IMS Magazine - Summer 2012 edition in PDF format - Institute of ...

IMSMAGAZINE
SUMMER
THINK, LEARN, DISCOVER.
2012
GENOMIC MEDICINE
ON THE CUSP OF INDIVIDUALIZED PATIENT CARE
PUBLISH
AND PERISH
Does a higher impact factor
equal better science?
SPIT
FOR SCIENCE
The Thoughts, Actions, and Genes project: exploring
the genetic basis of childhood neuropsychiatric disorders
Student-Led Initiative

IN THIS
ISSUE...
TABLE OF CONTENTS
Commentary ....................................03
Letter from the Editor ......................06
News at a Glance ...........................07
Director’s Message .........................10
IMS Scientific Day Highlight ...........11
Feature.............................................13
Spotlight ..........................................25
Book Reviews ..................................27
Close Up...........................................29
Viewpoint ........................................31
Expert Opinion .................................35
Future Directions .............................37
Research Highlight ..........................39
Ask the Experts ...............................40
Past Events.......................................41
Diversions .......................................42
13
FEATURE
Genomic Medicine
Our experts discuss how advances in genomic
technologies will soon allow genetic insights to
aid individual patient care, and the associated
challenges to consider.
Cover image by Inessa Stanishevskaya. Gone to the Dogs? photo by Jennifer Rilstone. Expert Opinion image courtesy of Igor Stagljar.
MAGAZINE STAFF
Editor-in-Chief Natalie Venier
Managing Editor Nina Bahl
Assistant Managing Editors Tetyana Pekar
Jennifer Rilstone
Allison Rosen
Adam Santoro
Departmental Advisor Marika Galadza
Kamila Lear
Design Editors Melissa Cory
Laura Greenlee
Michael Soong
Inessa Stanishevskaya
Andrea Zariwny
Sr. Design Editors Tobi Lam, Andreea Margineanu,
Merry Wang, Minyan Wang
Advertising Manager Corinne Daly
Laura Seohyun Park
Magazine Committee Salvador Alcaire
S. Amanda Ali
Rickvinder Besla
Danielle Desouza
Melanie Guenette
Aaron Kucyi
Rosa Marticorena
Anna Podnos
Brittany Rosenbloom
Karrie Wong
Zeynep Yilmaz
Photography Yekta Dowlati, Brett Jones
Laura Feldcamp, Paulina
Rzeczkowska, Mohammed Sabri
Copyright © 2012 by Institute of Medical Science, University of Toronto. All
rights reserved. Reproduction without permission is prohibited.
The IMS Magazine is a student-run initiative. Any opinions expressed by
the author(s) are in no way affiliated with the Institute of Medical Science
or the University of Toronto.
39
Gone to the Dogs?
Learn how Drs. Hannes Lohi and Berge
Minassian are using genomics to
improve the health of purebred dogs and
better understand human disease.
35
Expert Opinion: Proteomics
Dr. Igor Stagljar explains translational
aspects of proteomics research.
Cover Art
By Inessa Stanishevskaya
The cover was designed to illustrate how
the analysis of a person’s genome sequence
could potentially play a role in the development
of individualized patient care.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 02

COMMENTARY
Commentary
On ‘A Reconcilable Conflict’,
by Benjamin Mora (Spring 2012)
All ways of knowing are equal, but
some are more equal than others
By Adam Santoro, PhD student
I would like to thank Benjamin Mora for submitting
a thoughtful commentary in the previous
issue of the IMS Magazine. Mr. Mora
offered a contrasting opinion to that which
I presented in the Winter 2012 issue, stating
that “…flourishing dialogue between science
and religion in recent years is testimony to
the fact that, far from being irreconcilably
conflicted these two domains of human
knowledge can fruitfully interact.”
Mr. Mora presented three arguments: firstly,
that I was incorrect to state that scientists
who are religious have not thought deeply
about the issue, or are acting in a non-scientific
manner; secondly, that my views succumb
to an erroneous method of thinking
called scientism; and thirdly, that I can only
successfully support methodological (and
not philosophical) naturalism, which allows
for a great number of plausible and fruitful
interactions between science and religion.
As per his first argument: Mr. Mora contends
that there are numerous “top-thinking” scientists
who have thought deeply about the
issue at hand. He presented a list of “topthinkers,”
presumably to illustrate how some
individuals maintain a high degree of scientific
integrity and still think about the issue
deeply. To this I would simply state that an
individual’s scientific prowess does not necessarily
translate to matters not published in
Science or Nature; because an individual is a
leader within his scientific field, it does not
necessarily follow that he maintains sufficient
scientific integrity when dealing with issues
outside of the published literature (especially
those that enter the realm of philosophy).
Mr. Mora listed a plethora of scientists, all of
whom are Christian. This is indeed curious,
and raises numerous questions (i.e., why not
list names of top-thinking scientists who are
non-Christians?). I assume that it has to do
with Mr. Mora’s theological bias, which leads
me into the rest of the discussion.
As per his second and third arguments: Mr.
Mora implies that scientists who support my
viewpoint suffer from scientism, which states
that the scientific way of knowing is the only
way to discover truth. Those who share Mr.
Mora’s epistemic viewpoint acknowledge
that there are different ways of knowing,
and theology and science are merely two of
such ways. With this worldview, theological
knowing can inform one about the natural
world, and science can inform one about theology,
since both ways of knowing are equally
valid. There is a problem with this view. It is
undoubtedly the case that a priori theological
beliefs necessarily dictate those natural
phenomena that can be explained by science
(e.g., something inherently boring and obviously
un-divine as Brownian motion), and
those that seemingly require theology (e.g.,
evolution vs. Intelligent Design). To those
with this view, theology only succumbs to
science when it would be to approach insanity
to deny the scientific truth (see: the history
of evolution, the Heliocentric Model,
etc.). Thus, it is not a simple case of complementary
systems of knowing that can live in
harmony; all ways of knowing are apparently
equal, but some are more equal than others.
Regardless, straw-men aside, I was careful
to present an argument that did not depend
on a single way of knowing. Instead, I (perhaps
naively) assumed that scientists support
methodological naturalism – a viewpoint
that says all natural phenomena must be
explained by science, and theology cannot
dictate when it cannot. Mr. Mora should
take note that the theological way of knowing
is not lost with this worldview; instead
it is limited to the knowing of non-natural
things. So, much like how in some views
theology often dictates the limits of science,
from my perspective it is science that dictates
the limits of theology. Methodological naturalism
does not assume that the theological
way of knowing is invalid or incorrect; it simply
states that it cannot conflict with science
when dealing with the natural world. In my
article I merely interpolated some conclusions
from this viewpoint. Firstly, if theology
cannot step on the toes of science on matters
concerning the natural world, then nearly
all theistic religions are to be rejected (since
they all make naturalistic claims in some
capacity, all of which conflict with scientific
principles and natural laws). Second, deism
is the only position a scientist/methodological
naturalist can support, since this position
does not contain conflicting views of natural
phenomena. Thirdly, a scientist should support
methodological naturalism fully – to
pick and choose avenues where science is to
be usurped by theology is to lack scientific
integrity. Thus, an individual who is properly
scientific and truly accepts methodological
naturalism can be a deist, at most.
As a final point, it is commonly argued that
methodological naturalism can be in harmony
with theology since a theistic God can
act upon the natural world in ways that we
cannot detect (and hence, by their very nature
are in tune with natural laws and can
be studied with science). For example, God
could drive mutations during evolution in
subtle ways that we cannot detect. This is
merely a logical game (you cannot prove the
non-existence of the Tooth Fairy with 100%
certainty). This viewpoint would seriously
undermine the credibility and integrity of a
“top-thinking” scientist, since the invention
of ad hoc hypotheses is wonky at best.
03 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

COMMENTARY
Photo by Yekta Dowlati
The Sex of Stem Cells
Does sex have an effect on the regenerative
potential of stem cells?
By Anna Podnos, MSc student
In the last several decades, sex and gender
have become widely recognized as important
biological and social variables in human
research, and many strategies for incorporating
sex in research design have been developed.
However, as discussed in our Summer
2011 edition (see “Sexism in Biomedical
Research”), stratifying experiments by sex
is much rarer in animal and cell-based research
1 . Regenerative therapies, such as stem
cell transplantation, are being developed
based on animal and cellular models, and
a fundamental component may be missing.
Significant sex differences have recently been
found in the regenerative properties of various
stem cells. Stems cells have the unique
ability to differentiate into specific cell types
and self-renew, so they have the potential to
treat organ failure, cancers, and degenerative
diseases.
When patients’ own stem cells cannot be
used therapeutically, they may require a cellular
transplant from a donor. The success
of transplantation depends on the type of
donor stem cells, the characteristics of host
cells, and their interactions with pathways
associated with the illness 2 . Research using
animal models has found that biological sex
is an important variable in proliferation and
differentiation rates of stem cells 3 . For example,
animal studies of hematopoietic stem cell
transplantation (the only stem cell therapy
in standard medical practice 4 ) have found
that that the sex of both donor and recipient
animals affect the transplantation outcome 4 .
In addition, there are significant differences
in the activation of mesenchymal stem cells
(MSC) depending on their biological sex 3 .
Researchers found that female stem cells
produced more proliferation- and inflammation-promoting
factors than male cells.
Female muscle-derived stem cells (MDSC),
which have the capacity for myocardial repair,
were another type of stem cell found to
have more regenerative capacity than male
MDSC 5 . These sex differences may be therapeutically
relevant, but there are few studies
directly comparing different cell types in dis-
ease models 6 .
Given that sex differences exist in stem cells, it
is necessary to examine the causes of the dissimilarities,
which may arise on genetic, epigenetic
or hormonal levels. Male and female
cells differ genetically, and it is important to
investigate the differences both between and
within sexes. The hormonal environment is a
key covariate to sex, because it may also regulate
the differentiation and proliferation of
stem cells. Epigenetic differences resulting in
varying gene expression levels are covariates
as well. In mouse models of muscular dystrophy,
it was found that not only do female
MDSC promote more regeneration than
male MDSC, but also that the female recipient
animals undergo more regeneration than
male animals do, regardless of the sex of the
donor cells. However, this is not the case in
immune-deficient animals, which suggests
that the effect of host’s sex on the MDSC regenerative
potential may be immunologically
modulated, and therefore influenced by the
hormonal environment.
It is challenging to appropriately incorporate
sex as a variable in animal and cell-based
study designs, so an interdisciplinary approach
is often required. Recently, Stanford
University launched “Gendered Innovations”
2 (genderedinnovations.stanford.edu),
which has an abundance of information
about the inclusion of sex and/or gender in
engineering, science and medicine. It provides
practical methods and checklists for
considering biological sex in basic research.
The development and implementation of
specific guidelines for incorporating sex in
stem cell research as an informative variable,
rather than just a bias, will improve regenerative
therapies.
References
1. Beery, A., & Zucker, I. 2011. Sex Bias in Neuroscience and
Biomedical Research. Neuroscience and Biobehavioral Reviews,
35 (3), 565-572
2. genderedinnovations.stanford.edu
3. Crisostomo, P., Markel, T., Wang, M., Lahm, T., Lillemoe, K., &
Meldrum, D. 2007. In the Adult Mesenchymal Stem Cell Population,
Source Gender Is a Biologically Relevant Aspect of Protective
Power. Surgery, 142 (2), 215-221
4. Gahrton, G., Iacobelli, S., Apperley, J., Bandini, G., Björkstrand,
B., Bladé, J., Boiron, J., Cavo, M., Cornelissen, J., Corradini,
P., Kröger, N., Ljungman, P., Michallet, M., Russell, N.,
Samson, D., Schattenberg, A., Sirohi, B., Verdonck, L., Volin,
L., Zander, A., & Niederwieser, D. 2005. The Impact of Donor
Gender on Outcome of Allogeneic Hematopoietic Stem Cell
Transplantation for Multiple Myeloma: Reduced Relapse Risk in
Female to Male Transplants. Bone Marrow Transplantation, 35
(6), 609-617
5. Deasy, B., Lu, A., Rubin, R., Huard, J., Tebbets, J., Feduska,
J., Schugar, R., Pollett, J., Sun, B., Urish, K., Gharaibeh, B., &
Coo, B. 2007. A Role for Cell Sex in Stem Cell-Mediated Skeletal
Muscle Regeneration: Female Cells Have Higher Muscle Regeneration
Efficiency. The Journal of Cell Biology, 177 (1), 73-86
6. Zenovich, A., Davis, B., & Taylor, D. 2007. Comparison of
Intracardiac Cell Transplantation: Autologous Skeletal Myoblasts
versus Bone Marrow Cells. In Kauser, K., & Zeiher, A.
(Eds.), Bone Marrow-Derived Progenitors, pp. 117-165. Berlin:
Springer Verlag
Disclaimer: The opinions expressed by the author
are in no way affiliated with the Institute
of Medical Science or the University of Toronto.
Comments are welcome at theimsmagazine@
gmail.com.
What to look for next issue:
In continuation of our Genomic Medicine feature,
we highlight Dr. Berge Minassian’s work
in uncovering genetic causes of rare, profoundly
debilitating neurological diseases.
Contact Us
We encourage our readers to send their feedback
-- comments, questions, corrections, and
letters to the editor -- to theimsmagazine@
gmail.com.
www.facebook.com/groups/imsmagazine/
@IMSMagazine
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 04

NEWS AT A GLANCE
05 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

LETTER FROM THE EDITOR
Letter from
the Editor
Nearly sixty years ago in a letter to Nature, Watson and Crick wrote: “We wish to
suggest a structure for the salt of deoxyribose nucleic acid (DNA). This structure
has novel features which are of considerable biological interest.” This first identification
of DNA has paved the way for the field of medical genomics and, unknowingly to its
discoverers at the time, has given promise of revolutionizing the diagnosis and treatment
of many illnesses.
This milestone should once again remind us that a scientific discovery can open up a multitude
of opportunities for future research. In this issue of the IMS Magazine, we guide you
through a detailed timeline of the evolution of molecular medicine—from the principles of
heredity, to the first discovery of genomic DNA, to the identification of novel genes of various
diseases. I hope it will inspire young researchers to think about the long-term implications
of their research findings.
Furthermore, with the help of our experts, we hope to educate you about some of the innovative
research surrounding genomic medicine here at the IMS. We discuss next-generation
sequencing technologies, human genetic variation, pharmacogenomics, epigenomics, and
important ethical considerations of its translation to patient care. We hope that this will
improve your understanding of personalized medicine and inform you about the ongoing,
cutting-edge science at our institute.
I also encourage you to take a look at our Viewpoint section and weigh in on our more
contentious articles: we discuss the importance of understanding statistics in graduate education
and controversies centered around publishing in journals with high impact factors.
Be sure to also check out highlights from IMS Scientific Day, as well as our Close Up section
featuring the winner of the Mel Silverman Mentorship Award, Dr. Gary Remington.
Natalie Venier
Editor-In-Chief
Natalie Venier is a third year PhD Candidate
at the Institute of Medical Science.
She is currently studying prostate cancer
chemoprevention at Sunnybrook Health
Sciences Centre.
To conclude, I would like to thank Dr. Allan Kaplan and the IMS department for their
ongoing support, and congratulate our newest design team on their outstanding efforts in
the production of this issue. I must acknowledge the phenomenal IMS Magazine team for
their creativity and dedication, and our exceptional Managing Editor, Nina Bahl, whose
dedication has been integral to our production. Lastly, I strongly encourage comments and
feedback letters as we continue to aspire to bring you the best of the IMS.
Enjoy!
Photo by Paulina Rzeczkowska
Natalie Venier
Editor-In-Chief, IMS Magazine
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 06

