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<strong>IMS</strong>MAGAZINE<br />
SUMMER<br />
THINK, LEARN, DISCOVER.<br />
<strong>2012</strong><br />
GENOMIC MEDICINE<br />
ON THE CUSP OF INDIVIDUALIZED PATIENT CARE<br />
PUBLISH<br />
AND PERISH<br />
Does a higher impact factor<br />
equal better science?<br />
SPIT<br />
FOR SCIENCE<br />
The Thoughts, Actions, and Genes project: explor<strong>in</strong>g<br />
the genetic basis <strong>of</strong> childhood neuropsychiatric disorders<br />
Student-Led Initiative
IN THIS<br />
ISSUE...<br />
TABLE OF CONTENTS<br />
Commentary ....................................03<br />
Letter from the Editor ......................06<br />
News at a Glance ...........................07<br />
Director’s Message .........................10<br />
<strong>IMS</strong> Scientific Day Highlight ...........11<br />
Feature.............................................13<br />
Spotlight ..........................................25<br />
Book Reviews ..................................27<br />
Close Up...........................................29<br />
Viewpo<strong>in</strong>t ........................................31<br />
Expert Op<strong>in</strong>ion .................................35<br />
Future Directions .............................37<br />
Research Highlight ..........................39<br />
Ask the Experts ...............................40<br />
Past Events.......................................41<br />
Diversions .......................................42<br />
13<br />
FEATURE<br />
Genomic Medic<strong>in</strong>e<br />
Our experts discuss how advances <strong>in</strong> genomic<br />
technologies will soon allow genetic <strong>in</strong>sights to<br />
aid <strong>in</strong>dividual patient care, and the associated<br />
challenges to consider.<br />
Cover image by Inessa Stanishevskaya. Gone to the Dogs? photo by Jennifer Rilstone. Expert Op<strong>in</strong>ion image courtesy <strong>of</strong> Igor Stagljar.<br />
MAGAZINE STAFF<br />
Editor-<strong>in</strong>-Chief Natalie Venier<br />
Manag<strong>in</strong>g Editor N<strong>in</strong>a Bahl<br />
Assistant Manag<strong>in</strong>g Editors Tetyana Pekar<br />
Jennifer Rilstone<br />
Allison Rosen<br />
Adam Santoro<br />
Departmental Advisor Marika Galadza<br />
Kamila Lear<br />
Design Editors Melissa Cory<br />
Laura Greenlee<br />
Michael Soong<br />
Inessa Stanishevskaya<br />
Andrea Zariwny<br />
Sr. Design Editors Tobi Lam, Andreea Marg<strong>in</strong>eanu,<br />
Merry Wang, M<strong>in</strong>yan Wang<br />
Advertis<strong>in</strong>g Manager Cor<strong>in</strong>ne Daly<br />
Laura Seohyun Park<br />
<strong>Magaz<strong>in</strong>e</strong> Committee Salvador Alcaire<br />
S. Amanda Ali<br />
Rickv<strong>in</strong>der Besla<br />
Danielle Desouza<br />
Melanie Guenette<br />
Aaron Kucyi<br />
Rosa Marticorena<br />
Anna Podnos<br />
Brittany Rosenbloom<br />
Karrie Wong<br />
Zeynep Yilmaz<br />
Photography Yekta Dowlati, Brett Jones<br />
Laura Feldcamp, Paul<strong>in</strong>a<br />
Rzeczkowska, Mohammed Sabri<br />
Copyright © <strong>2012</strong> by <strong>Institute</strong> <strong>of</strong> Medical Science, University <strong>of</strong> Toronto. All<br />
rights reserved. Reproduction without permission is prohibited.<br />
The <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong> is a student-run <strong>in</strong>itiative. Any op<strong>in</strong>ions expressed by<br />
the author(s) are <strong>in</strong> no way affiliated with the <strong>Institute</strong> <strong>of</strong> Medical Science<br />
or the University <strong>of</strong> Toronto.<br />
39<br />
Gone to the Dogs?<br />
Learn how Drs. Hannes Lohi and Berge<br />
M<strong>in</strong>assian are us<strong>in</strong>g genomics to<br />
improve the health <strong>of</strong> purebred dogs and<br />
better understand human disease.<br />
35<br />
Expert Op<strong>in</strong>ion: Proteomics<br />
Dr. Igor Stagljar expla<strong>in</strong>s translational<br />
aspects <strong>of</strong> proteomics research.<br />
Cover Art<br />
By Inessa Stanishevskaya<br />
The cover was designed to illustrate how<br />
the analysis <strong>of</strong> a person’s genome sequence<br />
could potentially play a role <strong>in</strong> the development<br />
<strong>of</strong> <strong>in</strong>dividualized patient care.<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 02
COMMENTARY<br />
Commentary<br />
On ‘A Reconcilable Conflict’,<br />
by Benjam<strong>in</strong> Mora (Spr<strong>in</strong>g <strong>2012</strong>)<br />
All ways <strong>of</strong> know<strong>in</strong>g are equal, but<br />
some are more equal than others<br />
By Adam Santoro, PhD student<br />
I would like to thank Benjam<strong>in</strong> Mora for submitt<strong>in</strong>g<br />
a thoughtful commentary <strong>in</strong> the previous<br />
issue <strong>of</strong> the <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong>. Mr. Mora<br />
<strong>of</strong>fered a contrast<strong>in</strong>g op<strong>in</strong>ion to that which<br />
I presented <strong>in</strong> the W<strong>in</strong>ter <strong>2012</strong> issue, stat<strong>in</strong>g<br />
that “…flourish<strong>in</strong>g dialogue between science<br />
and religion <strong>in</strong> recent years is testimony to<br />
the fact that, far from be<strong>in</strong>g irreconcilably<br />
conflicted these two doma<strong>in</strong>s <strong>of</strong> human<br />
knowledge can fruitfully <strong>in</strong>teract.”<br />
Mr. Mora presented three arguments: firstly,<br />
that I was <strong>in</strong>correct to state that scientists<br />
who are religious have not thought deeply<br />
about the issue, or are act<strong>in</strong>g <strong>in</strong> a non-scientific<br />
manner; secondly, that my views succumb<br />
to an erroneous method <strong>of</strong> th<strong>in</strong>k<strong>in</strong>g<br />
called scientism; and thirdly, that I can only<br />
successfully support methodological (and<br />
not philosophical) naturalism, which allows<br />
for a great number <strong>of</strong> plausible and fruitful<br />
<strong>in</strong>teractions between science and religion.<br />
As per his first argument: Mr. Mora contends<br />
that there are numerous “top-th<strong>in</strong>k<strong>in</strong>g” scientists<br />
who have thought deeply about the<br />
issue at hand. He presented a list <strong>of</strong> “topth<strong>in</strong>kers,”<br />
presumably to illustrate how some<br />
<strong>in</strong>dividuals ma<strong>in</strong>ta<strong>in</strong> a high degree <strong>of</strong> scientific<br />
<strong>in</strong>tegrity and still th<strong>in</strong>k about the issue<br />
deeply. To this I would simply state that an<br />
<strong>in</strong>dividual’s scientific prowess does not necessarily<br />
translate to matters not published <strong>in</strong><br />
Science or Nature; because an <strong>in</strong>dividual is a<br />
leader with<strong>in</strong> his scientific field, it does not<br />
necessarily follow that he ma<strong>in</strong>ta<strong>in</strong>s sufficient<br />
scientific <strong>in</strong>tegrity when deal<strong>in</strong>g with issues<br />
outside <strong>of</strong> the published literature (especially<br />
those that enter the realm <strong>of</strong> philosophy).<br />
Mr. Mora listed a plethora <strong>of</strong> scientists, all <strong>of</strong><br />
whom are Christian. This is <strong>in</strong>deed curious,<br />
and raises numerous questions (i.e., why not<br />
list names <strong>of</strong> top-th<strong>in</strong>k<strong>in</strong>g scientists who are<br />
non-Christians?). I assume that it has to do<br />
with Mr. Mora’s theological bias, which leads<br />
me <strong>in</strong>to the rest <strong>of</strong> the discussion.<br />
As per his second and third arguments: Mr.<br />
Mora implies that scientists who support my<br />
viewpo<strong>in</strong>t suffer from scientism, which states<br />
that the scientific way <strong>of</strong> know<strong>in</strong>g is the only<br />
way to discover truth. Those who share Mr.<br />
Mora’s epistemic viewpo<strong>in</strong>t acknowledge<br />
that there are different ways <strong>of</strong> know<strong>in</strong>g,<br />
and theology and science are merely two <strong>of</strong><br />
such ways. With this worldview, theological<br />
know<strong>in</strong>g can <strong>in</strong>form one about the natural<br />
world, and science can <strong>in</strong>form one about theology,<br />
s<strong>in</strong>ce both ways <strong>of</strong> know<strong>in</strong>g are equally<br />
valid. There is a problem with this view. It is<br />
undoubtedly the case that a priori theological<br />
beliefs necessarily dictate those natural<br />
phenomena that can be expla<strong>in</strong>ed by science<br />
(e.g., someth<strong>in</strong>g <strong>in</strong>herently bor<strong>in</strong>g and obviously<br />
un-div<strong>in</strong>e as Brownian motion), and<br />
those that seem<strong>in</strong>gly require theology (e.g.,<br />
evolution vs. Intelligent Design). To those<br />
with this view, theology only succumbs to<br />
science when it would be to approach <strong>in</strong>sanity<br />
