life of proteins, oligonucleotides,
oligosaccharides, liposomes, imaging
Clinical trials for this game-changing new
molecule (AG10) has just started, focusing on
patients with cardiomyopathy
MPharm in pharmacy at the University
of Manchester, UK, and PhD in
drug targeting and delivery in Dr
Alhamdsheh’s lab at University of the
Pacific.
Contact
Mamoun Alhamadsheh, PhD
Associate Professor of Pharmaceutical
Chemistry
Thomas J. Long School of Pharmacy
and Health Sciences
3601 Pacific Avenue
Stockton, CA  95211
USA
agents and small molecule drugs. This
should broaden the scope and utility of
our approach.
Your research opens up new
possibilities for creating peptides
for many diseases and even imaging
and diagnostic agents. What are the
next steps for your research and for
developing peptide therapeutics
further?
Continue working on the half-life
extension technology. We are
interested in applying our technology
to improve the half-life and lower
toxicity of anticancer agents. This
would allow less frequent dosing
and better safety profiles for cancer
patients which would decrease
production cost and increase clinical
success rate.
www.researchoutreach.org 13
Thought Leader

ECCO: Improving outcomes for

all cancer patients in Europe
through multidisciplinarity
The European CanCer Organisation (ECCO) is a not-for-profit federation that exists to uphold the right of all European
cancer patients to the best possible treatment and care, promoting interaction between all organisations involved in cancer
at European level. ECCO aims to raise awareness and improve prevention, diagnosis, treatment and care of cancer patients.
CEO of ECCO Birgit Beger spoke with us at Research Outreach to discuss their work and more in greater detail.

A
ccording to the World Health
Organization, cancer causes 20%
of deaths in the European Region.
With more than 3 million new cases and
1.7 million deaths each year, cancer is
the most important cause of death and
morbidity in Europe after cardiovascular
diseases. But what about the lucky
survivors and the care and treatment they
need to recover? How can we ensure that
patients have access to the best possible
treatment and care? How can care for
cancer patients be improved across
Europe? These are the many questions
and key focuses for the European CanCer
Organisation (ECCO).
ECCO connects the European cancer
community by leveraging knowledge,
the organisation in a way that ensures the
fulfilment of its vision and core purpose.
What are ECCO’s core principles
in terms of history, heritage and
background, and which areas of cancer
research are you currently looking into?
ECCO was established in 1981 to unite all
healthcare professionals in oncology with
the aim to improve health outcomes for all
patients. Being a federation of European
Associations, ECCO needs to bridge
together different professional traditions
and cultures like those of surgeons,
radiologists, medical oncologists,
pathologists, pharmacists, researchers,
nurses, psychologists etc. ECCO is a
patient centric organisation that involves
a close and early collaboration with 15
Our research greatly reflects the debate
on quality cancer care. For selected
tumour types, ECCO has produced
‘Essential Requirements for Quality
Cancer Care’ (ERQCCs). These provide
oncology teams, patients, policymakers
and managers an overview of the
elements needed in any healthcare
system to provide high-quality care
throughout the patient journey.
How influential has ECCO been on
cancer research since it was first
established?
ECCO is contributing to cancer research
through several avenues. Firstly, ECCO
has organised scientific congresses for its
members. For example, ECCO organises
a joint symposium for the European
Thirdly, ECCO is a longstanding partner of
the Joint Research Centre, which provides
the European Union with scientific
knowledge when formulating policies and
legislation.
Lastly, ECCO also sets its own focus on
cancer research, by providing feedback
to the European Commission to its
consultation on the Advisory group report
for the Horizon 2020 Societal Challenge
on health, demographic change and
well-being.
From a more personal perspective,
are there any achievements you are
particularly proud of?
ECCO looks back to a heritage of
extensive engagement of its members
and a series of 18 very successful
congresses bringing science and research

ECCO’s vision is to improve outcomes for all cancer patients in
Europe through multidisciplinarity
promoting education and building
awareness. ECCO also plays an important
role in engaging with policymakers to
promote the interests of cancer patients,
research as well all other members of
the oncocommunity. We caught up with
ECCO’s CEO, Birgit Beger, who outlines
the role of the organisation, its influence
so far and, more importantly, the future of
cancer care.
Hey Birgit! Could you tell us what your
role involves as the CEO of ECCO?
Being CEO of ECCO is a very exciting
and enriching task where I learn every day.
As CEO, I implement the decisions of our
members and help to sustain and develop
forward and being a cornerstone in
scientific progress by representing inter
alia latest clinical trial data. Devising a
strategic renewal in 2013/2014, ECCO
has decided to put more focus on
oncopolicy, i.e., marrying science and the European Journal of Cancer have researchers, healthcare providers in
European patients’ organisation in all Organisation for Research and Treatment policy to help improve the outlook of on communicating cancer research oncology and the broader public on
ECCO’s activities. of Cancer (EORTC), the National oncology. between fellow researchers, and the burning topics in oncology. Our latest
Cancer Institute (NCI) and the American public? paper sets out that access to innovation is
ECCO’s vision is to improve outcomes Association for Cancer Research (AACR). In addition to this, we have set new The beauty of The European Journal of about more than pharmaceuticals alone. It
for all cancer patients in Europe through priorities for policy and advocacy, uniting Cancer is its true spirit of multidisciplinary challenges our own professions to identify
multidisciplinarity. There is no golden Secondly, ECCO is a founding member our members in fresh positions in respect enquiry and reflection. It ensures a real potential areas of inefficient or outdated
standard: recommendations can lead the of the Alliance of Biomedical Research to, not only quality cancer care, but also coming together of researchers in clinical practice and treatment. It also brings the
way to improve each health care system in Europe, which represents a unique access to innovation, integration of care, practice from a great variety of fields. use of real world data to the heart of the
by providing a toolbox for change. initiative of leading European medical as well as emerging oncology workforce access debate. These and more act as
societies that together include issues. Where there is a grand debate The abstracts of the ECCO Congress have an example of how ECCO would like to
Our core values are the following: more than 400,000 researchers and concerning the future of cancer care, always been part of the publications in bring about awareness and change into
• Patient Centricity  health professionals. In this context, ECCO intends to help its members to be the European Journal of Cancer (EJC). cancer research and beyond.
• Commitment to Science ECCO assisted in advocating for present, articulate, and advocate for the This allows fellow researchers to connect
• Cohesiveness  the establishment of the European interest of best quality patient care and in between the congresses and stay up-to In September next year, ECCO will
• Inclusiveness Commission’s Scientific Panel for Health outcomes. date with the latest research. be holding its 2018 European Cancer
• Equality and Fairness  (SPH). Summit in Vienna – What is the
• Openness and Transparency  What impact does ECCO’s link to ECCO tries to bridge the world of fellow significance of this and what influence

14 www.researchoutreach.org www.researchoutreach.org 15

do events like these have on installing
a community movement in cancer
research?
With ECCO’s strategic renewal, the format
of our congresses was redesigned. The
ECCO 2017 Congress in Amsterdam
in January 2017 showed the many
innovative concepts in bringing research,
science and policy closer together.
The ECCO 2018 European Cancer
Summit takes place in Vienna, Austria on
7–9th September 2018. It aims at taking
the congress to a higher level, namely to a
summit where worldwide leaders from the
cancer healthcare, patient advocacy and
stakeholder communities come together
in a unique multidisciplinary forum. The
idea is to complete the summit with the
agreement of consensus resolutions by
leaders in cancer policy, which will shape
oncopolicy in health care systems across
Europe.
To connect science with real life, outcome
research forms a decisive part, i.e., using
real-world data to observe how new
treatments and diagnostic modalities
have performed in cancer care delivery.
Health economics of cancer care is
another topic, which is highly connected
with outcome research and cannot be
surpassed in any oncology debate today.
Lastly, ECCO aims to focus on the patient
voice to determine an agreed vision
for guiding and supporting patients
through diagnosis, treatment and
follow-up in a world facing an ageing
population, increasing survivorship and
a technological revolution in e-health
resources.
Do you think cancer research receives
as much funding and attention as it
should?
From a European perspective, the
European Commission sees cancer
Our research greatly reflects the debate on quality cancer care:
what are the elements required to deliver high quality cancer
care for all patients in Europe?
research and cancer control still as an
important topic, though health policy
overall does not seem to be high on the
16 www.researchoutreach.org
Birgit Beger, ECCO CEO
priority list of the current Commission.
However, we are delighted that a new
EU ‘Joint Action’, following CanCon
and aiming to implement the CanCon
European Guide on Quality Improvement
in Comprehensive Cancer Control,
will start in 2018. The EU’s research
programme, Horizon 2020, has also set
aside substantive resources for cancer
research. This reflects the demographic
changes and the increase of cancer
incidences, but also the growing success
in treating cancer, which provides strong
motivation among politicians to invest
in cancer research. However, the more
research advances, the more it becomes
apparent how many gaps there are still
to close before science is anywhere
near mastering cancer. Though there is
the firm belief among researchers that
cancer will be curable, there needs to
be more research into the varieties of
cancer we discover. The perception and
understanding of cancer has become
much more differentiated and will have to
become even more so to help advance
with therapies delivering best health
outcomes.
Although your name has a European
focus in its title, do you extend your
research outreach to collaborate with
other countries internationally?
ECCO has longstanding relationships with
the American Society of Clinical Oncology
(ASCO) and with the Japan Society of
Clinical Oncology (JSCO) including via
joint sessions at each other’s congresses.
Established in 1999, ECCO has been co-
organising the Methods in Clinical Cancer
Research (MCCR) Workshop, which is an
educational programme that introduces
junior clinical oncologists in any oncology
subspecialty to the principles of good
clinical trial design. The workshop is the
product of co-operation between ECCO,
the American Association for Cancer
Research (AACR), European Organisation
for Research and Treatment of Cancer
(EORTC) and the European Society for
Medical Oncology (ESMO). The junior
clinical oncologists not only come from
all specialties, but also from all over the
world, which makes the workshop an
international and inspiring event.
Beyond this, ECCO also strives to
cooperate more on a policy level. For
example, the question of protocols for
clinical trials, clinical trial data and ethical
questions are of international relevance
and therefore, a joint approach is highly
desirable.
ECCO is also involved as a contributing
member of the Union for International
Cancer Control (UICC) and aims at
being an active partner internationally
wherever there is common ground for the
development of policy, for example via
the World Cancer Declaration.
Which direction would you like to see
cancer research going in the future and
how will ECCO’s leadership strategy
play into this?
Given the dimensions addressed above,
Thought Leader
Vytenis Andriukaitis,
Commissioner for Health
and Food Safety, speaking
at the ECCO 2017 European
Cancer Congress
the growing importance of cancer the challenge of data is managed
research, and the global co-operation appropriately in cancer research.
needs, ECCO’s role of fostering
multidisciplinary throughout the European • For more information about ECCO, their
region, but not stopping at this, is the upcoming events or the European Journal
right way forward. of Cancer, please visit ECCO’s website at
www.ecco-org.eu.
One large task is to deal correctly with
Contact
data. The means of our age, electronic
tools and systems seem to offer endless
opportunities if the society manages to
Birgit Beger CEO
harness them in an ethical and legally
ECCO - the European CanCer
correct manner.
Organisation
Avenue E. Mounier 83
One of the challenges that remains today B-1200 Brussels,
is the integration of data generated in Belgium
one component of healthcare delivery
into the wider healthcare IT system, so
E: birgit.beger@ecco-org.eu
that in terms of providing good patient
care, a more seamless record can be T: +32 2 775 02 01
W: http://www.ecco-org.eu/
shared across all three fields of primary,
secondary and social care. For cancer
research, the need to collect data as
well as to share results from clinical trials,
independent of whether they are positive,
negative or inclusive, is decisive. Despite
the establishment of Cancer Registries
and European Reference Networks,
there are still many steps ahead before
www.researchoutreach.org 17
Health & Medicine ︱ Dr Benjamin Haibe-Kains
Computational
methods of researching
cancer treatments
T
Artificial Intelligence (AI) and machine learning algorithms have the he computational analysis of big
potential to bring substantial advances in the fields of research exploring data is set to bring huge advances
complex diseases and trying to identify effective treatments. Dr Benjamin in terms of the methods used to
Haibe-Kains, working at The Princess Margaret Cancer Centre in Toronto, carry out medical and basic research. A
has spent over a decade developing machine learning tools and databases number of researchers worldwide have
that could help scientists gain a better understanding of different sub-types already started developing algorithms
of cancer and their response to pharmacological treatments, in order to that can analyse large amounts of
identify more effective drugs for individual patients. biological and medical data, identifying
new hypotheses for future investigation.
A particular field of medical research
that could highly benefit from the use
of machine learning algorithms is that of
exploring cancer genomics and trying to
determine the best treatments for different
subtypes of the disease.
THE VALUE AND CHALLENGES OF
BIG DATA
Throughout the years, scientists have
collected vast amounts of data from
experiments aiming to achieve a
better understanding of the molecular
dynamics behind complex diseases.
However, the complexity of such data
makes it difficult for human researchers
to run in-depth analyses and extract the
relevant information. This is where the
use of high performance computers,
coupled with the right programs could
be of great help. In the last decades,
computer scientists have worked hard
to develop machine learning algorithms
– programs allowing machines to
quickly analyse large amounts of data
and “learn” models useful to identify
the relevant pieces of information and
make predictions. These algorithms can
then be leveraged to develop artificial
intelligence (AI) tools that can assist
humans to analyse data that are beyond
our reach. As they become increasingly
advanced and sophisticated, AI tools are
opening up a new world of possibilities
for big data analysis, by transforming the
way in which studies and investigations
are conducted, leading to important
discoveries in a much shorter time.
18 www.researchoutreach.org
ARTIFICIAL INTELLIGENCE AND
CANCER RESEARCH
Artificial Intelligence and their underlying
machine learning algorithms could be
of particular value for research exploring
complex diseases, when trying to identify
effective pharmacological treatments for
them.
Cancer, one of the leading causes of
death worldwide, is a perfect example of
this. Scientists have not yet been able to
identify a systematic treatment for cancer
that is successful in curing the disease in
many of its most aggressive subtypes.
Cancer derives from an uncontrolled
division of abnormal cells in a given
part of the body, which can invade and
destroy surrounding healthy tissue
and organs. It is an extremely complex
disease, with more than 200 subtypes,
each of which is
often diagnosed and Dr Benjamin Haibe-Kains explores
treated differently.
As cancer arises from the potential of machine learning
algorithms, bioinformatics and
aberrations in the
genomic materials
of the cells, scientists
have developed
computational genomics to improve
sophisticated prediction of cancer patients’ survival
profiling
technologies to and response to therapies
measure these
aberrations and use them to personalise
therapies. Still, the most common
treatments for cancer are chemotherapy,
using drugs to kill the most proliferative
cells, and radiotherapy, using high energy
X-rays. These treatments can sometimes
be successful in reducing or eradicating
cancerous cells, yet they can be highly
toxic and are not tailored toward the
specific set of genomic aberrations that
make each tumour unique.
Artificial Intelligence tools could assist
researchers by analysing the complex
genomic make-up of each individual
tumour to develop accurate predictors
of treatment response. This would in turn
help to identify more effective treatments
for individual patients, a major step
towards personalised medicine.
COMPUTATIONAL METHODS FOR
CANCER RESEARCH
Throughout his career, Dr Benjamin
Haibe-Kains has explored the potential
of machine learning algorithms,
bioinformatics and computational
genomics to improve prediction
of patient survival and response to
therapies. During his graduate training
at the Université Libre de Bruxelles in
Belgium, he worked on developing
predictors of survival in breast cancer
patients based on high dimensional gene
expression (messenger RNA) data. He
continued his research as a postdoctoral
fellow at the Dana-Farber Cancer
Institute/Harvard School of Public Health,
leveraging a large collection of data to
develop “gene expression signatures” to
robustly identify molecular subtypes of
breast and ovarian cancers.
Using large collections of cancer
molecular data and machine learning
algorithms, Dr Haibe-Kains and
his collaborators identified several
“prognostic biomarkers”, that are
computational models using specific
molecular features to predict the
probability of survival of cancer patients
treated with standard-of-care treatments.
He says: “Amongst many discoveries,
my research unravelled the landscape of
cancer pathway activities associated with
patients’ survival in each of the molecular
subtypes, allowing me to further improve
my molecular prognostic models.”
EFFECTIVE TREATMENTS FOR
INDIVIDUAL PATIENTS
In 2012, Dr Haibe-Kains started his own
independent laboratory, broadening
his field of research to explore ways in
which machine learning algorithms could
be used to predict therapy response
in patients. With big players like IBM
announcing its Watson initiative to
develop AI to assist oncologists in their
treatment decision process, it was an
exciting opportunity for Dr Haibe-Kains
to extend the biomarker discovery
beyond patients’ survival, and to make
personalised medicine a reality. However,
Dr Haibe-Kains and his team quickly
recognised that, due to the high costs
of clinical trials, the existing clinical data
related to given treatment and cancer
subtypes were extremely scarce. Given
that machine learning usually requires
a large sample size to avoid artefactual
discoveries, it was time to investigate
“preclinical models”, which are cancer
cells derived from patient tumours that
one can replicate infinitely. These models
therefore provide a fantastic advantage
compared to clinical trials as the same
cancer cells can be tested with multiple
therapies to assess which one is the most
efficient, something impossible to do
with patients.
Dr Haibe-Kains’ laboratory invested most
of its resources in compiling and curating
the largest anticancer drug screens
in preclinical models. Such screens
contain not only the
genomic make-up
of the cancer cells,
but also the way
these cells react to
chemical treatments;
these complex data
are referred to as
pharmacogenomics.
These efforts
resulted in the
development
of PharmacoDB1, a web-application
allowing researchers to quickly access the
pharmacogenomic data to investigate
the possible associations between
genomic aberrations and drug response.
As part of his current research, Dr
Haibe-Kains is testing machine learning
algorithms on the database, to try
and pinpoint predictors of treatment
reaction. Paired with the right machine
learning algorithms, PharmacoDB could
be used to develop an AI tool assisting
in selection of the most effective
treatments for each individual cancer
patient. Dr Haibe-Kains’ laboratory also
leveraged these valuable data to address
another important issue in cancer
research: how to classify drugs based
on their mechanism of action? Although
biologists, chemists and pharmacologists
teamed up to develop a large portfolio of
drugs with high anticancer potential, it is
unclear for many of these drugs how they
actually inhibit the growth of cancer cells.
Dr Haibe-Kains and his team developed
the Drug Network Fusion (DNF), a
www.researchoutreach.org 19

new technique integrating multiple
pharmacogenomic data to design a
comprehensive drug similarity map
(or taxonomy). DNF allows researchers
to assess the similarity between a
drug with unknown mechanism of
action with well-characterised drugs,
therefore providing an efficient tool
to identify potential new indications
for approved or experimental drugs
(a process called “drug repurposing”).
As more pharmacogenomic data
becomes available and machine learning
algorithms are further improved,
databases such as PharmacoDB could
become extremely valuable resources.
A NEW ERA FOR RESEARCH
If developed and used correctly, the
use of machine learning and AI tools in
1 http://pharmacodb.pmgenomics.ca/ 2 PharmacoGx: An R package for analysis of large pharmacogenomic datasets. Smirnov P, Safikhani Z, El-Hachem N, Wang
D, She A, Olsen C, Freeman M, Selby H, Gendoo DM, Grossman P, Beck AH, Aerts HJ, Lupien M, Goldenberg A, Haibe-Kains B. Bioinformatics. 2015 Dec 9. 3
PharmacoDB: an integrative database for mining in vitro anticancer drug screening studies. Smirnov P, Kofia V, Maru A, Freeman M, Ho C, El-Hachem N, Adam GA, Ba-
alawi W, Safikhani Z, Haibe-Kains B. Nucleic Acids Res. 2017 Oct 9, gkx911. 4 Integrative cancer pharmacogenomics to infer large-scale drug taxonomy. El-Hachem N,
Gendoo DM, Soltan Ghoraie L, Safikhani Z, Smirnov P, Chung C, Deng K, Fang A, Birkwood E, Ho C, Isserlin R, Bader G, Goldenberg A, Haibe-Kains B. Cancer Res. 2017
Mar 17 5 Gene isoforms as expression-based biomarkers predictive of drug response in vitro. Safikhani Z, Smirnov P, Thu KL, Silvester J, Lupien M, Mak TW, Cescon D,
Haibe-Kains B. Nat Commun 2017 oct, in press.
20 www.researchoutreach.org
basic and translational cancer research
could mark the beginning of a new era
for personalised medicine, characterised
by quick and advanced data analysis,
Application of artificial intelligence in
basic and translational cancer research
could mark the beginning of a new era
for personalised medicine
which was previously unattainable. Dr
Haibe-Kains’ work is a perfect example of
this, as he has introduced computational
methods that could speed up cancer
research significantly, by analysing large
datasets and identifying predictors of
treatment response.
Behind the Bench
Dr Benjamin Haibe-Kains
E: benjamin.haibe.kains@utoronto.ca T: +1 416 581 8626 W: http://www.pmgenomics.ca/bhklab/
https://www.linkedin.com/in/benhaibekains/
Research Objectives
Dr Haibe-Kains’ research focuses
on the computational integration of
high dimensional molecular data to
simultaneously analyse multiple facets of
carcinogenesis.
Funding
Princess Margaret Cancer Foundation,
Canadian Institutes of Health Research,
Terry Fox Research Institute, Stand Up To
Cancer Canada, Cancer Research Society,
Natural Sciences and Engineering Research
Council of Canada, Canadian Cancer
Q&A
When and how did you first start
being interested in computational
models to be used in cancer genomics
research?
When I did my bachelor in Computer
Science, I was interested in the
development of Artificial Intelligence in
robotics. In the early 2000s, AI robotics
Dr Haibe-Kains’ approach to research is was still in its infancy and the applications
highly collaborative and multidisciplinary, were still limited. This is when my former
supervisor at the Université Libre de
merging the expertise of scientists from
Bruxelles, Prof Gianluca Bontempi
a number of different fields. In future,
advised me to consider bioinformatics,
a booming field in need of researchers
with expertise in machine learning. I
followed his advice and started a PhD
under a co-supervision with Dr Christos
Sotiriou, a breast cancer oncologist at the
Institut Jules Bordet. This is how I started
using computational models in cancer
genomics research.
So far, how effective have the
the computational methods developed machine learning tools developed
by him might lead to ground-breaking by you been in improving biomarker
discoveries, which could inform discovery and drug selection from
pharmacogenomic data?
oncologists on how to select the most
My lab was definitively not the first to
effective treatments for individual cancer tackle these important challenges.
patients in clinical settings. However, we built on our previous
experience in meta-analysis of large
compendium of gene expression data
to develop computational platforms
for pharmacogenomic data analysis.
PharmacoGx2 and PharmacoDB3
are open-source and freely available
https://twitter.com/bhaibeka
Research Society, Ministry of Economic
Development/Ministry of Research and
Innovation of Ontario, Ontario Institute for
Cancer Research
Bio
Dr Benjamin Haibe-Kains is Scientist at
the Princess Margaret Cancer Centre
and Assistant Professor in the Medical
Biophysics and Computer Science
departments of the University of
Toronto (Canada). He earned his PhD in
Bioinformatics at the Université Libre de
Bruxelles (Belgium), before conducting a
for the scientific community. With these
large amounts of pharmacogenomic data
in hand, we applied machine learning
techniques to better classify drugs (DNF4)
and discover new biomarkers predictive
of drug response in cancer cell lines5.
Even though these discoveries will have
to undergo further validation before
their translation into clinic, they show that
machine learning can yield promising
results with potential clinical relevance.
How long do you believe it might take to
start witnessing a major introduction of
AI technology within medical settings?
Not long, probably a few years from now.
As more hospitals have the patients’
electronic health records connected to
the experimental data derived from their
tumour materials, we will finally have access
to the large, high quality data required for
AI to show its full potential for biomedical
applications. Recognising that large
cohorts of patients and derived materials
are necessary to make major discoveries
and build the new generation of AI-based
tools in the clinic, hospitals are joining
forces, and even pharmaceutical companies
have started to share more and more
data related to clinical trials. These are the
necessary steps we must take to unleash the
power of AI for personalised medicine.
In the years to come, what role do you
feel AI will have in terms of research and
innovation within the medical field?
It is hard to predict the roles of AI in the
future of medicine; the applications are
close to limitless. It will help patients
postdoctoral fellowship at the Dana-Farber
Cancer Institute and Harvard School of
Public Health (USA).
Contact
Benjamin Haibe-Kains, PhD
Princess Margaret Cancer Research Tower,
Floor 11, Room 310
101 College Street
Toronto
ON M5G 1L7
Canada
better schedule the series of medical
appointments involved in the treatment
of complex diseases such as cancer. It
will help hospitals better monitor their
performance, and ensure the highest
standards of safety, diagnosis accuracy
and treatment efficacy. The mining of
data from wearable devices will allow
continuous monitoring and patients
to be more proactive when symptoms
arise. And of course, AI will enable new
discoveries, further expanding our
knowledge of cancer and other diseases.
Limitless.
What are your plans for future
research?
First, I want to validate our first
discoveries – predictors of drug
response and new drugs predicted
to be efficacious in aggressive cancer
types – in animal studies to get them
close to clinical applications. The Princess
Margaret Cancer Centre enjoys a strong
drug development group, which will be
key in this endeavour. Second, I want to
make our pharmacogenomic platforms
tools of choice for hospitals and
pharmaceutical companies, to further
facilitate data sharing and large-scale
computational analysis. Finally, I want to
integrate molecular data with imaging
data, both pathological and radiological
images, to predict the best course
of treatments and better follow the
patients over time. Our first application
of deep learning on radiological images
is promising, supporting this line of
research for future clinical applications.
www.researchoutreach.org 21
Health & Medicine ︱ Dr Bernard Robaire