NEWS AT A GLANCE
NEWS&VIEWS
JULY
28
AUGUST
5
12
13
15
16
IMSSA BBQ
IMS Wonderland trip
Blue Jays Game
SEPTEMBER
4
13
TBA
Registration for Fall session
begins
IMS Summer Undergraduate
Research Day
Artists for Autism: Talent
Show
School of Graduate Studies
– Graduate Orientation for
Incoming Students
IMS New Student
Orientation and Reception
IMSSA Executive Elections &
IMSSA Pub Night
For information on IMS news and events, please see:
http://www.ims.utoronto.ca
For more information on
IMSSA/IMSSA-related events, please visit:
http://imssa.sa.utoronto.ca
Please send your comments and suggestions to:
theimsmagazine@gmail.com
IMS ANNOUNCEMENTS
at a glance...
IMS Scientific Day – Recap!
This year’s IMS Scientific Day was held on May 15th, 2012. The day was a great success
with over 130 MSc and PhD student poster presentations, 6 Laidlaw Manuscript oral
presentations, and the Bernard Langer Lecture in Health Sciences—presented by Dr.
Thomas R. Insel, Director of the National Institute of Mental Health. For a glimpse of Dr.
Insel’s presentation, visit our website at www.ims.utoronto.ca. Thank you to all who
participated in this event. We look forward to another stimulating Scientific Day in 2013!
IMS Office Staff
Dr. Karen Davis has completed her 10-year term as Associate Director at the IMS. Among
her most lasting contributions are the establishment of ethical training modules and
development of the IMS Oath recited annually at September’s student orientation. Dr.
Davis is currently the Head of the Division of Brain, Imaging & Behaviour Systems at the
Toronto Western Research Institute and will continue her involvement with the IMS
through student supervision and as Professor of Surgery. Her vision and leadership will be
greatly missed.
Dr. Carol Westall has completed her term as Graduate Coordinator at the IMS. Outside
academia, Dr. Westall is a registered clinical optometrist and Director of the Visual
Electrophysiology Unit at SickKids. She served as a Graduate Coordinator at IMS for 3 years.
Dr. Westall’s sense of humour and tireless devotion to IMS students was much appreciated.
We wish them all the best in their future endeavours!
Dr. Mingyao Liu has accepted the position of Associate Director at the IMS effective July
1, 2012. Dr. Liu has many years of experience with the IMS, acting as a member of the
IMS faculty since 1997 and Graduate Coordinator between 2000 and 2005. Dr. Liu will
work closely with IMS Director, Dr. Allan S. Kaplan, to oversee faculty appointments and
spearhead the new IMS Strategic Plan Initiative slated for roll-out in fall of 2012.
We also welcome Dr. Cindi Morshead and Dr. Vasundara Venkateswaran as Graduate
Coordinators effective summer 2012. Both have served as active IMS faculty members for
over 5 years and will be a vibrant addition to our current roster.
Interim Staff Appointments
Michelle Rosen will be serving as the Interim Faculty and Student Affairs Coordinator.
Michelle will be responsible for administering awards, faculty appointments, and courses.
She will be covering Kaki Narh Blackwood, who is on medical leave until further notice.
Tania DaSilva has joined us as Interim Departmental Assistant. Tania worked at the IMS last
summer, and will assume the role of Summer Undergraduate Research Program Assistant
until July 27th, 2012. She will be responsible for general inquiries, room bookings, reception
and student document pick-up and drop-off.
Please join us in extending a warm welcome to all new staff and faculty members at the
IMS—we wish them a smooth transition in the months to come.
We would also like to take this opportunity to thank Cassandra Wysochanskyj for doing an
excellent job as former Interim Departmental Assistant. We wish Cassandra a safe journey
as she embarks on volunteer work in Eastern Europe.
07 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

NEWS AT A GLANCE
IMSSA ANNOUNCEMENTS
The annual IMS Talent Show Fundraiser, Artists for Autism, will be held on Thursday, August 16th, 6-10pm (Debates Room, Hart
House) featuring emcee Ori Rotstein. Acts will include piano and guitar performances, dancing, and more. Proceeds will be donated to
Unity for Autism. $15 ticket includes admission, free pizza and drink. Please contact artistsforautism2012@gmail.com to reserve your
ticket!
Come out on Saturday, July 28th to Cherry Beach, downtown Toronto, to hang out with fellow IMS students for a Corn roast/BBQ
beach day. There will be games, delicious food, great weather, and awesome people—mark your calendars! For further details, please
contact richard.foty@gmail.com.
A new academic year is around the corner, so please come out and join us at the 2012-2013 IMSSA Executive Council Elections in
late September. We will be holding elections for all positions, and immediately afterwards, we will be hosting a FREE pub night for
all IMS students! We strongly encourage registered IMS students of all years and degree programs to run for a position. If you have ideas
for new initiatives and events for your fellow students, this is your chance to carry them out and have a meaningful impact on your
student community! E-mail imssa@utoronto.ca for details.
AWARDS & SCHOLARSHIPS
NSERC AWARD RECIPIENTS
Jeffrey Cheung, MSc student; Stephane Paquette, PhD student; Tetyana Pekar, MSc
student
2012/2013 CIHR Banting and Best Master’s Award Recipients
Faizal Aminmohamed Haji
2012/2013 ONTARIO GRADUATE SCHOLARSHIPS RECIPIENTS
Kimberly Blom, Melanie Burger, Fernando Caravaggio, Jill Cates, Jeffery Cheung,
Charles de Mestral, Joana Dida, Laura Feldcamp, Gagandeep Fervaha, Erin Gibson,
Fervaha Haji, Marvin Hsiao, Stuart Jantzen, Salima Jiwani, David Kepecs, Ammar
Khairullah, Alex Laliberte, Tristram Lett, Biao Li, Jonathan Lipszyc, Anton Mihic,
Tetyana Pekar, Rachel Rabin, Natasha Radhu, Sofia Raitsin, Meghna Rajaprakash,
Grace Shen-Tu, Kevin Shield, Ivonne Suridjan, Weining Yang, Nima Zamiri, Boris Zevin
New Faculty Members
Daniel Blumberger
Associate Member,
Centre for Addiction and Mental Health
Sam Doesburg
Associate Member,
The Hospital for Sick Children
David Fisman
Member, University of Toronto,
Dalla Lana School of Public Health
Caitlin Gillan
Associate Member (Non-Supervisor),
ELLICSR, Toronto General Hospital
Christian Hendershot
Associate Member,
Centre for Addiction and Mental Health
Andrea Levinson
Associate Member,
Centre for Addiction and Mental
Health, Queen Street Site
Daniela Lobo
Associate Member,
Centre for Addiction and Mental Health
Jack Goodman
Member, Faculty of Kinesiology
and Physical Education
Rachel Wald
Associate Member,
Toronto General Hospital
Tom Schweizer
Member,
St. Michael’s Hospital
Find out more about faculty on the IMS faculty
database at http://www.ims.utoronto.
ca/faculty/directory.htm.
Welcome Dr. Liu, Dr. Morshead, and Dr. Venkateswaran!
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 08

SPOTLIGHT
Translational research and interdisciplinary graduate education that advances human health
2012 Undergraduate and International Summer Research Program
RESEARCH DAY
Wednesday, August 15, 2012, 9:00 a.m. – 3:40 p.m.
Medical Sciences Building, 1 King’s College Circle
9:00 am
9:05 am
9:15 am
10:00 am
10:30 am
12:00 pm
1:00 pm
3:30 pm
3:40pm
Welcome and Introduction – Macleod Auditorium, Room 2158
Dr. Allan S. Kaplan, Director, Institute of Medical Science
Introduction of Keynote Speaker
Dr. Vasundara Venkateswaran, Director, IMS Summer Undergraduate Research
Program
Keynote Address: Dr. Freda Miller
Professor, Department of Molecular Genetics and Senior Scientist, Developmental &
Stem Cell Biology, Sick Kids Hospital
“Stem Cells: Building and Rebuilding the Nervous System”
Coffee Break – Macleod Auditorium Lobby, Room 2158
Student Oral Presentations – Room 2158
Lunch – Macleod Auditorium Lobby, Room 2158
Poster Presentations – Stone Lobby, Room 2171 and Student Lounge (next to
Starbucks)
Concluding Remarks - Macleod Auditorium, Room 2158
Dr. Mingyao Liu, Associate Director, Institute of Medical Science
Award Presentations – Macleod Auditorium, Room 2158
We thank the presenters of our 2012 Seminar Series
Dr. Nick Wooldridge, Program Director, Associate Professor
Dr. Michael Szego, Fellow in Clinical and Organizational Ethics Joint Centre for
Bioethics, University of Toronto
Dr. Moloo Badru, Director, Animal Resources Centre, University Health Network
Dr. Neil Winegarden, Head of Operations, Microarray Centre, University Health
Network
Dr. Katalin Szaszi, Scientist, Associate Professor Department of Surgery, University
of Toronto
Dr.Xiao-Yan Wen, Assistant Professor, Department of Medicine, University of
Toronto
Dr. Art Petronis, Professor and Tapscott Chair, University of Toronto
Dr. Uri Tabori, Scientist, Staff NeuroOncologist, Associate Professor of Pediatrics,
University of Toronto
Dr. Moody, Radiologist-in-Chief Department of Medical Imagining, Sunnybrook
Health Science Centre
We Thank Our Generous Benefactors
UHN centre for research
09 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

DIRECTOR’S MESSAGE
Director’s
Message
The IMS Magazine continues to be the showcase publication of the Institute of Medical
Science student body. It has received rave reviews locally and from those internationally
who have seen it, including Dr. Thomas Insel, Director of the National Institute of Mental
Health, who was interviewed in the last issue of the magazine in anticipation of his Plenary Address
at IMS Research Day on May 15. Congratulations and thanks to Natalie Venier and her staff for all
their hard work, as well as to Kamila Lear for her ongoing assistance with this project.
This seventh issue of the magazine focuses on the important and related areas of genomic medicine,
epigenetics, and pharmacogenetics. These areas of research represent innovative work of our faculty
that is very much in keeping with the IMS’ strategic initiative related to translational research.
Recently, there have been a number of departmental leadership changes that I would like address.
First, Dr. Karen Davis and Dr. Carol Westall have finished their terms of service as Associate
Director and Graduate Coordinator, respectively. We at the IMS owe a great deal of gratitude and
thanks for their tireless efforts. As of July 1, Dr. Mingyao Liu will take over as the IMS Associate
Director, and Dr. Cindi Morshead will assume the role of Graduate Coordinator.
In the next few weeks, the IMS will also launch its first-ever Strategic Plan, which will guide us for the
next five years. The Plan is entitled “From Cell to Society: Becoming the Global Leader in Graduate
Education to Improve Human Health through Translational Research.” As we move forward with
the Plan, our new tagline underscores the five-year vision of the IMS: Translational research and
interdisciplinary graduate education that advances human health. Our plan has five themes that
will support us in making this vision as vibrant as possible: Uniqueness, Connectedness, Presence,
Belonging and Engagement. I look forward to working with our deeply committed faculty and
students to bring our vision to life.
Best wishes for a restful and enjoyable summer.
Sincerely,
Allan S Kaplan, MSc, MD,
FRCP(C)
Director, IMS
Allan S. Kaplan, MSc, MD, FRCP(C),
became the IMS Director in July 2011.
He is currently the Chief of Clinical
Research at the Centre for Addiction
and Mental Health (CAMH), Vice Chair
for Research in the Department of
Psychiatry, and Professor of Psychiatry
in the Faculty of Medicine. He is also
a Senior Scientist at both CAMH and
the Toronto General Hospital Research
Institute. He was the inaugural holder
of the Loretta Anne Rogers Chair in
Eating Disorders at the University
Health Network from 2002 to 2010.
Allan S Kaplan MD FRCP(C)
Director, Institute of Medical Science
Photo by Mohammed Sabri
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 10

IMS SCIENTIFIC DAY HIGHLIGHT
IMS SCIENTIFIC DAY
Compiled by
Karrie Wong
and Anna Podnos
AWARD WINNERS
Laidlaw Manuscript
Competition
Alan Wu Poster Competition &
Academic Development Award
Grand prize
Clinical Science
Christopher Tran
Basic Science
Brian Ballios
Honourable mentions
Clinical Science
Ann Montgomery
Basic Science
Nabilah Chowdhury
Marko Škrtić
Nadia Sachewsky
Grand prize
Clinical Science
Seham Chaker
Honourable mentions
Clinical Science
Ann Montgomery
Sean Barbour
Leigh Christopher
Sandeep Dhillon
Raymond Chang
Ayesha Malik
Laura Park
Tejas Sankar
Grand prize
Basic Science
Amanda Ali
Honourable mentions
Basic Science
Siba Haykal
Ana Konvalinka
Jeff Man
Stephane Paquette
Sally Yu Shi
Vanessa Zannella
Photos courtesy of the IMS Office.
11 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

IMS SCIENTIFIC DAY HIGHLIGHT
From the winners
“Sharing new ideas and scientific discourse
is at the heart of IMS Scientific
Day, and is a testament to the department’s
continued success at attracting
first-class investigators and trainees,
who are working to transform the future
of healthcare.”
“I am so grateful to the IMS for
almost every academic opportunity I
have received in the last two years.
As a graduate student here, I have
been granted access to mentors,
publications, and scholarships.”
“It was an honour to be afforded the
opportunity to present my research at
IMS Scientific Day - an event which
showcases the amazing breadth of
biomedical and clinical science research
across the department. All of
the speakers highlighted their cuttingedge
research, while emphasizing the
translational potential of their work.”
“My time spent with the IMS so far
has been challenging yet very enjoyable.
I am always amazed at the
high quality of research being done
around me.”
“I feel lucky to be a part of the IMS,
which really fosters a wide range of
research. IMS Scientific Day really
reflected this, [and] I was able to
meet fellow students and see their
work in topics completely different
from my own.”
“It has been very enlightening for me
to interact with so many fellow students
who are doing work in many
diverse areas of biomedical research.
The interdisciplinary nature of these
interactions, as well as of the seminar
series and courses offered through
the IMS, has helped me to think beyond
the narrow questions around
which my research is focused.”
“Thank you IMS administration,
faculty, and students.”
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 12

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13 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

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Illustration by Melissa Cory
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 14

FEATURE
Ethics and Challenges of Delivering
Genomic Medicine
Michael Szego, PhD, MHSc
Clinical Ethicist,
Centre for Clinical Ethics (A joint venture of
Providence Healthcare, St. Joseph’s Health
Centre, and St. Michael’s Hospital),
The University of Toronto Joint Centre for
Bioethics
Research Ethics Consultant,
The Centre for Applied Genomics,
The Hospital for Sick Children,
The University of Toronto McLaughlin Centre
for Molecular Medicine
In 2000, one of the most significant
milestones in genomics was achieved:
the first draft of the human genome
was completed 1 . The genomic sequence was
based on DNA samples pooled from several
individuals and it established a reference genome
for future sequencing projects. At the
press conference announcing this achievement,
Bill Clinton proclaimed that the completed
genome sequence would “revolutionize
the diagnosis, prevention and treatment
of most, if not all, human disease” 2 . Francis
Collins, who led the effort to complete the
human genome project, may have been trying
to manage expectations when he suggested
that a complete transformation of therapeutic
medicine would take up to 15 to 20
years 2 . One of the biggest hurdles that needed
to be overcome before Clinton’s claims could
be realized was the ability to sequence individual
genomes. This feat required technological
advances in sequencing and a drastic
reduction in sequencing costs.
Since 2000, whole genome sequencing
(WGS) of individual genomes has been developed,
enabling the identification of new
gene variants associated with disease that
can subsequently be used for genetic testing
in the clinical context 3 . The WGS is still
cost prohibitive with its use and is limited to
select research projects; however, its cost is
decreasing rapidly and will soon be cheaper
than currently employed genetic tests that assess
one gene at a time. The development of
affordable WGS may be the catalyst for the
transformation that Dr. Collins predicted
and the “revolution” that Clinton anticipated.
Since WGS has the potential to unlock every
person’s unique disease risk profile 4 , it may
be one of the most significant technological
breakthroughs in history. Therefore, WGS
deserves special consideration from an ethics
perspective. In this short article, I will
focus on two key ethical topics with respect
to WGS that are found in both research and
clinical settings, that is (1) informed consent
and, (2) return of results.
Informed consent
The principle of informed consent is recognized
as a main pillar in the practice of ethical
research and medicine. For consent to be
informed within the general research context,
the research subject must be informed
of the purpose for the research, its potential
applications, the methods that will be
employed, and any anticipated benefits and
risks 5,6 . However, many of these criteria are
unrealistic when applied to genomic research
specifically. At the time a DNA sample is
taken from the research subject, all possible
future research, its applications, and methods
are usually not known. One main risk/benefit
associated with most genomic research
projects is the potential identification of incidental
findings. For instance, the disclosure
of a pathogenic variant that is clinically actionable
which is identified over the course of
research is an example of a potential benefit,
while possible genetic discrimination is an
example of a potential risk. However, the actual
risks and benefits are not known beforehand
because they depend on the research
subject’s genomic sequence and the scientific
knowledge at the time the analysis.
In order for genomic research to be performed,
the traditional informed consent
process has been modified to include broad
consent. In the broad consent model, participants
consent to a range of possible research
activities 7 . Under this paradigm, research
subjects are educated about genomic research
to ensure they understand the general
risks and benefits. Consequently, they can
make the most informed decision possible,
even though the actual risks may not be completely
known.
Informed consent is a different process within
clinical medicine as compared to research.
In the clinical genetic testing context, patients
must be told the nature of the diagnostic
test, the expected risks and benefits of the
test, and any alternative tests for consent to
be informed. When WGS is used as a clinical
genetic test, the nature of the diagnostic test
and any alternative tests are known and can
be described to the patient. Current standards
of care for clinical genetic testing include patient
counseling about the risks and benefits
and potential outcomes of the proposed genetic
test. However, current genetic tests can
examine one or a handful of genes, making
counseling more straightforward than coun-
Photo by Yekta Dowlati
15 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