to deny the scientific truth (see: the history<br />
<strong>of</strong> evolution, the Heliocentric Model,<br />
etc.). Thus, it is not a simple case <strong>of</strong> complementary<br />
systems <strong>of</strong> know<strong>in</strong>g that can live <strong>in</strong><br />
harmony; all ways <strong>of</strong> know<strong>in</strong>g are apparently<br />
equal, but some are more equal than others.<br />
Regardless, straw-men aside, I was careful<br />
to present an argument that did not depend<br />
on a s<strong>in</strong>gle way <strong>of</strong> know<strong>in</strong>g. Instead, I (perhaps<br />
naively) assumed that scientists support<br />
methodological naturalism – a viewpo<strong>in</strong>t<br />
that says all natural phenomena must be<br />
expla<strong>in</strong>ed by science, and theology cannot<br />
dictate when it cannot. Mr. Mora should<br />
take note that the theological way <strong>of</strong> know<strong>in</strong>g<br />
is not lost with this worldview; <strong>in</strong>stead<br />
it is limited to the know<strong>in</strong>g <strong>of</strong> non-natural<br />
th<strong>in</strong>gs. So, much like how <strong>in</strong> some views<br />
theology <strong>of</strong>ten dictates the limits <strong>of</strong> science,<br />
from my perspective it is science that dictates<br />
the limits <strong>of</strong> theology. Methodological naturalism<br />
does not assume that the theological<br />
way <strong>of</strong> know<strong>in</strong>g is <strong>in</strong>valid or <strong>in</strong>correct; it simply<br />
states that it cannot conflict with science<br />
when deal<strong>in</strong>g with the natural world. In my<br />
article I merely <strong>in</strong>terpolated some conclusions<br />
from this viewpo<strong>in</strong>t. Firstly, if theology<br />
cannot step on the toes <strong>of</strong> science on matters<br />
concern<strong>in</strong>g the natural world, then nearly<br />
all theistic religions are to be rejected (s<strong>in</strong>ce<br />
they all make naturalistic claims <strong>in</strong> some<br />
capacity, all <strong>of</strong> which conflict with scientific<br />
pr<strong>in</strong>ciples and natural laws). Second, deism<br />
is the only position a scientist/methodological<br />
naturalist can support, s<strong>in</strong>ce this position<br />
does not conta<strong>in</strong> conflict<strong>in</strong>g views <strong>of</strong> natural<br />
phenomena. Thirdly, a scientist should support<br />
methodological naturalism fully – to<br />
pick and choose avenues where science is to<br />
be usurped by theology is to lack scientific<br />
<strong>in</strong>tegrity. Thus, an <strong>in</strong>dividual who is properly<br />
scientific and truly accepts methodological<br />
naturalism can be a deist, at most.<br />
As a f<strong>in</strong>al po<strong>in</strong>t, it is commonly argued that<br />
methodological naturalism can be <strong>in</strong> harmony<br />
with theology s<strong>in</strong>ce a theistic God can<br />
act upon the natural world <strong>in</strong> ways that we<br />
cannot detect (and hence, by their very nature<br />
are <strong>in</strong> tune with natural laws and can<br />
be studied with science). For example, God<br />
could drive mutations dur<strong>in</strong>g evolution <strong>in</strong><br />
subtle ways that we cannot detect. This is<br />
merely a logical game (you cannot prove the<br />
non-existence <strong>of</strong> the Tooth Fairy with 100%<br />
certa<strong>in</strong>ty). This viewpo<strong>in</strong>t would seriously<br />
underm<strong>in</strong>e the credibility and <strong>in</strong>tegrity <strong>of</strong> a<br />
“top-th<strong>in</strong>k<strong>in</strong>g” scientist, s<strong>in</strong>ce the <strong>in</strong>vention<br />
<strong>of</strong> ad hoc hypotheses is wonky at best.<br />
03 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
COMMENTARY<br />
Photo by Yekta Dowlati<br />
The Sex <strong>of</strong> Stem Cells<br />
Does sex have an effect on the regenerative<br />
potential <strong>of</strong> stem cells?<br />
By Anna Podnos, MSc student<br />
In the last several decades, sex and gender<br />
have become widely recognized as important<br />
biological and social variables <strong>in</strong> human<br />
research, and many strategies for <strong>in</strong>corporat<strong>in</strong>g<br />
sex <strong>in</strong> research design have been developed.<br />
However, as discussed <strong>in</strong> our <strong>Summer</strong><br />
2011 <strong>edition</strong> (see “Sexism <strong>in</strong> Biomedical<br />
Research”), stratify<strong>in</strong>g experiments by sex<br />
is much rarer <strong>in</strong> animal and cell-based research<br />
1 . Regenerative therapies, such as stem<br />
cell transplantation, are be<strong>in</strong>g developed<br />
based on animal and cellular models, and<br />
a fundamental component may be miss<strong>in</strong>g.<br />
Significant sex differences have recently been<br />
found <strong>in</strong> the regenerative properties <strong>of</strong> various<br />
stem cells. Stems cells have the unique<br />
ability to differentiate <strong>in</strong>to specific cell types<br />
and self-renew, so they have the potential to<br />
treat organ failure, cancers, and degenerative<br />
diseases.<br />
When patients’ own stem cells cannot be<br />
used therapeutically, they may require a cellular<br />
transplant from a donor. The success<br />
<strong>of</strong> transplantation depends on the type <strong>of</strong><br />
donor stem cells, the characteristics <strong>of</strong> host<br />
cells, and their <strong>in</strong>teractions with pathways<br />
associated with the illness 2 . Research us<strong>in</strong>g<br />
animal models has found that biological sex<br />
is an important variable <strong>in</strong> proliferation and<br />
differentiation rates <strong>of</strong> stem cells 3 . For example,<br />
animal studies <strong>of</strong> hematopoietic stem cell<br />
transplantation (the only stem cell therapy<br />
<strong>in</strong> standard medical practice 4 ) have found<br />
that that the sex <strong>of</strong> both donor and recipient<br />
animals affect the transplantation outcome 4 .<br />
In addition, there are significant differences<br />
<strong>in</strong> the activation <strong>of</strong> mesenchymal stem cells<br />
(MSC) depend<strong>in</strong>g on their biological sex 3 .<br />
Researchers found that female stem cells<br />
produced more proliferation- and <strong>in</strong>flammation-promot<strong>in</strong>g<br />
factors than male cells.<br />
Female muscle-derived stem cells (MDSC),<br />
which have the capacity for myocardial repair,<br />
were another type <strong>of</strong> stem cell found to<br />
have more regenerative capacity than male<br />
MDSC 5 . These sex differences may be therapeutically<br />
relevant, but there are few studies<br />
directly compar<strong>in</strong>g different cell types <strong>in</strong> dis-<br />
ease models 6 .<br />
Given that sex differences exist <strong>in</strong> stem cells, it<br />
is necessary to exam<strong>in</strong>e the causes <strong>of</strong> the dissimilarities,<br />
which may arise on genetic, epigenetic<br />
or hormonal levels. Male and female<br />
cells differ genetically, and it is important to<br />
<strong>in</strong>vestigate the differences both between and<br />
with<strong>in</strong> sexes. The hormonal environment is a<br />
key covariate to sex, because it may also regulate<br />
the differentiation and proliferation <strong>of</strong><br />
stem cells. Epigenetic differences result<strong>in</strong>g <strong>in</strong><br />
vary<strong>in</strong>g gene expression levels are covariates<br />
as well. In mouse models <strong>of</strong> muscular dystrophy,<br />
it was found that not only do female<br />
MDSC promote more regeneration than<br />
male MDSC, but also that the female recipient<br />
animals undergo more regeneration than<br />
male animals do, regardless <strong>of</strong> the sex <strong>of</strong> the<br />
donor cells. However, this is not the case <strong>in</strong><br />
immune-deficient animals, which suggests<br />
that the effect <strong>of</strong> host’s sex on the MDSC regenerative<br />
potential may be immunologically<br />
modulated, and therefore <strong>in</strong>fluenced by the<br />
hormonal environment.<br />
It is challeng<strong>in</strong>g to appropriately <strong>in</strong>corporate<br />
sex as a variable <strong>in</strong> animal and cell-based<br />
study designs, so an <strong>in</strong>terdiscipl<strong>in</strong>ary approach<br />
is <strong>of</strong>ten required. Recently, Stanford<br />
University launched “Gendered Innovations”<br />
2 (gendered<strong>in</strong>novations.stanford.edu),<br />
which has an abundance <strong>of</strong> <strong>in</strong><strong>format</strong>ion<br />
about the <strong>in</strong>clusion <strong>of</strong> sex and/or gender <strong>in</strong><br />
eng<strong>in</strong>eer<strong>in</strong>g, science and medic<strong>in</strong>e. It provides<br />
practical methods and checklists for<br />
consider<strong>in</strong>g biological sex <strong>in</strong> basic research.<br />
The development and implementation <strong>of</strong><br />