Swimming against LITTLE SWIMMERS

Unlike a woman’s eggs, which are
As sperm mature they pass through
the tubules and are stored until
Dr Robaire’s research aims to find
out exactly how these effects are

the stream:
all present in her body at birth and
released gradually throughout her
lifetime, sperm – the carriers of genetic
information from the male parent – are
continuously produced throughout
a man’s life – at a rate of about 1000
they are ready to be released. It was
previously thought that their constant
manufacture rendered sperm relatively
immune to the kind of damage that can
accumulate in a woman’s eggs over her
lifetime. However, Dr Robaire’s research
manifested. His team members are
investigating how the components of
the male reproductive system, and
the different processes involved –
hormone production and reception,
sperm production, maturation and

modern-day challenges to male reproductive health every time his heart beats. The male sex
organs, the testes, are filled with coiled
and that of his colleagues have shown
that this is not the case. Exposure
storage – are impacted by a range of
possible environmental factors, and are

The effects of a mother’s age, health and habits upon
her offspring are well documented. However, far
less attention has been paid to fathers. Dr Bernard
Robaire, Professor at McGill University, Montréal,
Canada, believes male reproductive health may be
just as important for future generations as that of
females, with a father’s age, health and exposure
to chemicals all having an impact on the quality and
genetic makeup of his sperm – and ultimately the
fitness of his children.
W
omen today are showered with advice regarding
their reproductive health and the health of their
future children. Some of the stories you hear typically
include: ‘older mothers are more at risk of fetal abnormalities’;
‘don’t drink alcohol, smoke, or eat soft cheese during pregnancy’;
‘take folic acid when you’re trying to conceive’; ‘avoid exposure
to chemicals such as pesticides’, etc. This is all good advice, of
course, but how about the fathers – do they get off scot-free?
Well, not for much longer! Dr Bernard Robaire’s research is set
to overturn the predominant view that a man’s age, health and
habits have little impact upon his future offspring. Bad news
for fathers-to-be, perhaps, but good news for the accuracy of
reproductive health guidelines.
tubes called ‘seminiferous tubules’ –
which are lined with sperm stem cells
Sperm are continuously produced
throughout a man’s life – at a rate of
about 1000 every time his heart beats
that divide to produce sperm – and
sperm nurse cells (‘Sertoli cells’), which
regulate the process, under the control
of sex hormones such as testosterone.
to drugs (therapeutic or otherwise),
smoking, environmental chemicals,
and conditions such as obesity, are
now known to have negative effects
on a man’s sperm, and, therefore,
his children, and these effects may
cumulate with age.
looking to characterise the molecular
mechanisms that mediate these effects.
THE AGE EFFECT
In today’s society, men and women
alike are increasingly delaying
parenthood until later in life. Now it
seems that this may not be such a
good plan. Dr Robaire’s animal studies
have shown that the progeny of older
male rats have lower weights and
are more likely to die in the neonatal
period than those of younger fathers.
When their sperm were examined, the

22 www.researchoutreach.org www.researchoutreach.org 23

offspring of the older rats were found
to have greater levels of damage to
their genetic material, DNA. In humans,
older men are reported to have testes
containing slower sperm, and a higher
proportion of these are abnormal. They
also show higher rates of infertility,
and their partners take longer to
get pregnant and are more likely to
miscarry. Increasing numbers of studies
have linked paternal age with higher
rates of diseases with a complex genetic
component, such as autism, ADHD,
schizophrenia, and bipolar disorder.
There is mounting evidence linking
paternal age with chromosomal and
genetic changes in offspring, increasing
the risk of breast cancer, heart defects,
and developmental, behavioural and
neurological disorders. Furthermore,
dominant genetic disorders such as
achondroplasia, the most common
form of dwarfism, are shown to be more
common in the children of older fathers.
These genetic changes have been
connected to deficits in the cellular
mechanisms for repairing damaged
DNA, which are essential in cells
undergoing genetic recombination such
as sperm cells. Dr Robaire’s research
has, in turn, linked these failings to
Behind the Bench
Dr Bernard Robaire
E: bernard.robaire@mcgill.ca T: +1 514 398 3630 W: http://www.medicine.mcgill.ca/pharma/robairelab/
Research Objectives
Dr Robaire’s research interests focus
on male-mediated reproductive
toxicology, ageing of the male
reproductive system, mechanisms of
androgen actions, and the structure,
function, and regulation of the
epididymis.
Funding
Canadian Institutes of Health Research
(CIHR)
Collaborators
Dr Robaire has collaborated with a
Testis section of a three-month-old mouse showing seminiferous tubules at various spermatogenic
stages highlighted using acrosome marker (red) lectin PNA from Arachis hypogaea (peanut), with
immunofluorescent markers for vimentin in Sertoli cells (green), and ZBTB16 in spermatogonia
(magenta). These markers were quantified using Imaris® to determine the mean number of positive
cells per tubule for select spermatogenic stages, and compared between different mice.
wide range of colleagues but most has remained and is currently a James
notably with Dr Barbara Hales for McGill Professor.
animal studies on male-mediated
reproductive toxicology and Dr Peter Contact
Chan for clinical studies. Dr Bernard Robaire, PhD, FRSC
James McGill Professor
Bio Departments of Pharmacology and
Bernard Robaire received his BA Therapeutics and of Obstetrics and
from UCLA and his PhD from McGill Gynecology
University. After a postdoctoral McGill University
fellowship at Johns Hopkins University, 3655 Promenade Sir William Osler
he returned to McGill to take up a joint room 104 Montréal
appointment in the Departments of QC Canada
Pharmacology & Therapeutics and of H3G1Y6
Obstetrics & Gynaecology where he

defects in the body’s defence against
oxidative stress, which can cause
mutations in the genetic material.
His studies in mice even suggest a
possible preventative measure – an
instance, older or younger than 45 years
– Dr Robaire hopes to conduct more
nuanced analyses in both human and
animal models, which will enable him
such as pesticides, fertilisers, flame
retardants and plasticisers can all leach
into our environment and, even at
minute quantities, have toxic effects
– particularly at certain stages of
Q&A
Why do you think men’s
reproductive health has been so
How does the population of sperm in a
man’s testes change as he gets older?
There is a debate as to whether the
number of sperm produced actually
decreases with age, but there is little
Is there a relationship between
the different factors that affect
sperm quality? For instance, does
the effect of chemicals on sperm
cumulate as men age?

Older men are reported to have testes
containing slower sperm, and a higher
proportion of these are abnormal
antioxidant molecule – which seems to
halt the losses associated with increased
oxidative stress during ageing.
His current grant, supported by
the Canadian Institute of Gender
and Health under the Canadian
Institutes of Health Research, brings
together a team of researchers with
complementary expertise, aiming to
explore the whole spectrum of impacts
male ageing has and to quantify the
risks in terms of sperm quality and
children’s health. While most previous
studies have simply divided their
participants into two groups – for
to track declines in fertility and perhaps
pinpoint a threshold above which
risks are significantly increased. He
aims to tease out whether the genetic
effects of age result from changes
in the sperm stem cells themselves,
in the environment provided by the
seminiferous tubule, or both.
INESCAPABLE IMPACTS?
Although age is a highly significant
factor, male fertility is also impacted by
environmental chemicals, particularly
the so-called ‘endocrine disrupters’
which disturb the balance of hormones
throughout the human body. Chemicals
development. For instance, brominated
flame retardants from soft furnishings
accumulate in the household dust
that we are exposed to every day. Dr
Robaire is working with a wide-ranging
team at McGill University to understand
more about the risks these chemicals
pose, their mechanism of action, and
to develop safer alternatives and
precautionary standards and policies to
protect our reproductive health.
With an ageing population and
increasing rates of delayed parenthood,
Dr Robaire and his colleagues’ research
into all aspects of male fertility will
facilitate reproductive counselling and
suggest changes men can make now,
to promote the health of their children
and decrease the impact of disease on
future generations.
little investigated compared to
women’s?
There are probably many factors.
For example, the fact that men can
continue to have children, even into
old age, while women lose the ability
to have children after menopause has
given the impression that good sperm
keep on being made throughout
life. The traditional concept that the
reproductive burden lies with women,
not men, is likely a social factor that
has weighed in. The complexity of
understanding the ongoing process
of sperm production is also likely
to have played a role. The fact that
most investigators in the field of
reproduction were men in the past may
have played a role too, but I do not
think that this is the case today.
doubt that the quality of sperm does go
down as men age. By quality I include
sperm motility, their appearance and the
integrity of their DNA and its packaging.
Do you think sperm quality declines
linearly, or declines suddenly after a
certain age?
All the studies to date indicate that
this is a steady, slow process – there
is no indication of a rapid change at a
particular age.
There is little doubt that the quality of
sperm (motility, appearance and DNA
integrity) does go down as men age
Few studies have looked at a
combination of factors such as age,
obesity, or exposure to chemicals that
could affect sperm. However, there is
no reason to think that these would not
be cumulative.
If you were hoping to father
children, what would be the most
important thing you could do now
to protect their future health?
Do not smoke! Keep your weight
down. Have your kids at a younger age,
preferably before 35.

24 www.researchoutreach.org www.researchoutreach.org 25
Health & Medicine ︱ Dr Bruce Zetter
A career in cancer
Dr Bruce Zetter is the Charles
Nowiszewski Professor of
Cancer Biology at Harvard
Medical School. He is known
internationally as an expert on
cancer biology, diagnosis and
treatment. He currently works
to find treatments for highly
aggressive, metastatic cancers
and also serves as an advocate
for young scientists and for
improved relationships between
academia and industry.
26 www.researchoutreach.org
D
r Bruce Zetter started out over
forty years ago as a graduate
student in microbiology, but
technological advances in studying
cancer cells, along with increased funding
for cancer research, encouraged him
to switch disciplines and turn to the
study of this deadly disease. Then at the
Massachusetts Institute of Technology in
Cambridge, MA, the lab he was working
in was just getting started in investigating
cancer, so he made the switch from
studying bacterial cells to cancer cells,
and has been driving this research forward
ever since.
DECLARING WAR ON CANCER
Cancer is the name for a group of
diseases which involve abnormal cell
growth and proliferation. Fortunately,
many tumours are benign and are
unable to spread to other parts of the
body. However, through a process called
metastasis, cancerous tumours have the
Science – both academic and otherwise
– remains a career that will continue to
enthral, engage and financially support
the coming generations of scientists
potential to invade other tissues and
organs. The majority of deaths from
cancer are due to this process rather
than the primary cancer, so it is clear
that targeting this feature of tumours is
important in managing cancer-related
mortality.
Dr Zetter’s work has focused on precisely
this feature of cancers, identifying a
variety of proteins which are implicated
in tumour progression and metastatic
potential. This has resulted in the
development of tests for biomarkers that
are useful in cancer diagnosis, prognosis,
recurrence monitoring and in determining
responsiveness to particular therapeutic
agents. More recently, his work has
turned to finding treatments for the most
aggressive, metastatic forms of cancer.
DRUGS AND DELIVERY
Drug resistance in cancers is another
major problem that Dr Zetter and his
colleagues have turned their attention to
in recent years. Many frontline treatments
have had their efficacy diminished by the
rapid development of drug resistance,
so the team is identifying biomarkers
(proteins expressed on the cell surface)
that can help screen patients for
resistance and even be used as targeting
tools to direct other drugs towards
resistant cells.
In searching for these effective drugs,
Dr Zetter has identified that some
drugs are particularly effective on the
most aggressive cancers, but less so on
milder versions of the disease. Several
of these selective drugs have been
previously approved as anti-parasitic,
suggesting some commonality between
the treatment of parasites and metastatic
tumour cells. Poor solubility of some
compounds means not all are suitable
for administration in cancer treatment
though. However, Dr Zetter has worked
with medicinal chemists such as Dr Lijun
Sun to devise new versions which can
be given to patients with very advanced
cancers and few treatment options.
This attitude of collaboration to bring
effective products to patients is a feature
of Dr Zetter’s career to date. Successful
partnerships have been forged with
bioengineers to develop novel delivery
mechanisms for innovative cancer
treatments. Nanoparticles capable of
delivering a payload of RNA molecules,
which would usually be degraded by the
body long before reaching the target
tumour, are helping the team to treat
tumours in animal models which were
impossible just a few years ago.
These RNA molecules are used either
as gene silencers to turn off cancer-
causing and -promoting genes, or to
replace tumour-suppressing functionality
lost during the evolution of the tumour.
The team’s latest work has successfully
delivered the tumour-supressing gene
PTEN (Phosphatase and tensin homolog,
a protein which inhibits the pathway
controlling many aspects of cell growth
and proliferation) to an active tumour site
via intravenous injection. Expressing this
gene in the tumour represses tumour
growth, allowing the animal to survive
much longer. It has the potential to be
coupled with gene silencing techniques
to further improve efficacy.
MENTORING THE YOUNG
This work has made Dr Zetter
internationally recognised as a leading
expert on cancer research and drug
development, but laboratory-based
investigations are just a part of his role as
a scientific authority in this area. Over the
course of his career, Dr Zetter has found
the time to write grants, patents and
opinion pieces; teach and direct university
courses; advise legislators and act as an
expert witness in court cases; and run all
the research at a large institution in the
shape of Boston Children’s Hospital.
Putting his knowledge and experience
to good use now means that Dr Zetter is
engaged in a mentoring role for young
investigators. “We are in a challenging
time for academic medicine. Funding
is, for now, harder to come by, papers
seem to be harder to get published, and
respect for science among the public
appears to be eroding,” as he puts it,
adding that this is potentially leading to
a deficit of academics to train the next the coming generations of scientists.” Dr Zetter knows only too well from his
generation of scientists. After many years of experience, he sums it early experiences with entrepreneurial
up simply: “I personally couldn’t envision colleagues and newly formed companies.
His approach to combatting this is to a better career choice.” A steady and experienced hand to guide
meet with young scientists, individually them around the pitfalls is almost essential
or in groups, to share his belief that “talk STARTING UP AND SPINNING OUT for anyone starting out.
of the sky falling is exaggerated and It is not just young scientists who need
science – both academic and otherwise this kind of clear and positive thinking. Over the years Dr Zetter has become
– remains a career that will continue to Starting a new biotech company is a one such influence and he now assists
enthral, engage and financially support complex and risky endeavour, a fact which others to find their feet. In the process, he
www.researchoutreach.org 27
Working with collaborators Omid Farokhzad and Jinjun Shi at Brigham and Women’s Hospital in Boston, Dr Zetter has been able to restore tumour suppressor
activity to tumours by delivering tumour suppressor messenger RNA by intravenous delivery into experimental animals. Unlike most therapies which seek to
block a cancer-causing gene, this approach restores tumour cells to a suppressed state, more similar to normal cells. The graphic depicts the messenger RNA Behind the Bench
Dr Bruce Zetter
delivery in the context of a “message in a bottle” that is delivered to the tumour by the blood stream. Image credit: Kristin Johnson.

E: Bruce.Zetter@childrens.harvard.edu T: +1 6179192331 /bruce-zetter-7a9b4a8

mRNA-nanoparticles W: www.politico.com/agenda/story/2016/04/biden-cancer-moonshot-needs-to-fix-000109

Research Objectives
Dr Zetter has dedicated his research career
to finding the means by which tumours
Tumour
spread to distant sites, looking to uncover
methods to predict this occurrence and
treat the metastases once they arise.
Funding
National Institutes of Health (NIH)
Collaborators
• Omid Farokhzad MD (Harvard Medical
School, Brigham and Women’s Hospital)
• Marsha Moses PHD (Boston Children’s
Hospital, Harvard Medical School
• Michael Rogers PhD (Boston Children’s for young scientists and for improved
Hospital, Harvard Medical School) academic-industry relationships.
• Jinjun Shi PhD (Brigham and Women’s
Contact
Hospital, Harvard Medical School)
• Lijun Sun PhD (Harvard Medical School, Dr Bruce Zetter
Beth Israel Deaconess Medical Center) Boston Children’s Hospital/Harvard Medical
School
Bio 300 Longwood Ave
Dr Bruce Zetter is the Charles Nowiszewski Boston, MA 02115
Professor of Cancer Biology at Harvard USA
Medical School. He is known internationally
as an expert on cancer biology, diagnosis
and treatment. He currently works to find
treatments for highly aggressive, metastatic
cancers. He also serves as an advocate

Q&A block cancer-promoting genes, while

has become passionate about ensuring
that research in academic environments
eventually finds its way to patients in
the form of effective treatments. This
process often involves small biotech
companies, so Dr
Zetter educates
academic This is all about ensuring that potential
disease cures don’t languish on the lab
investigators on
how they can
make their work
more attractive
bench top but get sent out the door to a
to companies, company that knows how to develop them
helps them find
commercial and eventually reach patients in the clinic
partners and
works with the companies to ensure
the partnership stays on track. Over
the years he has counselled dozens of
young entrepreneurs while also serving
as an advisor to more than 40 biotech
companies. He particularly likes to help
young companies avoid the pitfalls that
commonly occur in the first few years of
their existence.
MAKING RESEARCH RELEVANT
This isn’t just about making sure research
is profitable: “This is all about ensuring
that potential disease cures don’t languish
on the lab bench top but get sent out
the door to a company that knows how
to develop them and eventually reach
patients in the clinic.” Dr Zetter finds this
aspect of his role immensely satisfying,
and believes that it has benefitted
patients just as much as the research that
has taken place in his own lab.
Blood vessel
There remain significant challenges in
developing treatments for cancer, but with
the progress that has been made in recent
years Dr Zetter strikes a positive note. As
these new therapies and combinations
of therapies
come out of the
lab, perhaps
the biggest
challenge is how
to ensure they
reach patients.
From progression
through clinical
trials to ensuring
that physicians
have up-to-date information on which
treatments are most effective for specific
cancers and stages, there is a key role for
good communicators and facilitators. Dr
Zetter has proved to be one such breed
of scientist, able to push forward ground-
breaking research while simultaneously
helping others to realise their full
potential.
Why is targeting tumour metastasis
so important?
Quite simply, of the patients who
die of cancer, 90% succumb to the
consequences of their metastases,
not from their primary tumour. The
biggest challenge in cancer treatment
is to find a way to extend the lives of
patients with widespread metastases.
What is your lab currently focussing
on?
We are very interested in trying to find
treatments to late-stage metastatic
cancers, particularly from the types
of cancers that are hardest to treat.
By the time a cancer reaches this late
stage, it may be very different from
the initial cancer, so we have tried to
find new therapies that selectively
target these highly aggressive late-
stage cancers. Once we find them,
the next problem is to find ways to
deliver these therapies preferentially
to the tumour, wherever it may be.
This is why we are collaborating
with bioengineers such as Drs Omid
Farkhzad and Jinjun Shi to devise
nanoscale delivery systems that can
bring our new drugs directly to the
metastatic sites. We are currently
working on ways to simultaneously
restoring tumour suppressor genes to
the same cells at the tumour site.
What is the most important aspect
of developing a scientific career?
I don’t think this has ever changed.
The key to a successful scientific
career is to focus first on your science.
It sounds simple, but today’s scientists
have so many competing obligations
(funding, teaching, service to their
institutions, family, etc.), that they
sometimes need to be reminded to
keep the science first and everything
else will follow. The reason we all
chose this career was because we love
science. We should never lose sight
of that.
What would be your advice to
someone considering starting a
biotech company?
A. Focus on the ultimate goal. It’s not
actually the technology that is the
most important thing, it’s what you
want that technology to do. There
may ultimately be other ways to
accomplish the same goal. B. Know
your strengths. If you’re a scientist,
find the best business partners that
you can. Too many small companies
fail when the scientists try to run
the business side. C. Expect the
unexpected. Every small company
has a major crisis early on with the
technology, the funding or the
people. Being flexible is the key to
getting past these valleys.
How do you see the future of
cancer treatment developing in five
to ten years?
Over a long career in cancer research,
I have seen countless trends, and no
doubt will see many more. I’ve learned
to let them play out over time before
getting too excited. Yet there is clearly
accelerated progress right now –
greater than any time I can remember.
We have moved now to combining
many different kinds of cancer
treatment for the same patient –
sometimes all at once and sometimes
one after another. With combinations
of approaches, we sometimes
see much stronger responses, but
sometimes we see much stronger
toxicity. Today, we combine these
approaches in an almost random
way. To me, the key to the future of
cancer treatment is to find ways to
predict which combinations will work
on each patient. Let’s call it “rational
combination therapy”. It will require
some new ideas and some very
serious computing power but I think
it is the key to our greater success in
treating challenging cancers over the
next decade.

28 www.researchoutreach.org www.researchoutreach.org 29
Health & Medicine ︱ Dr Gillian Hawker
Helping patients
put their best
foot forward
Dr Gillian Hawker of the
University of Toronto is helping
potential knee replacement
patients to make informed
decisions about their health.
As an increasing number of us
require joint replacement, Dr
Hawker seeks to make sure
that only those who are best
suited will undergo surgery. By
developing standardised patient
assessment criteria for knee
surgery, Dr Hawker is striving
to make the most of precious
health care resources and create
better conversations between
patients and consultants.
30 www.researchoutreach.org
K
nee osteoarthritis is very common
and the numbers affected are on
the rise. For some people with
osteoarthritis, non-surgical therapies may
be insufficient to manage the pain and
functional limitations caused by their
knees and joint replacement surgery may
be recommended. Research undertaken
by Dr Gillian Hawker of the University of
Toronto seeks to improve the outcomes of
this increasingly common surgery.
More than 1.2 million knee replacement
surgeries are conducted across the
world in a single year and worryingly,
the rates of Joint Replacement Surgery
(JRS) are on the rise. Lengthening
lifespans and obesity are two of the
most likely culprits of this increase, but
it has also been found that patients are
seeking surgery earlier in the course
of their disease, raising concerns that
JRS may be becoming overused.
People aged between 20 and 59 have
The importance of collaborative
decision making when considering
knee replacement surgery cannot be
overstated
seen the biggest increase in rates of
knee replacement surgery. This is an
unsettling trend as a second knee
replacement later in life, known as
revision surgery, is less likely to be
successful and much more costly.
Furthermore, research has shown that
though largely successful, 15–30% of
JRS recipients are dissatisfied with the
results of their surgery.
Dr Hawker aims to ensure that only
patients who are suitable candidates for
knee replacement receive the surgery
and has conducted extensive research
into determining criteria to aid decision
making.
APPROPRIATENESS CRITERIA
By liaising with patients and
orthopaedic surgeons, Dr Hawker
and colleagues were able to establish
four criteria for deliberation when
considering knee replacement. These
are: despite appropriate non-surgical
treatment, patient’s joint symptoms
are negatively impacting quality
of life; patient is ready, willing and
able to undergo surgery; patient has
realistic surgical expectations; and the
likelihood of patient benefit from JRS
is greater than the risks. The question
is, how best to evaluate these criteria,
and can they predict at surgical
consult whether or not the patient
will benefit from surgery? This is the
focus of her current research. Findings
from this study will help patients
and their physicians make informed
healthcare decisions.
Candidates for this current study have
been recruited from one of two large
joint surgery clinics in Alberta, Canada.
To be included in the study patients
must have symptoms due to arthritis
of the knee, be aged 30 or above and
have undergone referral to a surgeon.
Each patient that agreed to participate
in the study was assessed using the
appropriateness criteria before they
saw the consulting surgeon. This
information was not shared with the
surgeon. After being seen by the
surgeon, the latter indicated if surgery
had been recommended and, if so,
whether or not the patient had realistic
expectations of knee replacement. The
surgery then continued as arranged.
In order to evaluate the effectiveness
of the surgery, Dr Hawker and the team
interviewed patients at six and twelve
months post-surgery. During these
interviews patients were asked about
their knee pain, physical function, and
whether or not their expectations of
knee replacement had been met.
One of the major challenges of the
study was defining, from patient
responses, whether knee replacement
had been of benefit to the patient.
As different people have different
expectations of surgery, as well as
different levels of acceptable pain,
it was necessary to prioritise some
factors over others. Pain is one of the
major factors which triggers people
with arthritis to undergo surgery.
Reduced level of pain was therefore
used as the primary measure of benefit.
Patients must express that their pain
was “much” or “somewhat” improved,
as well as being “very” or “somewhat”
satisfied with the results in order to
be considered as having benefited
from surgery. Alternative definitions of
benefit are also being considered.
While the attitudes and experiences
of patients is extremely important, the
decision to operate ultimately falls at
the feet of the surgeon. Dr Hawker
and her team intend to use the data
collected in this study to finalise their
appropriateness criteria and use them
to develop tools to aid surgeons in their
decision making.
MAKING GOOD DECISIONS
Though earlier work has helped
develop aids to support patients in
the decisions they make leading up to
surgery, surgeons have not previously
experienced similar attention.
Consistency is important in making
healthcare decisions and Dr Hawker
found that, “Participants agreed that
www.researchoutreach.org 31