FEATURE
seling on a WGS test, which examines over
20,000 genes and many of which have known
pathogenic variants. That said, counseling is
critically important within the WGS context;
however, the information needs to be more
general in nature, analogous to the research
setting. Healthcare providers need to educate
patients about genomic testing using theory
and case-based examples, identify any likely
clinical implications of WGS, and discuss
the general risks and benefits of undergoing
WGS in order for patients to make an
informed decision as to whether they want
their genome sequenced.
Return of results
Whether researchers have a duty to return
individual research results in genetic studies
has been the subject of much debate. Should
research be purely for research sake? This debate
is especially important within the WGS
context since the likelihood of identifying
pathogenic variants is high. Fortunately, a
consensus is emerging. The World Health
Organization has identified three conditions
to be met before disclosure should occur: (1)
the data should be clinically beneficial; (2)
disclosure should avert or minimize significant
harm; and (3) there is no indication that
the individual in question would prefer not
to know 8 . Consistent with this approach, Canadian
research ethics guidelines outline an
obligation to disclose any material incidental
findings or unanticipated discoveries made
during the course of research that are interpreted
as having a significant welfare implication
for the participant 9 .
Different strategies have been suggested to
manage the return of clinically relevant research
results in the WGS context. One approach
would categorize human genes according
to clinical parameters10. In such a
scheme, all gene mutations that are medically
actionable are labeled as “Bin 1” genes
and would trigger an automatic return of the
result. “Bin 2” genes are defined as gene mutations
associated with human disease that
could not be acted upon medically. Finally,
“Bin 3” contains all other genes whose association
with human disease is unknown. It has
been estimated that there are currently only
100 “Bin 1” genes in the human genome 10 .
The ClinSeq project at the National Institutes
of Health (NIH) has taken a different
approach that is more research-subject-centered
and engages research subjects to determine
the type and extent of information
they would find useful 11 . In the NIH project,
all pathogenic variants can be returned to research
subjects, provided consent is obtained
for disclosure. Additionally, they have set up
an independent panel to periodically review
any new evidence linking variants to human
disease and to determine if the evidence is
sufficient to warrant disclosure.
With all the effort spent on identifying variants
associated with human disease, new
clinically relevant variants will no doubt be
identified in the future. This reality necessitates
a long-term plan to deal with stored
sequences. Researchers returning individual
research results could implement software
that can reanalyze past genomes and flag new
clinically relevant data. Alternatively, if such
a measure was not possible, research subjects
should be informed during the informed
consent process that reanalysis will not occur
and that any results returned would only reflect
current knowledge.
It is generally understood that test results are
returned to patients, however, it is unclear
what should be returned to patients when
WGS is used as a genetic test. While any results
that inform the original differential diagnosis
seem appropriate to disclose, many
other variants of known and unknown significance
may also be detected that have nothing
to do with the original query. A “binning”
mechanism or a patient-guided approach
may be borrowed from the research context
described above. Lastly, the issue of clinical
reanalysis was addressed in a recent article
by the head of the NIH clinical sequencing
project mentioned previously, Leslie Biesecker
describes WGS as a resource not a genetic
test 12 . As such, a WGS dataset can be “interrogated
by the patient and clinician in situations
where it could be of potential use to
the patient, when both agree to this use” 12 .
This type of integration would also solve the
issue of reanalysis. If treated as a one off test,
the physician who ordered it would not have
a legal or ethical obligation to periodically
reanalyze each of her patient’s genome for
any new medical information. If comprehensively
integrated into primary care, a patient’s
whole genome could be part of the transformation
of healthcare Francis Collins and Bill
Clinton predicted over a decade ago.
Concluding remarks
While it is still unclear exactly how informed
consent and return of results are going to
look in the future context of WGS, many of
the research projects employing WGS have
an integrated ethics component, which includes
research subject engagement. As
such, I am confident we will establish ethical
best practices when it comes to WGS in
clinical and research settings. Furthermore,
as WGS is exploited clinically, opportunities
and challenges will be created for researchers
and clinicians. Clinical WGS datasets could
provide a rich source of data for researchers,
provided that appropriate informed consent
and privacy safeguards are put in place. This
environment would represent a paradigm
shift in which clinical medicine and research
could occur using the same platform, facilitating
knowledge exchange.
References
1. Lander ES, et al. Initial sequencing and analysis of the
human genome. Nature. 2001; 409(6822): 860-921.
2. Wade NA. Decade Later, Genetic Map Yields Few New
Cures, in New York TImes.2010: New York.
3. Tucker TM, et al. Massively parallel sequencing: the
next big thing in genetic medicine. Am J Hum Genet.
2009; 85(2): 142-54.
4. Tabor HK et al. Genomics really gets personal: how
exome and whole genome sequencing challenge the ethical
framework of human genetics research. Am J Med
Genet A. 2011; 155A(12): 2916-24.
5. Human T.-C.P.S.E.C.f.R.I. 1998 Aril 9, 2009]; Available
from: http://pre.ethics.gc.ca/eng/index/.
6. Beauchamp TL and Childress JF. Principles of biomedical
ethics. 6th ed. 2009, New York: Oxford University
Press. xiii, 417.
7. Singer PA and Viens AM. The Cambridge textbook
of bioethics. 2008, Cambridge ; New York: Cambridge
University Press. xvi, 538 p.
8. Organization, W.H. Genetic databases: assessing the
benefits and impact on human and patient rights. 2003
[cited 2009 December 15]; Available from: http://www.
law.ed.ac.uk/ahrb/publications/online/whofinalreport.
doc.
9. Canadian Institutes of Health Research, N.S.a.E.R.C
.o.C.a.S.S.a.H.R.C.o.C., Tri-Council Policy Statement:
Ethical Consult for Research Involving Humans, 2010.
10. Evans JP and Rothschild BB. Return of results: not
that complicated? Genet Med. 2012; 14(4): 358-60.
11. Biesecker LG et al. The ClinSeq Project: piloting
large-scale genome sequencing for research in genomic
medicine. Genome Res. 2009; 19(9): 1665-74.
12. Biesecker LG. Opportunities and challenges for the
integration of massively parallel genomic sequencing
into clinical practice: lessons from the ClinSeq project.
Genet Med. 2012; 14(4): 393-8.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 16

FEATURE
Psychiatric Pharmacogenetics
Maximizing Benefits While Minimizing Side Effects
By Zeynep Yilmaz, PhD candidate
lizing medications, essentially coining the
term “pharmacogenetics.” Prof. Kalow and
I trained students in my laboratory, and before
he passed away, he saw the fruits of these
labours with the delivery of genetic tests for
characterizing drug metabolism. Another
Toronto researcher, Dr. Victor Ling, discovered
the role of drug transporter proteins,
for which there are now DNA-based tests to
determine their variation across individuals.
Given this powerful history in pharmacogenetics
at the University of Toronto, I was
inspired to carry the science forward using
the developments in the human genome and
genetic testing technology.
James L. Kennedy, MD, MSc, FRCP(C)
Dr. James L. Kennedy is the Director
of the Neuroscience Research
Department at the Centre for Addiction
and Mental Health and the Co-Director
of the Brain and Therapeutics Division in
the Department of Psychiatry, University of
Toronto. Dr. Kennedy has an extensive, and
unique combination of training in psychiatry,
genetics, and neuroscience. As a professor
and full-member of IMS, he has supervised
well over a hundred trainees, including
undergraduate and graduate students, postdoctoral
fellows, and visiting scientists.
What is pharmacogenetics, and why is it
important to study?
Pharmacogenetics is the science of linking a
person’s DNA sequence with their response
to medication. Because DNA provides its
own unique blueprint of the body, we can
make specific predictions as to the right drug
and its correct dosage for a particular patient.
We hope to prevent patients from continuing
for weeks on ineffective medication and
then having to switch to another medication,
going through the entire disappointing sequence
of non-response. We need to move
beyond trial-and-error prescription of medications.
With pharmacogenetics, we can help
predict which patients will not respond to a
particular medication, and also predict the
best choice of medication on the basis of
their genotype and psychiatric condition.
How did you become interested in pharmacogenetics?
I became interested in pharmacogenetics
when I witnessed many patients suffer while
receiving the standard textbook dose of an
antidepressant or antipsychotic medication. I
saw the answer was in the power of new DNA
technology for testing patients to determine
their combination of genetic variants and
whether a given patient metabolized the
medication quickly or slowly. I had also read
seminal papers by Prof. Werner Kalow from
his work here at the University of Toronto in
the late-1950s and 1960s. He was the first to
point out that people were genetically predisposed
to having different rates for metabo-
What are some of the clinical applications
of pharmacogenetics in psychiatry?
We have a number of patented genetic discoveries
making their way into the clinic, including
a test using dopamine system genes
to predict risk for tardive dyskinesia (uncontrolled
muscle movements) as a result of
prolonged use of antipsychotic medications.
We also have a genetic test that identifies depressed
patients who are at risk for developing
mania as a result of their antidepressant
treatment. We have just published an important
paper showing the role of the melanocortin
4 receptor (MC4R) gene in determining
the risk for antipsychotic-induced weight
gain. The newer antipsychotic medications
have the side effect of substantial weight gain;
some patients will gain more than 100 lb during
one year of treatment and often go on to
develop diabetes and heart disease. After the
initial finding of this gene’s effect in the first
sample, we replicated the exact same result in
three independent samples.
It is now possible for the physician to see
a patient in the morning, for the patient to
have a quick sampling of their saliva using a
swab, and this sample to be shipped off to a
specialized lab where the genotyping of the
relevant genetic variants for common medications
can be done overnight. The results
are emailed to the physician the next day, and
the physician writes a prescription on the ba
Photos by Yekta Dowlati.
17 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

FEATURE
sis of the patient’s genetic profile. There is little
delay in starting treatment, and the choice
of medication is precise and targeted to avoid
side effects and achieve the best response.
On which psychiatric disorders are you
conducting pharmacogenetic studies?
I expect that pharmacogenetic information
will apply to virtually every psychiatric
disorder. Over the 20 years that I have
been doing research here at CAMH/UofT,
I have overseen the collection of more than
24,000 DNA samples for disorders including
schizophrenia, bipolar disorder, obsessive
compulsive disorder, attention-deficit/hyperactivity
disorder, addictions, eating disorders,
suicidality in teenagers treated with
antidepressants, as well as severe depression
in young children. Unfortunately, not all of
these patients have been characterized in
terms of medication response. These studies
are difficult because they require a patient to
be followed over an extended period of time.
Nonetheless, we have several thousand DNA
samples from psychiatric patients with drug
response and side effect information – one of
the largest collections in the world.
How do you predict the future of pharmacogenetics?
As we move into the future, I see many benefits
arising from pharmacogenetic testing
in the population. It is easy to imagine the
substantial healthcare savings when we can
prevent non-response or debilitating side effects
from medication treatment. If patients
are prescribed the right drug from the start,
they should have fewer doctor visits and stay
compliant with their medication. Currently,
under our large pharmacogenetic initiative
funded by the Ministry of Economic
Development and Innovation to test 20,000
patients, Ontario stands to be the leader, as
the largest single geographic region offering
pharmacogenetic testing in the world. Personalized
medicine with pharmacogenetics
is estimated to save Ontario at least $88
million in health care costs over the next 5
years. Pharmacogenetics is a very exciting
area benefiting from rapid increases in DNAbased
information, and computer-based algorithms
combining information from multiple
gene variants together to create more
powerful methods to define an individual’s
tailor-made treatment.
One of our recent projects is an innovative
treatment for anorexia nervosa. We believe
that one of the medications that has a calming
effect in schizophrenia patients, but causes
weight gain, may be helpful in anorexia nervosa
by reducing anxiety associated with eating.
It will be interesting to see if MC4R gene
variation can predict those individuals that,
in this case, gain weight in a helpful way. The
fact that MC4R is expressed in the appetite
centre of the brain may help demonstrate its
value in predicting the patients that would
get the most benefit from this medication.
Pick Your Brain...
A column by Aaron Kucyi
Illustration by Andreea Margineanu.
The human brain is the most complicated feature
of the human body, and it presents many unique
challenges to genomics research. The best, and
perhaps only, effective approach to understanding
the genetics of brain structure is to combine data
from multiple research sites to conduct studies
with very large and diverse population samples.
In the largest MRI study of the brain to date, researchers
from several sites around the world
reported new links between specific gene variants
and total brain volume, intracranial volume,
and hippocampal volume. The study was
possible because investigators in North America,
Europe, and Australia combined brain imaging and
genetics data from over 21,000 human subjects in a
“crowdsourcing” project. Some findings—such as
that of a strong link between hippocampal volume
and the rs7294919 variant—were not in agreement
with previous smaller studies. Because hippocampal
and other brain volume measures have relevance to
neuropsychiatric disorders, including Alzheimer’s disease,
schizophrenia, and depression, the new findings
may lead to personalized genomic approaches
to therapy.
The study highlights the usefulness of, and need
for, further large-scale multinational collaborations
in the field of brain imaging genetics. The
200+ authors of the study caution that their work is
just a preliminary step and that the findings need
to be confirmed and extended before this type of
work can lead to targeted treatments for neuropsychiatric
disorders.
Reference:
Stein et al. Identification of common variants associated with human
hippocampal and intracranial volumes. Nat Genet. 2012;44(5):552-561.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 18

FEATURE
Spit for Science:
A Population-based Genetic Study of Childhood Attention Deficit Hyperactivity Disorder
and Obsessive Compulsive Disorder
By Laura Seohyun Park
Would you like to spit for science?”
“SPIT! Why would I do THAT?” shouted the
10-year-old boy with both excitement and
disgust. As I explained to him that his spit
could contribute to science and help other
people, the boy was quick to agree to participate.
Our setup at the Ontario Science Centre
(OSC) looked like an arcade with computers,
game controllers, and toy prizes--but actually,
it was the scene of cutting-edge research.
I had the pleasure of being a part of the
Thoughts, Actions and Genes project (TAG),
a ground-breaking study exploring the genetic
basis of attention-deficit hyperactivity
disorder (ADHD) 1,2 and obsessive-compulsive
disorder (OCD) 3,4,5 . Led by Dr. Russell
Schachar, Dr. Jennifer Crosbie and Dr. Paul
Arnold from the Department of Psychiatry
at the Hospital for Sick Children, and in partnership
with the OSC, over 17,000 children
and adolescents (7-17 years of age) participated
in TAG. Each participant completed a
behavioural questionnaire, a cognitive task
called the Stop Signal Task (SST), and donated
a saliva sample. In a recent interview
with the investigators behind TAG, the IMS
Magazine learned about the project’s novel
and creative approach to study complex psychiatric
disorders.
Q What led you to conduct a research project
like TAG?
Schachar: Psychiatric conditions are highly
influenced by genetic risk factors as seen
in twin and family studies of affected individuals.
Thus far, candidate gene studies and
genome-wide association studies (GWAS)
have generated suggestive findings but either
with difficulty to replicate, or nothing that is
‘significant genome-wide’, respectively. While
global collaboration among scientists is a
TAG photos courtesy of Laura S. Park
19 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