specific guidel<strong>in</strong>es for <strong>in</strong>corporat<strong>in</strong>g sex <strong>in</strong><br />
stem cell research as an <strong>in</strong><strong>format</strong>ive variable,<br />
rather than just a bias, will improve regenerative<br />
therapies.<br />
References<br />
1. Beery, A., & Zucker, I. 2011. Sex Bias <strong>in</strong> Neuroscience and<br />
Biomedical Research. Neuroscience and Biobehavioral Reviews,<br />
35 (3), 565-572<br />
2. gendered<strong>in</strong>novations.stanford.edu<br />
3. Crisostomo, P., Markel, T., Wang, M., Lahm, T., Lillemoe, K., &<br />
Meldrum, D. 2007. In the Adult Mesenchymal Stem Cell Population,<br />
Source Gender Is a Biologically Relevant Aspect <strong>of</strong> Protective<br />
Power. Surgery, 142 (2), 215-221<br />
4. Gahrton, G., Iacobelli, S., Apperley, J., Band<strong>in</strong>i, G., Björkstrand,<br />
B., Bladé, J., Boiron, J., Cavo, M., Cornelissen, J., Corrad<strong>in</strong>i,<br />
P., Kröger, N., Ljungman, P., Michallet, M., Russell, N.,<br />
Samson, D., Schattenberg, A., Sirohi, B., Verdonck, L., Vol<strong>in</strong>,<br />
L., Zander, A., & Niederwieser, D. 2005. The Impact <strong>of</strong> Donor<br />
Gender on Outcome <strong>of</strong> Allogeneic Hematopoietic Stem Cell<br />
Transplantation for Multiple Myeloma: Reduced Relapse Risk <strong>in</strong><br />
Female to Male Transplants. Bone Marrow Transplantation, 35<br />
(6), 609-617<br />
5. Deasy, B., Lu, A., Rub<strong>in</strong>, R., Huard, J., Tebbets, J., Feduska,<br />
J., Schugar, R., Pollett, J., Sun, B., Urish, K., Gharaibeh, B., &<br />
Coo, B. 2007. A Role for Cell Sex <strong>in</strong> Stem Cell-Mediated Skeletal<br />
Muscle Regeneration: Female Cells Have Higher Muscle Regeneration<br />
Efficiency. The Journal <strong>of</strong> Cell Biology, 177 (1), 73-86<br />
6. Zenovich, A., Davis, B., & Taylor, D. 2007. Comparison <strong>of</strong><br />
Intracardiac Cell Transplantation: Autologous Skeletal Myoblasts<br />
versus Bone Marrow Cells. In Kauser, K., & Zeiher, A.<br />
(Eds.), Bone Marrow-Derived Progenitors, pp. 117-165. Berl<strong>in</strong>:<br />
Spr<strong>in</strong>ger Verlag<br />
Disclaimer: The op<strong>in</strong>ions expressed by the author<br />
are <strong>in</strong> no way affiliated with the <strong>Institute</strong><br />
<strong>of</strong> Medical Science or the University <strong>of</strong> Toronto.<br />
Comments are welcome at theimsmagaz<strong>in</strong>e@<br />
gmail.com.<br />
What to look for next issue:<br />
In cont<strong>in</strong>uation <strong>of</strong> our Genomic Medic<strong>in</strong>e feature,<br />
we highlight Dr. Berge M<strong>in</strong>assian’s work<br />
<strong>in</strong> uncover<strong>in</strong>g genetic causes <strong>of</strong> rare, pr<strong>of</strong>oundly<br />
debilitat<strong>in</strong>g neurological diseases.<br />
Contact Us<br />
We encourage our readers to send their feedback<br />
-- comments, questions, corrections, and<br />
letters to the editor -- to theimsmagaz<strong>in</strong>e@<br />
gmail.com.<br />
www.facebook.com/groups/imsmagaz<strong>in</strong>e/<br />
@<strong>IMS</strong><strong>Magaz<strong>in</strong>e</strong><br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 04
NEWS AT A GLANCE<br />
05 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
LETTER FROM THE EDITOR<br />
Letter from<br />
the Editor<br />
Nearly sixty years ago <strong>in</strong> a letter to Nature, Watson and Crick wrote: “We wish to<br />
suggest a structure for the salt <strong>of</strong> deoxyribose nucleic acid (DNA). This structure<br />
has novel features which are <strong>of</strong> considerable biological <strong>in</strong>terest.” This first identification<br />
<strong>of</strong> DNA has paved the way for the field <strong>of</strong> medical genomics and, unknow<strong>in</strong>gly to its<br />
discoverers at the time, has given promise <strong>of</strong> revolutioniz<strong>in</strong>g the diagnosis and treatment<br />
<strong>of</strong> many illnesses.<br />
This milestone should once aga<strong>in</strong> rem<strong>in</strong>d us that a scientific discovery can open up a multitude<br />
<strong>of</strong> opportunities for future research. In this issue <strong>of</strong> the <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong>, we guide you<br />
through a detailed timel<strong>in</strong>e <strong>of</strong> the evolution <strong>of</strong> molecular medic<strong>in</strong>e—from the pr<strong>in</strong>ciples <strong>of</strong><br />
heredity, to the first discovery <strong>of</strong> genomic DNA, to the identification <strong>of</strong> novel genes <strong>of</strong> various<br />
diseases. I hope it will <strong>in</strong>spire young researchers to th<strong>in</strong>k about the long-term implications<br />
<strong>of</strong> their research f<strong>in</strong>d<strong>in</strong>gs.<br />
Furthermore, with the help <strong>of</strong> our experts, we hope to educate you about some <strong>of</strong> the <strong>in</strong>novative<br />
research surround<strong>in</strong>g genomic medic<strong>in</strong>e here at the <strong>IMS</strong>. We discuss next-generation<br />
sequenc<strong>in</strong>g technologies, human genetic variation, pharmacogenomics, epigenomics, and<br />
important ethical considerations <strong>of</strong> its translation to patient care. We hope that this will<br />
improve your understand<strong>in</strong>g <strong>of</strong> personalized medic<strong>in</strong>e and <strong>in</strong>form you about the ongo<strong>in</strong>g,<br />
cutt<strong>in</strong>g-edge science at our <strong>in</strong>stitute.<br />
I also encourage you to take a look at our Viewpo<strong>in</strong>t section and weigh <strong>in</strong> on our more<br />
contentious articles: we discuss the importance <strong>of</strong> understand<strong>in</strong>g statistics <strong>in</strong> graduate education<br />
and controversies centered around publish<strong>in</strong>g <strong>in</strong> journals with high impact factors.<br />
Be sure to also check out highlights from <strong>IMS</strong> Scientific Day, as well as our Close Up section<br />
featur<strong>in</strong>g the w<strong>in</strong>ner <strong>of</strong> the Mel Silverman Mentorship Award, Dr. Gary Rem<strong>in</strong>gton.<br />
Natalie Venier<br />
Editor-In-Chief<br />
Natalie Venier is a third year PhD Candidate<br />
at the <strong>Institute</strong> <strong>of</strong> Medical Science.<br />
She is currently study<strong>in</strong>g prostate cancer<br />
chemoprevention at Sunnybrook Health<br />
Sciences Centre.<br />
To conclude, I would like to thank Dr. Allan Kaplan and the <strong>IMS</strong> department for their<br />
ongo<strong>in</strong>g support, and congratulate our newest design team on their outstand<strong>in</strong>g efforts <strong>in</strong><br />
the production <strong>of</strong> this issue. I must acknowledge the phenomenal <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong> team for<br />
their creativity and dedication, and our exceptional Manag<strong>in</strong>g Editor, N<strong>in</strong>a Bahl, whose<br />
dedication has been <strong>in</strong>tegral to our production. Lastly, I strongly encourage comments and<br />
feedback letters as we cont<strong>in</strong>ue to aspire to br<strong>in</strong>g you the best <strong>of</strong> the <strong>IMS</strong>.<br />
Enjoy!<br />
Photo by Paul<strong>in</strong>a Rzeczkowska<br />
Natalie Venier<br />
Editor-In-Chief, <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong><br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 06
NEWS AT A GLANCE<br />
NEWS&VIEWS<br />
JULY<br />
28<br />
AUGUST<br />
5<br />
12<br />
13<br />
15<br />
16<br />
<strong>IMS</strong>SA BBQ<br />
<strong>IMS</strong> Wonderland trip<br />
Blue Jays Game<br />
SEPTEMBER<br />
4<br />
13<br />
TBA<br />
Registration for Fall session<br />
beg<strong>in</strong>s<br />
<strong>IMS</strong> <strong>Summer</strong> Undergraduate<br />
Research Day<br />
Artists for Autism: Talent<br />
Show<br />
School <strong>of</strong> Graduate Studies<br />
– Graduate Orientation for<br />
Incom<strong>in</strong>g Students<br />
<strong>IMS</strong> New Student<br />
Orientation and Reception<br />
<strong>IMS</strong>SA Executive Elections &<br />
<strong>IMS</strong>SA Pub Night<br />
For <strong>in</strong><strong>format</strong>ion on <strong>IMS</strong> news and events, please see:<br />
http://www.ims.utoronto.ca<br />
For more <strong>in</strong><strong>format</strong>ion on<br />
<strong>IMS</strong>SA/<strong>IMS</strong>SA-related events, please visit:<br />
http://imssa.sa.utoronto.ca<br />
Please send your comments and suggestions to:<br />
theimsmagaz<strong>in</strong>e@gmail.com<br />
<strong>IMS</strong> ANNOUNCEMENTS<br />
at a glance...<br />
<strong>IMS</strong> Scientific Day – Recap!<br />
This year’s <strong>IMS</strong> Scientific Day was held on May 15th, <strong>2012</strong>. The day was a great success<br />
with over 130 MSc and PhD student poster presentations, 6 Laidlaw Manuscript oral<br />
presentations, and the Bernard Langer Lecture <strong>in</strong> Health Sciences—presented by Dr.<br />