surgeons did not consistently discuss/
assess all of the appropriateness
criteria that were identified.” Dr
Hawker and colleagues have also
found that health care funders and
hospital administrators would like a
greater level of transparency about
the selection criteria that surgeons
apply. Having criteria by which to
reliably identify those patients most
likely to benefit from surgery could
be used by surgeons alongside their
patients, could help them make better
informed decisions and help reduce the
32 www.researchoutreach.org
Dr Hawker seeks to emphasise the
importance of helping patients make
their own informed healthcare decisions
number of patients who experience a
suboptimal surgical result. The financial
implications of the increasing number
of surgeries are also an important
consideration. Within the study area of
Alberta, Canada more than $800 million
are spent each year solely on knee
replacement surgeries. The importance
Behind the Bench
Dr Gillian Hawker
E: gillian.hawker@wchospital.ca T: +1 416 323 7722 W: http://ihpme.utoronto.ca/faculty/gillian-hawker/
Research Objectives
Dr Hawker has established a record
of academic excellence in the field
of osteoarthritis (OA) outcomes. A
predominant theme of her research is
the appropriate use of hip and knee
joint replacement surgery for OA. Joint
replacement surgery reduces pain and
disability in people with hip and knee
arthritis. Her work has a broad impact,
important in understanding the roles of
arthritis severity, other health conditions,
patient preferences, and sex/gender and
physician bias in determining rates of use of
joint replacement surgery.
Funding
Canadian Institutes for Health Research
(CIHR)
Q&A
Will the development of this tool
allow patients and surgeons to
contribute equally to decisions
about healthcare?
No, surgeons and potentially the
health care system will always be able
to trump a patient’s decision to have
surgery when they won’t benefit from
it, but patients who understand their
likelihood of a good outcome with
surgery will hopefully make better
decisions.
How important do you think is
the psychological readiness of the
patient for surgery, compared with
the physical suitability?
Both are important, but I think we
have undervalued the importance of
psychological readiness – in our prior
work, patients talked about this a lot…
of collaborative decision making when And in research we clearly find that
considering knee replacement surgery the ‘optimists’ and ‘copers’ are more
cannot be overstated. With significant likely to adhere to their post-operative
human and financial implications, it rehabilitation, etc – so it matters!
seems clear that helping patients and
surgeons to make better decisions
together will benefit everyone.
Collaborators
Deborah Marshall, University of Calgary;
Tom Noseworthy, University of Calgary; Eric
Bohm, Concordia Hip and Knee Institute,
University of Manitoba; Michael Dunbar,
Dalhousie University; Peter Faris, Alberta
Health Services; Allyson Jones, University
of Alberta; Bheeshma Ravi, University of
Toronto; Linda Woodhouse, University of
Alberta
Bio
Dr Gillian Hawker is the Sir John and
Lady Eaton Professor and chair of the
Department of Medicine at the University of
Toronto, where she is also a rheumatologist
and clinician scientist at Women’s College
Hospital, University of Toronto. Dr Hawker
has published over 240 peer-reviewed
Do you find that patients are
becoming more interested in
understanding all their healthcare
options before commencing surgery?
Patients are definitely more engaged in
their health care decisions period… not
just for surgery. They are way more likely
now than a decade ago to arrive at their
doctor’s office having done their own
investigation into the treatment options
– our job now is to help them decipher
the good evidence based information
from the bad stuff – with respect to knee
replacement however, people are also
wanting more from the surgery than
in the past – whereas previously folks
wanted surgery mainly to be able to do
their basic activities of daily living, now
folks are wanting ALSO to be able to
exercise, travel, do sports – much more
vigorous high impact activities that knee
surgery wasn’t designed for.
As lifespans lengthen, are higher rates
of revision surgery sadly inevitable,
regardless of primary surgery success
or failure?
Yes and no… if we reduce need for the
articles and received a number of honours
for her research, including the Canadian
Rheumatology Association Distinguished
Investigator Award in 2011.
Contact
Dr Gillian Hawker
Women’s College Hospital
190 Elizabeth Street, Suite RFE 3-805
Toronto, ON M5G 2C4
first surgery, that will help a lot – knee
osteoarthritis is very much impacted
by our weight – reducing body weight
and maintaining a healthy weight
along with keeping physically active
would go a long way to reducing the
number of people who require a first
joint replacement. With respect to
the second or revision surgery, again,
guidance for people who receive a
first knee replacement about what will
enable the prosthesis to last longer or
need revision sooner can be helpful.
You were honoured by The
Arthritis Society of Canada with a
Queen’s Jubilee Medal in 2013 for
your continued contributions to
osteoarthritis research. What has
been the highlight of your career?
I am fortunate to have had many
highlights – the many successes of
my trainees over the years for sure is
amazing… especially those who are
now going on to establish their own
careers focused on improving the lives
of people with osteoarthritis.
www.researchoutreach.org 33
Health & Medicine ︱ Dr Jeffrey Savas
Let’s hear it
for the proteome
Hearing loss is one of the most common sensory
impairments, affecting 250 million people worldwide.
The causes of deafness, such as exposure to loud
noise, are relatively well known, but exactly how
they result in hearing loss remains unclear. Dr
Jeffrey Savas, Assistant Professor of Neurology
at Northwestern University, Feinberg School
of Medicine, USA, heads up a lab dedicated to
understanding neurological conditions, including
deafness, at the molecular and genetic level. His
current project focuses on the effects of loud noise
upon protein molecules and synapses in the inner ear.
34 www.researchoutreach.org
I
n a world dominated by verbal communication, deafness
or even partial hearing loss can be debilitating. Hearing
impairment is one of the most common sensory disabilities,
affecting one in five adults in the US: four times as many people
as MS, spinal cord injury, stroke, epilepsy, Parkinson’s and
Huntington’s diseases combined.
TURN DOWN THE VOLUME
The most common cause of hearing loss is exposure to
excessively loud noise, a situation faced by millions of people
daily in the course of their work. A key target, then, for deafness
research is to determine exactly how noise causes hearing
damage at the cellular and molecular level, and therefore how its
effects can be minimised, treated, or even prevented.
The work of Dr Savas’s lab focuses
on the role of the ‘proteome,’ the
total complement of protein types
found in any given cell or tissue,
in a range of neurodevelopmental
and neurodegenerative diseases
such as Alzheimer’s, Huntington’s,
and Parkinson’s, as well as hearing
impairment. By identifying differences
between the protein complement of
healthy and diseased tissues, he aims to
pinpoint potential protein targets that
contribute to these conditions. Dr Savas
describes this work as, “Searching for
hidden proteomes that can guide
us into previously underappreciated
and largely uncharted areas of
neuroscience.”
CRITICAL MASS
Dr Savas’s investigations centre
on an analytical technique, mass
spectrometry-based proteomics, which
is becoming increasingly prevalent in
bioscience research. The method can
identify and quantify the individual
molecules present in complex mixtures
based on minute differences in their
mass, and can simultaneously analyse
thousands of molecules in just a few
hours. Dr Savas calls this first step
“generating a protein parts list”. Using
mass spectrometry, he can identify the
proteins present in a healthy inner ear,
and then go on to study what happens
to those proteins when hearing is
impaired by exposure to high levels of
noise.
His team’s research involves subjecting
mice (which, being mammals, have
inner ears analogous in basic structure
to humans) to varying levels of noise,
and then extracting their main hearing
organ – a spiral, snail-shaped structure
called the cochlea – to undergo mass
spectrometry. This will determine
Above: Fluorescent image
of immunostained mouse
cochlea after noise exposure
(Myo7a = red, CtBP2=green,
GluR2=blue). Image credit:
Miguel Ramirez.
Above: Fluorescent image of
mouse cochlea expressing GFP
in hair cells. Image credit: Ann
C. Y. Wong.
A key advancement for deafness research
is to determine exactly how noise causes
hearing damage at the proteomic level
which proteins in the cochlea change in
concentration or structure after being
subjected to damaging noise causing
temporary or permanent hearing loss.
It is clear from the research so far that
loud noise causes substantial changes
to a surprisingly large number of
cochlear proteins. Furthermore, of
the thousands of proteins measured
in the mouse cochlea, Dr Savas’s
team identified a small number which
changed significantly in abundance
depending on the level of noise
exposure. Interestingly, many more
of these were found to increase in
response to noise rather than decrease,
and many of them were associated
with structures known as proteasomes,
collections of enzymes involved in
breaking down proteins. This indicates
that loud noise stimulates pathways
within the cochlea which cause protein
degradation. Key signalling proteins
were also enhanced, some of them as
noise progressed from temporarily- to
permanently-damaging levels. All of
these proteins provide potential targets
for further investigation.
SPLITTING HAIRS
However, to decipher the causes of
noise-induced hearing loss in detail,
Dr Savas needs to know where the
important proteins are localised
within the cochlea, a complex organ
comprising several different types
of cells. He has now made progress
towards isolating and purifying these
cell types, in particular the tiny inner ear
hair cells that actually perceive sound
when it enters the cochlea, so that mass
spectrometry can, for the first time ever,
determine protein composition.
Although hundreds of proteins were
more abundant in hair cells than in the
rest of the ear, including some found
only in the hair cells and nowhere else,
many of these are at very low absolute
concentrations, making them very
difficult to isolate and characterise.
Dr Savas’s lab are exploring different
methods and designing a targeted
mass spectrometry analysis protocol to
accurately quantify such small numbers
of molecules, many of which may be
critical to both hearing and balance.
Already, they have found a set of thirty,
www.researchoutreach.org 35
 Behind the Bench
Dr Jeffrey Savas
E: jeffrey.savas@northwestern.edu T: +1 312 503 3089 W: http://www.savaslab.com
W: http://www.feinberg.northwestern.edu/research/news/people/faculty/j-Savas.html

Research Objectives • Collaborators: Northwestern University in February

Dr Savas’ work focuses on noise-
induced hearing loss and the effect
that noise has on cochlear synaptic
proteins. He is particularly interested in
translating his results into treatment or
prevention methods.
Funding
National Institutes of Health (NIH)
Collaborators
• Lab members:
• Post-Doctoral Fellow: Nopporn
Jongkamonwiwat, PhD
• PhD student: Miguel Ramirez
• Allen F. Ryan, PhD, UC San Diego of 2015.
School of Medicine, La Jolla, CA
92093 Contact
• Joris de Wit, PhD, VIB and KU Leuven, Jeffrey N Savas, PhD
Leuven, Belgium Northwestern University
Ward Building Room 12-102
Bio 303 E Chicago Avenue
Jeffrey Savas received a Bachelor of Chicago IL 60611
Science in Biochemistry and Molecular USA
Biology at the University of California,
Santa Cruz and his PhD from New
York University School of Medicine. He
completed his postdoctoral training
at The Scripps Research Institute in
La Jolla. The Savas Lab opened at

Q&A of the National Institute of Aging (NIA)

previously-undetected proteins linked
to deafness and significantly enriched
within cochlea hair cells – suggesting
potential targets for genetic studies
into deafness.
The lab’s current research focuses on
determining how their newly-identified
cochlear proteins are affected by
moderate noise resulting in temporary
hearing loss, a process which appears
them. Dr Savas now aims to explore
the functions of Nrxn and Nlgn and
how they may contribute to stabilising
cochlear synapses to hopefully prevent
hearing loss.
This is ground-breaking research and
the inner ear proteome generated
in the Savas lab – although the most
comprehensive ever developed –
Above: Fluorescent image of mouse cochlea hair
cells. Image credit: Chelsee Strojny.
expression atlas’ of the mammalian ear.
Proteins do not, he says “function in
isolation … we aim to identify groups
of co-regulated proteins to accelerate
our understanding of noise-induced
hearing loss”.
Certain drugs are already known to
Could you briefly describe the
structure of the inner ear and
the importance of its different
components in your work?
Sound enters the outer ear, is
transmitted through the middle ear,
and is converted to fluid pressure
waves at the cochlear oval window.
In the cochlea, pressure variations
are distributed by frequency along
the length of the basilar membrane.
Vibration of this membrane stimulates
the hair cells through shearing forces
and the National Institute of Neurological
Disorders and Stroke (NINDS) were
both more than three times that of the
National Institute on Deafness and Other
Communication Disorders (NIDCD). One
of the major reasons for this difference in
the level of funding is that deafness, while
significantly lowering the quality of life,
does not kill.
You use mice as models for humans in
your work. How can you tell what a
mouse is hearing?
Good question. We use an approach
those driven by gene mutations like
cancer or autism, studying changes
at the level of changes in the DNA
sequence is essential. However, in the
case of noise-induced hearing loss,
caused by acute synaptic excitotoxicity,
stress, and physical damage, studying
changes in the actual cellular
machinery is a much more relevant
measure.
How could the results of your
research be translated into actual
treatments for, or protection
against, hearing loss?

An understanding of the inner protect against noise-induced hearing

loss, and Dr Savas hopes to be able to
ear proteome will accelerate our compare the proteome of mouse ears
treated or untreated with these drugs,
understanding of how the ear works in to explore their mechanism of action.
in their stereocilia that trigger neural
signals that are transmitted to the
auditory neurons across specialised
synapses at their base. While hair
cells, and spiral ganglion neurons are
called Auditory brainstem response
(ABR). In ABR audiometry, we place a
tiny microphone into the mouse’s ear,
provide stimulating sounds at increasing
intensities, and simultaneously measure
Recent data show that those synaptic
contacts formed between inner
ear hair cells and auditory nerve
fibres are the most noise sensitive
elements in the cochlea. Prolonged

healthy and pathological conditions

to be critically linked to changes
occurring at the junctions, known as
‘synapses’, between hair cells and
nerves. Two proteins in particular –
Nrxn and Nlgn – have been identified
as playing key roles in maintaining these
synapses and regulating signals across
remains incomplete. In a project funded
by the US National Institutes of Health
(NIH), Dr Savas will continue to explore
the role of the proteins responsive to
noise in the mouse ear, and to measure
those found at very low abundances,
ultimately generating a ‘protein
Working with clinical or industrial
partners, this could lead to therapeutic
strategies to protect inner ear hair cells
and synapses. Dr Savas believes his
first draft of the inner ear proteome
is set to accelerate the whole field of
research into hearing loss and, he says,
“kick start the development of effective
therapeutics to eventually treat and
prevent noise-induced hearing loss”.
certainly central cellular players in
the process of hearing, the cochlea
contains many other cells that provide
physical and chemical support.
Has hearing loss received enough
study over the years compared to
other neurological conditions?
No. For example, the 2017 NIH Budget
the neuronal responses emanating from
the cochlea all the way to the brain with a
recording electrode.
Why did you choose to study the
proteome rather than the genome?
What can the proteome tell us that the
genome cannot?
In some biomedical contexts such as
exposure to moderate levels of noise
causes a dissociation of the pre- and
post-synaptic membranes. We have
identified those proteins that physically
bridge these synapses and are actively
working to identify molecules that can
stabilise these interactions and prevent
noise-induced synapse loss.

36 www.researchoutreach.org www.researchoutreach.org 37
Health & Medicine ︱ Dr Brunhilde Wirth

Unravelling the cellular mechanism

of spinal muscular atrophy:
from gene and modifiers to therapy

Spinal muscular atrophy (SMA) is a common
neuromuscular disease characterised by weakness
and wasting of muscles. People with the most severe
form of the disease are unable to sit or walk and die
within the first two years of life. Although the genetics
of SMA are well understood, the cellular mechanisms
involved are unclear and there is currently no cure.
Professor Dr Brunhilde Wirth at the University of
Cologne is using advanced genetics to discover SMA
protective modifiers and various animal models to
unravel the cellular mechanisms responsible for SMA
and networks of protection, with the ultimate goal of
developing novel therapeutics.
T
here are currently ~50,000 people living with SMA in
Europe and the USA and, in the European population,
one in every 35 people is a carrier of the disease. SMA
is characterised by the progressive loss of motor neurons –
specialised nerve cells that innervate muscle and stimulate
contraction – and impaired neuromuscular junctions – the
synapses between motor neurons and muscle cells. In patients
with SMA, the muscles are under stimulated and so they weaken
and waste away in a process called atrophy.
SURVIVAL MOTOR NEURON
People with SMA have a deficit of a vital protein called
“survival motor neuron” (SMN). SMN is produced by all
body cells and is important for their survival. However, motor
neurons require fifty times more SMN than any other cell
type. Most individuals with SMA have inherited two absent
copies of the SMN1 gene (the gene responsible for SMN
production) from their parents.
Neuromuscular junction of a SMA mouse at postnatal day ten

Humans have an almost identical

second copy of the SMN gene, called
SMN2. This gene also produces SMN
protein but, due to a problem with
the splicing process, only 10% of the
protein is functional. In SMA-affected
individuals, SMN2 is the only source
of SMN, so its copy number (humans
can have between one and six copies)
affects the severity of disease. For
example, patients with two absent
SMN1 genes and only two copies of
SMN2 will usually have the most severe
form of SMA (type I). These babies will
develop symptoms before six months
of age, will never be able to sit or walk,
will be dependent on respiratory and
nutritional support, and have a life
expectancy of usually less than two
years. People with two absent SMN1
genes but three copies of SMN2 usually
have an intermediate SMA and learn
to sit but never to walk. Those with
two absent SMN1 genes and four to
six copies of SMN2 usually have a mild
Dr Wirth’s research highlights the power
of protective modifiers to unveil the
cellular mechanisms and develop novel
therapies for SMA
form of the disease (type III or IV).
Onset of symptoms is not until later in
childhood or adulthood and patients
are able to sit and walk despite some
muscle weakness.
PHYNOTYPICALLY DISCORDANT
FAMILIES TEACH US A LOT
In rare families, relatives of SMA-
affected individuals may have no SMA
symptoms despite carrying two absent
SMN1 genes together with three or four
SMN2 copies, a combination that would
usually cause SMA. This suggests
there are other factors involved in
determining the severity of SMA.
By using advanced technologies to
study the genes and proteins of family
members in these SMA-discordant
families, Professor Wirth has identified
two proteins that act as SMA protective
modifiers: Plastin 3 (PLS3) and
Neurocalcin Delta (NCALD).
Family members with two absent
SMN1 genes who are unaffected by
SMA produce much more PLS3 than
their affected relatives. Conversely,
unaffected family members with
two absent SMN1 genes produce
much less NCALD than their affected
counterparts. Both high PLS3 and low
NCALD levels have been shown to