FEATURE
necessary strategy for collecting sufficiently
large psychiatric patient samples for genetic
analysis, they can introduce new problems
such as the imprecision in measuring psychiatric
“phenotypes”. It is not clear that ADHD
or any other psychiatric disorder is assessed
and diagnosed in exactly the same way in
Brazil as it is in the Netherlands. Moreover,
global studies collect DNA from very divergent
ethnic groups. It is entirely possible
that the genetic risks for a common disease
may not be identical in every ethnic group.
Based on these limitations, it was clear to us
that novel methods were needed to break this
impasse.
Crosbie: Endophenotypes 6 , which are objective,
quantitative, and heritable “intermediate
phenotypes” or “biological markers”,
provide increased power to genetic studies
by pointing to a more homogeneous genetic
group of individuals and measuring a process
that is closer to the underlying genetic
mechanism. There is evidence that response
inhibition, which refers to the ability to stop
a speeded motor response and can be measured
by the SST, is a valid endophenotype
for ADHD based on the results of clinical,
family, functional imaging and preliminary
genetic investigations (response inhibition
influenced by the genetic risk factors that influence
ADHD) 2,7 .
Paul Arnold, MD, PhD
Russell Schachar, MD, FRCP(C)
Schachar: At that point, we will also generate
animal models and learn more about the proteins
that these genes play a role in.
Q How will this study contribute to the
field of psychiatric genetics?
Schachar: There is a great deal of enthusiasm
about the use of cognitive endophenotypes or
biomarkers in psychiatric genetic research.
Ours will be one of the first to be completed.
If it proves to be useful in identifying genetic
risks for inhibition and for these disorders,
the field will move rapidly.
Crosbie: With this potential to point to new
candidate genes of interest for ADHD and
OCD, the study may provide us with novel
information about the etiology and molecular
pathways of these disorders, as well as
further our understanding of other neuropsychiatric
disorders.
Arnold: Our approach with TAG is consistent
with previous work suggesting that we
should be thinking of neuropsychiatric disorders
as continuous rather than categorical
traits. If we are successful in identifying risk
variants for psychiatric disorders, others may
want to adopt a similar strategy of studying
large general population samples rather than
focusing solely on clinic-based populations.
Investigator photos by Brett Jones
Arnold: The general population-based design
of TAG provided a quick and cost-effective
way to collect a large sample of children
using a single and uniform assessment of
behavioural (ADHD, OCD, and other conditions
through questionnaire), cognitive (response
inhibition measured by SST) and genetic
(saliva DNA) traits. With this data, we
are able to draw from the full range of variation
in our traits of interest, and use an extreme
trait approach 8 to conduct a genomewide
association study comparing children
in the upper and lower extremes of specific
behavioural and cognitive traits.
Q What are the objectives of TAG?
Arnold: Once we have performed our
GWAS and identified interesting risk variants,
we intend to genotype these variants
in our entire sample and clinical samples.
By taking our results to clinical samples, we
can test if the identified variants [in the general
population] are also found in ADHD or
Jennifer Crosbie, PhD, CPsych
OCD patients, and also look for associations
with interesting phenotypes we can’t measure
in the general population (e.g. neuroimaging).
Another future direction is to look for
other genetic variations beyond the common
“single nucleotide polymorphisms” surveyed
in GWAS. For example, we will analyze copy
number variants and relatively rare but functional
single nucleotide variants found in
coding regions of genes.
References
1. Neale BM, et al. Meta-analysis of Genome-wide Association
Studies of Attention-Deficit/Hyperactivity
Disorder. J Am Acad Child Adolesc Psychiatry.
2010;49:884-897.
2. Crosbie J, et al. Validating Psychiatric Endophenotypes:
Inhibitory Control and Attention Deficit Hyperactivity
Disorder. Neurosci Biobehav Rev. 2008;32:40-
55.
3. Pauls DL. The Genetics of Obsessive Compulsive Disorder:
A Review of the Evidence. Am J Med Genet C Semin
Med Genet. 2008;148:133-139.
4. Boileau B. A Review of Obsessive-Compulsive Disorder
in Children and Adolescents. Dialogues Clin Neurosci.
2011;13:401-411
5. Menzies L, et al. Neurocognitive Endophenotypes of
Obsessive-Compulsive Disorder. Brain. 2007;130:3223-
3236.
6. Gottesman II, Gould TD. The Endophenotype Concept
in Psychiatry: Etymology and Strategic Intentions.
Am J Psychiatry .2003;160:636-645.
7. Schachar RJ, et al. Heritability of response inhibition
in children. J Int Neuropsychol Soc. 2011; 17(2):238-47.
8. Liu DJ, Leal SM. A Unified Framework for Detecting
Rare Variant Quantitative Trait Associations in Pedigree
and Unrelated Individuals via Sequence Data. Hum
Hered. 2012;73:105-122.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 20

FEATURE
Epigenomics
Beyond Genomic Sequencing
Darci Butcher, PhD, Postdoctoral
Fellow
Program in Genetics and Genome Biology,
Hospital for Sick Children
Rosanna Weksberg, MD, PhD
Staff Physician, Clinical and Metabolic
Genetics
Co-Director and Staff Geneticist, Cancer
Genetics Program
The Hospital for Sick Children
Professor,
Molecular and Medical Genetics
University of Toronto
Genome sequencing initiatives
have been unable to identify the
genetic causes or phenotypic modulators
of many of disorders seen in clinical
medicine. Layered on top of the DNA
sequence is epigenetic information, defined
as a “stably heritable phenotype resulting
from changes in a chromosome without alterations
in the DNA sequence” 1 . Identifying
the epigenetic marks and characterizing how
they are read to regulate the expression of the
primary genomic sequence is necessary for
our understanding of human development
and disease. Multiple epigenetic mechanisms
including DNA methylation at cytosine
residues in CpG dinucleotides, covalent
modifications of histone proteins, regulatory
non-coding RNAs, including small interfering
RNA (siRNA), microRNAs (miRNAs)
and long non-coding RNAs (lncRNAs) participate
in regulating gene expression and
chromatin architecture. Disruption of these
mechanisms is associated with a variety of
diseases with behavioural, endocrine or neurologic
manifestations and disorders of tissue
growth, including cancer. The involvement of
epigenetic alterations in many diseases has
been known for some time, but only recently
has it begun to be useful for clinical practice
to diagnose and monitor disease progression.
In the Weksberg laboratory we determine
genome-wide differential DNA methylation,
gene expression and histone modifications
for a number of disorders that have known
or suspected aberrations in their epigenomic
patterns. Many of these projects are collaborative
efforts between the research laboratory
and clinicians at the Hospital for Sick
Children and around the world. We are identifying
genes and pathways that have altered
DNA methylation to determine their contribution
to the overall disease phenotype. The
projects in the laboratory can be separated
into those related to growth, including genomic
imprinting and intrauterine growth
restriction and those related to neurodevelopment
including autism spectrum disorders
(ASD) and other paediatric neuropsychiatric
disorders.
A number of disorders are caused by aberrant
genomic imprinting resulting from unequal
contributions of maternal and paternal
alleles to the offspring 2 . Imprinted genes
typically function in growth regulation and
neurodevelopment, and the corresponding
disease phenotypes are due to genetic or epigenetic
aberrations in these genes often result
in abnormalities of intrauterine growth
or post-natal cognition and behavior. These
disorders include Beckwith-Wiedemann
(BWS), Silver-Russell (SRS), Prader-Willi
(PWS) and Angelman syndromes (AS).
The molecular and epigenetic causes of
Beckwith-Wiedemann syndrome have been
studied in depth in the Weksberg laboratory 3 .
This disorder is a rare, often sporadic, heterogeneous
congenital overgrowth disorder
which has many features including somatic
overgrowth, large tongue, abdominal wall
defects, ear creases and pits, kidney malformations
and neonatal hypoglycemia, as well
as in increased risk of embryonal tumours.
BWS is caused by epigenomic and/or genomic
alterations in the imprinted gene clusters
on chromosome band 11p15.5 4 can be subdivided
into two distinct imprinted domains.
Most cases of BWS are due to epigenetic lesions:
either a gain of CpG methylation at an
imprinting control region on the maternal allele
of the H19 upstream differentially methylation
region (DMR), which silences H19
and activates expression of the growth promoting
gene insulin growth factor 2 (IGF2),
or a loss of methylation at another imprinting
control region of the KCNQ1intronic DMR,
which silences the growth suppressor gene
CDKN1C plus several nearby maternally expressed
genes. Identifying specific molecular
defects in imprinting disorders provides im-
Photos by Brett Jones
21 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

FEATURE
portant information for patient management
and for estimating recurrence risk. Molecular
diagnostic testing for abnormal DNA methylation
in the relevant imprinted domains
can be done for a number of imprinting disorders
and is already widely applied in PWS/
AS and BWS/SRS. The majority of molecular
alterations within imprinting domains can be
identified by alterations in DNA methylation
in the respective imprinting control regions.
A few retrospective studies have shown an increased
incidence of epigenetic abnormalities
causing both BWS and AS following the use
of assisted reproductive technologies (ART).
Although the increased relative risk is small
for these DNA methylation errors these data
highlight the importance of understanding
the mechanisms behind genomic imprinting.
The number of imprinted genes in human
and mouse is currently just over 100 imprinted
transcripts. Approximately 63 of these
have been identified in humans. We designed
experiments using uniparental tissues and
DNA methylation at known imprinted genes
to identify new imprinted genes 5 . We took advantage
of two uniparental tissues; complete
androgenetic hydatidiform moles (CHMs)
and mature cystic ovarian teratomas. CHMs
have two copies of each paternal chromosome
and no maternal chromosomes. Mature
cystic teratomas, on the other hand, have two
copies of the maternal genome. Analyzing
the genome-wide DNA methylation patterns
in these tissues and comparing them to normal
biparental tissue we identified a number
of candidate imprinted genes and validated
one of those genes both mouse and humans 5 .
An expanded set of known imprinted genes
could lead to the identification of the molecular
cause of disorders of unknown etiology.
“Identifying the epigenetic
marks and characterizing
how they are read to
regulate the expression
of the primary genomic
sequence is necessary
for our understanding of
human development and
disease.”
The laboratory is also interested in the epigenetic
contribution to intrauterine growth
restriction (IUGR), a heterogeneous disorder
in which babies are born with a birthweight
less than the 10 th centile for gestational age.
IUGR has been associated not only with significant
maternal and fetal/neonatal mortality
and morbidity but also with adult-onset
disorders such as hypertension, coronary
artery disease, and type 2 diabetes. DNA
methylation alterations have been shown to
drive increased or decreased placental and
fetal growth. By determining DNA methylation
patterns in the placenta of children
born small for gestational age, we identified
that gain of methylation in WNT2 was significantly
associated with reduced WNT2
expression in placenta and with low birthweight
percentile in the neonate 6 . This gene
has been demonstrated to have important
function in mouse placental development.
These data suggest that WNT2 expression
can be epigenetically downregulated in the
placenta by DNA methylation of its promoter
and that high WNT2 promoter methylation
is an epigenetic variant that is associated
with reduced fetal growth potential 6. We expect
that future studies of the epigenome will
elucidate other candidate genes that undergo
epigenetic dysregulation and negatively impact
placental and fetal health.
The second focus in the Weksberg laboratory
is the investigation of DNA methylation
alterations in paediatric neurodevelopment
and neuropsychiatric disorders. A
number of neuropsychiatric disorders have
been described with mutations or deletions
in genes that are important for maintaining
normal epigenetic regulation. Loss of
function of these genes can disrupt normal
establishment, maintenance, or reading of
epigenetic marks, thereby resulting in altered
chromatin structure and gene expression. In
most disorders of this type, we still do not
understand precisely how the mutation is related
to the phenotype of the human disease.
Many of these disorders are associated with
intellectual disability (ID), as well as additional
features including various congenital
anomalies. The identification of alterations in
DNA methylation associated with mutations
in specific genes that function in epigenetic
regulation will teach us more about what the
responsibility of each epigenetic modifier is
in the normal patterning of the epigenome.
Other paediatric disorders we are investigat-
ing include autism spectrum (ASD), obsessive
compulsive (OCD) and attention deficit
hyperactivity (ADHD). For each of these disorders
there have been genetic factors identified
which explain a small proportion of such
cases. We have proposed that epigenetic factors
also contribute to the etiology of these
disorders. These studies are all in the initial
stages but we already have a number of interesting
and encouraging results. We are currently
investigating a number of candidate
genes and pathways that may be relevant to
these disorders.
The field of epigenetics is generating exciting
discoveries in parallel to genome sequencing
initiatives. The NIH Roadmap Epigenomics
Mapping Consortium was launched to
produce a public resource of human epigenomic
data to catalyze basic biology and
disease oriented research 7 . Parallel initiatives
include the NIH Epigenomics of Health and
Disease Roadmap Program and CIHR Canadian
Epigenomic Mapping Centres. These
initiatives interface with the International
Human Epigenomics Consortium, which
was established to accelerate and coordinate
epigenomics research worldwide 8 . This is an
exciting time for all researchers involved in
epigenetic research as we work towards deciphering
the language of the epigenome at an
exponential rate.
References
1. Berger, S.L., Kouzarides, T., Shiekhattar, R. & Shilatifard,
A. An operational definition of epigenetics. Genes
& development 23, 781-3 (2009).
2. Weksberg, R. Imprinted genes and human disease.
American Journal of Medical Genetics Part C: Seminars
in Medical Genetics 154C, 317-320.
3. Choufani, S., Shuman, C. & Weksberg, R. Beckwith–
Wiedemann syndrome. American Journal of Medical
Genetics Part C: Seminars in Medical Genetics 154C,
343-354.
4. Weksberg, R., Smith, A.C., Squire, J. & Sadowski, P.
Beckwith-Wiedemann syndrome demonstrates a role
for epigenetic control of normal development. Human
molecular genetics 12 Spec No 1, R61-8. (2003).
5. Choufani, S. et al. A novel approach identifies new differentially
methylated regions (DMRs) associated with
imprinted genes. Genome research 21, 465-76.
6. Ferreira JC, C.S., Keating S, Chitayat D, Grafodatskaya
D, Shuman C, Kingdom J, and Weksberg R. WNT2 promoter
methylation in human placenta is associated with
low birthweight percentile in the neonate. Epigenetics
(2011).
7. Bernstein, B.E. et al. The NIH Roadmap Epigenomics
Mapping Consortium. Nature biotechnology 28, 1045-8.
8. Eckhardt, F., Beck, S., Gut, I.G. & Berlin, K. Future potential
of the Human Epigenome Project. Expert review
of molecular diagnostics 4, 609-18 (2004).
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 22