Thomas R. Insel, Director <strong>of</strong> the National <strong>Institute</strong> <strong>of</strong> Mental Health. For a glimpse <strong>of</strong> Dr.<br />
Insel’s presentation, visit our website at www.ims.utoronto.ca. Thank you to all who<br />
participated <strong>in</strong> this event. We look forward to another stimulat<strong>in</strong>g Scientific Day <strong>in</strong> 2013!<br />
<strong>IMS</strong> Office Staff<br />
Dr. Karen Davis has completed her 10-year term as Associate Director at the <strong>IMS</strong>. Among<br />
her most last<strong>in</strong>g contributions are the establishment <strong>of</strong> ethical tra<strong>in</strong><strong>in</strong>g modules and<br />
development <strong>of</strong> the <strong>IMS</strong> Oath recited annually at September’s student orientation. Dr.<br />
Davis is currently the Head <strong>of</strong> the Division <strong>of</strong> Bra<strong>in</strong>, Imag<strong>in</strong>g & Behaviour Systems at the<br />
Toronto Western Research <strong>Institute</strong> and will cont<strong>in</strong>ue her <strong>in</strong>volvement with the <strong>IMS</strong><br />
through student supervision and as Pr<strong>of</strong>essor <strong>of</strong> Surgery. Her vision and leadership will be<br />
greatly missed.<br />
Dr. Carol Westall has completed her term as Graduate Coord<strong>in</strong>ator at the <strong>IMS</strong>. Outside<br />
academia, Dr. Westall is a registered cl<strong>in</strong>ical optometrist and Director <strong>of</strong> the Visual<br />
Electrophysiology Unit at SickKids. She served as a Graduate Coord<strong>in</strong>ator at <strong>IMS</strong> for 3 years.<br />
Dr. Westall’s sense <strong>of</strong> humour and tireless devotion to <strong>IMS</strong> students was much appreciated.<br />
We wish them all the best <strong>in</strong> their future endeavours!<br />
Dr. M<strong>in</strong>gyao Liu has accepted the position <strong>of</strong> Associate Director at the <strong>IMS</strong> effective July<br />
1, <strong>2012</strong>. Dr. Liu has many years <strong>of</strong> experience with the <strong>IMS</strong>, act<strong>in</strong>g as a member <strong>of</strong> the<br />
<strong>IMS</strong> faculty s<strong>in</strong>ce 1997 and Graduate Coord<strong>in</strong>ator between 2000 and 2005. Dr. Liu will<br />
work closely with <strong>IMS</strong> Director, Dr. Allan S. Kaplan, to oversee faculty appo<strong>in</strong>tments and<br />
spearhead the new <strong>IMS</strong> Strategic Plan Initiative slated for roll-out <strong>in</strong> fall <strong>of</strong> <strong>2012</strong>.<br />
We also welcome Dr. C<strong>in</strong>di Morshead and Dr. Vasundara Venkateswaran as Graduate<br />
Coord<strong>in</strong>ators effective summer <strong>2012</strong>. Both have served as active <strong>IMS</strong> faculty members for<br />
over 5 years and will be a vibrant addition to our current roster.<br />
Interim Staff Appo<strong>in</strong>tments<br />
Michelle Rosen will be serv<strong>in</strong>g as the Interim Faculty and Student Affairs Coord<strong>in</strong>ator.<br />
Michelle will be responsible for adm<strong>in</strong>ister<strong>in</strong>g awards, faculty appo<strong>in</strong>tments, and courses.<br />
She will be cover<strong>in</strong>g Kaki Narh Blackwood, who is on medical leave until further notice.<br />
Tania DaSilva has jo<strong>in</strong>ed us as Interim Departmental Assistant. Tania worked at the <strong>IMS</strong> last<br />
summer, and will assume the role <strong>of</strong> <strong>Summer</strong> Undergraduate Research Program Assistant<br />
until July 27th, <strong>2012</strong>. She will be responsible for general <strong>in</strong>quiries, room book<strong>in</strong>gs, reception<br />
and student document pick-up and drop-<strong>of</strong>f.<br />
Please jo<strong>in</strong> us <strong>in</strong> extend<strong>in</strong>g a warm welcome to all new staff and faculty members at the<br />
<strong>IMS</strong>—we wish them a smooth transition <strong>in</strong> the months to come.<br />
We would also like to take this opportunity to thank Cassandra Wysochanskyj for do<strong>in</strong>g an<br />
excellent job as former Interim Departmental Assistant. We wish Cassandra a safe journey<br />
as she embarks on volunteer work <strong>in</strong> Eastern Europe.<br />
07 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
NEWS AT A GLANCE<br />
<strong>IMS</strong>SA ANNOUNCEMENTS<br />
The annual <strong>IMS</strong> Talent Show Fundraiser, Artists for Autism, will be held on Thursday, August 16th, 6-10pm (Debates Room, Hart<br />
House) featur<strong>in</strong>g emcee Ori Rotste<strong>in</strong>. Acts will <strong>in</strong>clude piano and guitar performances, danc<strong>in</strong>g, and more. Proceeds will be donated to<br />
Unity for Autism. $15 ticket <strong>in</strong>cludes admission, free pizza and dr<strong>in</strong>k. Please contact artistsforautism<strong>2012</strong>@gmail.com to reserve your<br />
ticket!<br />
Come out on Saturday, July 28th to Cherry Beach, downtown Toronto, to hang out with fellow <strong>IMS</strong> students for a Corn roast/BBQ<br />
beach day. There will be games, delicious food, great weather, and awesome people—mark your calendars! For further details, please<br />
contact richard.foty@gmail.com.<br />
A new academic year is around the corner, so please come out and jo<strong>in</strong> us at the <strong>2012</strong>-2013 <strong>IMS</strong>SA Executive Council Elections <strong>in</strong><br />
late September. We will be hold<strong>in</strong>g elections for all positions, and immediately afterwards, we will be host<strong>in</strong>g a FREE pub night for<br />
all <strong>IMS</strong> students! We strongly encourage registered <strong>IMS</strong> students <strong>of</strong> all years and degree programs to run for a position. If you have ideas<br />
for new <strong>in</strong>itiatives and events for your fellow students, this is your chance to carry them out and have a mean<strong>in</strong>gful impact on your<br />
student community! E-mail imssa@utoronto.ca for details.<br />
AWARDS & SCHOLARSHIPS<br />
NSERC AWARD RECIPIENTS<br />
Jeffrey Cheung, MSc student; Stephane Paquette, PhD student; Tetyana Pekar, MSc<br />
student<br />
<strong>2012</strong>/2013 CIHR Bant<strong>in</strong>g and Best Master’s Award Recipients<br />
Faizal Am<strong>in</strong>mohamed Haji<br />
<strong>2012</strong>/2013 ONTARIO GRADUATE SCHOLARSHIPS RECIPIENTS<br />
Kimberly Blom, Melanie Burger, Fernando Caravaggio, Jill Cates, Jeffery Cheung,<br />
Charles de Mestral, Joana Dida, Laura Feldcamp, Gagandeep Fervaha, Er<strong>in</strong> Gibson,<br />
Fervaha Haji, Marv<strong>in</strong> Hsiao, Stuart Jantzen, Salima Jiwani, David Kepecs, Ammar<br />
Khairullah, Alex Laliberte, Tristram Lett, Biao Li, Jonathan Lipszyc, Anton Mihic,<br />
Tetyana Pekar, Rachel Rab<strong>in</strong>, Natasha Radhu, S<strong>of</strong>ia Raits<strong>in</strong>, Meghna Rajaprakash,<br />
Grace Shen-Tu, Kev<strong>in</strong> Shield, Ivonne Suridjan, We<strong>in</strong><strong>in</strong>g Yang, Nima Zamiri, Boris Zev<strong>in</strong><br />
New Faculty Members<br />
Daniel Blumberger<br />
Associate Member,<br />
Centre for Addiction and Mental Health<br />
Sam Doesburg<br />
Associate Member,<br />
The Hospital for Sick Children<br />
David Fisman<br />
Member, University <strong>of</strong> Toronto,<br />
Dalla Lana School <strong>of</strong> Public Health<br />
Caitl<strong>in</strong> Gillan<br />
Associate Member (Non-Supervisor),<br />
ELLICSR, Toronto General Hospital<br />
Christian Hendershot<br />
Associate Member,<br />
Centre for Addiction and Mental Health<br />
Andrea Lev<strong>in</strong>son<br />
Associate Member,<br />
Centre for Addiction and Mental<br />
Health, Queen Street Site<br />
Daniela Lobo<br />
Associate Member,<br />
Centre for Addiction and Mental Health<br />
Jack Goodman<br />
Member, Faculty <strong>of</strong> K<strong>in</strong>esiology<br />
and Physical Education<br />
Rachel Wald<br />
Associate Member,<br />
Toronto General Hospital<br />
Tom Schweizer<br />
Member,<br />
St. Michael’s Hospital<br />
F<strong>in</strong>d out more about faculty on the <strong>IMS</strong> faculty<br />
database at http://www.ims.utoronto.<br />
ca/faculty/directory.htm.<br />
Welcome Dr. Liu, Dr. Morshead, and Dr. Venkateswaran!<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 08
SPOTLIGHT<br />
Translational research and <strong>in</strong>terdiscipl<strong>in</strong>ary graduate education that advances human health<br />
<strong>2012</strong> Undergraduate and International <strong>Summer</strong> Research Program<br />
RESEARCH DAY<br />
Wednesday, August 15, <strong>2012</strong>, 9:00 a.m. – 3:40 p.m.<br />
Medical Sciences Build<strong>in</strong>g, 1 K<strong>in</strong>g’s College Circle<br />
9:00 am<br />
9:05 am<br />
9:15 am<br />
10:00 am<br />
10:30 am<br />
12:00 pm<br />
1:00 pm<br />
3:30 pm<br />
3:40pm<br />
Welcome and Introduction – Macleod Auditorium, Room 2158<br />
Dr. Allan S. Kaplan, Director, <strong>Institute</strong> <strong>of</strong> Medical Science<br />
Introduction <strong>of</strong> Keynote Speaker<br />
Dr. Vasundara Venkateswaran, Director, <strong>IMS</strong> <strong>Summer</strong> Undergraduate Research<br />