38 www.researchoutreach.org www.researchoutreach.org 39

Above: Neuromuscular junction at postnatal
day 21
protect against disease symptoms. For
example, in one SMA-discordant family,
in which two absent SMN1 genes
and only four copies of SMN2 usually
resulted in type III disease, low NCALD
levels protected five family members
across four generations.
The protective effects of high PLS3 and
low NCALD have been corroborated
by Prof Wirth’s group using animal
models of SMA, including mice, worms
and zebrafish. Here, high levels of
PLS3 or low levels of NCALD were
shown to reduce disease symptoms.
Using these same animal models, the
group also showed that both PLS3
and NCALD protect against SMA by
restoring endocytosis – a process that
is essential for recycling the synaptic
vesicles involved in transmission of nerve
impulses across the neuromuscular
junctions, which is impaired in SMA.
FROM GENE TO THERAPY
Having identified PLS3 and NCALD as
protective modifiers, Prof Wirth’s group
began to explore whether regulating
production of these proteins could be
used as a therapeutic strategy to treat
SMA. The group used mouse models
with either high PLS3 or low NCALD in
combination with a low dose of SMN
antisense oligonucleotides (ASOs),
small molecules that increase SMN
levels by targeting its production by
the SMN2 gene. Both approaches
dramatically reduced SMA symptoms.
Strikingly, small amounts of SMN-ASOs
in combination with low PLS3 increased
animal survival from 14 days to over 250
days. This situation is comparable to
severely affected type I SMA patients,
where ASO therapy increases SMN
production but not enough to cure the
40 www.researchoutreach.org
Cell body
Dendrite
Nerve
ending Myelin
People with the severe form of SMA need
a combinatorial therapy and a systemic
increase of SMN in every single cell
disease. In this instance, a combined
therapy with a second agent, such as
PLS3 or NCALD, could constitute a long
term therapeutic option.
The first SMN ASO-based therapy
(Spinraza) was recently FDA- and EMA-
approved. Since the Wirth group have
shown that a low dose of SMN-ASOs
in combination with high PLS3 or low
NCALD protects against even the most
severe type of SMA in mice, regulation
of these proteins could be used in
combinatorial therapies with Spinraza
to increase treatment efficacy.
Prof Wirth’s research highlights the
power of protective modifiers to unveil
Behind the Bench
Dr Brunhilde Wirth
Nucleus E: brunhilde.wirth@uk-koeln.de T: +49 221 478 86464 W: http://humangenetik.uk-koeln.de
Research Objectives
Professor Wirth’s research focuses on
the genetic and molecular roots of
neuromuscular disorders. Her team
have a particular interest in translating
their results into improved therapeutic
methods.
Funding
DFG, EU, SMA-Europe, CMMC
Collaborators
• Prof Matthias Hammerschmidt
Axon (Biocenter, Cologne)
• Dr Natalia Kononenko (CECAD,
Cologne)
• Dr Jay Gopalakrishnan (CMMC,
Cologne)
Q&A
Motor neurons are the most polarised cells in our
body with axons longer than one metre Does SMN deficit affect cells other
than motor neurons?
SMN has a housekeeping function
in snRNP biogenesis and splicing.
Therefore, when SMN falls below a
certain threshold, every single cell is
affected. Engineered SMA mice with
two absent mouse SMN genes and
two human SMN2 genes develop a
severe SMA, similar to people with
type I SMA. In addition, these mice
the cellular mechanisms and develop show impairment of almost every
novel therapies for SMA. The group single organ that has been analysed
are developing and using a number of so far. It is therefore very likely that
different methods and technologies to people with type I SMA and only two
identify the genetic cause of unsolved SMN2 copies also require more SMN in
motor neuron disorders and to every single cell and not only in motor
understand the genetic, biochemical, neurons to maintain their function
cellular and pathological basis of these lifelong.
disorders. They are also generating
and using mouse models, zebrafish Why is only 10% of SMN produced
and, most recently, Drosophila (fruit fly) by the SMN2 gene functional?
models as well as induced pluripotent SMN2 is an evolutionary recently-
stem cells to unveil the disease occurred duplication of SMN1 and
pathomechanism. Prof Wirth is now human-specific. The two SMN genes
extending her research to search for the differ by only five nucleotides. Each
molecular cause of osteoporosis. SMN gene has eight important
DNA pieces (exons) and seven less
• Prof Thomas Gillingwater (Univ.
Edinburgh)
• Dr Frank Bennett (IONIS
Pharmaceutical, Carlsbad)
• Prof Anja Niehoff (German Sport
University, Cologne)
• Prof Anne Hart (Brown University,
Rhode Island)
Bio
Professor Dr B. Wirth received her
Diploma in Biology and certificate
in Applied Genetics from University
Bucharest, and her PhD from University
Bonn. After a postdoc at the Imperial
Cancer Research Fund Laboratories in
London, she became a group leader
at the Institute of Human Genetics
important DNA pieces (introns). From
DNA to protein an intermediate product
(RNA) is generated, in which the introns
are removed (spliced). In SMN2 this
splicing process is impaired due to one
different nucleotide in exon 7. When exon
7 is lacking, the SMN protein is unstable
and rapidly degraded. Instead 10% of
SMN2 RNA carrying exon 7 produces
a SMN protein identical with the one
produced by the SMN1 gene.
Do people with mild SMA (types III
and IV) live relatively normal lives?
People with type III and IV have no
reduced life expectancy, but muscle
weakness. It is very likely that, if
presymptomatically-treated with Spinraza
or any other drug able to increase SMN
levels, these people will be cured.
Therefore, SMA needs to be included in
neonatal screening in Europe. Current
presymptomatic clinical studies with
Spinraza show the highest impact. In
cases of people with type I SMA, an
increase of SMN amount will most likely
turn them into a type II or III. For these
populations, we will need a combinatorial
treatment using the knowledge of our
independent protective modifiers.
in Bonn. In 2006 she received the
Venia legendi in Human Genetics
and became certified in Human
Genetics. In 2003 she was appointed
as full professor and chair of the newly
founded Institute of Human Genetics,
University of Cologne.
Contact
Professor Dr Brunhilde Wirth
Chair
Institute of Human Genetics
University of Cologne
Kerpener Str. 34
50931 Cologne
Germany
How are SMA-discordant families
identified?
In the past, when we tried to identify
the SMA-causing gene, we collected
all family members for linkage
(segregation) analysis. Shortly after
Dr Melki identified the SMN1 gene
in 1995, we analysed these unusual
families, in whom affected and
unaffected carried identical markers on
chromosome 5 where the SMN1 was
found. To our surprise, the unaffected
showed the same absence of both
SMN1 genes and identical copies of
SMN2 as the affected siblings. At first,
we even doubted whether SMN1 was
the SMA-causative gene, but then
more and more small mutations in
SMN1 were identified strengthening
the role of SMN1 in SMA.
How can production of PLS3 and
NCALD be regulated in patients?
Unfortunately, we neither understand
why in some individuals PLS3 is
upregulated nor why NCALD is
downregulated. We have some
interesting hypotheses and are working
on them to unravel the underlying
genetic mechanisms, but it will need a
lot of sophisticated work.
www.researchoutreach.org 41
Health & Medicine ︱ Dr C. James Lim
A shining light in the fight
against childhood leukaemia?
Dr C. James Lim, PhD, is an
Associate Professor at the
Department of Pediatrics,
University of British Columbia,
as well as Investigator at the
Michael Cuccione Childhood
Cancer Research Program at
British Columbia Children’s
Hospital, Vancouver, Canada.
His research group aims to
unravel the mechanisms
underlying acquired resistance
to chemotherapy in childhood
malignancies, with the goal
of identifying new treatment
strategies to improve the odds
for children fighting this disease.
42 www.researchoutreach.org
L
eukocytes (or white blood cells)
represent the body’s first line of
defence against infection, and an
effective immune response depends
largely on the timely mobilisation of
sufficient leukocytes to inflamed tissues.
Leukocyte targeting to infection sites is
orchestrated by a group of cell adhesion
receptor proteins that are present on
leukocyte surfaces. The α4-integrins
represent one group of cell adhesion
receptors that are highly expressed by
leukocytes, and the role of integrins
in leukocyte adhesion, migration and
resistance to chemotherapy has been the
focus of Dr Lim’s research.
Leukocyte targeting is fine-tuned via
an intricate balance in the interactions
between these cells and the environment
from which they originate, namely
the bone marrow stroma. The stroma
generates signalling cues and growth
factors for blood cell formation (a process
called haematopoiesis) in all types of
blood cells, e.g., red blood cells and
platelets, in the bone marrow.
ALL OUT OF CONTROL
Failures in the processes that regulate
leukocyte targeting can lead to leukaemia
and other immune diseases. Leukaemia
refers to a group of blood cancers that
often begin in the bone marrow, and are
characterised by very high numbers of
lymphoblasts, essentially abnormal and
underdeveloped white blood cells.
Dr Lim’s research group focuses on the
most common type of childhood cancer,
Dr Lim preparing samples to image on the microscope
acute lymphoblastic leukaemia (ALL). Dr The group made a breakthrough in 2013, role for α4-integrins in CAM-DR in ALL.
Lim points out that although treatment when they illustrated that the α4-integrins In a series of elegant experiments, the
outcomes are very good for childhood play a critical role in chemoresistance in group then showed that expression of a
leukaemia – with a success rate of ALL. Their findings corroborated with conserved region (known as a peptide
about 85% – there motif) common
is concern for the
remaining 15% of
In 2013, the group was the first to to all α-integrins
was sufficient to
cases that relapse
with drug-resistant
illustrate that the α4-integrins play a promote CAM-DR
in ALL cells, and this
forms. Treatment- critical role in chemoresistance in ALL process involves the
resistant relapsed coordinate influx of
leukaemia remains the leading cause for studies from other research groups calcium into and the efflux of doxorubicin
childhood disease-related mortality. showing that interactions between out of the cells. In essence, a process
integrins and associated proteins were initiated by cell adhesion via α-integrins
INTEGRINS IN CHEMORESISTANCE implicated in enhancing tumour cell pro- enhances the removal of doxorubicin from
A small number of cancerous cells that survival signalling and chemoresistance, the cells via molecular pumps, effectively
don’t succumb to initial chemotherapeutic in a process known as cell adhesion- reducing the drug’s dosage within the
intervention may persist as minimal mediated drug resistance (CAM‑DR). tumour cell and its efficacy.
residual disease. These incalcitrant
cells represent the most likely starting Dr Lim’s group first compared the The discovery by Dr Lim’s group that
point for relapsed cancers, which tend response to chemotherapy in ALL CAM-DR is not limited to a particular
to be multidrug-resistant in a manner lymphoblasts that either express α4- integrin or type of leukaemia provides
not limited to the agents used in initial integrins, or are engineered not to. hope that future attempts to target CAM-
chemotherapy. Dr Lim’s group examines When exposed to the widely used DR with new therapeutic agents will not
differences in cellular signalling between chemotherapeutic, doxorubicin, only improve treatment outcomes for
healthy and tumour cells in order to find leukaemic cells expressing α4-integrins leukaemia, but a broad spectrum of blood
clues about how chemoresistance gains a and adherent to the integrin substrate cancers.
foothold, and how exactly the α4-integrins were more resistant to elimination by
are involved in that process. doxorubicin compared to those without ENLISTING THE IMMUNE SYSTEM
α4-integrins, thereby supporting a direct The chemotherapeutic toolbox is rather
www.researchoutreach.org 43
versatile today, and Dr Lim reminds
us that “not all anti-cancer drugs are
created equal.” Here, he is referring to
the fact that certain drugs, including
doxorubicin, don’t just kill tumour cells,
but also stimulate the immune system
to recognise and eliminate cancer cells
in a sophisticated process known as
immunogenic cell death (ICD).
A key feature of ICD is the presentation
of a protein called calreticulin on the
surface of cells treated with drugs that
stimulate ICD. This cell surface calreticulin
then serves as an ‘eat me’ signal for
macrophages, a type of specialised white
blood cell, to engulf and destroy cancer
cells in a process known as phagocytosis.
SOLVING THE ‘EAT ME’ MYSTERY
Researchers investigating ICD were
fascinated by how calreticulin, which
is normally restricted to one particular
compartment inside the cell (the ER or
endoplasmic reticulum), reaches the cell
surface during ICD. Dr Lim’s research
group shed some light on this mystery
when they discovered that calreticulin,
released from the ER during periods of
drug-induced ER stress, moves through
the cytosolic compartment prior to its
appearance on the cell surface. While in
the cytosol, calreticulin can interact with
the cytosolic part of α-integrins, and this
interaction only occurs when integrins
are activated, either by cell adhesion or
upon stimulation with integrin agonists.
This means that when integrins are
activated, they bind calreticulin, thus
trapping it inside the cell, and the ‘eat
me’ signal (cell surface calreticulin) is
reduced. This finding, reported in a 2016
publication, is the first to demonstrate a
direct role for integrins and cell adhesion
in diminishing the likelihood of ICD, and
have implications in our understanding of
effective immunotherapy.
TARGETING THE TUMOUR
MICROENVIRONMENT
Once leukaemia has developed,
its continuous growth and ability to
metastasise (or spread) depends on
interactions between the leukaemic
cells and their surrounding cellular
environment, often called the tumour
microenvironment (TME). Within the TME,
the bone marrow stroma represents a
niche for leukaemic cells to interact with
microenvironmental factors (e.g., cell
44 www.researchoutreach.org
Colours: green - leukaemia cells (lymphoblasts); red - F4/80 labeled macrophages; blue - nucleus
Image shows leukaemia cells (green) phagocytosed/engulfed by macrophages (red). The leukaemia
cells were previously treated with a chemotherapeutic to induce immunogenic cell death. Photo credit:
Dr C-C Liu, UBC
adhesion factors such as integrins, which
promote their survival and contribute to
drug resistance).
The findings from Dr Lim’s group to date
support the notion of the TME being a
safe haven for cancer cells, and highlight
the TME as a promising target for the
therapeutic intervention of leukaemia.
UNANSWERED QUESTIONS
Based on Dr Lim’s findings to date, it
is conceivable that blocking integrin
Some chemotherapeutic drugs, including
doxorubicin, don’t just kill tumour cells,
they also stimulate the immune system to
eliminate cancer cells in a sophisticated
process known as immunogenic cell death
function might increase the ‘eat me’
signal to potentiate the effect of
chemotherapeutic drugs that induce
ICD. Targeting α4-integrin function with
neutralising antibodies can be an effective
therapeutic strategy. However, as Dr
Lim points out, complete abrogation of
α4 function can lead to potentially fatal
outcomes. This is due to the suppression
of immuno-surveillance, the coordinated
Behind the Bench
Dr C. James Lim
E: cjlim@mail.ubc.ca T: +1 604 875 2000 x 4795
W: http://bcchr.ca/our-research/researchers/results/details/chinten-james-lim
Research Objectives
Dr Lim’s work focuses on understanding the
effect of integrins, a group of cell adhesion
receptor proteins, on the development of
chemoresistance in acute lymphoblastic
leukaemia, the most common form of
childhood cancer.
Funding
• Canadian Institutes of Health Research
(CIHR)
• Natural Sciences and Engineering
Research Council of Canada (NSERC)
• Michael Cuccione Foundation
Collaborators
• BC Children’s Hospital Biobank (https://
activity of immune cells to seek and bcchr.ca/biobank/home)
detect foreign invaders such as bacterial
pathogens. Given the obvious importance
Q&A
of immuno-surveillance, novel strategies
that can selectively target α4-integrin
signalling in the context of CAM-DR are
preferable over complete α4-integrin Are integrin mutations known to be a
inhibition. feature of ALL or other blood cancers?
In general, mutated integrins is not a
The exact source of the protective feature associated with malignancies. The
signals that allow tumour cells to acquire roles associated with integrin function
in tumour cells are not unlike their roles
chemoresistance is not yet known, but
in normal cells. However, increased
it is likely that the bone marrow stroma
expression of certain integrins will likely
impact upon treatment response and
metastasis. In leukaemias and other
blood cancers, increased expression
of α4-integrins is a feature of minimal
residual disease and a prognostic
indicator of poor treatment outcomes.
How far away do you think we are
from seeing new anti-cancer drugs
targeting the integrins?
Due to the fact that integrins are
harbours these protective stimuli in the cell surface receptors and therefore
form of adhesion substrates and other readily targetable, a number of integrin
immune mediators that promote integrin therapeutics are in various stages of
activation. Future work in Dr Lim’s group clinical trials, with some already in clinical
aims to shed more light on the identity of use. The majority of these biologics take
these stimuli. This research could provide the form of inhibitory or neutralising
further insight into the potential of antibodies, facilitating the specific
integrin signalling as a novel therapeutic targeting of any one of the many forms of
integrins expressed in various cells and
target for the treatment of childhood
leukaemia and other malignancies.
Bio
Dr Lim is an Associate Professor with
the Dept of Pediatrics, University of
British Columbia. His lab is located at
the BC Children’s Hospital Research
Institute, where he studies the tumour–
immune microenvironment and how
their interactions influence treatment
efficacy. The major focus is evaluating how
cell adhesion via integrins and integrin
associated proteins provides cell survival
cues that diminishes the effectiveness of
certain chemotherapeutics.
tissues. For leukaemias and other blood
malignancies, pre-clinical studies show
that neutralising the adhesive function of
α4-integrins can enhance the susceptibility
of tumour cells to chemotherapy, while also
mobilising those cells that are ‘hiding’ within
the bone marrow stroma and other tumour
microenvironmental niches.
How likely are we to see resistance to
integrin-targeting chemotherapies?
I believe the goal for therapeutically
targeting integrins in leukaemia is to
mobilise the cells from the tumour-
microenvironment to achieve effective
chemotherapy, thus minimising the
occurrence of the residual tumour cells. It
is the residual tumour cells that become
chemoresistant upon relapse, so the
clinical aim will be to minimise minimal
residual disease. Resistance to the integrin
therapeutic in itself is unlikely. However, the
expression of specific integrins within the
tumour cells may shift to ones not being
targeted, facilitating CAM-DR from another
integrin instead.
What would be your biggest concern
about treating cancer via integrin
targeting?
The majority of biologics targeting integrins
Contact
C James Lim, PhD
Associate Professor, UBC Dept of Pediatrics,
3092-950 West 28th Ave
Vancouver, BC V5Z 4H4
Canada
Key Publications
Liu et al (2016) α-Integrin Expression
and Function Modulates Presentation of
Cell Surface Calreticulin. Cell Death Dis.
7:e2268. PMID:27310876
Liu et al (2013) The Membrane Proximal
KxGFFKR Motif of α-Integrin Mediates
Chemoresistance. Mol. Cell. Biol. 33:4334-
45. PMID:24001772
prevent the adhesion of the cells to target
tissues. It is important, in the context of
chemotherapy, that integrin antagonists
not only prevent cell adhesion, but also
prevent the integrins from becoming
activated. As implied from our studies
on the effect of integrins on ICD
(presented as surface calreticulin), certain
antibodies may neutralise the cellular
adhesive function while activating the
integrins (with nothing to adhere to but
the antibodies). In this context, we may
undermine the immune-stimulating
effects of drugs that induce ICD.
Do you expect that integrin-targeting
therapies will work for everyone, or
are we likely to see groups of patients
that won’t respond?
It is unlikely to be a ‘one size fits all’ form
of therapeutic as the various makeup
of the integrins within the types of
malignancies may dictate response. In
addition, on-going monitoring of the
tumour cell biology will be required to
determine whether shifts in the types of
integrins expressed are seen.
www.researchoutreach.org 45
Health & Medicine ︱ Dr Mari Golub
Fluoxetine (Prozac) F
luoxetine therapy has been used to
treat children with Major Depressive
use in children:
Disorder (MDD) and Obsessive
Compulsive Disorder (OCD) for over 14
years in the USA, and its use has recently
been expanded to other behaviour
disorders, including Attention Deficit
Hyperactivity Disorder (ADHD), anxiety
and autism. The drug, which has been
working towards a customised approach used in adults since 1987, was approved
More startling, and entirely new, was the
Dr Mari Golub from the Environmental Toxicology Department at the University of California at Davis, has
recently completed a five-year research project looking at the behavioural effects of fluoxetine (Prozac) on brain
development. Her findings, which have so far been published in eight academic papers, supplement information on
observation that behavioural responses
the safety of fluoxetine use in children, and show for the first time that an individual’s genetic make-up can influence to fluoxetine were influenced by
their reactiveness to the drug.
variations in the monkeys’ genes
46 www.researchoutreach.org
for use in children by the US Food & Drug
Administration (FDA) in 2003, following
a 19-week clinical trial in children. Apart
from the findings of this trial, and those
from a later toxicology study in rats,
experiments evaluating the safety of
fluoxetine use in children are limited. Dr
Golub’s work has focused on the potential
adverse effects of fluoxetine on brain
development, using the juvenile rhesus
monkey as a model.
Monkeys were given a dose of fluoxetine
each day for two years before the onset
of puberty. The dose used was selected
because it produced comparable levels
of fluoxetine and its metabolites in the
monkeys’ blood serum as found in the
blood serum of children successfully
treated with the recommended dose
of 20 mg per day. The monkeys were
assessed for growth, impulsivity, activity,
sleep, social interaction, attention and
emotional response, after one and two
years of dosing.
RESPONSES: BEHAVIOURAL AND
BIOLOGICAL
The results showed that monkeys treated
with fluoxetine had poor sustained
attention, were more impulsive, had
more disrupted sleep and displayed
more social interaction compared to
vehicle-treated controls (counterparts
who received a sham preparation with
no active ingredient). These results
confirmed some previously described
effects of fluoxetine in adults and
children. More startling, and entirely new,
was the observation that behavioural
responses to fluoxetine were influenced
by variations in the monkeys’ genes, and
the identification of several metabolic
biomarkers of response to fluoxetine.
DRUG-GENE INTERACTIONS
Fluoxetine belongs to a group of drugs
known as selective serotonin uptake
inhibitors (SSRIs). SSRIs are believed
to work by blocking reabsorption of the
neurotransmitter serotonin into the pre-
synaptic cell, thus increasing the level of
extracellular serotonin available to bind
to the post-synaptic receptor. Regulating
the level of extracellular serotonin helps
neurons to transmit messages, resulting
in a more stable mood.
Under normal circumstances,
serotonin levels are intrinsically
regulated. Monoamine oxidase A
(MAOA) is a protein that catalyses
the degradation of amines, such as
serotonin. The amount of MAOA
produced by an individual can vary
depending on their genetic make-up.
www.researchoutreach.org 47

When shown pictures with different affective content, the monkeys with low-MAOA genotypes had fewer emotional responses when they were treated
with fluoxetine. Reprinted from Golub MS et al. Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions.
Eur Neuropsychopharmacol. 2016 Dec;26(12):1920-1929.
In Dr Golub’s study, the monkeys’
genetic make-up was characterised
to establish for each individual whether
they had versions of the gene that
produced higher or lower levels of
MAOA. Using this information, Dr Golub
has shown, for the first time, that genetic
variation between individual monkeys
can influence their responsiveness to
fluoxetine. This was most significant when
looking at emotional responsiveness.
Monkeys treated with fluoxetine who
produced low levels of MAOA were less
emotionally reactive than their vehicle-
treated counterparts. Genes also affected
aspects of other behaviours. For example,
social invitations and initiations were
greater in treated monkeys with the
high MAOA version of the gene, whilst
grooming was enhanced in treated pairs
with the low MAOA version.
CORRELATING BIOMARKERS
WITH BEHAVIOURS
The outcome of fluoxetine treatment
can be uncertain for patients. In a recent
clinical trial, around 57% of children with
MDD or OCD were found to respond
to fluoxetine (compared to 33% who
were treated with a placebo). Prolonged
dosing is often the only way to determine
48 www.researchoutreach.org
The biomarkers were correlated with
impulsivity – a behavioural test affected
by fluoxetine after one year of treatment
whether the treatment will work.
Clearly, it would be more advantageous
if clinicians could predict how their
patients might respond to fluoxetine
before recommending it as a course of
treatment, and the results of Dr Golub’s
study could be a first step towards the
development of such precision medicine.
Precision medicine seeks to use
biomarkers to optimise the use of drugs
such as fluoxetine in individual patients.
With this in mind, Dr Golub looked for
metabolites that appeared in the blood
serum, cerebrospinal fluid and fibroblasts
(skin cells) of monkeys after one year of
treatment with fluoxetine. To understand
whether these biomarkers of fluoxetine
response predicted behavioural effects,
the biomarkers were correlated with
impulsivity – a behavioural test affected
by fluoxetine after one year of treatment.
The MAOA genotype of the subjects
was also included in the analysis to define
Behind the Bench
Dr Mari S. Golub
E: msgolub@ucdavis.edu T: +1 916 205 9892 W: http://www.cnprc.ucdavis.edu/mari-golub/
W: http://etox.ucdavis.edu/directory/adjunct-professors/golub-mari/
Research Objectives
Dr Golub’s research has focused on the
effects of drugs, toxicants and poor
nutrition on brain development using the
rhesus monkey model. Her most recent
project assessed the effects of fluoxetine
(Prozac) on brain development.
Funding
• HD065862 – this grant supported
research to supplement information
on the safety of fluoxetine for children
by using a juvenile non-human primate
model
• OD011107 – this grant supports the facility
and staffing of the California National
Primate Research Center
Q&A
Why were juvenile rhesus monkeys
chosen as a model to study human
brain development?
Non-human primates, like humans, have
a prolonged period of development
between infancy and puberty. During this
individual response. time, which we call childhood, the brain
continues to develop higher cognitive
abilities and acquire experiences that
Several metabolic pathways that were will guide the individual in the future. For
influenced by fluoxetine treatment were this reason, the effects of psychoactive
identified through the course of the drugs on children are most appropriately
study, including some which were also studied in non-human primates.
influenced by MAOA genotype and
associated with the impulsivity measure.
Continued research in this area could
yield potentially useful biomarkers for
predicting response to fluoxetine in
young patients.
At its completion, this five-year study
has advanced our understanding of the
effects of fluoxetine treatment on juvenile
brain development, helping to maintain
safe and effective use of this therapy, and
provided a glimpse of future treatment
options that may be available to children
with mood and behavioural disorders.
Dr Golub with her great-nephew Alex,
who has been a source of inspiration for
her research
• OD010962 – this grant supported the
genotyping of infants, to study genetic
sensitivity to the drug
Collaborators
• Christoph Turck, Max Planck Institute of
Psychiatry
• Csaba Leranth, Yale University
• Richard Sherwood, University of Missouri
• Casey Hogrefe, University of California at
Davis
• Alicia Bulleri, University of California at
Davis
Bio
Mari Golub received graduate degrees in
psychology, pharmacology and toxicology
What motivated you to research the
possible adverse effects of fluoxetine
treatment in children?
After fluoxetine was approved for children,
an increase in suicidal thinking was reported
in young people. This alarmed the medical
community and activated biomedical
researchers like myself to investigate the
side effects of this drug in children versus
adults. Also, our family has a young member
with autism who had been prescribed
psychoactive drugs. When I spoke to his
mother, she described her concern about
using the drugs and the value of more
information on their safety.
What other genetic variations could
interact with fluoxetine treatment?
Researchers are studying several genes
for interaction with fluoxetine in adults,
and also in transgenic mice. Prominent
among these is the gene for the serotonin
transporter (SERT). Monkeys will continue
to be valuable for this research as they
share many polymorphisms with humans,
including SERT polymorphisms.
This study has advanced our
understanding of the effects of
fluoxetine treatment on juvenille brain
development
from University of Michigan and the
University of California. Over a 40-year
career at the University of California at
Davis she has conducted studies of adverse
effects on brain development in animal
models including poor nutrition, drugs and
toxicants.
Contact
Mari S. Golub, Ph.D., DABT
CNPRC, Neuroscience and Behavior Unit
University of California at Davis
One Shields Ave, Davis, CA 95616
USA
When will we see the use of precision
medicine in prescribing drugs such
as fluoxetine?
Our monkey subjects were not selected
for any of the behavioural disorders that
occur in children, like depression, anxiety,
ADHD or autism. We hope that our study
will encourage physicians to look into a
possible role of MAOA polymorphisms in
response to treatment in children. Only at
that point will we have contributed to the
use of precision medicine in childhood
fluoxetine therapy.
As you near retirement, what have
been the highlights of your career
in developmental neurotoxicology
research?
When I began studying
psychopharmacology in the 1960’s, this
class of drugs was just being developed
and coming into widespread use. Our
fluoxetine study in non-human primates
was a fitting conclusion of my research in
this area.
www.researchoutreach.org 49
Thought Leader
High pressure talk with
Professor Rhian Touyz
At the Institute of Cardiovascular and Medical Science (ICAMS) at the University of Glasgow, world-renowned researchers
are dedicated to discovering mechanisms of cardiovascular disease (CVD) in their quest to advance new treatments and
to develop improved prevention, management and diagnostic strategies. Professor Rhian Touyz takes an innovative new
approach to preventing CVD by conducting extensive research into other intricately linked critical conditions. She spoke
with us at Research Outreach to discuss the institute’s aim, outlining the vital research and vision for the future.
P
rofessor Rhian Touyz is the Director
of the Institute of Cardiovascular
and Medical Sciences (ICAMS)
at the University of Glasgow, the
British Heart Foundation (BHF) Chair
of Cardiovascular Medicine and
Director of the ICAMS BHF Award of
Research Excellence. She specialises
in hypertension, abnormally high blood
pressure which increases the risk of
heart attacks, strokes, kidney failure
and cognitive decline (dementia). Her
mission is to help enhance human health
through her research into the causes
of cardiovascular disease.
Research Outreach caught up with Prof
Touyz to talk about the latest ICAMS
research and her role as leader in the
400-member institute. Here she discusses
the development of her fascination with
hypertension as one of the key causes
of CVD and provides an insight into the
organisation’s excellent contribution
to cardiovascular research. She also
discusses her earlier career and shares
her hopes for the future.
Hi Rhian! Can you tell us more about
the relationship between the Institute
of Cardiovascular and Medical
Sciences (ICAMS) and the British Heart
Foundation Glasgow Cardiovascular
Research Centre?
The Institute of Cardiovascular Medical
Sciences is a research-intensive institute
that focuses on cardiovascular research,
both basic and clinical, in the College
of Medical, Veterinary and Life Sciences
within the university. In 2014, ICAMS
was recognised by the BHF as a
Centre of Research Excellence, where
it was successfully awarded a highly
competitive grant. Through the award,
ICAMS established the BHF Centre
50 www.researchoutreach.org
of Research Excellence in Vascular
Bioscience and Medicine. The BHF
Research Excellence Award represents
an outstanding achievement, recognising
the calibre of expertise in pioneering
cardiovascular research here at ICAMS.
It’s very competitive and in the last round
of applications, there were thirteen
applications from the UK, of which six
institutions were awarded, including:
Oxford, Cambridge, Kings, Imperial,
Edinburgh, and Glasgow. We are very
proud to be part of these big-name
institutions, especially given the high level
of competition
Our institute focuses on cardiovascular
research, specifically cardiovascular
diseases. The diseases we focus on
relate to heart disease, especially heart
failure and ischemic heart disease or
heart attacks. We conduct research in
pulmonary hypertension, hypertension
or high blood pressure, along with
diabetes and metabolic disease as it
is implied in cardiovascular disease. In
addition to this, we have a very strong
programme in stroke research and kidney
failure because these pathologies are also
intricately linked to cardiovascular disease.
Those are our main areas of research in
terms of disease processes, and alongside
this, we also research the basic science
that feeds into the mechanisms of these
diseases, such as: molecular biology, cell
biology, redox biology, experimental
models, physiology, genetics, proteomics,
imaging, and electrophysiology. Taking
our research and discoveries from the
laboratory to the patients and population
is a major goal, and as such, we have
a very strong programme on ‘healthy
lifestyle’ and cardiovascular protection,
enabling us to interact very closely with
doctors in the hospitals.
Could you provide us with more detail
as to what hypertension is?
Some people often get confused and
they think hypertension means anxiety
or high stress levels but essentially,
hypertension means high blood pressure
or high pressure in the blood vessels.
Every time the heart beats, it contracts
and then relaxes, allowing the pressure
to be pushed along the vessel so that
the blood vessels can drive the blood
flow, supplying all the tissues and organs
with nutrients, especially oxygen. If that
pressure gets too high, it can cause Imaging arteries with fluorescent
damage to the blood vessels and organs. probes using high powered specialised
I always say that the best way of thinking microscopes allows researchers to
detect proteins and cells that regulate
about this is if you consider a hose pipe vascular function
with a tap at the end. If you turn the tap
on and the water flows through the hose
pipe, then this can be viewed as a healthy
working flow. But if you constrict the hose
pipe, or make the lumen or inside of the I believe we’re going to see big advances in using new
hose pipe narrower, the pressure naturally
must increase to allow for water to flow
technologies and methods to understand the fundamental
through, and that’s exactly what happens
with hypertension. The heart is the tap in
processes of cardiovascular disease
this analogy; it must pump harder to make
the blood flow through the vessels when
the pressure is higher, and this is what maintaining cardiovascular health. I’m inflammation, and also how that may play influential in the change to guidelines
causes damage to the kidneys, heart, embarrassed to say I don’t cycle myself a role in the injuries that underlie most for clinical practice.
brain and other organs. but I think that this research will make me cardiovascular diseases.
and many others start. Also, the research work conducted in
Are there any recent breakthroughs What impact has the BHF GCRC had Glasgow has historically played a major
or interesting projects that you’re We have conducted a vast amount on cardiovascular medicine since it was role in the management of stroke,
particularly excited about? of research on statins and how established? and in setting up a stroke unit that has
Yes, there’s a lot of exciting work going they influence cardiovascular and The BHF GCRC has played a very effectively improved the outcomes for
on. Our institute has greatly contributed cardiometabolic disease, especially in important role in several large clinical stroke patients. In fact, Glasgow has
and made a substantial impact to new relation to the treatment of diabetes. trials related to hypertension, heart generally played a very important role
treatments and clinical guidelines for heart These new breakthroughs will be failure and to statins or treatment of high in neurological disorders. For example,
failure, stroke, diabetes and hypertension. published later this year. cholesterol. We were very instrumental the universal Glasgow Coma Scale,
In fact, there was an enormous amount in some of the earliest studies in the devised right here by our neurologists,
of publicity recently from one of our My personal interest, at the basic field several years ago, and these have is the most common scoring system used
researchers who showed that cycling science level is to examine how small really impacted clinical cardiovascular to describe the level of consciousness in
exercises are particularly important for blood vessels undergo damage and medicine. Ultimately, those trials were a person following a traumatic brain injury.
www.researchoutreach.org 51