FEATURE SPOTLIGHT
Advancing Genomic Medicine in Toronto
An Interview with Stephen W. Scherer, PhD
By Tetyana Pekar
The McLaughlin Centre
Advancing Genomic Medicine
You may not have yet heard
about it – and you certainly won’t
find it on the map – but McLaughlin
Centre scientists and collaborators
are making scientific breakthroughs, developing
new diagnostic tests, and making
a lasting impact on clinical management
in Toronto and internationally.
The McLaughlin Centre derives its name
from the founder of General Motors of
Canada, Colonel Robert Samuel McLaughlin,
“an entrepreneur and a brilliant man”
in the words of Dr. Stephen Scherer, the
Director of the McLaughlin Centre. “When
he passed away, he put a large portion of
his money into a foundation and said to
dissolve it in 50 years, because no one will
remember who he is in 50 years.” And so
the Foundation ran a competition and
University of Toronto put in an application
and won. The original 50 million dollar
investment, which is protected, was leveraged
to 200 million by the university, government,
and partner hospitals.
For about two years now, the McLaughlin
Centre has been focused on advancing the
field of genomic medicine.
“When I became the Director, we refocused
on the concept of using genomewide data
to try to identify risk genes for particular
diseases, and equally importantly, to move
those into the hospital diagnostic setting,”
says Scherer. Their goal is to fund science
that will not only impact the patients and
their families, but will also generate information
and data that will be used for
things like drug development.
The McLaughlin Centre runs an open competition
and funds approximately 10 grants
a year, all in the area of genomic medicine.
Funding research, however, is just one part
of its mandate.
One of the McLaughlin Centre’s goals in
the next 5–10 years is to ensure that Toronto
becomes a leader in genomic medicine.
The IMS Magazine asked Dr. Scherer how
the centre plans to achieve this goal.
“The short answer: training programs,
funding research projects… and bringing a
community of scientists together.”
Scherer emphasizes that “close to 25 percent
of the funding is applied to education,
training, investing in the MD/PhD program;
and many of these students are doing
their PhDs in the IMS.” The McLaughlin
Centre also supports projects that are
investigating the downstream effect of
genetic information, supporting genetic
counselling programs, and determining
the best way to collect data and deliver it
to the patient.
“[The] McLaughlin Centre is
a unique experiment, and it’s
going incredibly well.”
A unique feature of the centre is the Accelerator
Grant program. “[Currently] if
you have a new idea, it is hard to get money
right away to explore that.” The accelerator
program provides scientists with the opportunity
to get seed funding for a year to
get preliminary data and see whether the
project will be fruitful. Scientists can then
apply to receive funding to complete the
project.
Finally, the third goal is to bring a community
of scientists together. Scherer points
out that this is a new field, and having critical
mass of clinicians and scientists will
create momentum for research in genomic
medicine and lead to more innovations and
breakthroughs. Indeed, collaboration is a
requirement in the grants that McLaughlin
funds: “there need[s] to be two or more
partner institutions involved.”
In this new and rapidly developing field,
it is challenging to stay on top of research
findings and innovations in technology.
An important part of the McLaughlin Centre’s
mandate is to develop tools and databases
that will be continuously updated
with new information available in the literature
about genes and genetic diseases. An
equally important component is educating
clinicians, nurses, and healthcare professionals
(as well as scientists both in and
outside of the field) to access and properly
interpret this data.
The breadth and calibre of McLaughlin
Centre scientists is truly remarkable. The
accelerator grants that were funded in 2011
have already led to exciting new findings.
Dr. Danielle Andrade’s research on the genetics
of juvenile myoclonic epilepsy identified
a causative mutation in the CLN6
gene; this work is currently in press in the
Pediatric Neurology journal. Dr. Anne Bassett’s
work has identified rare copy number
variants that could play an important role
in the development of a common heart defect,
the tetralogy of Fallot; these findings
are soon to be reported in PloS Genetics.
Other studies funded by the McLaughlin
Centre include investigating how alternative
splicing may contribute to Alzheimer’s
disease (Dr. Blencowe); development of a
service to centralize clinical pharmacogenetic
information and counseling (Dr.
Koren); examining the impact and integration
of genetic technologies in adult and
pediatric care (Dr. Shuman); as well as research
identifying disease-causing genes in
immunoglobin A neuropathy (Dr. Pei) and
renal diseases (Dr. Paterson), to name a
few. “[The] McLaughlin Centre is a unique
experiment, and it’s going incredibly well.”
The IMS Magazine agrees, and awaits with
excitement the novel findings and technological
breakthroughs that are sure to come
to fruition from McLaughlin Centre scientists.
23 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

FEATURE SPOTLIGHT
cystic fibrosis gene). Together, they founded
TCAG, which houses all of the latest
genomic technologies to enable research
studies. Scherer estimates that TCAG facilitates
well over 1000 laboratories in a
given year.
During his PhD, he made a pioneering discovery:
the identification of genomewide
copy number variations (CNVs) as an important
source of genetic variation in humans.
His lab continues to investigate the
role of CNVs in autism, as well as other
disorders, through collaborations.
“You have to be persistent,
and you have to want
to do it yourself, because
no one is going to do it for
you.”
Scherer’s job requires him to assume many
different roles and responsibilities – from
running his lab to running two very different
centres – so, is there an aspect of his
many roles that he most enjoys?
“I’m the ‘idea’ guy. I have to kind of set
the vision of where I think things should
be five or ten years down the road and …
figure out how to get there – [the challenging
part]. I have a job that allows me to
capitalize on my strengths. It took a long
time to get here, but I get to use my brain –
people pay me to think about new things.”
Photo by Yekta Dowlati
Dr. Stephen W. Scherer
The “Idea” Guy
Scherer is a highly influential
and very successful scientist. In addition
to serving as the Director of
the McLaughlin Centre and The Centre for
Applied Genomics (TCAG), he is also a Senior
Scientist at the Hospital for Sick Children,
a Professor at the University of Toronto,
as well as a scientist who never stays
far away from the public eye–often making
appearances on TV, news, and radio.
The IMS Magazine wanted to find out
more about Scherer’s career trajectory and
the key to his success. Scherer completed
his PhD in the Molecular Genetics Department
at the University of Toronto, with
Professor Lap-Chee Tsui (discoverer of the
Finally, I asked if he had any advice for
incoming graduate students. What advice
would have benefited him at the start of
his graduate career? He laughed, and said
that’s a very easy question: learn statistics.
“What we are seeing over and over and
over again is that we need to have more biologists
who have a strong statistical background.
You should be taking statistical
classes, it is the one thing that will benefit
you the most … [it is] absolutely critical.”
(See Allison Rosen’s article on page 33.)
But, he warns, it takes more than just a
good grasp of statistics to succeed in graduate
school. “You have to be persistent,
and you have to want to do it yourself, because
no one is going to do it for you.”
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 24

SPOTLIGHT
Wenjun Xu
The best of both worlds
I
t is no secret that the world of
science can be a frustrating one in
which every successful experiment is
preceded by numerous experimental failures.
Whenever frustration threatens to spoil her
day in the lab, Wenjun Xu – a PhD student in
the IMS – simply reminds herself of a different
world that she experienced during a volunteering
trip to Nicaragua and Costa Rica
last year. “I think of how people there make
the most out of what little they have every
day, and how in comparison my problems
can all be overcome.”
The two-week long trip, which Xu organized
through VIDA (a non-profit organization
that facilitates volunteer-based public health
STREAM PhD student
SUPERVISOR Dr. Cindi Morshead
services in Central America), is a highlight
of Xu’s graduate experience. Along with 15
students from various graduate departments
within the Faculty of Medicine, Xu and her
peers traveled through remote regions in the
two Central American countries, stayed in
local homes, visited orphanages and AIDS
centres, worked with local medical personnel,
and helped to set up mobile clinics. It
was long hours of hard work every day under
smothering heat, but the group’s efforts were
returned in the form of warm smiles and
appreciation from the local communities.
When asked how the experience had influenced
her research and outlook on graduate
school in general, she offered: “Although we
were physically exhausted every day during
the trip, at the end of the trip I felt as though
my mind was recharged. I came back with a
new perspective and more ready for the challenges
and potential frustrations ahead.”
Not that Xu has ever really minded the challenges
of science in the first place: “I love basic
science because it answers fundamental questions.”
Having completed her undergraduate
degree in forensic science at the University of
Toronto, Xu chose to pursue graduate studies
at the IMS rather than a CSI-style career.
In particular, she was fascinated by regenerative
medicine and stem cell research. “I took
a course that focused a lot on stem cells and
biotechnology, and after that course there
was no turning back – I was determined to
take part in stem cell research,” Xu recalls.
That opportunity arrived when she met with
her now supervisor, Dr. Cindi Morshead, an
expert in neural stem cells whose energy and
passion for science Xu found inspiring. Xu
has been a happy member of the Morshead
lab ever since.
Now in the third year of her PhD studies,
Xu is involved in two distinct projects. She
is exploring the activation and mobilization
of endogeneous spinal cord stem cells in spinal
cord injury by infusion of cyclosporine
A; at the same time, she is investigating a
novel adult neural stem cell population that
expresses markers of pluripotent stem cells in
mice. Xu finds her involvement in these two
simultaneous projects both challenging and
satisfying, as they allow her exposure to both
translational and basic science.
Despite her strong commitment to research,
Xu is also determined to find the time in her
schedule to continue to gain inspiration outside
of the laboratory through her work with
VIDA. She is currently working to organize
another volunteer trip that is planned for
next year. With her efforts, she hopes that
more graduate students will be inspired to
get involved and take part in the unforgettable
experience (for more information on
VIDA, please contact Xu at wenjun.xu@utoronto.ca).
Asked when she expects to finish her PhD,
Xu smiles, “Hopefully in about three years.”
Undoubtedly, the next three years for Xu will
be as stimulating and exciting as the past
three have been.
By Karrie Wong
Photo by Brett Jones
25 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

SPOTLIGHT
Cindy Lau
Brain games
STREAM MSc Biomedical Communications
SUPERVISOR Michael Corrin
proached me with the problem. Michael Corrin
also really encouraged this—especially
because it’s a tool that might actually be used
by students in a practical, and hopefully helpful
way.”
A demo of the game reveals a sleek interface,
an engaging method of learning, and
remarkable visuals, including the ability to
examine the spinal cord at individual vertebral
levels. The objective is to build a neural
pathway between the brain and body region
of interest, as chosen by the user from available
cases. “It’s a game in the sense that if you
build an incorrect pathway, you lose—but we
also try to mimic the temporal element of
nervous signal propagation,” comments Lau.
“The game is as much about accuracy as it is
about time: can you build the correct neural
pathway so that the nervous signal propagates
without interruption?”
Of her scholarship, Lau relays her gratitude
for the guidance and support she has received
from both her advisors and peers. “I feel really
lucky to have been the recipient,” she continues.
“There is a relatively small circle of us
in the biomedical communications community,
so it’s quite an honour to be recognized
among a group of really talented individuals.”
Photo by Laura Feldcamp
Motivated by a steadfast interest
in both biology and art, Cindy
Lau found her professional niche
when she discovered the Biomedical Communications
(BMC) program two years after
completing her undergraduate biomedical
engineering degree. This past year, the second-year
MSc BMC student was awarded the
prestigious Alan W. Cole Scholarship in the
Vesalius Trust’s 2012 scholarship competition—an
honour that undoubtedly reflects
her enthusiasm for her work.
The Trust was established by a professional
organization of medically-trained visual
communicators—the Association of Medical
Illustrators—to support education and
research programs in the field. Specifically,
competitive research scholarships are awarded
annually to students enrolled in accredited
North American medical illustration
programs, with the Alan W. Cole scholarship
granted to the top scholar across all institutions.
Applicants are evaluated based on
background, education, project concept, design,
and production plan.
Lau received the award for her master’s research
project “NeuroPath: Creating Neural
Pathways In Play and In Mind,” an interactive
computer game designed to help medical
students learn neural pathways. Supervised
by BMC advisor Michael Corrin and content
expert Dr. Barbara Ballyk, who teaches
neuroanatomy as part of the medical school
curriculum, Lau is eager to make the highly
visual and complex content as understandable
as possible.
“Learning how electrical signals travel from
the brain to motor segments, or from sensory
nerves to the brain—it can be fairly complicated
to learn because many pathways cross
over at different levels [of the nervous system],”
explains Lau. “It’s challenging to learn
just through rote memorization and reading
textbooks.”
Lau credits her supervisors for prompting
her involvement in the project. “Dr. Ballyk
encourages her students to draw out the
pathways as they learn them. She sees the
difficulty they can have firsthand, so she ap-
As she nears graduation from BMC, Lau
doesn’t lose sight of her goals: “I am determined
to finish this project to the best of
my ability—not just for the sake of finishing,
but to really create a tool that achieves
its intended goals. Especially in light of the
Vesalius Trust scholarship, I want to give it
my absolute best.”
A still from the current NeuroPath demo: users
will be able to construct neural pathways (right)
from a selection of different patient cases (left).
By Nina Bahl
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 26

BOOK REVIEWS
Book Reviews
Excellent Very Good Good Average
Worth missing a day at the lab Try to squeeze in between experiments Wait for the weekend Wait until degree is complete
Jeff Brown and Mark Fenske, with Liz Neporent
The Winner’s Brain: 8 Strategies
Great Minds Use to Achieve Success
Da Capo Press, 2011; 240 pages
In the creative collaboration between
clinical psychologist Jeff Brown and
cognitive neuroscientist Mark Fenske, the
book The Winner’s Brain: 8 Strategies Great Minds
Use to Achieve Success combines cutting-edge
neuroscientific research with well-established
cognitive-behavioural psychological strategies
to reveal how highly successful brains function.
The authors give practical guidance to enhance
cognitive performance and to allow the reader to
achieve unique, personal ideas of success.
The Winner’s Brain starts by taking the reader
through an engaging tour of the history of neuroscience
and a brief overview about what we
currently know about the inner workings of the
human brain.
The authors then reveal the importance of neuroplasticity,
which is defined in the book as the
neurocircuitry changes that occur with every experience,
and using this to take control of your
brain “in order to position yourself to achieve
your goals and dreams.” According to Fenkse, in
a recent communication with the IMS Magazine,
“The saying ‘old dogs can’t learn new tricks’ is obviously
wrong.”
The Winner’s Brain outlines five “Brain Power
Tools” that all Winning Brains have in common:
the Opportunity Radar (knowing which opportunity
will lead to success and which will not), the
Optimal Risk Gauge (calibrating a risk threshold
to decide whether or not a chance is worth taking),
the Goal-Laser (intentionally and deliberately
taking steps to accomplish important goals),
the Effort Accelerator (keeping motivated), and
the Talent Meter (knowing your strengths and
weaknesses). All of these Brain Power Tools can
be strengthened by strategies termed “Win Factors,”
which include Self-Awareness, Motivation,
Focus, Emotional Balance, Memory, Resilience,
Adaptability, and Brain Care.
These tools and strategies are derived from highly
complex concepts in neuroscience and cognitivebehavioural
psychology that are not easily translated
into a language accessible for individuals outside
of these fields. However, Brown and Fenske,
ably assisted by health-writer Liz Neporent, master
this feat of knowledge translation with playful
and clear writing that offers an adequate foundation
in science (highlighting applicable pieces of
information), step-by-step instructions on how
to master change, and interviews conducted with
individuals with a range of real-life success stories.
Some inspirational stories of success include
interviews from Trisha Meili (also known as the
Central Park Jogger), Kerri Strug (gymnastics
Olympian), Kevin Clash (Sesame Street’s ‘Elmo’),
Andy (a London Black Cab driver), Camille Mc-
Donald (Bath & Body Works’ President of Brand
Development), and one of Fenske’s most inspirational
interviews, B.B. King (Blues guitar legend).
Fenske states that when he and his colleagues
were writing the book, they wanted to include
“real world examples of people and the science in
action, exemplifying the science and research behind
each [particular Win Factor].” Fenske went
on to tell us about his interview with B.B. King,
in which B.B. King “talked about humble beginnings,
being very poor, and how being a black
artist was full of challenges when he started out.”
Fenske heard the “resilience and dedication of
[B.B. King] pushing through time after time, and
how he had the mental strategies at [the beginning
of his career] that he still uses as a performing artist,
such as practicing and constantly and continually
working on himself and what he does.”
As this book is about translating the complex
concept of neuroplasticity into easily accessible
terms for many audiences, B.B. King’s interview,
amongst many others, “illustrates how the brain
is constantly changing and that each of us can be
proactive by taking part in how our brain changes
over the course of a lifetime.” Fenske reflected on
what he has come to know about neuroscience
and said, “This is a message of hope…We don’t
just have to settle with what we are or what we can
do at any point in time.”
The Winner’s Brain is a valuable combination of
expertise of neuroscience and clinical practice.
And Fenske added, “The book benefitted tremendously
from interactions with students, which facilitated
discussion and helped in brainstorming
ways that [this knowledge] can be translated into
a language that anyone can use.” Fenske cleverly
pointed out that there are “more than just scientists
who can use this new knowledge to increase
their Brain Power in their day-to-day lives.”
Column by Brittany N. Rosenbloom
27 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