Program<br />
Keynote Address: Dr. Freda Miller<br />
Pr<strong>of</strong>essor, Department <strong>of</strong> Molecular Genetics and Senior Scientist, Developmental &<br />
Stem Cell Biology, Sick Kids Hospital<br />
“Stem Cells: Build<strong>in</strong>g and Rebuild<strong>in</strong>g the Nervous System”<br />
C<strong>of</strong>fee Break – Macleod Auditorium Lobby, Room 2158<br />
Student Oral Presentations – Room 2158<br />
Lunch – Macleod Auditorium Lobby, Room 2158<br />
Poster Presentations – Stone Lobby, Room 2171 and Student Lounge (next to<br />
Starbucks)<br />
Conclud<strong>in</strong>g Remarks - Macleod Auditorium, Room 2158<br />
Dr. M<strong>in</strong>gyao Liu, Associate Director, <strong>Institute</strong> <strong>of</strong> Medical Science<br />
Award Presentations – Macleod Auditorium, Room 2158<br />
We thank the presenters <strong>of</strong> our <strong>2012</strong> Sem<strong>in</strong>ar Series<br />
Dr. Nick Wooldridge, Program Director, Associate Pr<strong>of</strong>essor<br />
Dr. Michael Szego, Fellow <strong>in</strong> Cl<strong>in</strong>ical and Organizational Ethics Jo<strong>in</strong>t Centre for<br />
Bioethics, University <strong>of</strong> Toronto<br />
Dr. Moloo Badru, Director, Animal Resources Centre, University Health Network<br />
Dr. Neil W<strong>in</strong>egarden, Head <strong>of</strong> Operations, Microarray Centre, University Health<br />
Network<br />
Dr. Katal<strong>in</strong> Szaszi, Scientist, Associate Pr<strong>of</strong>essor Department <strong>of</strong> Surgery, University<br />
<strong>of</strong> Toronto<br />
Dr.Xiao-Yan Wen, Assistant Pr<strong>of</strong>essor, Department <strong>of</strong> Medic<strong>in</strong>e, University <strong>of</strong><br />
Toronto<br />
Dr. Art Petronis, Pr<strong>of</strong>essor and Tapscott Chair, University <strong>of</strong> Toronto<br />
Dr. Uri Tabori, Scientist, Staff NeuroOncologist, Associate Pr<strong>of</strong>essor <strong>of</strong> Pediatrics,<br />
University <strong>of</strong> Toronto<br />
Dr. Moody, Radiologist-<strong>in</strong>-Chief Department <strong>of</strong> Medical Imag<strong>in</strong><strong>in</strong>g, Sunnybrook<br />
Health Science Centre<br />
We Thank Our Generous Benefactors<br />
UHN centre for research<br />
09 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
DIRECTOR’S MESSAGE<br />
Director’s<br />
Message<br />
The <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong> cont<strong>in</strong>ues to be the showcase publication <strong>of</strong> the <strong>Institute</strong> <strong>of</strong> Medical<br />
Science student body. It has received rave reviews locally and from those <strong>in</strong>ternationally<br />
who have seen it, <strong>in</strong>clud<strong>in</strong>g Dr. Thomas Insel, Director <strong>of</strong> the National <strong>Institute</strong> <strong>of</strong> Mental<br />
Health, who was <strong>in</strong>terviewed <strong>in</strong> the last issue <strong>of</strong> the magaz<strong>in</strong>e <strong>in</strong> anticipation <strong>of</strong> his Plenary Address<br />
at <strong>IMS</strong> Research Day on May 15. Congratulations and thanks to Natalie Venier and her staff for all<br />
their hard work, as well as to Kamila Lear for her ongo<strong>in</strong>g assistance with this project.<br />
This seventh issue <strong>of</strong> the magaz<strong>in</strong>e focuses on the important and related areas <strong>of</strong> genomic medic<strong>in</strong>e,<br />
epigenetics, and pharmacogenetics. These areas <strong>of</strong> research represent <strong>in</strong>novative work <strong>of</strong> our faculty<br />
that is very much <strong>in</strong> keep<strong>in</strong>g with the <strong>IMS</strong>’ strategic <strong>in</strong>itiative related to translational research.<br />
Recently, there have been a number <strong>of</strong> departmental leadership changes that I would like address.<br />
First, Dr. Karen Davis and Dr. Carol Westall have f<strong>in</strong>ished their terms <strong>of</strong> service as Associate<br />
Director and Graduate Coord<strong>in</strong>ator, respectively. We at the <strong>IMS</strong> owe a great deal <strong>of</strong> gratitude and<br />
thanks for their tireless efforts. As <strong>of</strong> July 1, Dr. M<strong>in</strong>gyao Liu will take over as the <strong>IMS</strong> Associate<br />
Director, and Dr. C<strong>in</strong>di Morshead will assume the role <strong>of</strong> Graduate Coord<strong>in</strong>ator.<br />
In the next few weeks, the <strong>IMS</strong> will also launch its first-ever Strategic Plan, which will guide us for the<br />
next five years. The Plan is entitled “From Cell to Society: Becom<strong>in</strong>g the Global Leader <strong>in</strong> Graduate<br />
Education to Improve Human Health through Translational Research.” As we move forward with<br />
the Plan, our new tagl<strong>in</strong>e underscores the five-year vision <strong>of</strong> the <strong>IMS</strong>: Translational research and<br />
<strong>in</strong>terdiscipl<strong>in</strong>ary graduate education that advances human health. Our plan has five themes that<br />
will support us <strong>in</strong> mak<strong>in</strong>g this vision as vibrant as possible: Uniqueness, Connectedness, Presence,<br />
Belong<strong>in</strong>g and Engagement. I look forward to work<strong>in</strong>g with our deeply committed faculty and<br />
students to br<strong>in</strong>g our vision to life.<br />
Best wishes for a restful and enjoyable summer.<br />
S<strong>in</strong>cerely,<br />
Allan S Kaplan, MSc, MD,<br />
FRCP(C)<br />
Director, <strong>IMS</strong><br />
Allan S. Kaplan, MSc, MD, FRCP(C),<br />
became the <strong>IMS</strong> Director <strong>in</strong> July 2011.<br />
He is currently the Chief <strong>of</strong> Cl<strong>in</strong>ical<br />
Research at the Centre for Addiction<br />
and Mental Health (CAMH), Vice Chair<br />
for Research <strong>in</strong> the Department <strong>of</strong><br />
Psychiatry, and Pr<strong>of</strong>essor <strong>of</strong> Psychiatry<br />
<strong>in</strong> the Faculty <strong>of</strong> Medic<strong>in</strong>e. He is also<br />
a Senior Scientist at both CAMH and<br />
the Toronto General Hospital Research<br />
<strong>Institute</strong>. He was the <strong>in</strong>augural holder<br />
<strong>of</strong> the Loretta Anne Rogers Chair <strong>in</strong><br />
Eat<strong>in</strong>g Disorders at the University<br />
Health Network from 2002 to 2010.<br />
Allan S Kaplan MD FRCP(C)<br />
Director, <strong>Institute</strong> <strong>of</strong> Medical Science<br />
Photo by Mohammed Sabri<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 10
<strong>IMS</strong> SCIENTIFIC DAY HIGHLIGHT<br />
<strong>IMS</strong> SCIENTIFIC DAY<br />
Compiled by<br />
Karrie Wong<br />
and Anna Podnos<br />
AWARD WINNERS<br />
Laidlaw Manuscript<br />
Competition<br />
Alan Wu Poster Competition &<br />
Academic Development Award<br />
Grand prize<br />
Cl<strong>in</strong>ical Science<br />
Christopher Tran<br />
Basic Science<br />
Brian Ballios<br />
Honourable mentions<br />
Cl<strong>in</strong>ical Science<br />
Ann Montgomery<br />
Basic Science<br />
Nabilah Chowdhury<br />
Marko Škrtić<br />
Nadia Sachewsky<br />
Grand prize<br />
Cl<strong>in</strong>ical Science<br />
Seham Chaker<br />
Honourable mentions<br />
Cl<strong>in</strong>ical Science<br />
Ann Montgomery<br />
Sean Barbour<br />
Leigh Christopher<br />
Sandeep Dhillon<br />
Raymond Chang<br />
Ayesha Malik<br />
Laura Park<br />
Tejas Sankar<br />
Grand prize<br />
Basic Science<br />
Amanda Ali<br />
Honourable mentions<br />
Basic Science<br />
Siba Haykal<br />
Ana Konval<strong>in</strong>ka<br />
Jeff Man<br />
Stephane Paquette<br />
Sally Yu Shi<br />
Vanessa Zannella<br />
Photos courtesy <strong>of</strong> the <strong>IMS</strong> Office.<br />
11 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
<strong>IMS</strong> SCIENTIFIC DAY HIGHLIGHT<br />
From the w<strong>in</strong>ners<br />
“Shar<strong>in</strong>g new ideas and scientific discourse<br />
is at the heart <strong>of</strong> <strong>IMS</strong> Scientific<br />
Day, and is a testament to the department’s<br />
cont<strong>in</strong>ued success at attract<strong>in</strong>g<br />
first-class <strong>in</strong>vestigators and tra<strong>in</strong>ees,<br />
who are work<strong>in</strong>g to transform the future<br />
<strong>of</strong> healthcare.”<br />
“I am so grateful to the <strong>IMS</strong> for<br />
almost every academic opportunity I<br />
have received <strong>in</strong> the last two years.<br />
As a graduate student here, I have<br />
been granted access to mentors,<br />
publications, and scholarships.”<br />
“It was an honour to be afforded the<br />
opportunity to present my research at<br />
<strong>IMS</strong> Scientific Day - an event which<br />
showcases the amaz<strong>in</strong>g breadth <strong>of</strong><br />
biomedical and cl<strong>in</strong>ical science research<br />
across the department. All <strong>of</strong><br />
the speakers highlighted their cutt<strong>in</strong>gedge<br />
research, while emphasiz<strong>in</strong>g the<br />