The wonderful Touyz lab – comprised of dedicated young researchers, students, post doctoral
fellows and technicians. This is a truly international lab with staff from Brazil, Poland, Greece,
France, UK, Canada, South Africa and Sweden
Can your research significantly change
the outcome of a stroke?
Well, we do know for example, that one
of the biggest ways to prevent stroke is
by maintaining normal blood pressure.
Hypertension is a major cause of stroke,
and so if we can control hypertension,
then we can prevent stroke by about
20–40%, and that’s been well proven.
Our scientists and clinical researchers
have discovered a treatment called
thrombolysis, otherwise known as
thrombolytic therapy, which is a treatment
to dissolve dangerous clots in blood
vessels, improve blood flow, and prevent
damage to tissues and organs. They
discovered that the sooner you complete
thrombolytic treatment, the greater the
chance of survival for stroke patients.
One of our stroke specialist doctors has
also played a very important role in the
establishment of a stroke unit, in terms of
when the patient comes in, what should
be done and how the stroke unit should
be organised effectively – this makes
Modern medicine of the near future will focus on treatment
of the specific disease characteristics of each individual
patient using a personalised or precision medicine approach
52 www.researchoutreach.org
a greater difference to the outcomes
for stroke patients.
As well as being the director, you are a
clinician scientist carrying out research
into hypertension, with an active role in
patient care. How do you find the time
to balance each of these positions?
To be honest, it is demanding and
challenging. Although, I am very
fortunate because I have a great network
of wonderful supportive staff along
with an outstanding PA who helps run
everything. Hence it boils down to great
team work. I am truly blessed because
I thoroughly enjoy every aspect of
my work – from the leadership to the
discovery science as well as mentoring
students to treating patients.
In terms of balancing my leadership,
clinical, and research role, it all comes
down to effective time management and
prioritising the work that really needs to
get done. These skills allow me to carry
out these roles successfully.
That sounds like a good recipe. What
initially triggered your interest in
hypertension research?
My interest in hypertension research
goes back many years ago to when I was
a medical student on a hospital ward
and I witnessed a very young man have
a terrible stroke. He essentially became
a quadriplegic, (a person affected by
paralysis of all four limbs). I asked the
consultant at the time, why did this young
man have a stroke and change from being
healthy to totally incapacitated? The
consultant said, “This patient had severely
high blood pressure and had that blood
pressure been controlled, the stroke could
have most likely been prevented”. At that
time, I asked, “What are the causes of
high blood pressure?” with the reply that,
“We don’t know exactly what the causes
of high blood pressure are”. Therefore,
my interest all stems from this first-hand
experience. I became intrigued to try to
discover the causes of hypertension, and
since then, I have specialised in that field.
I’m very interested in trying to understand
what causes high blood pressure, as
we already know that if you prevent
hypertension or properly control blood
pressure, other conditions directly
linked to cardiovascular disease can be
prevented. By preventing patients from
getting strokes, heart failure, heart attacks,
atrial fibrillation, dementia, or becoming
dependent upon on dialysis, where they
can’t work anymore and where they
spend a lot of time in hospital, we would
have a much healthier population; from
a public and economic health point of
view, this is much more attractive. That’s
why I’m so committed to this research and
study to try to prevent it or at least better
manage it.
So you’re now based in Scotland, but
were originally from South Africa, and
have worked across North America – do
you find that attitudes to cardiovascular
disease differ in each region?
Cardiovascular disease is a really important
Prof Touyz – a clinician scientist – working at the bench and the bedside
cause of both morbidity and death across
the whole world. We used to believe that
it was only in the more developed western
world that this was a problem. However,
today we now know that globally,
cardiovascular disease is the major cause
of morbidity and death. We believe this
is down to the fact that cardiovascular
disease, especially hypertension, causes
strokes, heart failure, kidney disease, and
even vascular dementia.
In terms of the attitudes of the
professionals, I think today everybody
appreciates that cardiovascular disease
is a medical priority that needs attention.
In each region I’ve worked in, I found
that the focus on prevention is very
important, especially in terms of lifestyle
modifications. Although, in Canada, South
Africa and here in Scotland, some of the
treatment protocols are a little bit different.
Of course, while all patients are
appreciative of good medical care, there
are a few notable difference in patient
attitudes across the different regions.
Thought Leader
I think this is all going to become much
clearer in the years ahead, and hopefully
modern medicine of the near future
will focus on treatment of the specific
disease characteristics of each individual
patient using a personalised or precision
medicine approach.
I also believe that we might see the
emergence of different methods in the
way we treat patients. Maybe we’ll use
different strategies, rather than using
drugs as we know them today. We
may use things like nanotechnology,
enabling more sophisticated diagnostic
opportunities and yielding improved
treatment. Essentially, new technologies
and new approaches will advance
over the next few years, along with the
development of a greater understanding
about the very fundamentals of disease
processes. Finally, we may even see more
management and treatment done within
the home, where patients and doctors will
be ‘hooked up’ through mobile apps and
other technologies.
• For more information about the Institute
of Cardiovascular and Medical Sciences
at the University of Glasgow, please
visit their website at www.gla.ac.uk/
researchinstitutes/icams/
In North America for example, patients
tend to assume more responsibility for
Professor Rhian M Touyz
their own health and medical situations.
British Heart Foundation (BHF)
Whereas here in Scotland, patients give Chair in Cardiovascular
most of the decision-making responsibility Medicine
to the doctors. Of course, this is just Director - Institute of
from my personal observations and Cardiovascular
experiences. At the end of the day, it’s & Medical Sciences
really important that patients get the best BHF Glasgow Cardiovascular
medical care that is appropriate for their Research
particular disease. Centre
University of Glasgow
How do you think cardiovascular 126 University Place
research will develop during the next Glasgow G12 8TA, UK
decade?
I think we’re at the start of a very exciting E: Rhian.Touyz@glasgow.ac.uk
time for cardiovascular research; in fact, T: + 44 (0)141 330 7775/7774
for all biomedical research. I believe W: www.gla.ac.uk/
we’re going to see big advances in researchinstitutes/icams
using new technologies and methods to
understand the fundamental processes
of cardiovascular disease. For example,
we talk about precision medicine today,
understanding the exact genetic make-
ups in each individual patient, in terms
of protein, metabolism and fats that can
contribute to the formation of diseases.
The University of Glasgow, Charity Number : SC004401
www.researchoutreach.org 53
Behavioural Sciences ︱ Dr Bipasha Baruah
How to promote
gender equity in the
green economy
C
The realities of climate change have prompted many nations to strive for ountries around the world are
greener industries. This includes the development of new technologies trying to make their economies
which are less carbon-intensive, and the overhaul of sectors such as energy less carbon-intensive by creating
and transportation where women are traditionally poorly represented in new green jobs, developing less polluting
the workforce. As the green economy develops, thousands of jobs will
technologies, and by retrofitting existing
be created, but it is unlikely that women will have equal access to these
sectors such as forestry, agriculture,
opportunities. Dr Bipasha Baruah, Professor and Canada Research Chair
tourism, manufacturing, water and waste
in Global Women’s Issues, Western University, Canada, examines the
management, construction, transportation
reasons for this inequality.
and energy production (ILO, 2011). A
gendered analysis of such green growth
and development strategies reveals two
blind spots. First, women are known to
have weaker access to new technologies
almost everywhere in the world (Hafkin
and Huyer, 2006) so there are likely to
be unequal access issues inherent in
the transition to low-carbon economies.
Second, it is well-established not only
that 70 percent of the world’s poorest 1.3
billion people are women and children
but also that women are already very
poorly represented globally in some
of the sectors that are critical to the
green economy. Women account for
nine percent of the global workforce in
construction, 12 percent in engineering,
15 percent in financial and business
services, and 24 percent in manufacturing.
Women have also long been marginalised
in the energy sector, where they constitute
less than six percent of technical
staff and below one percent of top
managers (UN Women, 2012). Without
appropriately targeted training, education,
apprenticeships, employment placement,
financial tools and supportive social
policies, transitioning to a green economy
may exacerbate existing gender inequities
and hinder global human development
goals. Dr Bipasha Baruah provides
recommendations for optimising women’s
54 www.researchoutreach.org
employment in four sectors that are
critical for the Canadian and global green
economy, namely, energy, manufacturing,
construction and transportation.
HIGHLIGHTING INEQUALITIES
More than 50 percent of university
students in Canada are women. So is
half the labour force. But women remain
severely underrepresented in sectors that
are going to witness dramatic growth
in the transition to a green economy.
For example, only 25 percent of those
employed in clean energy, 23 percent in
transportation, 12 percent in construction,
and 28 percent in manufacturing are
women. Within these sectors, women are
much more likely to be employed in lower-
paid clerical and administrative positions
than in high-skilled technical or managerial
positions.
Most green initiatives in Canada
have been driven by the private
sector, municipalities and provincial
governments. The federal government
has, at least until very recently, not
played an active role in framing and
implementing effective policies to enable
the transition to a low-carbon economy.
Despite growing evidence of the potential
for the green
economy to
generate a much
Without appropriately targeted training,
larger volume
of employment
education, employment, and financial
than the “brown” and social opportunities, transitioning
to a green economy may exacerbate
(fossil-fuel based)
economy, even
organisations
committed to
existing gender inequities and hinder
advocating for global human development goals
equity and social
justice in environmental sustainability in
Canada have never specifically addressed
gender inequity.
STICKY FLOORS AND
GLASS CEILINGS
Most future green job creation in Canada
will be in occupations in which women
are currently underrepresented, such
as engineering and the skilled trades.
A Statistics Canada study found that
in 2007, women only accounted for
one to two percent of completions in
apprenticeship training in major trade
groups (McMullen et al. 2010). Another
report published by Statistics Canada
shows that in 2011, women comprised
just 23 percent of engineering graduates
aged 25–34 (Hango, 2013). Since workers
are likely to transition from jobs in the
“brown” economy (which is heavily male
dominated) to the “green,” it is inevitable
that women will also be underrepresented
in green jobs unless gender equity in
employment is planned and implemented
proactively. Recent media reports confirm
this trend, indicating, for example, that
laid-off oil and gas workers in Alberta
are beginning to find employment in the
clean energy sector (Bickis, 2016).
The conversation about gender equity or
social justice (more broadly) in Canada’s
green economy is at best incipient and
tokenistic. Raising awareness is therefore
urgent and critical. Canada performs
better than the OECD average for the
gender employment gap (6.1 percent
compared to 11.7 percent), but the
gender wage gap in Canada is above the
OECD average (19 percent compared
to 15.5 percent). Not only does Canada
have a bigger gender wage gap than
other OECD countries, but women are
also severely underrepresented in all
high-growth green sectors (Thirgood et
al. 2017).
It is estimated that 200,000 new jobs will
be created in the Canadian construction
industry over the next decade but
women only account for four percent
of new registrants in the construction
trades (Status of Women, 2017). There
is also presently an estimated shortfall
of 20,000 employees in manufacturing
that could be filled more easily if
women were part of the manufacturing
workforce in larger numbers. New green
jobs in manufacturing will be linked to
the use of clean processing techniques
and pollution control equipment. The
transportation sector will also contribute
substantially to green employment
through new infrastructure, fuel-efficient
vehicles and the expansion of public
transportation systems.
The barriers and opportunities women
face in energy, transportation, construction
and manufacturing are similar because
they are all non-traditional occupations
for women. Our research points to
three major challenges for women in
these fields: lack of information about
employment, gender bias and gender
stereotyping, and masculinist work
cultures and working conditions. Women
encounter both “sticky floors and glass
ceilings” in these fields. In other words,
careers may never get off the ground
because of persistent and confining
stereotypes of feminised roles. And the
absence of role models and gender-
balanced initiatives makes moving up the
ranks more challenging for women.
OFFERING SOLUTIONS
We need targeted goals, monitoring
and enforcement to improve women’s
access to jobs in the growing green
economy. Much of the workforce in
low-carbon construction, manufacturing
and transportation will come from the
fossil-fuel dependent versions of these
sectors. We must start planning for
equity in the “brown”
versions of these
sectors if we expect
to see any changes in
the green economy.
Careers in these fields
must be targeted
more specifically
to women and girls
through avenues such
as recruitment sessions
and employment fairs.
Girls must be introduced at an early age to
the potential in these fields. Encouraging
young women to study science,
technology, engineering and math (STEM)
is critical since most technical jobs in these
sectors require STEM training.
Apprenticeships are often a requirement
before a worker can secure full-time
employment in these fields. Women have
difficulty completing apprenticeships
because the processes for entering them
remain highly informal and unregulated.
Additionally, many apprenticeships are
either unpaid or pay a nominal stipend.
This is also a major barrier for many
www.researchoutreach.org 55
 Behind the Bench
Dr Bipasha Baruah
E: baruah@uwo.ca T: +1 (519) 661 2111 (ext. 86316) W: http://publish.uwo.ca/~bbaruah/

Lawson Hall 3244 interdisciplinary research on gender, Funding

The University of Western Ontario
1151 Richmond Street
London, Ontario
Canada N6A 5B8
Bio
Bipasha Baruah is the Canada
Research Chair in Global Women’s
Issues and a tenured full professor in
the Department of Women’s Studies
and Feminist Research at Western
University. Dr Baruah conducts
development and globalisation;
women and work; and social, political
and economic inequality.
Collaborators
Sandra Biskupski-Mujanovic, a
PhD student in Women’s Studies
and Feminist Research at Western
University, provided very able
assistance on this research project.
Social Sciences and Humanities
Research Council of Canada (SSHRC)
Research Objectives
Dr Baruah’s research programme is
aimed broadly at understanding how
to ensure that a global green economy
will be more gender equitable and
socially just than its fossil-fuel based
predecessor.

Q&A substantial participation in STEM

workers. Having the opportunity to learn
a trade while supporting a family is crucial
in breaking down barriers many poorly
What are the major reasons for
women’s underrepresentation in
STEM fields?
I would say that there are three
major reasons for women’s
The barriers and opportunities women face underrepresentation in STEM fields.
First, there is systemic misperception
in energy, transportation, construction and and devaluation of women’s scientific
through progressive social policies
that include state-funded tuition and
scholarship awards at the undergraduate
and graduate level. Equity and access
policies that have been adopted by
other countries are often linear and
positivist. They do not seek any special
privileges for women and simply demand
that everyone receive consideration
like Brazil, India and China, at least
partially because they are perceived
as well-paid high-status occupations.
In 1998, women accounted for 43.3
percent of engineers in Russia. By
2002, that number had dropped to
40.9 percent. And the numbers have
continued to further decline. I use the
Russian example not to advocate a
return to Soviet-style central planning

manufacturing are similar because they are Q&A

represented groups, including women,
face in accessing skilled employment.
Fair and equitable access to paid
apprenticeships is critical for promoting
equity in green jobs.
and technical abilities. Women in
technical fields are deemed less
all non-traditional occupations for women competent than men even when they
are better qualified than their male
... women encounter both “sticky floors and peers. Second, public policies and
without discrimination based on sex.
They are inadequate because they fail
to address the wide range of social
and institutional factors that prevent
women from succeeding, and because
but rather to emphasise the value of
state initiatives aimed at improving
representation and removing barriers
for career advancement for women
in STEM fields. The Baltic nations of

glass ceilings” in these fields

Since women are already
underrepresented in key sectors of the
green economy, growth in these sectors
may further exclude women if proactive
measures are not adopted. Based on
women’s current patterns of participation
in jobs and training in these sectors,
almost none of the skilled green jobs
created in the next ten years, would go
to women. This highlights the dire need
for equity programmes and goals that are
monitored and enforced. Canada needs
all stakeholders – government, civil society
organisations, corporations, trade unions,
labour associations, public policy institutes
and think-tanks – to work together
to ensure equity in access to employment
in the green economy.
REFERENCES
Bickis, I. 2016. http://www.
huffingtonpost.ca/2016/01/27/oil-and-
gas-career-change_n_9089360.html
Hafkin, Nancy and Sophia Huyer. 2006.
https://www.amazon.ca/Cinderella-
Cyberella-Empowering-Knowledge-
Society/dp/1565492196
Hango, D. 2013. http://www.statcan.
gc.ca/pub/75-006-x/2013001/
article/11874-eng.htm
ILO. 2011. http://www.ilo.org/wcmsp5/
groups/public/@ed_emp/@emp_ent/
documents/publication/wcms_152065.
pdf
McMullen, K., J. Gilmore and C. Le Petit.
2010. http://www.statcan.gc.ca/pub/81-
004-x/2010001/article/11151-eng.htm
Status of Women Canada. 2017.
http://www.swc-cfc.gc.ca/rc-cr/bc-cb/
index-en.html
Thirgood, J., McFatridge, S., Marcano,
M. and J. van Ymeren. 2017.
https://mowatcentre.ca/decent-work-in-
the-green-economy/
UN Women. 2012. http://www.unwomen.
org/en/news/stories/2012/6/fast-
forwarding-women-s-leadership-in-the-
green-economy
corporate policies to enable equity
in training and employment in STEM
are either very weak or absent in many
contexts. And finally, the persistence
of patriarchal social norms and
assumptions about breadwinning and
caregiving make it difficult for women
to assert themselves at par with men
in these fields.
How can we enable more women to
succeed in these fields?
It is extremely important for
governments to create policy
frameworks to ensure gender equity
in STEM employment. We see
promising results in countries that
have done this. Brazil, for example,
has succeeded in enabling women’s
they do not demand preferential hiring
and promoting practices to correct
historical and current inequalities.
More comprehensive and finely-tuned
state and corporate policies that take
structural constraints into consideration
will optimise women’s entry into and
advancement in STEM fields.
Are similar patterns seen worldwide
with regard to the marginalisation of
women in certain industries?
The professional STEM community
in OECD countries may not be optimally
leveraging the message that these fields
are prestigious and socially important. By
contrast, much larger numbers of middle-
class women study engineering and other
technical fields in emerging economies
Estonia, Latvia, and Lithuania, which
were formerly part of the USSR but
joined the EU in the 1990s, revealed
similar patterns of comparably high
but declining rates of participation
by women in engineering and
technology fields. Female professional
and technical workers in Estonia still
outnumber men two to one. Estonia
offers significant tuition incentives
to draw high-school graduates into
fields such as engineering. The World
Economic Forum still identifies Estonia
as the country with the highest per-
capita number of female engineers,
even though, as in Russia, the numbers
of women joining the field in Estonia
have declined over the 1990s
and 2000s.

56 www.researchoutreach.org www.researchoutreach.org 57
Behavioural Sciences ︱ Professor Diana Brydon
W
hat exactly is globalisation
and how does it work?
Globalisation through
Globalisation is best
understood as a process by which people
and societies become increasingly
integrated or interconnected. Technology
a post-colonialist lens:
is at the heart of this process but so
are imaginaries, the unexamined ways
through which people make sense of
their changing world, establish their
values and tell their stories. As a result,
globalisation is characterised by both
understanding our past is key to our present frictions and flows, new sensitivities to
risks, and changing understandings of
home. The development of the internet,
portable communication devices
Professor Diana Brydon is a leading research scholar, working at the intersections of globalisation and post-colonial (phones and tablets) and the twentieth
cultural studies. Through her work, we can see how processes of globalisation have changed many aspects of our daily century development of air travel have
lives. She frames her study of concepts such as autonomy, community and democracy with the understanding that the enabled significant changes to the ways
history of colonialism is still entangled in contemporary research and knowledge systems: central to her work is the
we connect. A vital part of this relates
belief that we must learn from the past in order to ask better questions in the future.
to speed. Applications such as Skype
58 www.researchoutreach.org
have the potential to transform the
experiences of immigrants: a loved one
living thousands of miles away can be
contacted as easily as someone living in
the same town. It is as participants of such
processes that we find Professor Diana
Indigenous voices have been silenced
in the historical record [and] Indigenous
groups are woefully under-represented
by scholars in academic institutions
Brydon’s contributions so illuminating;
throughout her academic career she has
challenged the notion that globalisation
is solely a homogenising and economic
force. Her research goals are to evaluate
and advance the study of globalisation
and cultural practices in order to broaden
trans-cultural understanding, challenging
all the time the Eurocentrism and
methodological nationalism of many
disciplinary practices which have until
this point excluded and marginalised
women, cultural and ethnic minorities and
Indigenous Peoples.
THE ROLE OF THE IMAGINATION
IN CONTEMPORARY LIFE
Professor Brydon’s belief that the history
and continuing impact of colonialism
show us the many ways in which the
research imagination has shaped the
daily lives of people throughout the world
is at the root of her work. She looks to
literature, in particular, for insights into
the ways individuals and communities
negotiate belonging during times of
change. Since her early research on the
nature of Australian expatriate fiction,
Brydon’s work has studied the mobilities
of people and ideas across borders of
various kinds. Research into Canadian
settler colonialism is involving her in a very
current dialogue about Canadian culture,
history, and possible futures. Her country
is rethinking its colonial past and her city
is the home of a new national centre
of learning, the Canadian Museum for
Human Rights, established in Winnipeg in
2014, with its mission statement to ‘build
[…] a new era of global human rights
leadership’ and take visitors ‘on a journey
to erase barriers and create meaningful,
lasting change.’
This suggests a sea change in thought and
a desire to not just bring people together
now, but to make sense of how existing
cultural rifts came to be, and how they
might be healed.
Much of Brydon’s research which has
aimed to penetrate the entanglement
of Canada’s colonialist history within
global systems has been done through
collaboration with scholars, creators and
www.researchoutreach.org 59
 Behind the Bench
Prof Diana Brydon
E: Diana.Brydon@umanitoba.ca T: +1 204 474 8109 W: https://dianabrydon.com/

St. John’s College University of Manitoba,
92 Dysart Rd.,
Winnipeg, MB,
R3T 2M5
Canada
Brydon with colleagues Dr Roberto Bezerra da Silva (Federal University of
Rio de Janeiro) and Dr Vanderlei Jose Zacchi (Federal University of Sergipe)
posing with guides during their visit to the Escola Nacional Florestan Bio
Fernandes - Movimento dos Trabalhadores Rurais Sem Terra (MST) Diana Brydon (BA and MA University
of Toronto, PhD Australian National
University) took up the Tier 1 Canada
Top: April 27, 2015, the 2014 John M. Bowman
Her work is highly relevant in a
Research Chair in Globalization and
Memorial Winnipeg Rh Institute Foundation
Cultural Studies at the University of
Award was presented to Dr Brydon at a
world that is becoming increasingly
ceremony at the University of Manitoba Manitoba in 2006. Elected to the Royal
Society of Canada in 2008, she won the
uncomfortable with its past and anxious
Above: Following the Bowman ceremony, Dr Bowman Research Award in 2015, and
Brydon delivered a lecture: “Canada in the received an honorary doctorate from
about its future
World Today: Insights from the Humanities”. Linnaeus University, Sweden, in 2016.
Research Objectives
Professor Brydon’s research aims
to improve understanding of how
globalisation and culture interact and
what humanities-based study can
contribute to meeting global challenges.
Funding
Dr Brydon’s research is supported by
the Canada Research Chairs Program.
Additional funding received from: the
Social Sciences and Humanities Research
Council of Canada, the Aid to Scholarly
Publications Program (CFHSS), the
Canada Foundation for Innovation, the
Province of Manitoba, the University
of Manitoba, the Humanities Research
Institute (ANU), the Concurrences Centre
in Colonial and Postcolonial Studies
(Linnaeus University), and the Ford
Foundation.
Collaborators
Brydon thanks research collaborators
William D. Coleman, Marta Dvorák,
Gunlög Fur and Peter Forsgren, Irena
Makaryk, Lynn Mario Menezes de Souza
and Walkyria Monte Mór, Jan Aart
Scholte, and Helen Tiffin and graduate
student research assistants: Ademola
Adesola, Chigbo Arthur Anyaduba,
Ifeoluwapo Adeniyi, Vanessa Almeida
Nunes, Jeremy Strong, and Melanie
Dennis Unrau.