BOOK REVIEWS
John Robbins
Healthy at 100: The Scientifically Proven
Secrets of the World’s Healthiest and
Longest-Lived Peoples
Random House Publishing, 2007; 348pages
Where in the world do people
often live to be over 100? That
is the question that begins this
interesting and well-referenced book. The answer
is intricately described by John Robbins,
heir to the Baskin-Robbins ice cream corporation,
though ironically, a firm advocator of
healthy lifestyles. In search for answers, he takes
the reader on a tour of four diverse and isolated
regions: Abkhasia in the Caucasus region of Russia,
the Hunza region of Pakistan, Vilcabamba
in Ecuador, and the island of Okinawa in Japan.
These dispersed and unconnected regions have
one thing in common: some of the healthiest
and oldest living people on the planet. During
the readers’ literary journey from place to place,
Robbins illustrates that it is a complex aggregate
of factors that enable these populations to have
more centenarians than in the Western world.
Firstly, while geographically, ethnically, and
culturally distinct, these populations have
similar plant-based and meat-less diets. And of
course, they are free of processed-food. Equally
important, exercise is incorporated into their
daily life, allowing these populations to stay lean
and active in late life. Secondly, these communities
are socially healthy; they foster a strong
sense of spirituality and social support. Elders
are highly respected in these communities, and
as individuals age, they gain more stature and
become revered for their wisdom and knowledge.
This is in stark contrast to the common
mentality in Western societies where older citizens
can be seen as a burden.
Striking, as well, is the longevity of these populations
compared to the mental and physical deterioration
that occurs in Western societies, and
in particular, the high incidence of old-age diseases.
Communities in these regions remain vibrant,
healthy, and free of disease; remarkably,
they do not have an abundance of cancers, neurological
diseases, and the host of cardiovascular
diseases that plague our society. A doctor
would be unneeded there!
Robbins is thorough in his analysis of the literature.
He considers the similarities and differences
between these populations and our
culture carefully, down to the level of genes and
hormones. He emphasizes the link between animal-based
foods – dairy, meat and eggs – and
cancers, cardiovascular diseases and diabetes,
with strong primary research articles. Moreover,
he investigates the link between white
foods – sugars, rice, and breads – with health
abnormalities, including dental deformations
and decay.
Finally, the third section of his book is the “how
to”: how to adopt and learn skills and lifestyles
from these populations while balancing the realities
and demands of our society (sounds too
good to be true). He delves into the research of
the mind and body and the benefits of regular
exercise, and interestingly, designates an entire
chapter to love and healthcare – the benefits of
being in healthy and loving relationships (and
the negative effects of ‘toxic’ relationships).
Overall, an interesting and important read!
Robbins makes meaningful claims about health
and well-being, backed by solid scientific evidence.
Robbins is convincing because he not
only presents the scientific evidence, but also
analyzes the studies’ strengths, weaknesses, limitations
and possible interpretations.
And if you’re wondering whether Robbins currently
bears the torch to the Baskin-Robbins
corporation, the answer, as you may have
guessed, is a firm no. He declined that offer.
Column by Salvador Alcaire
What are you reading?
Aaron Kucyi, PhD candidate, recommends Free
Will by Sam Harris
“The concept of free will has taken a
beating in light of recent neuroscience
discoveries. Harris offers no mercy in
his succinct set of essays—he had no
choice—but convincingly argues that determinism
is not all awful: rather, accepting
your ‘biochemical puppet’ status can
be both humbling and awe-inspiring.”
Brett Jones, MSc candidate, recommends The
Head Master’s Wager by Vincent Lam
“The Head Master’s Wager is the third
book written by U of T lecturer, physician,
and award-winning author of Bloodletting
and Miraculous Cures, Vincent Lam.
Set during the Vietnam/American war,
Lam tells a story of the compulsive gambling,
womanizing Percivel Chen, who is
the head master of the most prestigious
English school in Saigon. This story of
Percivel Chen, a fictional character based
on Lam’s own grandfather, is a wonderful
work of fiction on love, betrayal, and sacrifice.”
Tetyana Pekar, MSc candidate, recommends
The Trouble with Physics by Lee Smolin
“A defining feature of a good theory is
that it makes testable and unique predictions.
In this book, Lee Smolin, a theoretical
physicist at the Perimeter Institute,
argues that this feature is lacking in
string theory. Smolin cogently lays out
the problems with string theory, why it is
a dead-end, and how the theory’s popularity
is detrimental to progress in fundamental
physics. Best of all, it is easy to
read, passionate, critical and insightful.”
If you are an IMS faculty member or student
and would like to have your book
review published in a future issue of the
IMS Magazine, please send a 50-word review
to theimsmagazine@gmail.com.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 28

CLOSE UP
Interview with
Dr. Gary Remington
Renowned clinicianscientist
and unparalleled
mentor
By Melanie Guenette
Dr. Gary Remington is the 2012
recipient of the IMS Mel Silverman
Mentorship Award. If you were to
ask him about this momentous accomplishment,
he would likely shake his head and immediately
credit his students for nominating
him. That is just the sort of man he is: understated,
humble, and selfless. I am biased
of course, because he is my supervisor, but
no one misses an opportunity to sing the
praises of this formidable clinician-scientist;
the proof lies in the half dozen letters of support
that went into his nomination package.
Dr. Remington is busy; he is the Director
of the Medication Assessment Clinic in the
Schizophrenia Program at the Centre for Addiction
and Mental Health (CAMH), as well
as Deputy Head of Research and Education
for the same program. He is also Schizophrenia
Head, Division of Brain and Therapeutics
and Professor in the Department of Psychiatry
at the University of Toronto. As if that
were not enough, Dr. Remington has been
a member and graduate supervisor with the
IMS for a decade, and he currently supervises
seven students in his laboratory.
Starting out as an undergraduate at Waterloo
Lutheran University (now Wilfred Laurier),
Dr. Remington met and worked with Dr.
Hymie Anisman, whom he identifies as his
first mentor. Their partnership lasted a number
of years, as Dr. Remington completed
Photo by Laura Feldcamp
29 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

CLOSE UP
a PhD under his supervision in the area of
neurotransmitter development and hyperactivity.
Set to undertake a post-doctoral
position at the University of Minnesota, Dr.
Remington had a choice to make: “I was torn
between the basic sciences and doing work at
the clinical level. I realized that if I wanted to
make a career out of this work, I would have
to marry the clinical with the basic, and to do
so would require a medical degree.”
Having completed medical school at McMaster
University, Dr. Remington declared a specialty
in neurology and began his residency
at the University of Western Ontario. A year
into his training, he was pulled aside by neurologist
Dr. John Brown. “He said I’d make
a better psychiatrist than neurologist,” recalls
Dr. Remington. “I called up the Psychiatry
folks in Toronto and they accepted me over
the phone.” He then began his psychiatry
residency at CAMH. I ask him about what
would eventually become the focus of his
career—schizophrenia—and Dr. Remington
says the fascination was instant. “I had never
seen anything like it, nor have I since.” In his
second-to-last year of training, Dr. Remington
was approached and offered a staff position
at CAMH; he has now been there almost
thirty years.
When asked to describe his research, Dr.
Remington remarks that it is a reflection of
why he left his post-doctoral position for
medicine. “I feel an obligation to ask a basic
science question that can almost immediately
be translated into changes in clinical
practice,” he continues. Strictly speaking,
Dr. Remington studies schizophrenia, but
identifies one of his shortcomings as his “inability
to focus on a single research question—something
that is usually preferred
by scientists.” To illustrate the breadth of his
work, Dr. Remington and his students study
an array of research questions that include
schizotypy, the metabolic side effects of antipsychotic
drugs, antipsychotic tolerance and
adherence, and the manifestations of negative
symptoms of schizophrenia through virtual
reality techniques.
Given that Dr. Remington is being recognized
for his mentorship abilities, our talk
shifts to students and student supervision. I
ask him how he chooses his students and he
says, “It all depends on the interview. I get a
sense of whether or not the fit is right after
speaking to them.” When I ask him to describe
his students, he takes a minute, a smile
forming on his face, and says his students are
“motivated, able to work independently, and
hopefully enjoy their research.” He adds, “I
really enjoy the enthusiasm and excitement
my students bring to the laboratory every
day. I remain inspired by them.”
“I find it stimulating to see the
scope and quality of research being
done by the students at the IMS. I
really like seeing the passion they
have for their work.”
Dr. Remington is known for his eloquence
and candor, so when I ask him about his mentoring
style, I am initially surprised when he
pauses and says, “I don’t know how others
mentor—it’s not like there’s a book for this
sort of thing.” He then continues, “I mentor
the way I was mentored [by Dr. Anisman]:
I ensure close and regular contact with my
students. I make myself available and try to
provide a supportive environment, giving my
students the resources they need to succeed.
It’s nothing fancy.” At this last point I laugh,
knowing all too well how rare this situation
can be: Gary Remington is an absolutely fantastic
mentor, he pours everything into his
students, and they know it. So why does he
do it? “I was there. Somebody did it for me.
Dr. Anisman categorically changed my approach,
not only to medicine, but also to life.
He was amazing—a role model to me. I feel
I have an obligation to do that for as many
people as possible moving forward.”
Of the IMS, Dr. Remington says, “I think it
has an innovative approach to bringing people
together from diverse backgrounds, and
offering them the opportunity to cross traditional
research boundaries.” He adds that
the challenge remains in “bringing people together
from many areas and levels of expertise
in an environment that rewards absolute
focus on a single area or research question.”
Dr. Remington’s involvement in the IMS
doesn’t only include his role as a graduate
supervisor; he has been on countless Project
Advisory Committees (PACs) and has been
a judge in both the Summer Undergraduate
Research Program (SURP) and IMS Scientific
Days. “I find it stimulating to see the
scope and quality of research being done by
the students at the IMS. I really like seeing
the passion they have for their work.”
I ask Dr. Remington what he sees himself
doing in ten years: “I hope to still be coming
into work every day. I don’t see what I do as
a job. It’s a well kept secret how much I enjoy
this.” Admitting that he sleeps about four
hours a night, he adds, “I am blessed with doing
something that I love so much and still
want to be doing. I am so lucky—I hope no
one catches on!”
For students, Dr. Remington says the largest
obstacle is the “incredible competition to
capture a spot in this research environment.”
I ask him what is key to selecting the right
supervisor, to which he replies, “Find a mentor
as early on as you can. The goal is to find
someone you respect. Respect is fundamental.”
Dr. Remington sees the potential in his students
and treats them as valued members of
the scientific community. His ability to effectively
guide and support his students, while
always remaining committed to their success,
makes him the true definition of a mentor.
Although he would never admit to it, I can
think of no one more deserving of the Mel
Silverman Mentorship Award. Congratulations
Dr. Remington.
Student sentiments
“Dr. Remington is friendly, warm, and encouraging,
while remaining entirely professional.
He is respectful and sensitive to the
needs of his students.”
- George Foussias, MD, PhD candidate
“Dr. Remington allows his students to
demonstrate their success, easily stepping
aside to enable personal growth and accomplishment.”
- Gagan Fervaha, MSc candidate
“Dr. Remington sees the potential in his
students and treats them as creative, intelligent,
and responsible scientists.”
- Laura Schulze, MSc candidate
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 30

VIEWPOINT
Publish
and Perish
Why science takes two steps forward and one step back
By S. Amanda Ali
It is the dream of every scientist to
publish a research article in Nature, Cell,
or Science. For a graduate student working
towards a PhD, a publication in one of
these prestigious journals almost guarantees
a successful defense examination, a reputable
post-doctoral fellowship, and a subsequent
tenure-track position. For a senior scientist
managing a research lab, publications of this
calibre provide an advantage in grant competitions
and give greater stability in funding.
For a research institution, high-impact publications
draw global spotlight, attract better
scientists, and earn the institution prestige.
It therefore appears to be in everyone’s best
interest to publish in the highest impact
journals possible, but this dream could be a
nightmare in disguise.
The higher the journal’s impact factor, the
higher its retraction rate 1 . Reasons for retraction
are distributed between misconduct and
honest error, but the underlying causes for
these occurrences remain largely unexamined.
Executive editor of Science, Monica M.
Bradford, defended this finding in The New
York Times by suggesting that high-impact
journals have a higher retraction rate because
they receive more attention and are subject to
more scrutiny 2 . While this may be the case, it
implies that other, lower-impact journals also
publish articles that violate ethical guidelines,
contain scientific misconduct or error,
or plagiarize previously published work, but
that those articles go unnoticed. The end result
is the same—our scientific literature is
full of error, and that error is on the rise.
A recent article in Nature reported that the
number of retraction notices has increased
10-fold over the past decade, while publications
have increased by only 44% 3 . Although
improved vigilance is a convenient and plausible
explanation for this trend, there are
other possible culprits. Astoundingly, 1-2%
of scientists have admitted to fabricating, fal-
sifying, or modifying data or results at least
once 4 . A close examination of the publishing
pipeline reveals several points where the
pressure to publish may overwhelm an otherwise
honest scientist, leading them to transgression.
As mentioned, graduate students
need to publish to build their future, and
senior scientists need to publish to secure
their future. This pressure to publish is compounded
by the predominant bias to publish
positive results more than negative results.
(For a complete discussion of the research bias
towards positive results, see “Positive Pressure,”
in our Fall 2011 issue.) While only a minority
of scientists may be willing to fabricate or
falsify results to fit their hypotheses, a majority
of scientists may be inclined to select data
which support their hypotheses, and ignore
data which do not.
There lies the danger of predicating the success
of a scientist on their publication record;
the purpose for publishing shifts toward
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31 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

VIEWPOINT
survival of the fittest author, and away from
disseminating authentic results. Scientists
are increasingly being evaluated using metrics
such as the h-index, which is based on
number of publications and number of citations
per publication 5 . Assessing a scientist’s
performance using such metrics creates undeniable
desire, need, and pressure to publish
often, and in highly cited journals. Countries
such as China, South Korea, and Turkey offer
cash incentives to encourage local scientists
to submit their manuscripts to high-impact
journals 6 . Despite the low probability of success,
the high volume of submissions overwhelms
reviewers and congests the publishing
pipeline. Given these circumstances, how
can the literature be trusted, and how can
scientific progress be made?
The soaring retraction rate observed
in high-impact journals may
be an accelerated manifestation of
the decline effect. Because highimpact
journals publish studies
with novel and dramatic results,
those results are more likely to be
overstated, and are less likely to be
reproducible. The lack of reproducibility
is unsurprising considering
the tweaking, selecting, and beautifying
of data that oftentimes precedes
publication.
First reported in the 1930s, an established
barrier to scientific advancement is the decline
effect, which is observed in the literature
as scientifically discovered effects that
diminish over time. Schooler suggests that
“if early results are more likely to be reported
when errors combine to magnify the apparent
effect, then published studies will show
systematic bias towards initially exaggerated
findings, which are subsequently statistically
self-corrected” 7 . The soaring retraction rate
observed in high-impact journals may be an
accelerated manifestation of the decline effect.
Because high-impact journals publish
studies with novel and dramatic results, those
results are more likely to be overstated, and
are less likely to be reproducible. The lack of
reproducibility is unsurprising considering
the tweaking, selecting, and beautifying of
data that oftentimes precedes publication.
Detrimentally, if the studies in high-impact
journals are reaching the widest audiences
and are conveying less-than-accurate results,
the scientific field is being misguided.
The argument can be made that science is an
imperfect field, with enormous variability. In
biomedical research, there are innumerable
known and unknown variables that influence
experimental outcomes, some as significant
as the strain of mouse used, some as innocuous
as the time of day an experiment is conducted.
Every experiment contains outliers,
inconsistent replicates, and unexpected findings,
but these are rarely reported, and perhaps
that is the bigger issue. As Dr. Karen Davis,
Associate Director of the IMS and Editor
of Pain, previously communicated to the IMS
Magazine (“Positive Pressure,” Fall 2011), an
incomplete or incorrect scientific record can
lead to propagation of unfounded ideas, unnecessary
replication of experiments, clinical
translation of harmful therapies, or delayed
development of alternate hypotheses. Once
flawed ideas are published, they can never
truly be retracted. Budd et al. report that
even after an article is retracted, it continues
to be cited, without acknowledgement of the
retraction 3 . Understandably, once digital versions
of articles are downloaded, researchers
are unlikely to consult the original source
again, and are therefore unlikely to be aware
of corrections.
What is needed is a more complete account
of scientific findings, be they negative or
positive, consistent or inconsistent, surprising
or expected. During the IMS Scientific
Day 2012 Bernard Langer Lecture in Health
Sciences, Dr. Thomas R. Insel, MD, Director
of National Institute of Mental Health, posited
that if experiments are soundly designed
and flawlessly executed, then those results
should be disseminated, regardless of what
they are. Furthermore, Schooler believes “we
need a better record of unpublished research
before we can know how well the current
scientific process, based on peer review and
experimental replication, succeeds in distinguishing
grounded truth from unwarranted
fallacy” 7 . He recognizes the difficulties in
implementation, but suggests an open-access
database of research methods, which allows
scientists to log their hypotheses and methodologies
prior to experiments, and their
published and unpublished results afterwards
7 .
Schooler believes “we need a better
record of unpublished research
before we can know how well the
current scientific process, based on
peer review and experimental replication,
succeeds in distinguishing
grounded truth from unwarranted
fallacy.”
To purify the publication pool, the current
publishing paradigm should be restructured
to diffuse the pressure experienced by researchers.
Among other strategies, graduate
students should be given avenues to publish
their negative results, and senior scientists
should be evaluated on metrics other than
their publishing records. To purify the publication
pool, more focus should be placed
on honest accounting of data in its entirety,
and less focus should be placed on polishing
of data for high-impact journals. Researchers
should be mindful of the permanence of
published results, and wary that embellished
or modified data can significantly hinder
scientific progress. To alleviate current publishing
pressures is to purify the publication
pool, and move science forward.
Disclaimer: The opinions expressed by the
author(s) are in no way affiliated with the Institute
of Medical Science or the University of Toronto.
Comments are welcome at theimsmagazine@
gmail.com.
References
1. Fang FC, Casadevall A. Retracted science and the retraction
index. Infect Immun. 2011;79(10):3855-3859.
2. Zimmer C. A Sharp Rise in Retractions Prompts Calls
for Reform. The New York Times. 2012 Apr 17;Sect. D-1.
3. Van Noorden R. Science publishing: The trouble with
retractions. Nature. 2011;478(7367):26-28.
4. Fanelli D. “Positive” results increase down the Hierarchy
of the Sciences. PLoS One. 2010;5(4):e10068.
5. Hirsch JE. An index to quantify an individual’s scientific
research output. Proc Natl Acad Sci U S A.
2005;102(46):16569-16572.
6. Stephan P. Research efficiency: Perverse incentives.
Nature. 2012;484(7392):29-31.
7. Schooler J. Unpublished results hide the decline effect.
Nature. 2011;470(7335):437.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 32