translational potential <strong>of</strong> their work.”<br />
“My time spent with the <strong>IMS</strong> so far<br />
has been challeng<strong>in</strong>g yet very enjoyable.<br />
I am always amazed at the<br />
high quality <strong>of</strong> research be<strong>in</strong>g done<br />
around me.”<br />
“I feel lucky to be a part <strong>of</strong> the <strong>IMS</strong>,<br />
which really fosters a wide range <strong>of</strong><br />
research. <strong>IMS</strong> Scientific Day really<br />
reflected this, [and] I was able to<br />
meet fellow students and see their<br />
work <strong>in</strong> topics completely different<br />
from my own.”<br />
“It has been very enlighten<strong>in</strong>g for me<br />
to <strong>in</strong>teract with so many fellow students<br />
who are do<strong>in</strong>g work <strong>in</strong> many<br />
diverse areas <strong>of</strong> biomedical research.<br />
The <strong>in</strong>terdiscipl<strong>in</strong>ary nature <strong>of</strong> these<br />
<strong>in</strong>teractions, as well as <strong>of</strong> the sem<strong>in</strong>ar<br />
series and courses <strong>of</strong>fered through<br />
the <strong>IMS</strong>, has helped me to th<strong>in</strong>k beyond<br />
the narrow questions around<br />
which my research is focused.”<br />
“Thank you <strong>IMS</strong> adm<strong>in</strong>istration,<br />
faculty, and students.”<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 12
FEATURE<br />
13 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
FEATURE<br />
Illustration by Melissa Cory<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 14
FEATURE<br />
Ethics and Challenges <strong>of</strong> Deliver<strong>in</strong>g<br />
Genomic Medic<strong>in</strong>e<br />
Michael Szego, PhD, MHSc<br />
Cl<strong>in</strong>ical Ethicist,<br />
Centre for Cl<strong>in</strong>ical Ethics (A jo<strong>in</strong>t venture <strong>of</strong><br />
Providence Healthcare, St. Joseph’s Health<br />
Centre, and St. Michael’s Hospital),<br />
The University <strong>of</strong> Toronto Jo<strong>in</strong>t Centre for<br />
Bioethics<br />
Research Ethics Consultant,<br />
The Centre for Applied Genomics,<br />
The Hospital for Sick Children,<br />
The University <strong>of</strong> Toronto McLaughl<strong>in</strong> Centre<br />
for Molecular Medic<strong>in</strong>e<br />
In 2000, one <strong>of</strong> the most significant<br />
milestones <strong>in</strong> genomics was achieved:<br />
the first draft <strong>of</strong> the human genome<br />
was completed 1 . The genomic sequence was<br />
based on DNA samples pooled from several<br />
<strong>in</strong>dividuals and it established a reference genome<br />
for future sequenc<strong>in</strong>g projects. At the<br />
press conference announc<strong>in</strong>g this achievement,<br />
Bill Cl<strong>in</strong>ton proclaimed that the completed<br />
genome sequence would “revolutionize<br />
the diagnosis, prevention and treatment<br />
<strong>of</strong> most, if not all, human disease” 2 . Francis<br />
Coll<strong>in</strong>s, who led the effort to complete the<br />
human genome project, may have been try<strong>in</strong>g<br />
to manage expectations when he suggested<br />
that a complete trans<strong>format</strong>ion <strong>of</strong> therapeutic<br />
medic<strong>in</strong>e would take up to 15 to 20<br />
years 2 . One <strong>of</strong> the biggest hurdles that needed<br />
to be overcome before Cl<strong>in</strong>ton’s claims could<br />
be realized was the ability to sequence <strong>in</strong>dividual<br />
genomes. This feat required technological<br />
advances <strong>in</strong> sequenc<strong>in</strong>g and a drastic<br />
reduction <strong>in</strong> sequenc<strong>in</strong>g costs.<br />
S<strong>in</strong>ce 2000, whole genome sequenc<strong>in</strong>g<br />
(WGS) <strong>of</strong> <strong>in</strong>dividual genomes has been developed,<br />
enabl<strong>in</strong>g the identification <strong>of</strong> new<br />
gene variants associated with disease that<br />
can subsequently be used for genetic test<strong>in</strong>g<br />
<strong>in</strong> the cl<strong>in</strong>ical context 3 . The WGS is still<br />
cost prohibitive with its use and is limited to<br />
select research projects; however, its cost is<br />
decreas<strong>in</strong>g rapidly and will soon be cheaper<br />
than currently employed genetic tests that assess<br />
one gene at a time. The development <strong>of</strong><br />
affordable WGS may be the catalyst for the<br />
trans<strong>format</strong>ion that Dr. Coll<strong>in</strong>s predicted<br />
and the “revolution” that Cl<strong>in</strong>ton anticipated.<br />
S<strong>in</strong>ce WGS has the potential to unlock every<br />
person’s unique disease risk pr<strong>of</strong>ile 4 , it may<br />
be one <strong>of</strong> the most significant technological<br />
breakthroughs <strong>in</strong> history. Therefore, WGS<br />
deserves special consideration from an ethics<br />
perspective. In this short article, I will<br />
focus on two key ethical topics with respect<br />
to WGS that are found <strong>in</strong> both research and<br />
cl<strong>in</strong>ical sett<strong>in</strong>gs, that is (1) <strong>in</strong>formed consent<br />
and, (2) return <strong>of</strong> results.<br />
Informed consent<br />
The pr<strong>in</strong>ciple <strong>of</strong> <strong>in</strong>formed consent is recognized<br />
as a ma<strong>in</strong> pillar <strong>in</strong> the practice <strong>of</strong> ethical<br />
research and medic<strong>in</strong>e. For consent to be<br />
<strong>in</strong>formed with<strong>in</strong> the general research context,<br />
the research subject must be <strong>in</strong>formed<br />
<strong>of</strong> the purpose for the research, its potential<br />
applications, the methods that will be<br />
employed, and any anticipated benefits and<br />
risks 5,6 . However, many <strong>of</strong> these criteria are<br />
unrealistic when applied to genomic research<br />
specifically. At the time a DNA sample is<br />
taken from the research subject, all possible<br />
future research, its applications, and methods<br />
are usually not known. One ma<strong>in</strong> risk/benefit<br />
associated with most genomic research<br />
projects is the potential identification <strong>of</strong> <strong>in</strong>cidental<br />
f<strong>in</strong>d<strong>in</strong>gs. For <strong>in</strong>stance, the disclosure<br />
<strong>of</strong> a pathogenic variant that is cl<strong>in</strong>ically actionable<br />
which is identified over the course <strong>of</strong><br />
research is an example <strong>of</strong> a potential benefit,<br />
while possible genetic discrim<strong>in</strong>ation is an<br />
example <strong>of</strong> a potential risk. However, the actual<br />
risks and benefits are not known beforehand<br />
because they depend on the research<br />
subject’s genomic sequence and the scientific<br />
knowledge at the time the analysis.<br />
In order for genomic research to be performed,<br />
the traditional <strong>in</strong>formed consent<br />
process has been modified to <strong>in</strong>clude broad<br />
consent. In the broad consent model, participants<br />
consent to a range <strong>of</strong> possible research<br />
activities 7 . Under this paradigm, research<br />
subjects are educated about genomic research<br />
to ensure they understand the general<br />
risks and benefits. Consequently, they can<br />
make the most <strong>in</strong>formed decision possible,<br />
even though the actual risks may not be completely<br />
known.<br />
Informed consent is a different process with<strong>in</strong><br />
cl<strong>in</strong>ical medic<strong>in</strong>e as compared to research.<br />
In the cl<strong>in</strong>ical genetic test<strong>in</strong>g context, patients<br />
must be told the nature <strong>of</strong> the diagnostic<br />
test, the expected risks and benefits <strong>of</strong> the<br />
test, and any alternative tests for consent to<br />
be <strong>in</strong>formed. When WGS is used as a cl<strong>in</strong>ical<br />
genetic test, the nature <strong>of</strong> the diagnostic test<br />
and any alternative tests are known and can<br />
be described to the patient. Current standards<br />
<strong>of</strong> care for cl<strong>in</strong>ical genetic test<strong>in</strong>g <strong>in</strong>clude patient<br />
counsel<strong>in</strong>g about the risks and benefits<br />
and potential outcomes <strong>of</strong> the proposed genetic<br />
test. However, current genetic tests can<br />
exam<strong>in</strong>e one or a handful <strong>of</strong> genes, mak<strong>in</strong>g<br />
counsel<strong>in</strong>g more straightforward than coun-<br />
Photo by Yekta Dowlati<br />
15 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
FEATURE<br />
sel<strong>in</strong>g on a WGS test, which exam<strong>in</strong>es over<br />
20,000 genes and many <strong>of</strong> which have known<br />
pathogenic variants. That said, counsel<strong>in</strong>g is<br />
critically important with<strong>in</strong> the WGS context;<br />
however, the <strong>in</strong><strong>format</strong>ion needs to be more<br />