students, highlighting the importance of

an interdisciplinary approach to post-
colonial studies. By shining a light on
the literature of colonised peoples, she
presents the world with a new resource
by which to better understand – and learn
to respect – the perspectives of others.
In placing Canadian literature in settler
colonial, post-colonial and international
contexts, Brydon has also advocated
for the study of Canadian literature with
postcolonial reading strategies and
decolonising imperatives. Her current
research examines how speculative fictions
from around the world enable readers to
imagine a future beyond the limits of the
present.
COLONIALISM AND RESEARCH
PRACTICES
The forces that led to globalisation may
be reaching their limits. By its act of
‘shrinking’ the world, colonialism has
since the fifteenth century oppressed
and eradicated minority cultural practices
and groups while also preserving
records that may be consulted with
new sets of questions posed from the
perspectives of the previously colonised.
The legacies of such globalising
processes in the twenty-first century
include institutionalised misogyny and
ignorance of Indigenous culture. There
has been positive action more recently;
active resistance to such oppression
led to the United Nations Declaration
of the Rights of Indigenous Peoples in
2007, which not only affirms that any
doctrine advocating the superiority of any
peoples based on culture or ethnicity is
socially unjust but acknowledges that the
suffering of Indigenous Peoples historically
has prevented themselves and their
cultures from developing in accordance
with their own needs and interests. It is
time to listen to their stories and attend to
their visions of the future.
Indigenous voices have been silenced
in the historical record. In addition,
Indigenous groups are woefully under-
represented by scholars in academic
institutions. As Brydon’s research has
pointed out though, it is these voices
that are critical to coming to terms
with what it means to be, for example
‘Canadian’, today. Indigenous story-telling
is changing the literary landscape and
shifting understandings of land. Brydon’s
research has consistently advocated
I am proud of the trans-national, trans-
generational, trans-disciplinary research
for increased transnational and trans-
cultural engagement in cultural studies,
arguing that Indigenous resurgence,
multiculturalism and globalisation can best
be understood through contextualisation
of their entanglements at local, national
and global scales.
IMAGINING OTHERWISE
Professor Diana Brydon has been a force
in post-colonial studies of globalisation
and Canadian and international culture,
grappling throughout her career with the
idea that our understanding of history and
the world today can only be improved by
acknowledging and considering previously
(and often still) marginalised perspectives.
Her work is highly relevant in a world that
is becoming increasingly uncomfortable
with its past and anxious about its future.
Our best chance at co-existing in our
progressively integrated society is tied up
with our willingness to reflect on our past
and listen to the stories we have been
previously unable to hear.
Q&A
Your research has consistently
strived for a global understanding
of the past and the present; why do
you think this is so important now,
in 2018?
We still only have a partial view of our
history: that of the victors. The seeds
of the challenges we face were sown
many years ago and are now looming
so large we can no longer ignore
them. A lack of respect for other living
beings, human and non-human, is
now bearing fruit in rising seas, water
shortages, desertification, and the
social unrest they cause. I have turned
to fiction and poetry seeking answers
to the question of why people put up
with the way things are and how, when
they don’t, they can create a more just
world.
You have recently completed a
partnership project working on
Developing Transnational Literacies
with colleagues from Sao Paulo
University, Brazil. Can you tell us
briefly about the objectives of this
research partnership?
We aimed to create a reciprocal
dialogue between scholars working
and so many stereotypes separate
us. Our goal was to learn more about
each other’s countries and the different
challenges we face in teaching English
language and literature as a route toward
engaged critical thinking in global
times. Our focus fell on the challenge of
decolonising both English studies and
teaching practices. For us, transnational
literacy involves relearning how to learn,
questioning what counts as knowledge,
and the relations between knowledge
and privilege. For example, we visited
the National School run by the Landless
Workers Movement outside Sao Paulo to
learn more about their initiatives.
How far do you think research
practices have changed with regards
to post-colonialist/feminist readings
since you began your career in the
1970s?
Enormous progress has been made.
When I began my doctoral research,
I was warned I would never get a job
if I worked in these areas. Both fields
have benefitted from the development
of analyses of the structures of power,
within and beyond the academy, that
have prevented the contributions of
women and the colonised from being
taken seriously. The activism of social
a difference. The full challenge of
decolonisation, changing those
inequitable structures inherited from
the past, remains before us but we now
have a better understanding of what
meeting that challenge may involve.
Some of your publications have
been described as game-changing
and seminal; what work are you
personally most proud of?
I am proud of the trans-national,
trans-generational, trans-disciplinary
research team building I have been
involved in, training new generations
of scholars, and learning with others
how to think beyond the borders of
the training we ourselves received.
Those partnerships don’t end when
the research funding is over. Each
of my publications, individual and
collective, emerged from a moment
in time that seemed to require that
particular intervention. Most of my
work continues to ask questions
deriving from the “Globalisation and
Autonomy” project, especially those
set out in Renegotiating Community:
Interdisciplinary Perspectives, Global
Contexts, and further explored in
subsequent articles and books. But it is
always my latest project about which I

team building I have been involved in

racism, a dearth of opportunities for in Brazil and Canada. So much history justice advocates continues to make am most excited.
young people and a widespread societal

60 www.researchoutreach.org www.researchoutreach.org 61
Behavioural Sciences ︱ Dr Danie Meyer-Parlapanis & Dr Mareike Augsburger

A fascination
well as the development of appetitive
aggression.

Appetitive aggression is a form

with violence:
of biologically-driven aggressive
behaviour that does not serve the
purpose of resisting a threat, but
implies finding a certain pleasure in the
observation or perpetration of violence.
At a biological level, appetitive
aggression is accompanied by a surge

appetitive aggression in males and females in adrenaline, as well as the release of

cortisol and endorphins, hormones
that have a variety of physiological
functions, some of which include pain
Exposure to violence during childhood or at later stages of life can result in severe trauma, mental health issues, and alleviation and euphoria. A typical
in some instances, appetitive aggression, an acquired fascination by or pleasure in violence. Under the leadership of example is the aggressive disposition
Prof Dr Thomas Elbert, Dr Danie Meyer-Parlapanis and her co-author Dr Mareike Augsburger, from the University associated with hunting, resulting in
of Konstanz in Germany and the University of Zurich in Switzerland respectively, have been studying the effects bloodlust and taking pleasure in ‘the
of violence-related trauma on the appetitive aggression of male and female individuals, carrying out research on a kill’. Enhanced appetitive aggression
sample of war combatants. has been found to reinforce the cycle of
violence, leading to a positive feedback

H
uman beings have been found
to be traumatised or adversely
affected by victimisation and
by the witnessing of violent acts.
However, some seem to find the
perpetration of aggression appealing,
developing a form of ‘bloodlust’. It is
possible that this pleasure in violence,
named appetitive aggression, is part
of our species’ natural spectrum of
behaviours, but it also appears to be
affected or accentuated by particular life
experiences. While studies have found
exposure to childhood violence to be
the main driver for ongoing aggression,
recent research on war combatants has
revealed that high exposure to violence
in adulthood can be associated with
greater levels of appetitive aggression.
Importantly, these studies have focused
on the role of sex in the development of
appetitive aggression, shining a light on
its previously overlooked prevalence in
females.
THE STUDY OF
APPETITIVE AGGRESSION
During childhood or at later stages of
life, human beings might unavoidably
be exposed to violence, whether
in the role of witnesses, victims,
or perpetrators. The results and
consequences of this exposure can
be varied, including mental health
and behavioural issues, such as post-
traumatic stress disorder (PTSD),
depression, anxiety, and addiction, as
loop in which an individual repeatedly
seeks out acts of violence to feel a
degree of pleasure or satisfaction.
Exposure to contexts in which human
beings repeatedly perpetrate acts of
violence against one another, such as
domestic violence, organised crime,
or armed conflicts, can increase
the likelihood
of appetitive
aggression. Drs
Meyer-Parlapanis The researchers found no difference
and Augsburger
have carried out
in the level of appetitive aggression
extensive research displayed by combatants of different sex
into the effects
of exposure to
different forms of violence throughout
the lifespan, with a particular focus on
sex similarities and differences in the
development of appetitive aggression.
LUST FOR VIOLENCE IN WAR
COMBATANTS
In many war combatants returning from
the battlefield, appetitive aggression
has been found to provide resilience
against the development of PTSD
after being repeatedly exposed to
high levels of violence. Dr Meyer-
Parlapanis and Dr Augsburger have
carried out research on a sample of war
combatants in Burundi, examining the
relationship between their exposure to
or perpetration of violent acts and their
appetitive aggression.
Images taken by Dr Danie Meyer-Parlapanis during field work in Burundi
They found that exposure to war
and armed conflicts resulted in an
increased likelihood for the experience
of appetitive aggression, with all
combatants displaying substantially
greater aggressive tendencies than
males and females in civilian control
groups. “Furthermore, the more
violence perpetrated, often the higher
the levels of appetitive aggression,”
explains Dr Meyer-Parlapanis. Overall,
participating combatants suffered more
severely from PTSD symptoms than
civilians and had a significantly more
positive attitude towards aggression.
A GROUND-BREAKING
SEX COMPARISON
Aggression is often considered to
be a predominantly masculine trait.
Perhaps as a result of this, most studies
of appetitive aggression have been
carried out on male samples. Dr Meyer-
Parlapanis and Dr Augsburger, however,
incorporated both male and female
combatants, investigating potential
sex similarities and differences in the
observed post-war lust for violence.
In contrast to observations collected
on non-combatant
samples, the
researchers found
no difference in the
level of appetitive
aggression
displayed by
combatants of
different sexes. This
suggests that all individuals, regardless
of their sex, can display both mental
health complications and an increase
in appetitive aggression after being
repeatedly exposed to acts of violence.
Their studies did, however, reveal sex
differences in combatants who were
also victims of childhood maltreatment
and traumatic events. In males, both of
these factors were positively associated
with appetitive aggression; in females,
traumatic events had no association
with appetitive aggression and
childhood maltreatment was negatively
associated, suggesting that appetitive
aggression was less likely to develop
in those individuals. Furthermore,
perpetrated events were more strongly
correlated with levels of appetitive

62 www.researchoutreach.org www.researchoutreach.org 63

aggression for females than males,
and, unlike males, females’ acquired
dispositions towards aggression did
not appear to attenuate their mental
health issues after repeated exposure
to violence.
One of the research papers by Drs
Meyer-Parlapanis and Augsburger
suggests that “in both sexes, appetitive
aggression may have evolved as a
biologically prepared response to
cruel environments but might develop
along different trajectories”. Dr Meyer-
Parlapanis has further explored the
theme of sex similarities and differences
in appetitive aggression in her doctoral
thesis as a means to deconstruct what is
commonly understood as the ‘cycle of
violence’.
BREAKING THE CYCLE
OF VIOLENCE
The research carried out by Drs
Meyer-Parlapanis and Augsburger
highlights the need for further initiatives
to expand appetitive aggression to
actively include females. Appetitive
aggression is a key factor in fuelling
cycles of violence, often resulting in
recurring maltreatment and conflict,
frequently with ripple effects across
generations. Ultimately, the work of
Drs Meyer-Parlapanis and Augsburger
suggests that while some sex
differences have been observed in
the way individuals react to repeated
exposure to violence, ultimately both
Behind the Bench
Dr Danie
Meyer-Parlapanis
E: daniejmeyer@gmail.com
T: +49 7531 88 4065
W: http://loop.frontiersin.org/
people/257588/bio
64 www.researchoutreach.org
Research Objectives
Drs Meyer-Parlapanis and Augsburger’s
work looks at the psychobiology
of proactive human aggression.
In particular, they focus on the sex
similarities and differences in the
development of appetitive aggression.
Funding
ERC, DFG
Collaborators
• University of Konstanz: Prof Dr
Thomas Elbert; Dr Maggie Schauer,
Dr Anselm Crombach, Dr Corina
Nandi
Q&A
The left side depicts reactive aggression as is typical when one is in a threatening situation. Emotional
arousal increases, associated with negative emotions such as fear or disgust, as the body prepares
for fight or flight. The right side depicts appetitive aggression as is typical when one is hunting or
attacking. Emotional arousal similarly increases, associated, however, with positive emotions such as
excitement or desire. POMC is the precursor protein involved in the activated stress axis modulating
pain, whether it be triggering cortisol release in the hunted or endorphins in the hunter. (Figure Is appetitive aggression part of
adapted from one originally published in: Elbert, Moran & Schauer, 2017. Lust for violence: Appetitive human nature for both sexes and,
aggression as a fundamental part of human nature. e-Neuroforum, 23(2), pp. 77-84.) if yes, what evidence is there to
support this?
Danie: Elbert, Moran and Schauer
An enhanced appetitive aggression has
(2017) delineated that “…appetitive
been found to reinforce the cycle of aggression…is… an intrinsic part of
the human behavioural repertoire”
violence (p77). However, scientific discourse
continues to generalise appetitive
aggression as a human experience
sexes may be comparably vulnerable such in the consideration of mental while simultaneously limiting it as a
to experiencing appetitive aggression. health interventions and reintegration primarily male experience.
As Dr Meyer-Parlapanis says, “Neither programs.”
sex is immune to appetitive aggression Our studies have provided evidence
and should not be underestimated as that we cannot have it both ways:
females are capable of experiencing
appetitive aggression and further
studies investigating appetitive
aggression in all members of a
population are crucial if we want to
continue making the claim that, sex
aside, appetitive aggression is a part
of our human condition.
What main differences have
you found in the appetitive
aggression of male and female war
Dr Mareike combatants?
Augsburger Danie: Appetitive aggression in male
combatants was associated with
E: m.augsburger@psychologie.uzh.ch abuse or trauma experienced as
children. For female combatants, on
T: +41 44 635 73 05
the other hand, life-threatening events
W: www.psychologie.uzh.ch/de/bereiche/hea/ experienced in childhood were not
associated with appetitive aggression
psypath/Team/Augsburger-Mareike.html
and there was even a negative
• Université Lumière de Bujumbura:
Prof Manassé
• Medical School Hamburg: Prof Dr
Roland Weierstall
• vivo international: www.vivo.org/en/
Bio
Danie comes from Atlanta, Georgia,
USA and studied under Prof Dr
Thomas Elbert at the University of
Konstanz, Konstanz, Germany. She
submitted her doctoral dissertation
entitled “Deconstructing the Cycles
of Violence: A focus on female
experiences of appetitive aggression”.
She currently works in Cologne,
association for those who experienced
child abuse.
We also saw that the more violence
female combatants had perpetrated, the
greater the association with appetitive
aggression compared to their male
comrades, whose appetitive aggression
was more associated with general
combat experience.
Mareike: Most likely, males and females
develop appetitive aggression along
different trajectories. Cumulated
exposure to childhood violence
contributes to the evolvement of
aggressive behaviour in both sexes.
However, regarding specifically the
joy of acting violently (i.e. appetitive
aggression), the impact of child
maltreatment differs. Whilst it boosts the
development of appetitive aggression
in males, it has the opposite effect on
females: the more childhood violence,
the less appetitive aggression. In
females, active participation in war-
related violence (also if forced to do
so) seems to be a lot more relevant for
becoming appetitively aggressive.
How do these differences compare
to those observed in the appetitive
aggression of males and females
among the general population?
Mareike: This is a very interesting
question. Up to now, most research
has been done in populations affected
by long-term war and crisis. As a
consequence, empirical evidence for
the concept of appetitive aggression in
non-war affected general populations
Germany on trauma and aggression
related to displacement and
integration.
Mareike is currently affiliated with
the University of Zurich working on
associations between experiences of
sexual violence, risk behaviour (a “co-
actor” of aggression) and gender role
perceptions.
Contact
Dr Danie Meyer-Parlapanis, M.S.
University of Konstanz, 78457
Konstanz,
Germany
is rather limited. When it comes to
female appetitive aggression outside
a warzone, research is almost non-
existent so far.
Danie: Our first appetitive aggression
venture into civilian populations
investigated the sporting form,
Appetitive Competition Motivation
(ACM), in high-level, female football
players. These civilian women
reported experiencing forms of
appetitive aggression, in this case
manifested in unsanctioned fouls in
a high contact sport. The higher the
league level, the more accessible was
ACM.
In this study, we also considered the
impacts of upbringing style and other
socialisation factors. Less traditional
households and increased access to
toys and role models that were not
considered traditionally feminine
seemed to play a role later in these
female athletes savouring some
aspects of the aggression displayed
on the pitch.
What are your next steps in terms
of research and investigation?
Mareike: We are currently
investigating the female cycle of
violence by means of a meta-analytical
approach. This will give us a great
overview about the current state of
research regarding female aggression,
its predictors and consequences.
Based on findings derived from the
meta-analysis, we will develop further
studies.
www.researchoutreach.org 65
 O
Behavioural Sciences ︱ Dr Raul Acosta Garcia
Emerging forms
ver the last few decades, Latin
America has had a roller-
coaster type of economic
development, albeit with a somewhat
upward trend. This has meant that an
of metropolitan
increased proportion of the region’s
population has become middle class,
although, this has often resulted in high
levels of economic vulnerability. With an
governance in
increase in affluence levels, education
levels have risen and an increase in leisure
travel has been observed as well. An
aspect of this process that has not often
Latin America
been investigated, is its implications for
the political sphere, especially regarding
non-governmental
In a previous project,
forms of organisation
and engagement.
Dr Acosta García’s
research project
Dr Acosta-Garcia explored the role
As Latin America’s middle classes have expanded considerably in the last few years, so have their aspirations for
entitled “Aspirational of dialogue in activists’ aspirations
Activism in Urban
improved living standards, especially in metropolitan areas. Since 2007, Dr Raúl Acosta García of the University
of Konstanz has been investigating the efforts of grassroots activists in Guadalajara, Mexico. During this time, he
Latin America” for improved forms of democracy
seeks to examine a
has witnessed a wave of activism through which people without any previous political experience have creatively growing demand for better metropolitan
challenged local government decisions. He has named their engagements ‘aspirational activism’ as they are not
governance models in the region in
driven mainly by ideology, but by yearnings for a better quality of collective life.
a context where stark socioeconomic
inequalities remain.
INCREASED EXPECTATIONS
Latin American cities have grown at
a rapid pace. Four-fifths of these city
populations now live in towns or urban
centres and a large proportion of these
urban dwellers live in shanty towns.
There has been a somewhat steady,
albeit slow, improvement in the quality
of infrastructure and housing. However,
corruption remains one of the most
difficult challenges to overcome, as it
wears down the quality of government
services and supervision, which in
theory should ensure a greater quality
of life and help avoid problems. In this
context, Dr Acosta García has chosen
to focus on activists who work towards
improved policies for mobility and
public space. The individuals who
engage in these issues strive for good
metropolitan governance through
specific proposals, knowledgeable
contributions, and creative
performances in the public sphere.
Through a social anthropological
focus, Dr Acosta García’s research
Activists from the collective Ciudad para scrutinises the cultural underpinnings
Todos (City for All) celebrate World Car-Free of what he identifies as a cultural shift
Day in Guadalajara, on September 22nd, 2013.
© Raúl Acosta García
in perceptions and practices of power.
Numerous Latin American countries
66 www.researchoutreach.org
have gone through various periods of
dictatorship or rulership under semi-
authoritarian regimes. These played
a role in the Cold War by suppressing
leftist movements that were considered
a threat by the United States. (An
example of this is how Mexico has been
analysed as living a ‘soft dictatorship’
during most of the twentieth century.)
This has meant that many dissatisfied
populations in Latin America either
rebelled in outright desperation
and with violence (for example, in
guerrilla fighting), or remained quiet
and adopted a submissive attitude.
As the Cold War came to an end and
there was a global resurgence of the
ideals of organised civil society, the
1990s witnessed a surge in citizenship
initiatives and expectations. These
coincided with an economic upsurge in
the region.
CYCLING AS A SYMBOL
Dr Acosta García focuses on the
activists that have chosen the bicycle as
a symbol of their aspirations. With little
to no infrastructure to provide safety
for its users, its promotion presented
clear potential. On the one hand, the
bicycle was already used by thousands
of poor workers and self-employed
retailers. On the other, it was becoming
an increasingly trendy vehicle for
middle- and upper-class individuals
to explore the city and countryside.
This combination allowed activists to
address some the region’s structural
inequalities by promoting safety for all
cyclists. This has come hand-in-hand
with efforts by international agencies
to reduce greenhouse emissions, and
with some cities’ goals of attracting
innovative companies and creative
individuals. Therefore, there has been
a convergence of goals which in cases
like Guadalajara, has seen the influence
of activists shaping visible changes such
as more cycleways, better public areas,
and improved public transport.
Dr Acosta García has witnessed this
movement in Guadalajara, one of his
field sites, which has become one of the
leading metropolises in Latin America.
Several of his research participants
now work for various local government
offices as experts in the activist issues
they previously participated in. Others
belong to networks that span the
whole of Mexico, Latin America, and
beyond, through which they can learn
from others and share their experience
with activists and government officials
from other cities. For many smaller
cities throughout the region, it is much
easier to relate to
a successful case
in the region, than
to try to imitate
what happens
in Europe or the
United States. This is
known as a south-
south connection,
which is increasingly important as the
most rapidly growing metropolises are
situated in the global south.
METROPOLITAN GOVERNANCE
Many challenges exist when it comes to
managing large cities. This is especially
the case when the population is not
used to basic democratic practices
that occur in Latin America. A key
change that Dr Acosta García has
identified is urban activists’ desire to
do away with the usual model followed
in the region of trusting that a single
person (usually a caudillo, or big
man) would carry out the necessary
changes. Many of the activists involved
are scholars or specialists in issues
like urbanism, environmental law, or
mobility. Therefore, they seek to put
forth models of governance that are
adapted to regional practices but avoid
unhealthy concentrations of power.
Through a savvy combination of
technical data and moral judgments,
activists have positioned their struggles
as radical changes in political culture.
Dr Acosta García’s research ultimately
aims to find out if this is the case, or if
the protagonists end up reproducing
what they have so strongly criticised.
As this project has progressed, Dr
Acosta García has noticed how the
legitimacy many activists have gained
has positioned them as strong men.
www.researchoutreach.org 67