VIEWPOINT
A Numbers Game
Why an article about statistics shouldn’t make you want to turn the page
By Allison Rosen
What do Chi-squared tests,
t-tests and ANOVAs all have in
common? Some might contend
that they are all statistical tests, but others
will attest that they are all things that give
graduate students a headache. But why do
so many students harbor negative attitudes
towards statistics? These tests are there to
help us—to validate our results and help our
interpretations. Right? The IMS Magazine
conducted a series of interviews to provide
a snapshot of what graduate students face
when approaching statistics.
“I’m not comfortable with statistics.”
IMS MSc Student Jack* professed this view,
and he certainly does not stand alone. Many
graduate students interviewed for this article
confessed that they do not feel they have
enough knowledge of statistics to perform
the tests necessary to properly interpret their
experiments. Poor knowledge of statistics
can have a big impact in graduate school.
Jack explains, “It has made my ability to
analyze and interpret my own research data
more challenging. I have had to teach myself
things along the way, or seek significant help
from labmates and outside sources; it’s been
… a definite source of frustration.” Another
IMS student agreed with this sentiment: “I
am only confident using very basic statistical
tests that apply to my data,” claims Lauren*,
a PhD student.
“Statistical analysis is a huge part of my research.
My limited knowledge on the subject
often limits my interpretation of my data
and ability to clearly understand research articles,”
Lauren elaborates. Jack confessed that
although he has not yet been affected by his
lack of adequate statistical knowledge, this
problem will become more prominent as he
prepares to defend his thesis. “We use a statistician,
so really I just need to know how to
make data look pretty in Excel.”
But not all students share these negative
views. Corinne Daly, who recently defended
her MSc, and Richard Foty, currently working
on his PhD, share their thoughts. “As an
epidemiologist, I spend a good portion of my
day analyzing data or reviewing articles, so
over time I’ve gotten comfortable with the
math. It’s the interpretation of those results,
however, that I am most interested in. Statistical
analysis is just the tool I use to get me
there,” explains Richard. Corinne expands by
explaining that her familiarity with statistics
has been helpful in understanding rounds
presentations, publications, and explaining
her research. “An understanding and appreciation
of statistics has been indispensable in
my research career,” states MSc student Benjamin
Mora.
Contrasting feelings towards statistics aside,
all of these students agree that knowing statistics
is important. Amy*, an IMS student
completing her MSc, explains that despite her
discomfort with statistics, she understands
its importance. “Better knowledge of statistics
can help tremendously in understanding
papers beyond simple P-values; it allows for
critical analysis, which is a skill all graduates
need to learn.” Amy further elaborates on the
level of statistical knowledge she believes to
be necessary for graduate students. “Whether
or not they complete their own analysis or
send results off to a statistician, I absolutely
believe graduate students should be familiar
with statistics—and I’m speaking as someone
who currently has very limited statistical
knowledge. It’s difficult to gauge the exact
level of knowledge needed, but I think it
would be universally helpful to understand
the various types of analyses available, and
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VIEWPOINT
more importantly, why they are appropriate
under different circumstances.”
“You can collect all the high quality data you
want, but…you need to have the statistics to
back it up,” Corinne emphasizes. However,
she also concedes that the issue is more complex
than that. “There is never [one] right answer
in statistical methods. Most times there
are a few ways of looking at the same problem.
Problem solving and discussing which
method is best for a specific question is necessary
sometimes.”
Given that most students understand how
important statistics are to their research, why
do some students still feel negatively about
statistics?
“I personally think in the IMS, not enough
people know much of anything about statistics,”
Corinne shares. “[This] makes me
question how individuals read and understand
other publications out there. However,
I definitely think it is the responsibility of a
supervisor and surrounding research group
to discuss common methods in their field so
that graduate students can independently analyze
their data and then consult the proper
resources when necessary.”
While the supervisor holds some responsibility
in ensuring a student has adequate statistical
knowledge to successfully design and
interpret experiments, students also have an
onus to take courses to improve their skills.
Corinne has taken two statistics courses
within the IMS: Biostatistics for Health Scientists
and Introduction to Clinical Biostatistics,
and recommends that other graduate
students follow suit in order to understand
the statistics necessary for their research
projects. “These courses definitely provided
a foundation for understanding methods
and theory behind basic and more advanced
statistical methods. However, applying what
you know…is a whole new ball game. Only
through repeated practice and discussion
with my research group have I learned the
meaning of statistical tests that I learned
about in those courses.”
While Corinne has already taken many
courses to become familiar with statistics,
most students have not. “My only formal introduction
to statistics was through a very
brief component of an undergraduate biol-
ogy course that touched upon biostatistics. I
have never taken an entire course dedicated
to statistics at either the high school or undergraduate
level,” confides Amy.
Enter Dr. Paul Corey. Corey has a number of
positions teaching statistics within the University
of Toronto. He teaches both Biostatistics
for Health Scientists and Introduction to
Clinical Biostatistics in the IMS. “Every good
researcher asks whether [an] observed difference
is likely to be due entirely to chance,”
Corey explains. However, he also recognizes
that a problem does exist and shares a story
of a former student who, after completed a
class assignment on a paper she had published,
realized “the published analysis was
wrong.”
Smaller, more focused courses circumvent
current dilemmas involving
bloated statistics courses that
overwhelm students.
“Many students do not have a statistician on
their thesis committee and some unfortunate
analyses get published,” Corey explains.
“There is enormous variation in the statistical
literacy of my scientific colleagues.”
Surely we do not want to lower the quality of
published science. But how extensive should
a graduate student’s knowledge of statistics
be? Corey discussed his future vision of statistics
education in graduate departments. “I
think that we are in a stage where there will
be more modular courses that will enable students
to choose to study only those topics of
use for the type of analyses they will need to
do in their thesis research. This will increase
the interest and dedication of some students.
In the future, I predict that there will be more
short statistics courses with fewer students in
each.”
Smaller, more focused courses circumvent
current dilemmas involving bloated statistics
courses that overwhelm students. Such
an approach changes not only research quality,
but also opinions and attitudes towards
statistics among graduate students. As Corey
describes, “Many students begin to truly
appreciate the power of statistics when they
have to perform the analyses on their own
thesis data. A proper teaching and under-
standing of statistics rests on a few important
and basic concepts. These concepts can only
be understood by frequent repetition using
language and logic.”
Corey warns that not all students may be
pleased by the changes. “Sometimes students
are impatient and just want the facts. That is,
they want a cookbook course. This is where
the danger lies.”
“Students should be able to analyze their own
data with a little help from their friends,” Corey
goes on to suggest, mirroring the thoughts
of many IMS students. “I generally seek help
from someone in the lab when I can’t figure
out how to analyze my data,” shares Lauren.
Even Benjamin, who feels comfortable
with statistics, agrees that “in cases where
the analysis becomes more convoluted, it is
helpful to receive assistance from more experienced
researchers or from statisticians.”
Corinne also stresses the importance of getting
help: “I definitely think that labs and research
groups should have access to biostatistical
assistance.”
“Start by reviewing the literature and see
what kinds of tests other scientists have used
to answer similar questions,” Richard suggests.
“Once you’ve come up with a few possibilities,
research them thoroughly and consult
a statistician if you can. Finally, present
the different methods to your supervisor and
committee members and get their recommendations.”
Planning ahead and consulting
others early on can be a big time saver.
Richard advises students to “not be intimidated
by statistics; they’re a useful tool. Remember
that we all have to look things up.
If we knew exactly what we were doing, they
wouldn’t call it research.”
* Names have been changed to protect the anonymity
of the students interviewed
Disclaimer: The opinions expressed by the
author(s) are in no way affiliated with the Institute
of Medical Science or the University of Toronto.
Comments are welcome at theimsmagazine@
gmail.com.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 34

EXPERT OPINION
Interactive proteomics with MYTH:
Identifying protein puzzles and putting them into their correct cellular pathway
By Igor Stagljar, PhD
Every process in a cell is affected
by interactions between proteins,
which determine everything from the
cell shape to the function of a particular biochemical
pathway. Just as we tailor our own
conversations depending on setting, proteins
exhibit many different modes of interaction.
Long-term protein-protein interactions
(PPIs) result in protein complexes, while
briefer protein liaisons may lead to a range
of possible chemical modifications. Because
they are so integral to the physiological function
of any organism, PPIs are essential to
many lines of research, both basic and clinical.
In the past decade, scientists working in the
emerging field of “interactive proteomics”
have initiated numerous projects to build
comprehensive maps of all PPIs (also called
“interactomes”) of a given cell or organism
with the ultimate goal of understanding the
functions of the many proteins whose roles
are not yet known (Figure 1). This is based
upon the principle that if two proteins interact
with each other they very likely partici-
pate in the same or related cellular functions
(the principle of “guilt by association”). In
other words, clues about the function of one
protein whose role is not understood can be
gained by observing that it interacts with another
protein whose function is known. Such
an approach, when applied on a large-scale
with all proteins of a certain organism, can
result in the identification of novel components
of previously known pathways, or, vice
versa, one may conclude that a protein previously
known to be involved in one biological
pathway also functions in another.
A special focus of our laboratory is on proteins
associated with biological membranes,
also called membrane proteins, which total
approximately one third of all proteins in any
cell 1 . These proteins mediate a wide range
of fundamental biological processes such as
cell signaling, transport of membrane-impermeable
molecules, cell-cell communication,
and cell adhesion. Interestingly, many
of these membrane proteins have been found
to have disease-associated function, and notably
most of the drugs on the market today
are targeted towards membrane proteins. As
such, there is a strong demand from both
academic researchers and biotech/pharma
companies to gain further insight into pathways
and interactions involving membrane
proteins. It is therefore of utmost importance
to build a comprehensive interactome of this
crucial class of proteins. However, despite extensive
research in the past decade, there is
a lack of in-depth understanding of PPIs associated
with this class of proteins because of
their unique biochemical features and enormous
complexity. This is a major obstacle
for designing improved and more targeted
therapies, and importantly, understanding
the biology of deregulation of these integral
membrane proteins which leads to numerous
human diseases.
Previously, our lab developed the Membrane
Yeast Two-Hybrid (MYTH) system, a powerful
proteomic tool for identifying the interactors
of membrane proteins in an in vivo
setting using baker’s yeast as a model organism
(Figure 2). Using the MYTH system, an
interaction between two proteins can be converted
into an ‘observable signal’, specifically
the growth, and blue coloration, of yeast on
a specialized media. A unique advantage of
MYTH is that it can detect proteins associated
with almost any membrane protein in
a high-throughput screening format, and
is therefore perfectly suited for building interactomes
of this difficult class of proteins.
Since the development of MYTH, it has been
applied successfully to identify both transient
and stable interactions among various membrane
proteins from yeast, plant, fly, worm,
and humans 2-5 . It became a valuable proteomic
tool by creating a bridge between the
basics of protein biochemistry and practical
applications in the field of medicine and disease
management. Along this notion, MYTH
has recently been applied to ATP13A2, a human
lysosomal membrane protein involved
in Kufor-Rakeb syndrome characterized by
early-onset parkinsonism, neurodegeneration
and dementia. MYTH identified dozens
of ATP13A2-associated proteins many of
which showed to be functionally and mechanistically
interconnected to ATP13A2 6 . This
and other studies showed that MYTH is an
interesting translational research tool, allowing
researchers to study the interactions of a
disease-associated protein of interest in both
the presence and absence of drugs and observe
how these compounds affect the protein’s
interaction profile. This information,
in turn, can be used to help understand how
these compounds affect the physiology of
diseased cells.
Our lab has currently been involved in using
MYTH and variations of MYTH to investigate
various key areas of research that have
direct disease relevance. For example, one
large on-going project in the lab is the study
of ABC transporters 3 , a major class of proteins
responsible for the transport of a wide
range of substances across various cellular
membranes. ABC transporters are of intense
clinical interest because of the key role they
play in the multidrug resistance of pathogenic
microorganisms and tumor cells, as well
Photo by Paulina Rzeczkowska
35 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

EXPERT OPINION
In keeping with the tradition of our research
group, we are still active in developing new
technologies which can further the field of interactive
proteomics. Recently, we have been
working on developing a mammalian version
of MYTH named MaMTH. The fundamentals
of the yeast-based and mammalian technologies
are similar, however MaMTH will
allow for testing of human membrane proteins
in the context of human cell lines. Our
initial proof of concept experiments were a
success and we are currently in the process
of upscaling MaMTH to a high-throughput
screening format by building cDNA libraries
that contain all 21,000 human Open Reading
Frames (ORFs). The groundbreaking aspect
of this technology is that it can be used to
study PPIs in a drug and/or agonist dependent
manner in the context of the human cell,
which has the potential to change the way
drug screening is performed in industry.
Figure 1. Interactive proteomics is a subdiscipline of proteomics whose goal is to map all protein-protein
interactions of a given cell or organism. Here, the interactome of the 50 selected human G-protein
coupled receptors is shown (recent unpublished work from the Jurisica & Stagljar lab).
the observation that dysfunction of these
transporters is associated with a range of
human diseases. Similarly, we are also working
on building a comprehensive interaction
map between the human receptor tyrosine
kinase (RTKs) and selected human G-protein
coupled receptors (GPCRs). These two
families of membrane proteins play a crucial
role in cell signaling, a process by which cells
respond to cues in their internal or external
environment. The finished interactomes of
RTKs and GPCRs represent a robust bank
of knowledge which will greatly contribute
to therapeutic research and shed new light
on the mechanism of natural control circuits
that regulate biological systems. As an example,
one of our recent findings showed that a
protein called HDAC6 regulates degradation
of an RTK called Epidermal Growth Factor
(EGFR), a receptor that is overactive in
several human cancers 5 . Based on this work,
we are investigating the possibility of treating
those cancers in which EGFR is involved
by using drugs to inhibit HDAC6, thereby
speeding up degradation of the oncogenic
EGFR protein.
Figure 2. An example of a positive (upper row) and negative (lower row) interaction detected by MYTH.
Proteins X and Y are synthesized in yeast and tested for interaction via MYTH by assessing their growth
on specific media. The blue staining and growth of yeast cells on specific media are indicative of two
proteins interacting in MYTH.
In summary, although membrane proteins
play a very crucial role in maintaining a
healthy cell state, and dysfunction of membrane
proteins has been linked to a plethora
of diseases, there are still huge gaps remaining
in our knowledge and understanding of
this group of proteins. MYTH and MaMTH
can be used to fill in this gap, which in turn
will have great implications in our understanding
of various diseases and how to better
create effective treatments for them.
References
1. Stagljar, I. and Fields, S. (2002) Analysis of membrane
protein interactions using yeast-based technologies.
Trends Biochem Sci 27, 559-563.
2. Thaminy, S., Auerbach, D., Arnoldo, A., and Stagljar,
I., (2003) Identification of novel ErbB3- interacting factors
using the split-ubiquitin membrane yeast two-hybrid
system, Genome Res 13, 1744–1753.
3. Paumi, C.M., Menendez, J., Arnoldo, A., Engels, K.,
Iyer, K., Thaminy, S., Georgiev, O., Barral, Y., Michaelis,
S., and Stagljar, I. (2007) Mapping Protein-Protein Interactions
for the Yeast ABC Transporter Ycf1p by Integrated
Split-Ubiquitin Membrane Yeast Two-Hybrid
(iMYTH) Analysis, Mol Cell 26, 15-25.
4. Gisler, S.M., Kittanakom, S., Fuster, D., Radanovic,
T., Wong, V., Bertic, M., Hall, R.A., Engels, K., Murer,
H., Biber, J., Markovic, D., Moe, O.W., and Stagljar, I.
(2008) Monitoring protein-protein interactions between
the mammalian integral membrane transporters and
PDZ-interacting partners using a modified split-ubiquitin
membrane yeast two-hybrid system, Mol Cell Proteomics
7, 1362-1377.
5. Deribe, Y. L., Wild, P., Chandrashaker, A., Curak, J.,
Schmidt, M. H., Kalaidzidis, Y., Milutinovic, N., Kratchmarova,
I., Buerkle, L., Fetchko, M. J., Schmidt, P., Kittanakom,
S., Brown, K. R., Jurisica, I., Blagoev, B., Zerial,
M., Stagljar, I., and Dikic, I., (2009) Regulation of
epidermal growth factor receptor trafficking by lysine
deacetylase HDAC6, Sci Signal 2, p. ra84.
6. Usenovic, M., Knight, A. L., Raj, A., Wong, V., Brown,
K. R., Caldwell, G. A., Caldwell,K. A., Stagljar, I., Krainc,
D. (2012) Identification of novel ATP13A2 interactors
and their role in α-synuclein misfolding and toxicity,
Hum Mol Genet, in press (PMID: 22645275).
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 36