general <strong>in</strong> nature, analogous to the research<br />
sett<strong>in</strong>g. Healthcare providers need to educate<br />
patients about genomic test<strong>in</strong>g us<strong>in</strong>g theory<br />
and case-based examples, identify any likely<br />
cl<strong>in</strong>ical implications <strong>of</strong> WGS, and discuss<br />
the general risks and benefits <strong>of</strong> undergo<strong>in</strong>g<br />
WGS <strong>in</strong> order for patients to make an<br />
<strong>in</strong>formed decision as to whether they want<br />
their genome sequenced.<br />
Return <strong>of</strong> results<br />
Whether researchers have a duty to return<br />
<strong>in</strong>dividual research results <strong>in</strong> genetic studies<br />
has been the subject <strong>of</strong> much debate. Should<br />
research be purely for research sake? This debate<br />
is especially important with<strong>in</strong> the WGS<br />
context s<strong>in</strong>ce the likelihood <strong>of</strong> identify<strong>in</strong>g<br />
pathogenic variants is high. Fortunately, a<br />
consensus is emerg<strong>in</strong>g. The World Health<br />
Organization has identified three conditions<br />
to be met before disclosure should occur: (1)<br />
the data should be cl<strong>in</strong>ically beneficial; (2)<br />
disclosure should avert or m<strong>in</strong>imize significant<br />
harm; and (3) there is no <strong>in</strong>dication that<br />
the <strong>in</strong>dividual <strong>in</strong> question would prefer not<br />
to know 8 . Consistent with this approach, Canadian<br />
research ethics guidel<strong>in</strong>es outl<strong>in</strong>e an<br />
obligation to disclose any material <strong>in</strong>cidental<br />
f<strong>in</strong>d<strong>in</strong>gs or unanticipated discoveries made<br />
dur<strong>in</strong>g the course <strong>of</strong> research that are <strong>in</strong>terpreted<br />
as hav<strong>in</strong>g a significant welfare implication<br />
for the participant 9 .<br />
Different strategies have been suggested to<br />
manage the return <strong>of</strong> cl<strong>in</strong>ically relevant research<br />
results <strong>in</strong> the WGS context. One approach<br />
would categorize human genes accord<strong>in</strong>g<br />
to cl<strong>in</strong>ical parameters10. In such a<br />
scheme, all gene mutations that are medically<br />
actionable are labeled as “B<strong>in</strong> 1” genes<br />
and would trigger an automatic return <strong>of</strong> the<br />
result. “B<strong>in</strong> 2” genes are def<strong>in</strong>ed as gene mutations<br />
associated with human disease that<br />
could not be acted upon medically. F<strong>in</strong>ally,<br />
“B<strong>in</strong> 3” conta<strong>in</strong>s all other genes whose association<br />
with human disease is unknown. It has<br />
been estimated that there are currently only<br />
100 “B<strong>in</strong> 1” genes <strong>in</strong> the human genome 10 .<br />
The Cl<strong>in</strong>Seq project at the National <strong>Institute</strong>s<br />
<strong>of</strong> Health (NIH) has taken a different<br />
approach that is more research-subject-centered<br />
and engages research subjects to determ<strong>in</strong>e<br />
the type and extent <strong>of</strong> <strong>in</strong><strong>format</strong>ion<br />
they would f<strong>in</strong>d useful 11 . In the NIH project,<br />
all pathogenic variants can be returned to research<br />
subjects, provided consent is obta<strong>in</strong>ed<br />
for disclosure. Additionally, they have set up<br />
an <strong>in</strong>dependent panel to periodically review<br />
any new evidence l<strong>in</strong>k<strong>in</strong>g variants to human<br />
disease and to determ<strong>in</strong>e if the evidence is<br />
sufficient to warrant disclosure.<br />
With all the effort spent on identify<strong>in</strong>g variants<br />
associated with human disease, new<br />
cl<strong>in</strong>ically relevant variants will no doubt be<br />
identified <strong>in</strong> the future. This reality necessitates<br />
a long-term plan to deal with stored<br />
sequences. Researchers return<strong>in</strong>g <strong>in</strong>dividual<br />
research results could implement s<strong>of</strong>tware<br />
that can reanalyze past genomes and flag new<br />
cl<strong>in</strong>ically relevant data. Alternatively, if such<br />
a measure was not possible, research subjects<br />
should be <strong>in</strong>formed dur<strong>in</strong>g the <strong>in</strong>formed<br />
consent process that reanalysis will not occur<br />
and that any results returned would only reflect<br />
current knowledge.<br />
It is generally understood that test results are<br />
returned to patients, however, it is unclear<br />
what should be returned to patients when<br />
WGS is used as a genetic test. While any results<br />
that <strong>in</strong>form the orig<strong>in</strong>al differential diagnosis<br />
seem appropriate to disclose, many<br />
other variants <strong>of</strong> known and unknown significance<br />
may also be detected that have noth<strong>in</strong>g<br />
to do with the orig<strong>in</strong>al query. A “b<strong>in</strong>n<strong>in</strong>g”<br />
mechanism or a patient-guided approach<br />
may be borrowed from the research context<br />
described above. Lastly, the issue <strong>of</strong> cl<strong>in</strong>ical<br />
reanalysis was addressed <strong>in</strong> a recent article<br />
by the head <strong>of</strong> the NIH cl<strong>in</strong>ical sequenc<strong>in</strong>g<br />
project mentioned previously, Leslie Biesecker<br />
describes WGS as a resource not a genetic<br />
test 12 . As such, a WGS dataset can be “<strong>in</strong>terrogated<br />
by the patient and cl<strong>in</strong>ician <strong>in</strong> situations<br />
where it could be <strong>of</strong> potential use to<br />
the patient, when both agree to this use” 12 .<br />
This type <strong>of</strong> <strong>in</strong>tegration would also solve the<br />
issue <strong>of</strong> reanalysis. If treated as a one <strong>of</strong>f test,<br />
the physician who ordered it would not have<br />
a legal or ethical obligation to periodically<br />
reanalyze each <strong>of</strong> her patient’s genome for<br />
any new medical <strong>in</strong><strong>format</strong>ion. If comprehensively<br />
<strong>in</strong>tegrated <strong>in</strong>to primary care, a patient’s<br />
whole genome could be part <strong>of</strong> the trans<strong>format</strong>ion<br />
<strong>of</strong> healthcare Francis Coll<strong>in</strong>s and Bill<br />
Cl<strong>in</strong>ton predicted over a decade ago.<br />
Conclud<strong>in</strong>g remarks<br />
While it is still unclear exactly how <strong>in</strong>formed<br />
consent and return <strong>of</strong> results are go<strong>in</strong>g to<br />
look <strong>in</strong> the future context <strong>of</strong> WGS, many <strong>of</strong><br />
the research projects employ<strong>in</strong>g WGS have<br />
an <strong>in</strong>tegrated ethics component, which <strong>in</strong>cludes<br />
research subject engagement. As<br />
such, I am confident we will establish ethical<br />
best practices when it comes to WGS <strong>in</strong><br />
cl<strong>in</strong>ical and research sett<strong>in</strong>gs. Furthermore,<br />
as WGS is exploited cl<strong>in</strong>ically, opportunities<br />
and challenges will be created for researchers<br />
and cl<strong>in</strong>icians. Cl<strong>in</strong>ical WGS datasets could<br />
provide a rich source <strong>of</strong> data for researchers,<br />
provided that appropriate <strong>in</strong>formed consent<br />
and privacy safeguards are put <strong>in</strong> place. This<br />
environment would represent a paradigm<br />
shift <strong>in</strong> which cl<strong>in</strong>ical medic<strong>in</strong>e and research<br />
could occur us<strong>in</strong>g the same platform, facilitat<strong>in</strong>g<br />
knowledge exchange.<br />
References<br />
1. Lander ES, et al. Initial sequenc<strong>in</strong>g and analysis <strong>of</strong> the<br />
human genome. Nature. 2001; 409(6822): 860-921.<br />
2. Wade NA. Decade Later, Genetic Map Yields Few New<br />
Cures, <strong>in</strong> New York TImes.2010: New York.<br />
3. Tucker TM, et al. Massively parallel sequenc<strong>in</strong>g: the<br />
next big th<strong>in</strong>g <strong>in</strong> genetic medic<strong>in</strong>e. Am J Hum Genet.<br />
2009; 85(2): 142-54.<br />
4. Tabor HK et al. Genomics really gets personal: how<br />
exome and whole genome sequenc<strong>in</strong>g challenge the ethical<br />
framework <strong>of</strong> human genetics research. Am J Med<br />
Genet A. 2011; 155A(12): 2916-24.<br />
5. Human T.-C.P.S.E.C.f.R.I. 1998 Aril 9, 2009]; Available<br />
from: http://pre.ethics.gc.ca/eng/<strong>in</strong>dex/.<br />
6. Beauchamp TL and Childress JF. Pr<strong>in</strong>ciples <strong>of</strong> biomedical<br />
ethics. 6th ed. 2009, New York: Oxford University<br />
Press. xiii, 417.<br />
7. S<strong>in</strong>ger PA and Viens AM. The Cambridge textbook<br />
<strong>of</strong> bioethics. 2008, Cambridge ; New York: Cambridge<br />
University Press. xvi, 538 p.<br />