What they do with this power in the
next couple of years, will determine
if they fall into the cyclic regional
co-optation through which numerous
movements have become parts of
the institutional landscape or, if they
manage to form an alternative political
culture with repercussions beyond
metropolitan governance.
EXPERIENCING CHANGE
An interpretation that has been
advanced by Dr Acosta García is that
whatever activists do, their influence
among wider populations can already
be identified as a positive form of
empowerment. As the activists
focused primarily on presenting live
performances in public spaces (i.e.,
public theatre on streets, parks, and
sidewalks), this helped onlookers to
develop a type of empathy for how
others experience the city. Drivers who
previously reacted aggressively towards
cyclists, for example, reflected on how
vulnerable they are on busy roads. In
addition to this, cyclists and pedestrians
themselves were also able to identify
how vulnerable they were in their day
to day cycling in a way they had not
previously done so beforehand. This
may provide a key insight into how to
address long-standing socioeconomic
inequalities and their effects.
Changes are already visible in
some cities, like Guadalajara,
where the number of cyclist deaths
has dramatically fallen as cycling
infrastructure has greatly improved.
Dr Acosta García’s project aims to
examine not only the physical changes
that governments have carried out,
but also the cultural adjustments that
activists have achieved. The future
goals are to provide more tools for
both government officials and activists
from other cities and regions that may
potentially develop good practices
in metropolitan governance. These
goals are aligned with funding bodies
increasing interest in research to
positively influence social development.
• For more information, please
visit http://gepris.dfg.de/gepris/
projekt/298748707
68 www.researchoutreach.org
Behind the Bench
Dr Raúl Acosta García
E: raul.acosta@uni-konstanz.de T: +49 (0) 7531 885671 W: http://gepris.dfg.de/gepris/
projekt/298748707 W: www.soziologie.uni-konstanz.de/en/chair-of-social-and-cultural-anthropology-
prof-dr-thomas-g-kirsch/team/staff/weitere-ethnologen-an-der-universitaet-konstanz/raul-acosta/
Ethnology and Political Anthropology
Department of History and Sociology
University of Konstanz
D-78457 Konstanz, Germany
Office: Y324
Funding
DFG
Q&A
What drew you to study
aspirational activism in Latin
America (Guadalajara and Sao
On November 9th, 2013, activists painted signs along six kilometres of a busy avenue to mark a
‘shared lane’ in order to make it safer for cyclists. © Raúl Acosta García Paulo) in the first place?
Social anthropology is the study
of human society and cultures.
Social anthropologists seek to
understand how people live in
societies and how they make their
lives meaningful. My interest in the
political sphere has been focused
on non-governmental efforts to
address issues that individuals felt
were not adequately dealt with by
government institutions. In studying
forms of collaboration between
non-governmental organizations
(NGOs) and social movements in
Guadalajara, I noticed a double trend
of increasing interaction among
similar groups across Latin America
and more sophisticated expectations
derived from the growing prosperity
throughout the region. To study the
resulting phenomenon, I developed
the term ‘aspirational activism’.
What were some of the main
challenges with getting so involved
with the subjects of your study?
To go beyond what people say,
For a long time, major infrastructure
anthropologists seek to socialise with
the communities we investigate. In
projects in Guadalajara were car-centric. the study of activism, this also means
taking part in the public interventions
Over the last couple of years, cycleways and meetings that activists carry out.
The main difficulty this generates
have become more common is distrust among the people one
Bio
Raúl Acosta García holds a DPhil (PhD) in
Social Anthropology from the University
of Oxford. Before joining the University
of Konstanz, he was an assistant
professor in ITESO, Guadalajara, Mexico,
and Research Fellow at the University of
Deusto, Bilbao, Spain.
is most interested in, as nobody likes
being observed as a ‘lab rat’. This is
addressed by trying to give something
back. Thus, I always clarify that with my
analysis, I want to provide feedback
for activists and government officials
to improve public decision-making
processes.
What do you expect some of the
main conclusions to be?
After a few decades of stifled processes
of democratisation in the region,
various Latin American countries have
gone through interesting processes
of more assertive citizens’ initiatives
regarding metropolitan governance. I
foresee that my conclusions will point
towards a changing political culture
that derives from more awareness of
the value of pressuring government
officials to account for whether they
reach their various targets or not and,
with an overall vision of the expected
result. This may provide clues to more
complex political developments that
are also currently taking place, like the
rise of independent candidates for
various offices, or the increasing role of
consultancy firms in drafting policies.
Are you aware of similar strategies
from other similar citizen activist
groups outside of Latin America?
What have been the outcomes of
their efforts?
The concept of ‘aspirational activism’
can be applied to similar phenomena
around the world. My aim is to develop
it to an extent that it becomes a useful
Research Objectives
Dr Acosta García’s research project
seeks to examine the way in which a new
generation of activists demands changes
in metropolitan governance to improve
the quality of life for urban dwellers.
analytic tool to investigate them.
With the purpose of both seeking to
position the concept and exploring
its relevance, in 2019, I will organise
an international workshop among
anthropologists investigating the
emerging middle classes around
the world, but especially in the
global south. Geopolitical shifts in
power models may also play a role
in reducing the influence of certain
development agencies, so home-
grown initiatives can become even
more relevant.
Once you’ve finished drawing
your conclusions of this study, do
you have any other areas of Social
Anthropology that you would like
to investigate?
There is plenty more that interests
me in the field of political
anthropology, but I am also
increasingly engrossed by issues
relating to biosociality and ethics.
Regarding the first area, interactions
between humans and other species
of animals, plants, or microorganisms.
But here, I also find the implications
for political decision-making
fascinating, (for example, regarding
animal rights). My interest in ethics
is very much linked to the political
sphere. I intend to explore complex
negotiations that occur among
people whose moral frameworks are
in stark contrast to each other. This
approach could also be carried out in
terms of aesthetics, materiality, and
embodiment.
www.researchoutreach.org 69
Biology ︱ Dr Meghann Jarchow
A sustainable approach to
environmental management
Ten faculty members from the
University of South Dakota
and eleven undergraduate
students from across the
United States including Puerto
Rico, came together through
the Sustainable RIVER
(Remediating InVasives
to Encourage Resilience)
program to study how a
complex suite of historical and
contemporary factors affect
the current functioning and
management of the Upper
Missouri River.
Map of the Missouri River Basin. The six
mainstem dams managed by the US Army
Corps of Engineers and their resulting
reservoirs are shown in addition to the
Native American reservations that had
significant flooding from the damming of
the Upper Missouri River.
70 www.researchoutreach.org
M
ost of society’s grand
challenges involve complex
and interdisciplinary systems,
and new approaches are needed to
effectively address these challenges
and create opportunities for enhanced
sustainability in the future. This includes
teaching upcoming leaders in science
and society how to delve into research
and action on these unwieldy systems
that are biophysically, culturally, and
historically complex.
For the Sustainable RIVER project, the
Upper Missouri River (UMR) was used
as the focal system. The Missouri River
is the longest in the United States, and
its watershed drains approximately
17% of the contiguous United States.
The UMR contains the unchannelised,
but dammed, portions of the river.
The lands surrounding the UMR were
home to numerous Native American
communities, including the Očéthi
Šakówiŋ (the Great Sioux Nation) and
the Arikara, Mandan, and Hidatsa
tribes, and today, are dominated by
agricultural land uses, primarily grazing
lands and annual row crops.
A COMPLEX SYSTEM
Six mainstem dams were constructed
by the US Army Corps of Engineers on
the UMR from the 1930s through to the
1960s, largely for flood control, and
the reservoirs created from those dams
make up the largest reservoir system
in the United States. The siting of the
dams resulted in disproportionate
flooding of Native American
reservation land. Reservations comprise
approximately 10% of the land area
of the Upper Missouri River Basin,
yet approximately 30% of the land
that was flooded in the creation of
the reservoirs, was reservation land.
Although the Native Americans who
have cared for the UMR for millennia
do not believe in ownership of land
or water, the UMR is now heavily
managed, and that management has
dramatic effects – both positive and
negative – on functioning of the river
itself and the associated uplands.
The dams on the Missouri River
produce approximately 9 GW
(gigawatts) of hydroelectric power
annually. The Missouri River provides
water to millions of people and crop
fields, and acts as cooling water for
power plants. Recreational benefits
from the UMR have been estimated
at $68 million annually. The frequency
of flooding on the UMR has changed
from two annual flood pulses with
periodic larger flooding to no annual
flooding and two major floods on the
UMR in the past 60 years, which has
prevented most city and farmland
flooding but disconnects the river from
its floodplain. The dams have caused
downcutting of the river below the
dams and delta formation above the
dams. The physical impediment of the
dam, reductions in abundance of prey
fishes and aquatic insects, reductions
in spawning habitat, and oxygen-
depleted conditions at the head of the
reservoirs have contributed to the pallid
sturgeon being listed as an endangered
species. The marked reduction in the
number and area of open sandbars,
due to the cessation of flooding,
has caused the least tern to be
Rebecca Krasky presenting a poster summarising her research
at the South Dakota EPSCoR Undergraduate Research
A systems-thinking approach
considers a variety of
environmental, social and economic
factors to produce an outcome that
explicitly considers trade-offs and
opportunities for synergies
endangered and the piping plover to
be a threatened species. Yet the dams
have prevented some invasive species
from moving upstream. The dams
also provide services to the millions
of people who live downstream. The
lands surrounding the Lower Missouri
River and subsequent Mississippi River
require the reservoir system of the
UMR to prevent large-scale flooding
while maintaining sufficient water for
navigation.
All the above, combined with
differences in the uses and value placed
on the river by different people and
communities, call for an approach
to management that considers the
needs of the river’s ecosystem and
environment, as well as those of the
people who use it.
SUSTAINABLE RIVER RESEARCH
Selena Olvera, a member of the
Sisseton-Wahpeton Oyate, analysed
the use of the river by Native
American tribes throughout history by
interviewing members of two tribes
Symposium in Pierre, SD.
within the basin, and highlighted the
impacts that European settlement
has had on them. The building of the
Garrison Dam in North Dakota in 1947
took swaths of land away from the
Arikara, Manda, and Hidatsa tribes.
This forced the members of these
tribes upland of the floodplain, which
are generally more infertile, making
agriculture to support populations
difficult. Olvera stated that “The river
is the source of life that connects us
all to the Mother Earth and together
as relatives. The people of the Očéthi
Šakówiŋ (Seven Council Fires) are the
caretakers of the Mníšoše (Missouri
River) which in turn takes care of its
inhabitants.”
Geoffrey Gray-Lobe and Sebastian
Ruiz studied the effects of invasive tree
and shrub species on breeding birds in
riverine forests. They determined the
success of nesting efforts by birds in
forests with different levels of invasive
species, and found that some bird
species performed better in woodland
with higher levels of invasive trees
www.researchoutreach.org 71
and shrubs. Other species, however,
performed worse with increased
presence of invasive trees and shrubs.
“The current flow regulation patterns
on the Missouri River are the ‘new
normal’ for the river, so the flora and
fauna along the floodplain will have
to respond to these changes,” noted
Dr David Swanson, “Whether or not
they are capable of responding is a
further question that will need to be
addressed.”
Bethany Vázquez Maestre studied
how drought affected suspended
sediment loads in three tributaries of
the UMR. The tributaries studied are
downstream of the last dam on the
Missouri River, and sediment from
This ultimately aids in the creation of a generation of
scientists who will help advance society in creating a more
sustainable future
those tributaries are an important
contribution to the sediment-deprived
waters due to the dam upstream. They
found that although the Vermillion
River had the lowest discharge of the
tributaries studied, it had the highest
suspended sediment load. This raises
the question of whether the Vermillion
River is contributing disproportionally
to the sediment load in the Missouri
River compared to other, larger
tributaries. “Our previous results
suggest that sediment contributions
vary greatly among tributaries. Since
Sustainable RIVER students participated in six field trips,
including two interpretive paddles on the river, covering
more than 1000 km of the UMR.
72 www.researchoutreach.org
the suspended load is nutrient rich,
it is critical that we learn more about
tributary contributions to the Missouri
River,” stated Dr Mark Sweeney.
Tyler Seidel evaluated the extent to
which aquatic organisms, especially
fishes, affect the quantity of insects
emerging into terrestrial ecosystems
and therefore available in terrestrial
food webs. When fishes were excluded,
the abundance of emerging insects
increased by up to 900%. This increase
in food resources caused an increase
to the number of spiders that build
webs above the water to capture
emerging insects. “Although aquatic
and terrestrial ecosystems are often
thought of as distinct,” stated Dr Jeff
Wesner, “There is a strong connection
between what the fishes are eating
and the resources that are available to
terrestrial animals. In other words, rivers
feed forests, and vice versa.”
DEVELOPING STUDENT
SUSTAINABILITY LEADERS
Sustainable RIVER aims to affect
the students beyond their specific
research projects by enabling them to
utilise a systems-thinking approach to
evaluating research and opportunities
for creating change.
STUDENT PERSPECTIVES
This summer, I learned about the
many complicated issues that arise
when human values do not align with
Behind the Bench
what is best for the natural habitat. I
witnessed the effects of anthropogenic
intervention during my own research
Dr Meghann Jarchow
E: Meghann.jarchow@usd.edu T: +1 605 677 3115
when we did not find any false map
turtles within the reservoir lake
created by the Oahe Dam. This was
disappointing since this stretch of Research Objectives
The Sustainable RIVER project had
the river used to be riddled with the
two primary research objectives: one
false map turtle before the dam was
focused on education and one focused
built. Sustainability is about trying to
on research. The first was to train
find a balance between taking and
student scientists who will become
conserving. I’m honoured to have had a
leaders in interdisciplinary research and
small part in seeking that balance for the in creating a more sustainable society
Missouri River basin.” through their appreciation of using a
-SHAYLYN AUSTIN multi-perspective, systems-thinking
approach to understanding and
addressing challenges. The second
objective was to better understand
how invasive elements in the Upper
Missouri River affect the sustainability
of the river and the humans who
depend on it.
This program has taught me so much
not just about the Missouri River but Funding
the whole world. I have learned how the National Science Foundation (NSF)
geological, ecological, and sociological
Q&A
issues all work hand in hand. Each
area affects the other issues and this
program has taught me that you must
look at the bigger picture to try to What initially inspired you to
address all the issues. coordinate this project?
-ALEISA LABELLE To be a successful researcher in
sustainability, I believe that you
• To find out more about this project must be able to do interdisciplinary
visit www.SustainableRIVER.org. research. This includes being able to
understand systems from multiple
disciplinary perspectives, to have a
broad enough understanding of the
system to ask insightful questions, and
to develop technical skills to allow for
deep exploration into questions of
interest. There is a tendency in student
research training to focus on building
© Thomas Hatzenbuhler/University of South Dakota
technical skills to answer specific
research questions, but this fails to
train the students on how to approach
their research from a more holistic
perspective. The goal of this project
was to offer broader student research
training.
What have been some of the most
interesting outcomes of the project
so far?
It has been rewarding to see the value
Research Team
Expertise included: sustainability,
ecology, geology, anthropology, and
Native American studies.
Student Researchers: Ethan Jennings,
Kriston Lynn, Selena Olvera and Tyler
Seidel (University of South Dakota).
Aleisa LaBelle and Shelley Kosola
(Nebraska Indian Community College).
Shaylyn Austin (University of Michigan),
Geoffrey Gray-Lobe (Augustana
University), Rebecca Krasky (Macalester
College), Sebastian Ruiz (Florida
International University), and Bethany
Vázquez Maestre (University of Puerto
Rico – Río Piedras).
Faculty Mentors: (University of South
Dakota): Drs Brennan Jordan, David
that the students got from working with
one another. One student commented
“Being able to see the varying
perspectives of my fellow participants
truly expanded my way of thinking and
analysing problems.” This begins to show
students that they can be experts and the
creators of knowledge.
What are some of the difficulties
faced in addressing the sustainability
challenges of the Upper Missouri
River?
A goal of this project was to evaluate how
to “Cultivate a more resilient Missouri
River that meets the needs of multiple
stakeholders and sustains diverse,
functioning ecosystems,” and our group
identified many ways through which we
could cultivate a more resilient Missouri
River. Yet the obstacles to realising a
more resilient Missouri River can seem
intractable. In sustainability work, there
is tension between the sadness that
comes with deeply understanding the
challenges we face and engaging with
the fact that we all can have a positive
role in creating a better, more sustainable
future.
Posthumus, David Swanson, Jacob
Kerby, Jeff Wesner, Mark Dixon, Mark
Sweeney, Matthew Sayre, Meghann
Jarchow, and Silvana Rosenfeld.
Bio
Dr Jarchow is the Director of the
Sustainable RIVER program. She is also
the Coordinator of the Sustainability
Program at the University of South
Dakota.
Contact
Meghann Jarchow, PhD, Assistant
Professor, Sustainability Program
Coordinator, University of South
Dakota,
USA
How easy would it be to apply the
approaches developed here to other
fields?
Although this project is focused on
the Upper Missouri River, many of the
foundational themes that exist in this
system are present in other systems.
The interdisciplinary, systems-based
approach used in the Sustainable
RIVER project can be applied to a
broad range of other fields.
How do you expect the project will
advance in the upcoming years?
We will continue to improve our
methods for developing students who
are able to work in interdisciplinary
teams. For upcoming years, we will
have more of the students work in
teams of peers to promote peer-to-
peer learning and to better utilise the
diversity of experiences and expertise
of the students. We will also offer more
opportunities for the students to work
with stakeholders and other faculty
mentors.
www.researchoutreach.org 73
Biology ︱ Dr Tracy Johnson
From beer to brains
How yeast molecular genetics prove the importance of introns
Scientific discoveries often
come from the most unlikely of
places, and Dr Tracy Johnson’s
work is no exception. Using a
yeast system typically used to
make beer or bread, Dr Johnson
and her team at UCLA have
uncovered important genetic
findings that could highlight the
importance of intron retention
during gene expression. Her
research looks at the science of
gene expression, investigating
the way in which cells synthesise,
splice, and process RNA to
generate the key proteins that
regulate how we, as humans,
continue to function.
74 www.researchoutreach.org
W
hen you think of the human
body, you probably think of
the bones, organs, or the skin.
But what about the genes that make each
of us unique – the biological fingerprints
that denote our hair colour, eye colour,
and how tall we become?
The 46 chromosomes we receive
from our parents at conception go
on to shape our bodies later in life.
The 20,000 genes they carry are
responsible for producing the many
proteins and enzymes that are vital for
keeping all the cellular processes inside
of our body functioning properly.
Genes provide the biological
information that dictate how every cell
in our body functions – from producing
key enzymes, to manufacturing proteins
critical to cell growth and proliferation.
To synthesise these important proteins
though, the gene must first go through
the key process of transcription.
TRANSCRIBING AND
TRANSLATING GENES
Transcription is the process by which
DNA is copied into messenger RNA
(mRNA), using an enzyme called RNA
polymerase. This enzyme effectively
“unzips” the DNA’s double-helix,
breaking apart the hydrogen bonds
between DNA nucleotide bases –
adenosine (A), cytosine (C), guanine (G)
and tyrosine (T). The RNA polymerase
then matches complementary
nucleotide bases (C–G; G–C; A–U;
U–A) to the existing single DNA strand,
to form an mRNA strand (uracil (U)
replaces the tyrosine found in DNA).
This mRNA strand is then exported so
that it can be translated into a protein.
Translation is the process by which the
mRNA strand is used as a template to
make a protein. During this process, the
mRNA strand is decoded by a ribosome
outside of the nucleus to produce
a specific chain of amino acids. This
Figure 1. Mechanism of pre-mRNA splicing.
Intron
Exon Exon
5’ 3’
Precursor RNA
chain later folds to become the active,
functioning protein of the cell.
SPLICING RESEARCH TOGETHER
During the transcription phase of
gene expression, the RNA undergoes
“processing” before it can be exported
and translated. A key reaction, RNA
splicing edits the nascent pre-cursor
messenger RNA (pre-mRNA) into the
mature mRNA strand needed to form
the protein (Figure 1). This process
removes nucleotide sequences, known
as introns, from the pre-mRNA. The
molecular machine which carries out
this process is called the spliceosome.
This leaves the mature mRNA strand
comprised only of exons, and it is these
nucleotide
Genes provide the biological information that
sequences
which encode
the final protein.
dictate how every cell in our body functions –
It’s a little like from producing key enzymes, to manufacturing
proteins critical to cell growth
having a bag of
Skittles sorted
by colour and
aligned. RNA splicing removes the
green, yellow and red Skittles (introns),
leaving only the purple and orange
Skittles (exons) behind. These purple
and orange Skittles form the mature
RNA that can go on to encode the final
protein.
Dr Johnson’s research focuses on this
area, looking at how cells synthesise,
splice, and process RNA to regulate
gene expression. Through her role as
Professor of the Molecular, Cell and
Developmental Biology in the Division
of Life Sciences at the University of
California, Los Angeles (UCLA), she and
her team have recently investigated
how introns contribute to gene
expression.
RNA SPLICING:
AN INTRON-DUCTION
RNA splicing has long been an area
5’ OH 3’
Reaction Intermediate
of particular interest for Dr Johnson
and her team. For her recent National
Science Foundation (NSF) grant, she is
studying the influence not only of intron
removal, but also intron retention in
protein synthesis.
As she explains herself: “Most studies
into gene function focus on RNA
post-splicing – after the introns have
been removed and the mature mRNA
is exported. Since introns are generally
degraded after removal, little attention
is paid to what functions these introns
could have. In some cases, however,
it appears that intron removal is
surprisingly inefficient, and therefore,
intron retention is a reality that merits a
deeper understanding.”
To this end, Dr Johnson’s research has
uncovered a remarkable example for
how important intron retention could
be. Using a single-celled yeast called
Saccharomyces cerevisae as a model
system, her work has pinpointed a gene
that could harness several important
observations within gene expression
– called GCR1. This gene provides an
effective example of the importance
of splicing regulation in cells: in
Saccharomyces cerevisae, GCR1’s RNA,
both spliced and unspliced, allows
the cell to adapt to certain cellular
conditions.
YEAST GENETICS
The GCR1 gene encodes a protein
responsible for the regulation of genes
that support glucose metabolism –
yeast’s preferred source of energy.
Excised
Intron
OH
5’ 3’
Ligated Exons
In fact, 75% of the genes in actively-
growing yeast are believed to rely on
the protein GCR1 encodes. The cell’s
‘decision’ to produce this protein
depends on the cellular environment
and the availability of glucose. Dr
Johnson and her team have now
discovered that regulated splicing
and intron retention appear critical for
this – ensuring GCR1 gene expression,
and ultimately glucose metabolism,
can continue regardless of cellular
conditions.
In differing levels of glucose, Gcr1
protein (Gcr1p) expression varies in
order to support the cell’s metabolic
needs. To regulate this and ensure
Gcr1p
expression can
suitably adapt
to the changing
environment,
the cell relies
on regulated
splicing of the
GCR1 RNA.
Remarkably, both spliced RNA and
unspliced RNA produce Gcr1p, with the
intron containing the regulatory code
needed to initiate translation from the
unspliced RNA. The level of spliced
vs. unspliced GCR1 is dependent on
the cellular conditions, yet both are
essential for ensuring effective glucose
metabolism.
Now, here’s where it gets interesting. Dr
Johnson and her colleagues have found
that the proteins from the unspliced
and spliced GCR1 RNAs associate
with each other to form “dimers” –
homodimers and heterodimers. So,
instead of one Gcr1 protein, there are
at least three different functional forms
of the protein from three combinations
of Gcr1 protein dimers (see Figure 2).
In other words, one gene leads to three
functional forms of the protein, and
www.researchoutreach.org 75

Figure 2. Model depicting how different Gcr1 proteins are produced and how they function.
RNA synthesis and processing
Unspliced
RNA export and translation
these can then regulate the expression
of GCR1 target genes. In essence, both
RNAs, with and without the intron, are
necessary to produce the proteins that
are crucial for the cell to fulfil its key
metabolic function. This consequently
highlights the importance of intron
retention.
INTRON RETENTION
Dr Johnson’s work opens several
avenues for further research, and
creates a paradigm for exploration into
the influence of intron retention. One
such avenue could include investigating
the ‘quality control’ mechanisms
hypothesised to prevent the export
of unspliced RNA, which appear to be
evaded in the GCR1 example.
Another avenue could look into the
translational start site of protein
synthesis. In typical circumstances, the
protein synthesis machinery scans the
RNA strand starting from the end until
it finds the first triplet codon (a group
of three nucleotide bases) to initiate the
start of translation. In the GCR1 system,
76 www.researchoutreach.org
Spliced
Gcr1 target genes involved
in glucose metabolism
Dr Johnson’s research has
established innovative new findings
from a yeast system typically used
to create beer or bread
however, this appears not to be, as the
protein synthesis machinery seems to
be preferentially attracted to the intron,
rather than the initial starting codon.
Both of these avenues are currently
being investigated by Dr Johnson and
Dr Munshi Azad Hossain, a research
scientist in Dr Johnson’s laboratory.
BEER, BREAD AND BRAINS
Dr Johnson’s further research will also
look to apply her yeast-derived findings
to mammalian cells – which she is
confident will come to fruition. In fact,
research has recently suggested the
potential benefit on intron retention in
the mammalian brain, which Dr Johnson
cites as a source of excitement for her
own work.
DNA
© Hadar Goren
RNA
Gcr1
proteins
Gcr1 proteins
function in the
nucleus to help
regulate gene
expression
She said: “A recent report in mammalian
neurons provides a remarkably similar
example of how a retained intron can
be crucial for RNA function in the
mammalian brain.” This report highlights
that Nxf1 protein RNA contains a
retained intron in both hippocampal
and neocortical neurons, with proteins
produced from RNAs that also form
important dimers (Li Y et al. Mol Biol Cell
2016). This mechanism proves vital in
modulating cellular function.
Dr Johnson’s research has established
innovative new findings from a yeast
system typically used to create beer or
bread. Her research challenges existing
beliefs that introns are simply a “genetic
refuse” and demonstrates that there is a
lot more to introns than meets the eye.
Behind the Bench
Dr Tracy Johnson
E: tljohnson@ucla.edu T: +1 310-206-2416 W: http://www.mcdb.ucla.edu/faculty/tljohnson
W: http://bioscience.ucla.edu/faculty/tracy-johnson
Research Objectives
Dr Johnson’s research focuses on
investigating how cells synthesise,
splice, and process RNA to regulate
gene expression. Her recent NSF-
funded research highlights importance
of intron retention, using the GCR1
gene found in yeast as a model system.
Funding
National Science Foundation (NSF)
Q&A
How did you first become interested
in gene expression? And what
particularly peaked your interest in
investigating RNA splicing?
I’ve always been intrigued by the fact
that, although the DNA in each cell of
an individual’s body is the same, those
cells must perform specific functions.
So, clearly there must be important
mechanisms that control which genes
are expressed in different cells under
different conditions.
I find RNA splicing to be an absolutely
fascinating process. The typical human
gene is interrupted, on average, 10–12
times by introns. In human genes,
most of the sequence of any given
gene is intron – 98% vs. 2% exons.
Nonetheless, there is still so much to
learn about the functions of introns
and the remarkable machinery that
removes them (and in some cases,
does NOT remove them), i.e., the
spliceosome.
As your research has largely used
yeast as a model system so far, when
Collaborators
• Munshi Azad Hossain
• Julia Claggett
Bio
Professor Johnson earned her
Bachelor’s degree from UCSD and her
PhD from UC Berkeley. She was a Jane
Coffin Childs postdoctoral research
fellow at the California Institute of
Technology and joined the faculty at
UCSD in 2003. In 2013, she moved her
do you hope to replicate your findings
within mammalian-derived genes?
Actually, we have already started using
a particular type of immune cell called
a macrophage to examine how splicing
is regulated in response to specific
signals. In this case, instead of asking
how yeast cells regulate splicing to
respond to glucose, we are asking how
splicing regulation helps the immune cell
respond to the presence of a pathogen.
We think that many of the lessons that
we learn about yeast gene regulation will
inform our thinking about the same basic
processes, like transcription and splicing
in mammals.
What applications could your work
have pharmaceutically, in terms of
developing effective medicines or
therapeutics?
A first step toward developing effective
drugs and therapies is understanding,
in fine molecular detail, how basic gene
expression processes work.
You mention that introns are a
relatively ignored area of research.
Why do you think this is, and what
more needs to be done to improve
laboratory to UCLA in the department
of Molecular, Cell and Developmental
Biology.
Contact
Tracy L Johnson, PhD
Professor
UCLA, Department of Molecular, Cell
and Developmental Biology
Los Angeles, CA 90095
USA
understanding?
Actually, a better way of phrasing this is
that when we think of intron-containing
genes, there is an assumption that
the only important parts of the genes
are the exons, the protein coding
region. Perhaps since introns are
removed and, usually, degraded
we’ve underestimated their potential
for coding functional RNAs or even,
as is the case of GCR1, functional
proteins. However, with the advent of
increasingly sophisticated sequencing
technologies, it is clear that there is
likely to be more intron retention that
we’ve previously appreciated. 
Where do you hope to see your
research progressing to over the
next five years?
I would like to understand how
sophisticated regulation of genes like
GCR1 allow cells to respond to their
environments. While S. cerevisiae
has been a powerful tool for gaining
detailed mechanistic insights, we
would also like to see how the basic
mechanisms apply to other more
complex systems such as mammalian
cells.
www.researchoutreach.org 77
Biology ︱ Dr Diego Bernal
Into the deep
understanding swordfish eco-physiology
A
Cold-blooded vertebrates, such as fish, are extremely susceptible to s terrestrial animals, we are
changes in the temperature of their surroundings. Yet one successful accustomed to an environment
ocean predator, the swordfish, migrates from tropical to temperate seas, that undergoes dramatic
and dives daily from warm surface waters to cooler depths, with seeming temperature change that occurs over
ease. Drs Diego Bernal and Chugey Sepulveda of the University of both long (i.e., from summer to winter)
Massachusetts Dartmouth and the Pfleger Institute of Environmental and short time frames (from day to
Research (PIER), are working together to explain the physiological night). As warm-blooded mammals, we
mechanisms underpinning this ability, with implications for understanding have the capacity to regulate our body
vertebrate respiratory and muscle function, and for maintaining healthy temperature to mitigate the physiological
populations of swordfish and other marine species. effects of these environmental changes.
Other groups, like marine fish, aren’t so
lucky, as drastic changes in temperature
can have lethal repercussions.
In the marine realm, the high heat
capacity of water provides fish with
a buffer against rapid changes in
environmental temperature. For this
reason, most marine species have
evolved to inhabit relatively narrow
and homogeneous thermal niches.
Thus, even though most fish do not
have physiological control over their
body temperature, they still are able to
maintain a relatively constant thermal
environment in which metabolic
processes are optimised. However,
certain fish species do not follow this
trend, with body temperatures and
physiological processes subject to
extreme thermal variation on both a
daily and seasonal basis. These thermal
fluctuations are primarily in response to
daily and seasonal migrations in search
of rich prey sources that aggregate in
temperate and polar regions as well as
the waters well beneath the thermocline.
A LIFE OF EXTREMES
One remarkable species has been shown
to possess great tolerance to changing
thermal environments. The swordfish
(Xiphias gladius) – a large marine
predator that roams all the world’s
oceans – is among the few fish species
known to traverse extreme thermal
barriers on a daily basis, spending
78 www.researchoutreach.org
prolonged periods hunting both at
the surface at night and at great depth
during the day. This diurnal activity
pattern results in extreme thermal
fluctuation, with physiological processes
subject to temperature changes in
excess of 15°C within a matter of
minutes. Although many fish species also
exhibit tolerance to short-lived changes
in temperature, the swordfish has been
shown to reside and hunt for prolonged
periods in very disparate conditions,
providing a daily pattern that subjects
physiological
Understanding how swordfish tolerate
processes to
extreme and
contrasting
conditions. This
extreme conditions and segregate from
daily pattern other species has led to the development
provides
swordfish with a of selective, low-impact fishing gears
unique foraging
opportunity that allows them to feed on
rich prey resources both during the day
and at night.
Understanding how swordfish tolerate
extreme conditions and segregate
from other species has also led to
the development of selective, low-
impact fishing gears. By documenting
depth trends and dive characteristics,
researchers have been able to
identify times and locations that lead
to increased selectivity in swordfish
fisheries. This is critical given that world-
wide swordfish fisheries have been
routinely implicated with high levels
of bycatch of sensitive species like sea
turtles and marine mammals.
From a physiological perspective,
understanding how swordfish tolerate
extreme thermal conditions and how
they transition rapidly between them,
offers insights not just into this species,
but also into how other organisms
respond physiologically to changing
environmental temperatures. It may even
help managers of fisheries develop new,
more sustainable fishing practices. Drs
Bernal and Sepulveda are bringing their
complementary expertise in physiology,
ecology, and marine resource
conservation together to answer these
fascinating questions.
MUSCLE MATTERS
A diving swordfish faces two
fundamental issues as it moves from
warm to cool water and back again.
Firstly, the effect that changing
temperatures may have on the muscles
Swordfish caught using deep-set
techniques developed by the PIER team.
that power swimming – particularly
significant in such fast-moving predators
– and secondly the low levels of oxygen
experienced at the depth where
swordfish hunt during the day.
Every sprinter knows that muscles work
better when they are warm. In their US
National Science Foundation-funded
project, Dr Bernal and Dr Sepulveda
aim to quantify this effect in swordfish.
Their work documents any changes in
muscle temperature in free-swimming
fish during dives
and subsequently
assesses in-
vitro muscle
performance at
the same range of
temperatures in a
laboratory setting.
Swordfish have several anatomical
adaptations that may help maintain their
swimming muscles at temperatures that
are warmer than their surroundings: the
main swimming muscles are held close to
the centre of the body and are supplied
with blood via an elaborate network
of vessels that act as a heat exchanger,
effectively conserving body heat. This
mechanism, known as ‘regional muscle
endothermy’, clearly enables swordfish
to maintain high swimming performance
while at depth in cold water, but it does
not fully account for their ability to
www.researchoutreach.org 79