FUTURE DIRECTIONS
Dr. Gabriella Farcas-Chan
JD, PhD
By Danielle D. DeSouza
If during her undergraduate degree
you were to ask Dr. Gabriella Farcas-
Chan if she could imagine pursuing career
in law, her answer would have been an
assured “no.” So how is it that this former
IMS student established herself as the Vice
President of Legal Affairs at a rapidly growing
biotechnology company?
Farcas-Chan started her post-secondary education
at the Loyola University of Chicago
where she studied biology and art history.
To help with the steep costs of obtaining an
undergraduate degree in the USA, she participated
in a work-study program that allowed
her to gain valuable medical research
experience while also earning an income.
Although her main interest at the time was
cardiac research, Farcas-Chan kept an open
mind towards other research topics; when
the principal investigator of her choice research
topic was between grants and unable
to accommodate any work-study students,
she was recommended to work with a group
Photo by Laura Feldcamp.
37 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

FUTURE DIRECTIONS
that focused on quality of life research in
lung transplant patients. They noticed that a
number of problems faced by these patients,
including organ rejection, were caused by cytomegalovirus
(CMV), a virus belonging to
the herpesviruses family. Farcas-Chan was
fascinated with the literature on infectious
diseases and soon became inspired to pursue
a graduate degree in the field.
Under the supervision of Dr. Kevin Kain, a
clinician-scientist specializing in the diagnostics
and surveillance of infectious diseases,
Farcas-Chan enrolled in the Institute
of Medical Science (IMS). During her studies,
she was an active member of the IMS
Students’ Association, carrying out two
terms as president. She began her thesis
work examining the impact of non-steroidal
anti-inflammatory drugs on malaria, but her
project soon took an interesting turn. In the
midst of her studies, health officials declared
the global epidemic of severe acute respiratory
syndrome (SARS), a condition caused
by a novel coronavirus (CoV). Approached
by companies trying to develop kits to diagnose
SARS as early as possible, Farcas-Chan
was given an exciting research opportunity:
she analyzed tissue samples from individuals
that had died of SARS using real-time PCR.
Using this method, she could assess viral load
as measured by CoV RNA in different parts
of the body. Her flexibility in taking on this
unexpected project resulted in seminal work
showing the dissemination of SARS-CoV
throughout all major organs, not just the
lungs in fatal SARS patients. 1
“Students need to know
what their rights are, especially
in labs where
there are collaborations
with companies. Students
need to make sure
they’re not being taken
advantage of.”
After completing her PhD and while working
for Fio Corporation, a privately held Canadian
company working to develop a por-
table device capable of molecular diagnosis
of infectious diseases using nanotechnology,
Farcas-Chan participated in a young entrepreneurship
program that greatly impacted
her career path. She had been heavily involved
in intellectual property (IP) searches
on patent databases at Fio when she attended
the Biotechnology YES (Young Entrepreneurs
Scheme) competition held by the UK
government. This competition, aimed at doctoral
students, addressed all aspects of starting
a biotechnology company. Farcas-Chan
was part of the only Canadian team that was
selected to attend the week-long training session
in Oxford, UK. Here, she was further
exposed to IP law, as she began conversing
with lawyers about the patent application
process. Shortly after these discussions, Farcas-Chan
applied to law school.
Although her first semester at Osgoode Hall
Law School at York University was a difficult
transition, Farcas-Chan knew that a career
in law was the right move. Her goal was to
do patent management in a field where she
could also apply the knowledge accumulated
in her graduate degree. To Farcas-Chan, going
to law school was a natural progression.
Achieving her goal, Farcas-Chan is currently
the Vice President of Legal Affairs at Cytodiagnostics
Inc., a biotechnology company
that focuses on the development and distribution
of nanotechnology derived products.
In speaking about this role she said you have
to be a “jack-of-all-trades,” as you need to liaise
between both the scientific and the law
worlds. Remarkably, she is doing this while
balancing family life. When I asked her how
she manages to do it all, she said, “Flexibility
is key. I have a hugely supportive husband
and I am lucky that I have the option to work
from home [to be with my son].”
So what’s next on the horizon for Farcas-
Chan? In addition to continuing her work
at Cytodiagnostics Inc., she would like to be
more involved in teaching and, in particular,
would like to be involved with the IMS.
Just this past April, she was a panel member
for the IMS Career Seminar Series entitled,
“A Graduate Student Alumni Perspective.”
In the future, she discussed the desire to develop
courses for IMS students that integrate
training in IP. She discussed the importance
of bringing awareness to students about protecting
their property: “It’s crucial. Students
need to know what their rights are, especially
in labs where there are collaborations
with companies. Students need to make sure
they’re not being taken advantage of.” She
also discussed the pros of having a patent on
a grant or scholarship application and said,
“You never know when you have something
that somebody may be interested in purchasing
or using.”
“I think the most important
thing is to know
who you are and what
you want. Participate in
things and go to seminars
and lectures and meet
people who are outside
of your field.”
When I asked Farcas-Chan what advice she
would give to current IMS students she said,
“I think the most important thing is to know
who you are and what you want. Participate
in things and go to seminars and lectures
and meet people who are outside of your
field.” She went on to say it is in these situations
where you can have a seed planted in
you for a new idea or career path, or when
you will have the opportunity to network.
She also discussed the importance of being
involved in activities and groups outside of
lab work. Throughout her education she did
more than just her schoolwork, whether it
was participating in research for her undergraduate
work-study program, or serving
as the president of the IMS Students’ Association.
She said, “You should get as much as
you can out of the grad-school experience.”
Given Farcas-Chan’s many successes, current
graduate students would be wise to take this
advice whole-heartedly.
References
1. Farcas GA, Poutanen SM, Mazzulli T, Willey BM, Butany
J, Asa SL, Faure P, Akhavan P, Low DE, Kain KC. Fatal Severe
Acute Respiratory Syndrome is Associated with Multiorgan Involvement
by Coronavirus. J Infect Dis. 2005;191:193-197.
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 38

RESEARCH HIGHLIGHT
Genomic medicine: gone to the dogs?
How genomics are helping to improve the health of purebred dogs
By Jennifer Rilstone
Paula ballak travelled to france
in 2010 to pick up the puppy of her
dreams—a black-and-white, wavyhaired
Barbet (French water dog) named
Rocket. Like other Barbet breeders, Ballak
is dedicated to reviving this rare, historical,
working breed—persecuted in WWII as the
national dog of France—which is no small
feat considering its limited numbers and genetic
diversity. Rocket represented a distinct
genetic line to breed with her own dogs, and
in the first year, he excelled as a retriever.
However, just after his first birthday, Rocket
began to have seizures. The seizure disorder
progressed quickly, affecting his behaviour
and quality of life, and was determined to
probably have a genetic cause. Recently—at
just over the age of 2—Rocket had to be put
down after having no response to antiepileptic
medications.
Canine epilepsy is not rare, occurring in as
many as 1 –5% of purebred dogs (compared
with 1% of the general human population),
and up to 20% of some breeds. Considered
a side effect of selective breeding, the insidious
condition occurs in multiple forms and
with multiple genetic causes. The insight of
veterinary neurologists has shown that these
many varieties of canine epilepsy are remarkably
similar to the many forms of human epilepsy.
Beyond epilepsy, dogs and humans are
physiologically similar and many canine diseases
mimic human conditions. Researchers,
therefore, have begun to study canine genetic
diseases with two hopes—improving the
health of purebred dogs, and gaining insights
about related diseases that afflict humans.
The study of canine epilepsy to aid human
health has a proud history in Toronto. Drs.
Hannes Lohi and Berge Minassian at the
Hospital for Sick Children discovered the
first canine epilepsy gene in 2005. Mutations
in this gene caused myoclonic epilepsy in the
miniature wire-haired dachshund (MWHD)
breed 1 . Mutations in the same gene were concurrently
discovered to cause Lafora progressive
myoclonic epilepsy in children. While
research into the human disease continues,
breeders of the MWHD dogs are now able to
identify carriers of the epilepsy mutation by
genetic testing. As a result of this testing and
responsible breeding practices, the incidence
of epilepsy has decreased and the health of
the breed has improved. Dr. Lohi has since
moved on to establish a canine genetic research
laboratory at the University of Helsinki,
where more canine disease genes have
since been identified—including the gene
causing epilepsy in the Barbet’s close relative,
Lagotto Romagnolo (Italian water dog) 2 . Ballak
hopes that Rocket’s DNA will lead to similar
success for the imperiled Barbet breed.
Amid growing controversy about the declining
health of purebred dogs, Lohi hopes to
harness advancing genomic technologies to
address health concerns and genetic diversity
in all breeds. With a worldwide network of
collaborating scientists, breed clubs who are
passionate about the health of their dogs, and
tireless veterinarians (including Dr. Fiona
James, the veterinary neurologist at Ontario
Veterinary College who cared for Rocket),
Lohi collects health records and generates
genetic data for vast pedigrees of purebred
dogs. The age of genomic medicine has come
not only to people, but also to the veterinary
clinic. And with the promise of new insights
into our own health that can be gleaned by
studying canine diseases, we are again indebted
to man’s best friend.
References
1. Lohi H, Young EJ, Fitzmaurice SN, et al. Expanded Repeat in
Canine Epilepsy. Science 2005;307(5706):81.
2. Seppälä EH, Jokinen TS, Fukata M, et al. LGI2 truncation
causes a remitting focal epilepsy in dogs. PLoS Genet
2011;7(7):e1002194.
Photo courtesy of Jennifer Rilstone
39 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

Ask
Experts
the
Expert Tips: Enriching your Graduate Experience
Column By Laura S. Park & Brittany N. Rosenbloom
Student Involvement in Forming Their PAC
A number of decisions need to be made at
the beginning of a graduate student’s studies.
Aside from the obvious choices, such as
choosing a supervisor and a project, a critical
decision that graduate students quickly face
is who should serve on their Program Advisory
Committee (PAC). As the IMS website
indicates, PAC members should include
faculty who have expertise complementing
the supervisor’s research and within the students’
proposed area of research. The balance
between advisors (i.e. committee members
and supervisor(s)) is one that can certainly
help students thrive in their studies, especially
by utilizing the guidance and encouragement
from each advisor to navigate through
some of the challenges that may arise during
the course of each student’s research career.
As such, students not only need to feel comfortable
with their committee members (e.g.
to ask research questions), but also need to
make sure that PAC members are willing
to be available for additional meetings as
needed. To achieve this, it is imperative that
students are a part of deciding who is on
their own committee. This requires a series
of iterative discussions between student and
supervisor about project goals, the guiding
expertise needed to accomplish these goals,
and the best learning/teaching style that will
maximize the student’s experience. A crucial
factor to consider in this process is how
much time and guidance each potential PAC
member can provide.
Many newly admitted students leave this decision
up to the supervisor, and it is common
for supervisors to choose their close colleagues
or collaborators. Therefore, students
should share any potential PAC members in
mind and take an active role in this process.
Putting together the best-suited PAC is important
for students to be successful in their
graduate training while having a fun and exciting
time!
What Supervisors Expect From Their Students
One of the challenges for many graduate students
is having a productive and meaningful
relationship with their supervisors. Problems
may range from inadequate communication
to more serious issues such as lab bullying
and ethical misconduct. Unfortunately, these
difficulties do arise and it is important to realize
them early on and to seek assistance. Both
the IMS office and the IMS Students’ Association
(IMSSA) provide student-supervisor
relationship advice whether one-on-one, or
through workshops such as the one held last
March.
Listed are some general but key pieces of advice
shared by Dr. Carol Westall, one of our
graduate coordinators.
These are some basic points to keep in mind
as a graduate student. It is likely that most
supervisors will expect more from their students;
it is the student’s job to fulfill more
than the minimum. Also, each supervisor has
their own unique mentoring style and students
should apply these guidelines at their
own discretion. Nevertheless, having a good
student-supervisor relationship is not only in
the hands of the students, but also in those of
their supervisors.
Things Supervisors Wished Students Knew:
Students should/can
1. give regular, written updates regarding
their work
2. know that it takes time to get a PAC/
exam committee together
3. tell their PAC they want to transfer to
PhD/go to medical school
4. refer to PAC members, other students,
lab mates, and IMSSA if they
need help or advice
5. know all deadlines
6. find external funding
7. tell their supervisor if they can’t live
on the stipend amount
8. tell their supervisor if the pressure
and stress is too great
9. tell their supervisor if they are having
problems writing their thesis, grant
applications, or papers
EXPERT TIP
Any discussion with a Graduate Coordinator
will remain confidential unless you choose
otherwise. Don’t shy away from asking for
guidance.
Do you have a question for the experts? Please
send it to theimsmagazine@gmail.com. (ATTN:
Experts).
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 40

PAST EVENTS
PAST
EVENTS
This year’s IMS Scientific Day again allowed students to showcase
their research and learn of the diverse science being conducted
across the department. Above, a student engages in discussion
during the afternoon poster session.
The Biomedical Communications
Department
took a field trip to the
zoo! Along with having
a lot of fun, students
practiced drawing and
photography skills. (left
and right)
Can’t hide their smiles!
Friends unwind during
IMSSA’s Wine and
Cheese event, one of
the many social events
hosted throughout the
year for IMS students.
Photos courtesy of the IMS Office, IMS/IMSSA. & Laura E. Smith.
41 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

DIVERSIONS
CROSSWORD
Down:
2. The I in IMS.
3. The A in IMSSA.
5. A plea, essay, speech etc., in support of
something.
6. A subject for composition or essay.
10. A group of people gathered in answer
to a summons.
11. A section of the thesis.
12. An act or operation for the purpose of
discovering something unknown or of testing
a principle.
14. One who runs your assays.
15. What every student wants, maybe in
Cell or Nature.
16. The interpretation of numerical facts
and data.
20. A supply of money or pecuniary resources,
as for some purpose.
Across:
1. The charge or fee for instruction.
4. The A in PAC.
7. A meeting for consultation or discussion.
8. A sum of money or other aid granted to
a student, because of merit, need, etc., to
pursue his or her studies.
9. A system of moral principles.
13. Your mentor, one who guides you.
17. Where one runs experiments.
18. Current director of the IMS (2 words).
19. The kind of research done at the IMS.
Summer Student Writing
Competition
Passionate about your research and eager to write for the IMS
Magazine? We are currently welcoming research article submissions
from SURP students as we hope to feature at least
one article in our Fall 2012 magazine edition.
What to include with your submission: title, author name,
supervisor name, article text, references (10 maximum). 750
word limit not including references/title. Figures (2 maximum)
are also welcome with appropriate captions and permissions
wherever applicable.
Please send your complete article to theimsmagazine@gmail.
com by Friday, August 17, 2012 in .doc/.docx formats only.
Please feel free to email with any questions or comments.
Thank you for your interest!
“Piled Higher and Deeper” by Jorge Cham www.phdcomics.com
IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE | 42

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