survive such rapid dives and to spend
such long periods at depth. In fact, other
predatory fish including tuna and some
sharks have a much greater capacity
for regional muscle endothermy than
swordfish, however, they cannot sustain
such long dives.
Drs Bernal and Sepulveda proposed
an explanation for this discrepancy:
from the data collected to date, the
team has proposed that swordfish use
physiological thermoregulation coupled
with muscles that operate across a large
range of environmental temperatures.
When their empirical measurements of
body and water temperature from free-
swimming diving swordfish were put into
computer-generated thermodynamic
models, they found that swordfish can
alter and control
Bernal and Sepulveda postulate that the
the rate at which
their entire
body exchanges
heat with the
basis for physiological thermoregulation
surrounding in swordfish lies in their complex,
two-part circulatory system
water, effectively
slowing down
the rate at which
their body cools during a dive and
accelerating the rate of rewarming when
they return to the surface. Their work
has also shown that swordfish muscle
can function at a range of temperatures,
including very cold conditions that have
been shown to be lethal to many other
pelagic fish.
PERFECT PREDATOR
Bernal and Sepulveda postulate that the
basis for physiological thermoregulation
in swordfish lies in their complex, two-
part circulatory system. When diving into
cooler water, the fish may slow down
80 www.researchoutreach.org
Onboard disections aimed at isolating
live muscle preparations for in-vitro
studies of muscle function.
cooling by routing blood through vessels
armed with heat-exchanging manifolds
deep inside their bodies, keeping them
warmer and defending against the cold.
Conversely, when returning to warm
surface waters, swordfish may accelerate
heat exchange with their surroundings
by routing blood through vessels that
short-circuit the heat exchange systems.
The net result is that swordfish operate
at warmer temperatures than their
surroundings for a longer proportion of
the time than other fish. This may give
them a competitive advantage relative
to other predators and their prey. In
addition, the ability to warm up rapidly
decreases the amount of time swordfish
spend ‘basking’ on the surface, freeing
up more time to exploit the rich food
resources of the ocean depths.
The next question for the research
team is how these prolonged dives
influence the swordfish’s muscle function
and its ability to uptake oxygen from
the water. Certain layers of the deep
oceans tend to be lacking in dissolved
oxygen compared to the surface
waters, and in most fish the ability of
the blood to bind oxygen varies with
temperature, producing a complex
set of interactions for fish to tend with.
Bernal and Sepulveda have teamed up
with colleagues in the US and Canada
to examine how temperature affects the
oxygen-binding capacity of swordfish
blood, and to explore potentially unique
ultrastructural adaptations in their
gills and muscles that enhance their
oxygen-transporting ability. They hope
to shed light on the physiological basis
of swordfish tolerance to extremes of
temperature and oxygen deficits: as the
researchers describe it, “adaptations for
life on the edge.”
FINE-TUNING FISHERIES
A final, fundamental aspect of Bernal
and Sepulveda’s research lies in how the
detailed physiological and ecological
data garnered during the study relate
to local fisheries. Sepulveda and his
team at PIER have dedicated much
of the past decade trying to develop
alternative means to harvest swordfish,
ones that are more selective than some
of the more traditional fisheries used
around the world. The key to this work
is understanding where and when
swordfish segregate from other species
and developing alternative fishing
gears that selectively target swordfish
at depth. Increasing gear selectivity and
minimising unwanted interactions with
protected species like sea turtles and
marine mammals is a win-win scenario
for both managers and fishers. It is the
teams hope that new knowledge on
their physiological specialisations can be
used to develop cleaner fisheries that
offer new opportunities for dwindling
fishing communities.
The collaborator’s
physiological data may
also provide crucial
insights into how
swordfish movements
and behaviours change
with our changing
climate. As our oceans
change with time, factors including prey
distribution and abundance, oxygen
availability and sea temperature can
influence the movements of this global
resource. They hope their research may
provide a set of biological insights that
help explain how swordfish are capable
of the feats they accomplish daily and
how this information may help keep
populations of swordfish and other
marine species at sustainable levels in
the future.
Behind the Bench
Dr Bernal
E: dbernal@umassd.edu T: +1 508 415 1975 W: http://www.umassd.edu/cas/biology/facultystaff/diegobernal/
W: http://www.pier.org W: https://www.fishecophysiology.net/
Research Objectives
This collaborative work is focused on
documenting and better understanding
the physiological specialisations that allow
certain fish species to exploit some of the
harshest conditions on the planet. The work
specifically tests hypotheses related to the
effect that temperature has on muscle and
cardio-respiratory performance in pelagic
fish species. Additionally, this work has
coupled these physiological investigations
with movement studies to aid in the
development of new, low-impact fishing
gears that increase selectivity and reduce
bycatch in modern-day fisheries.
Q&A
The swordfish is clearly a unique
species. How did you first discover
its remarkable combination of
behaviours?
Despite the presence of global fisheries
dedicated to the harvest of swordfish,
very little biological information exists
for this species. Since the 1960s, there
have been numerous reports from the
open-ocean fisheries showing that
swordfish were captured at depth during
the day and in shallower water at night.
That work indicated their capacity to
move extensively up and down the
water column. Then, in the 1970s and
80s, there were a series of papers by
Francis Carey and his group that began
to uncover some of the swordfishes
unique physiological and morphological
adaptations that allows them to be active
predators in the deep, dark, and cold
layers of the ocean. For example, they
can warm their eyes and brain to enhance
sensory perception. Since then, we have
continued that line of work but have
focused on how swordfish can sustain
swimming during their descents into cold
water and to try understand if, and how
they can maintain their active swimming
ecology, even when other top predators
apparently cannot.
What are the implications of your
findings for our understanding of
muscle function in other species?
Swordfish are not the only fish that dive
deep and cold, but they are unique
Funding
• National Science Foundation (NSF)
• National Oceanic and Atmospheric
Administration (NOAA)
Collaborators
Drs Jeanine Sepulveda (MiraCosta College),
Douglas Syme (University of Calgary), Colin
Brauner (University of British Columbia),
Mark Okihiro (California Department of
Fish and Wildlife), Nick Wegner (NOAA
Southwest Fisheries Science Center).
in that they stay at depth for prolonged
periods of time. How they can do that
without markedly affecting their capacity
to swim is what makes them unique.
By learning how swordfish muscles can
continue to function, even when facing
rapid and large changes in temperature and
potentially under low oxygen conditions,
we will better understand how animals
have adapted to inhabit environmental
conditions that should be limiting.
How do swordfish cope with the longer-
term changes of temperature they
experience during migration between
cooler and warmer latitudes?
We do know that many migratory fishes
appear to acclimate their bodies throughout
their slow progression to cooler waters.
However, some other species that migrate
more rapidly (tunas and swordfish) and
appear to spend more time in cooler
waters have evolved a suite of unique
adaptations to stay warm. This allows them
to potentially swim longer and faster, and
increase sensory perception and maybe
enhance their rate of growth. Although we
are just beginning to understand how these
animals can cope with short-term (minutes)
changes in environmental conditions, we
still have more to learn about their long-
term (months) strategies to deal with these
changes, which takes on a new sense of
importance in the face of the potential
oceanographic shifts associated with global
climate change.
How would you like to see fishing
practices change as a result of your
studies?
Dr Sepulveda
Bio
Dr Bernal is a member of the Biology
Department at the University of
Massachusetts Dartmouth.
Dr Sepulveda is the director of research
and education at the Pfleger Institute of
Environmental Research (PIER) in Oceanside
California.
Contact
Diego Bernal, PhD
Professor
University of Massachusetts Dartmouth
285 Old Westport Road
Dartmouth, MA 02747-2300, USA
We hope that our work will help provide
fisheries with species-specific information
that can lead to increased gear selectivity
and reduced bycatch. Furthermore, we
hope that this type of data can also be
collected from other species and used to
increase fishery selectivity based upon
ecological and physiological differences.
Expanding the scope of traditional
fisheries and looking outside of the box
for bycatch solutions continues to be
a goal of both Sepulveda and Bernal’s
laboratories.
What do you each bring to the
project? And what can you achieve
together that you could not achieve
alone?
The two laboratories have unique
attributes and areas of expertise. Bernal
has spent more than a decade working in
the laboratory coupling his work with the
field. In contrast, Sepulveda has diverged
from his colleagues’ path and focused
more heavily on field studies that have
fishery relevance. The coupling of the
Bernal and Sepulveda laboratories has
resulted in some strong well-rounded
studies that tie the field to the laboratory.
This synergistic research has bridged the
traditional gap that separates field and
laboratory investigation and broadened
our understanding that allows us to work
on questions that others cannot.
www.researchoutreach.org 81
Biology ︱ Drs Tim Griffin and Pratik Jagtap

Open-source Mass
Determine

bioinformatic solutions
Galaxy-P workflows novel
spectrometry peptide
data sequence

for ‘Big Data’ analysis

variants

Sequence Peptide Proteogenomics

database spectral

Drs Tim Griffin and Pratik
Jagtap along with the Galaxy-P
team from the University of
Minnesota are working to
develop workflows on an open
source platform for the analysis
of multi-omic data. They are
currently focusing on using a
Galaxy-based framework to
investigate the integration of
genomic datasets with mass
spectrometry-based ‘omics’
data. But in the long term, they
aim to expand the platform to
cope with many other ‘Big Data’
domains.
C
urrently, a major limitation to what
we can discover from complex
datasets derived from next-
generation technologies is our ability to
analyse them. This is where the work of
Dr Tim Griffin, Dr Pratik Jagtap and their
research team will play an important role.
THE ‘BIG DATA’ ERA
Moore’s Law predicts that computing
power will double approximately
every two years, and with this, the
cost of high-powered machines will
also decrease. However, this cannot
continue indefinitely and 2017 may
be the crunch point at which physical
limitations intervene, with the rate
of progress becoming ever more
saturated.
But what influence has this increase
in computer power had on science?
One of the major advances has been
the ability to generate data using
next generation, high throughput
techniques, resulting in ‘Big Data’.
Although ‘Big Data’ has been used
to define many datasets, the term
often corresponds to what are now
commonly known as ‘omics datasets’ –
genomics, metabolomics, proteomics,
transcriptomics and epigenomics
to name but a few. For example, in
biomedical science, we see large scale,
search matches Metaproteomics
Functional
Database
& taxonomy
generation
analysis
system-wide approaches being used a multi-disciplinary, collaborative GALACTIC PLATFORM
more and more commonly. These project between Dr Griffin’s lab and the Galaxy was originally developed over
include the 1000 Genomes Project, the Minnesota Supercomputing Institute, a decade ago to solve problems in
emergence of personalised medicine – which involves software developers, genomic informatics. It can be hosted
tailored to an individual’s needs – and data scientists and wet-bench on a scalable compute infrastructure,
systems biology, examining multiple, biological researchers. Specifically, helping to cope with the problem
interacting pathways concurrently as the team are focusing on mass of large data volume, and can be
one giant network. spectrometry (MS)-based ‘omics’ data accessed remotely by researchers
(metabolomics and proteomics) and across the globe. Supported by a team
However, the analysis of these large how they can harness an existing open- of experts and software developers,
and complex datasets requires an source framework, called Galaxy. Galaxy integrates many individual
analytical platform which can cope with ‘omics tools in a single environment,
the intense informatics requirements, Put simply, mass spectrometry and also has many functionalities
as well as the ability to access disparate represents a high throughput technique that promote workflow sharing and
software from different ‘omics’ that sorts ions based on their mass to reproducibility. The latter is particularly
domains. Many wet- important, as there may
bench researchers will
not have access to this
One of the major advancements is be multiple research
projects that can utilise
level of compute-power
or expertise locally,
the ability to generate data using one particular dataset or
workflow. Data sharing
and therefore there is next generation, high throughput and transparency

techniques, resulting in ‘Big Data’

an increase in remote,
or cloud, open-access
platforms being used
to access the necessary bioinformatic
tools needed to cope with the complex
results that researchers are obtaining.
ONE SOLUTION FOR ALL
At the University of Minnesota, Drs
Tim Griffin, Pratik Jagtap and team
are working on solutions to analyse
these complicated datasets. This is
charge ratio. Once certain signatures
have been recorded for individual ions,
this information can, for example, be
extrapolated to identify peptides, the
building blocks of proteins. Tandem
mass spectrometry (MS/MS) further
expands on this by using at least two
stages of mass analysis.
also encourages
collaboration, and
increases the number
of expert approaches that can be
combined to maximise novel findings.
In particular, the Galaxy for proteomics
(Galaxy-P) team investigates ways in
which genomic and transcriptomic
data can be integrated with MS-
based proteomics data. From here,
they aim to verify the expression of

82 www.researchoutreach.org www.researchoutreach.org 83
 Behind the Bench
Professor Professor
Tim Griffin Pratik Jagtap
E: tgriffin@umn.edu E: pjagtap@umn.edu T: +1 612 624 5249 W: http://galaxyp.org/ @usegalaxyp

Research Objectives Bio Contact

Drs Griffin and Jagtap’s research focuses on
the Galaxy-P project – developing, testing,
optimising and applying multi-omics
software tools to a variety of biological
questions, including cancer and big data
research.
Funding
• National Science Foundation (NSF)
• National Institutes of Health (NIH)
Collaborators
• Minnesota Supercomputing Institute
• Galaxy software platform developers
• Jetstream research computing resource
Professor Tim Griffin serves as the Dr Tim Griffin PhD
Principal Investigator on the Galaxy for Professor and Director, Center for Mass
proteomics (Galaxy-P) project, as well as Spectrometry and Proteomics
the Faculty Director for the Center for University of Minnesota
Mass Spectrometry and Proteomics at the Dept. of Biochemistry, Molecular Biology
University of Minnesota. and Biophysics
6-155 Jackson Hall
Research Assistant Professor Pratik Jagtap 321 Church Street SE
has been the co-leader of the Galaxy-P Minneapolis, MN 55455
project since its inception in 2012, USA
helping to develop and apply software
and workflows in metaproteomics,
proteogenomics and more recently data-
independent acquisition methods.

Members of the Galaxy-P team, (http://galaxyp.
org/people/)
protein sequence variants that result
from sequence variations at the DNA
or RNA level. This approach, known
as proteogenomics, commonly uses
transcriptomic data translated in silico
to produce a customised protein
sequence database. This database is
subsequently used to match proteins
obtained through MS technologies.
The major advantage of this approach
is that no existing reference sequence
is required, and so novel protein
sequence variants, which may
previously have gone undetected, can
be identified. The analysis can also be
extended to compare expression levels
of genes and proteins.
Similar to proteogenomics,
metaproteomics is also based on
integration of metagenomic data with
MS-derived proteomics data. However,
unlike the previous approach, this
concentrates on integrating these with
sequence data derived from bacterial
communities (microbiomes). As before,
metagenomic data are translated in
silico to create a protein sequence
database. MS/MS peak lists, derived
from the raw data, are matched against
the database. Once peptides of interest
have been identified, they are assigned
to taxonomies and verified. Additional
analysis using tools for functional analysis
such as MEGAN, provide information
about the functional categories
of microbial protein expression.
Metaproteomics can provide us with
functional data to complement the
taxonomical findings of a metagenomic
approach. The main draw of this
approach is that it can potentially be
used to analyse data from diverse
sample types – ranging from clinical to
environmental samples.
An example of where Galaxy-P
(galaxyp.org) provides ideal tools
could be in helping cancer researchers
identify which protein sequences may
have a functional role in causing a
specific cancer. Not only does Galaxy-P
provide the necessary tools required for
complex analyses, it can also potentially
train non-expert, bench scientists
through public Galaxy platforms (tiny.
cc/galaxyp-proteogenomics; z.umn.
edu/metaproteomicsgateway). This
platform provides small-scale data for
users to access and use with already
published workflows. Existing studies
have already used the Galaxy-P
platform successfully to look at a range
of topics, from proteogenomic analysis
of hibernating mammals, to protein
expression in the lungs of patients with
acute respiratory distress syndrome.
TO INFINITY AND BEYOND
Drs Griffin and Jagtap hope their work
will provide a novel environment to
integrate multiple ‘omics’ datasets, and
that this approach will provide unique
opportunities for future discovery.
So far, the Galaxy-P team has advanced
the abilities of Galaxy to cope with
the many challenges of multi-omics
informatics. An accessible, unified
environment now exists to help non-
experts navigate the analysis of MS-
based proteomics and metabolomics
data, in addition to a platform with
the potential to develop workflows for
proteogenomic and metaproteomic
analyses.
The next steps will continue to
involve the consultation of biological
researchers to help the team translate
their informatics findings into basic
biological contexts, and to aid projects
which address human diseases. The
team will also continue to develop
visualisation tools that can help with the
interpretation of outputted data.
There is also potential to add extra
layers of omics to the analysis. So,
for example, metabolomics could
be included in the mix. Using this
approach, the possibilities for new
discoveries are endless.
Q&A
If your research were awarded a
considerable amount of money and
granted access to the world’s most
powerful computer – which informatics
tool would you develop?
A tool that integrates outputs from all
‘omics’ platforms and provides a ‘Google
earth’ like interactive visual data. Such
a tool would be extremely useful to a
biological researcher in both providing
an overview of ‘data landscape’ for
biological interpretation while providing
opportunities to dive-in into regions of
interest for validation and actionable
intervention/follow-up. We continue to
be amazed and fascinated by the depth
of analyses that the Galaxy platform
offers in challenging fields of research.
Another avenue might be to use such a
powerful compute platform to re-analyse
existing publically available proteomic and
transcriptomic datasets using newer multi-
omic tools, and develop tools to mine for
new discoveries.
What was the biggest challenge you
had to overcome when developing
Galaxy-P?
The development of tools and workflows
for multi-omic analysis of mass
spectrometry data provided challenges at
many levels. Be it at the conceptualisation
stage, or at grant seeking stage, or at tool
selection or workflow stage, we looked
at all the challenges as opportunities.
Deciding which of the many effective
software tools to implement in Galaxy
has been a challenge, as well as
understanding the many different ‘omic
sub-fields and how different software
tools work, as well as which are at the
forefront in terms of functionalities.
However, the biggest challenge and
priority in efforts has been to maintain
the relevance of workflows in a constantly
emerging environment where the inputs
are diverse and outputs offer deeper and
newer interpretations.
What is the most niche/unexpected
dataset that you’ve been asked to
analyse?
The breadth of biological research and
flexibility of the Galaxy-P workflows has
exposed us to many interesting datasets.
These range from human salivary datasets
for metaproteomics and proteogenomics,
to dental plaque metaproteomes
in presence of sugar to the study of
metaproteomes from the North Pacific
Oceans. But the most unexpected dataset
has been the study of cardiomuscular
protein expression in hibernation of
ground squirrels. Human hearts lose the
ability to function at temperatures of 20°C
and below. The study tried to shed light
on how the heart of hibernating animals
can withstand these low temperatures.
We are certain that we will continue to see
more of these interesting datasets as we
continue our research work.
In the future, do you see Galaxy-P
becoming a desk-based tool that can
easily and universally used by anyone,
anywhere in the world?
The research community has been using
Galaxy platform for genomics studies
for quite some time now and there is a
stable ecosystem of developers and users,
which makes this sustainable. We have
seen a gradual increase in interest in using
Galaxy-P amongst researchers as we have
promoted it via research publications,
workshops and presentations worldwide.
Along with the Galaxy community of
developers and researchers, we have
been working on making the workflows
available via downloadable tool containers
or by making public instances available so
that researchers can access pre-installed
tools and workflows for the research areas
of their interest. The vision for the future is
that researchers will access these software
tools remotely, where they are housed on
powerful cloud based hardware.
Leading on from this, do you think
that younger students and early
career researchers should be given
compulsory bioinformatic training as
part of their studies?
Absolutely! Bioinformatics has become
a necessary research skillset for
experimental researchers. Programming
skills enable young researchers to
perform novel analyses of previously
acquired data. For users, analytical
and data interpretation skills expand
their ability to seek newer avenues
in their research fields. We strongly
believe that bioinformatics training will
help in introducing and honing skills in
programming and data processing, and
helps in continuing to expand the breadth
and depth of questions that can be sought
by the future generation of scientists. ‘Big
Data’ will only continue to be generated
in biological research, and having the
ability to speak both languages in terms of
biology and computational science will be
a critical skill, and one that is very much in
demand in years to come.

84 www.researchoutreach.org www.researchoutreach.org 85
COMMUNICATION
The changing perception
of climate change
In the 2016 nature documentary Before The Flood, Leonardo DiCaprio summarised the need to combat climate change by
saying: “You [humans] are the last best hope of Earth. We ask you to protect it or we, and all living things we cherish, are
history” – he has a point.
B
ack in 1896, a Swedish scientist
named Svante Arrhenius found that
doubling the amount of carbon
dioxide in the atmosphere would increase
the surface temperature of Earth between
5 and 6OC.
However, his claims were widely disputed
and largely ignored by the scientific
community, with scientists believing that
the instruments used at the time would
not have been accurate enough to
calculate such an association. They also
believed that the Earth’s oceans would
quickly absorb any excess atmospheric
carbon dioxide.
GLOBAL WARMING: REAL OR HOAX?
This controversy of opinion surrounding
climate change has not gone away over
the years. It’s been over 120 years since
Arrhenius’ research was first published
and yet many still believe the concept of
climate change and global warming to
be a ‘hoax’, blown out of proportion by
governments and the media.
And yet, climate change is happening.
Polar ice caps are melting. The planet
is getting warmer. So, why do some still
insist that it’s not as bad as people think?
You’d be hard-pushed to find a polar bear
with the same outlook.
A GROWING CONTROVERSY
Despite the abundance of scientific
evidence showing that the planet has
86 www.researchoutreach.org
Social Media
got warmer year on year, and the strong
consensus that this is due to human-
induced greenhouse gas emissions, many
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So, herein lies the million-dollar question:
how do you shape public perception to
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whether there is a need to act against
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science and the media to ensure that
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see a real benefit in connecting
As Donald Trump has recently proven
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yet easy to comprehend.
with a broad audience over an
through his withdrawal from the Paris
Agreement for climate change, leaders The risk of simply ignoring global
ongoing basis. Social Media can
are ignoring the science put in front of
them. Instead, the public are manipulated
warming is not even worth contemplating.
With increased ignorance comes
now be considered one of the
into thinking that climate change isn’t as
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increased danger – only through a united
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isn’t going away. be managed effectively.
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A CHANGING WORLD
More needs to be done to spread the
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