8. Organization, W.H. Genetic databases: assess<strong>in</strong>g the<br />
benefits and impact on human and patient rights. 2003<br />
[cited 2009 December 15]; Available from: http://www.<br />
law.ed.ac.uk/ahrb/publications/onl<strong>in</strong>e/wh<strong>of</strong><strong>in</strong>alreport.<br />
doc.<br />
9. Canadian <strong>Institute</strong>s <strong>of</strong> Health Research, N.S.a.E.R.C<br />
.o.C.a.S.S.a.H.R.C.o.C., Tri-Council Policy Statement:<br />
Ethical Consult for Research Involv<strong>in</strong>g Humans, 2010.<br />
10. Evans JP and Rothschild BB. Return <strong>of</strong> results: not<br />
that complicated? Genet Med. <strong>2012</strong>; 14(4): 358-60.<br />
11. Biesecker LG et al. The Cl<strong>in</strong>Seq Project: pilot<strong>in</strong>g<br />
large-scale genome sequenc<strong>in</strong>g for research <strong>in</strong> genomic<br />
medic<strong>in</strong>e. Genome Res. 2009; 19(9): 1665-74.<br />
12. Biesecker LG. Opportunities and challenges for the<br />
<strong>in</strong>tegration <strong>of</strong> massively parallel genomic sequenc<strong>in</strong>g<br />
<strong>in</strong>to cl<strong>in</strong>ical practice: lessons from the Cl<strong>in</strong>Seq project.<br />
Genet Med. <strong>2012</strong>; 14(4): 393-8.<br />
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FEATURE<br />
Psychiatric Pharmacogenetics<br />
Maximiz<strong>in</strong>g Benefits While M<strong>in</strong>imiz<strong>in</strong>g Side Effects<br />
By Zeynep Yilmaz, PhD candidate<br />
liz<strong>in</strong>g medications, essentially co<strong>in</strong><strong>in</strong>g the<br />
term “pharmacogenetics.” Pr<strong>of</strong>. Kalow and<br />
I tra<strong>in</strong>ed students <strong>in</strong> my laboratory, and before<br />
he passed away, he saw the fruits <strong>of</strong> these<br />
labours with the delivery <strong>of</strong> genetic tests for<br />
characteriz<strong>in</strong>g drug metabolism. Another<br />
Toronto researcher, Dr. Victor L<strong>in</strong>g, discovered<br />
the role <strong>of</strong> drug transporter prote<strong>in</strong>s,<br />
for which there are now DNA-based tests to<br />
determ<strong>in</strong>e their variation across <strong>in</strong>dividuals.<br />
Given this powerful history <strong>in</strong> pharmacogenetics<br />
at the University <strong>of</strong> Toronto, I was<br />
<strong>in</strong>spired to carry the science forward us<strong>in</strong>g<br />
the developments <strong>in</strong> the human genome and<br />
genetic test<strong>in</strong>g technology.<br />
James L. Kennedy, MD, MSc, FRCP(C)<br />
Dr. James L. Kennedy is the Director<br />
<strong>of</strong> the Neuroscience Research<br />
Department at the Centre for Addiction<br />
and Mental Health and the Co-Director<br />
<strong>of</strong> the Bra<strong>in</strong> and Therapeutics Division <strong>in</strong><br />
the Department <strong>of</strong> Psychiatry, University <strong>of</strong><br />
Toronto. Dr. Kennedy has an extensive, and<br />
unique comb<strong>in</strong>ation <strong>of</strong> tra<strong>in</strong><strong>in</strong>g <strong>in</strong> psychiatry,<br />
genetics, and neuroscience. As a pr<strong>of</strong>essor<br />
and full-member <strong>of</strong> <strong>IMS</strong>, he has supervised<br />
well over a hundred tra<strong>in</strong>ees, <strong>in</strong>clud<strong>in</strong>g<br />
undergraduate and graduate students, postdoctoral<br />
fellows, and visit<strong>in</strong>g scientists.<br />
What is pharmacogenetics, and why is it<br />
important to study?<br />
Pharmacogenetics is the science <strong>of</strong> l<strong>in</strong>k<strong>in</strong>g a<br />
person’s DNA sequence with their response<br />
to medication. Because DNA provides its<br />
own unique bluepr<strong>in</strong>t <strong>of</strong> the body, we can<br />
make specific predictions as to the right drug<br />
and its correct dosage for a particular patient.<br />
We hope to prevent patients from cont<strong>in</strong>u<strong>in</strong>g<br />
for weeks on <strong>in</strong>effective medication and<br />
then hav<strong>in</strong>g to switch to another medication,<br />
go<strong>in</strong>g through the entire disappo<strong>in</strong>t<strong>in</strong>g sequence<br />
<strong>of</strong> non-response. We need to move<br />
beyond trial-and-error prescription <strong>of</strong> medications.<br />
With pharmacogenetics, we can help<br />
predict which patients will not respond to a<br />
particular medication, and also predict the<br />
best choice <strong>of</strong> medication on the basis <strong>of</strong><br />
their genotype and psychiatric condition.<br />
How did you become <strong>in</strong>terested <strong>in</strong> pharmacogenetics?<br />
I became <strong>in</strong>terested <strong>in</strong> pharmacogenetics<br />
when I witnessed many patients suffer while<br />
receiv<strong>in</strong>g the standard textbook dose <strong>of</strong> an<br />
antidepressant or antipsychotic medication. I<br />
saw the answer was <strong>in</strong> the power <strong>of</strong> new DNA<br />
technology for test<strong>in</strong>g patients to determ<strong>in</strong>e<br />
their comb<strong>in</strong>ation <strong>of</strong> genetic variants and<br />
whether a given patient metabolized the<br />
medication quickly or slowly. I had also read<br />
sem<strong>in</strong>al papers by Pr<strong>of</strong>. Werner Kalow from<br />
his work here at the University <strong>of</strong> Toronto <strong>in</strong><br />
the late-1950s and 1960s. He was the first to<br />
po<strong>in</strong>t out that people were genetically predisposed<br />
to hav<strong>in</strong>g different rates for metabo-<br />
What are some <strong>of</strong> the cl<strong>in</strong>ical applications<br />
<strong>of</strong> pharmacogenetics <strong>in</strong> psychiatry?<br />
We have a number <strong>of</strong> patented genetic discoveries<br />
mak<strong>in</strong>g their way <strong>in</strong>to the cl<strong>in</strong>ic, <strong>in</strong>clud<strong>in</strong>g<br />
a test us<strong>in</strong>g dopam<strong>in</strong>e system genes<br />
to predict risk for tardive dysk<strong>in</strong>esia (uncontrolled<br />
muscle movements) as a result <strong>of</strong><br />
prolonged use <strong>of</strong> antipsychotic medications.<br />
We also have a genetic test that identifies depressed<br />
patients who are at risk for develop<strong>in</strong>g<br />
mania as a result <strong>of</strong> their antidepressant<br />
treatment. We have just published an important<br />
paper show<strong>in</strong>g the role <strong>of</strong> the melanocort<strong>in</strong><br />
4 receptor (MC4R) gene <strong>in</strong> determ<strong>in</strong><strong>in</strong>g<br />
the risk for antipsychotic-<strong>in</strong>duced weight<br />
ga<strong>in</strong>. The newer antipsychotic medications<br />
have the side effect <strong>of</strong> substantial weight ga<strong>in</strong>;<br />
some patients will ga<strong>in</strong> more than 100 lb dur<strong>in</strong>g<br />
one year <strong>of</strong> treatment and <strong>of</strong>ten go on to<br />
develop diabetes and heart disease. After the<br />
<strong>in</strong>itial f<strong>in</strong>d<strong>in</strong>g <strong>of</strong> this gene’s effect <strong>in</strong> the first<br />
sample, we replicated the exact same result <strong>in</strong><br />
three <strong>in</strong>dependent samples.<br />
It is now possible for the physician to see<br />
a patient <strong>in</strong> the morn<strong>in</strong>g, for the patient to<br />
have a quick sampl<strong>in</strong>g <strong>of</strong> their saliva us<strong>in</strong>g a<br />
swab, and this sample to be shipped <strong>of</strong>f to a<br />
specialized lab where the genotyp<strong>in</strong>g <strong>of</strong> the<br />
relevant genetic variants for common medications<br />
can be done overnight. The results<br />
are emailed to the physician the next day, and<br />
the physician writes a prescription on the ba<br />
Photos by Yekta Dowlati.<br />
17 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
FEATURE<br />
sis <strong>of</strong> the patient’s genetic pr<strong>of</strong>ile. There is little<br />
delay <strong>in</strong> start<strong>in</strong>g treatment, and the choice<br />
<strong>of</strong> medication is precise and targeted to avoid<br />
side effects and achieve the best response.<br />
On which psychiatric disorders are you<br />
conduct<strong>in</strong>g pharmacogenetic studies?<br />
I expect that pharmacogenetic <strong>in</strong><strong>format</strong>ion<br />
will apply to virtually every psychiatric<br />
disorder. Over the 20 years that I have<br />
been do<strong>in</strong>g research here at CAMH/U<strong>of</strong>T,<br />
I have overseen the collection <strong>of</strong> more than<br />
24,000 DNA samples for disorders <strong>in</strong>clud<strong>in</strong>g<br />
schizophrenia, bipolar disorder, obsessive<br />
compulsive disorder, attention-deficit/hyperactivity<br />
disorder, addictions, eat<strong>in</strong>g disorders,<br />
suicidality <strong>in</strong> teenagers treated with<br />
antidepressants, as well as severe depression<br />
<strong>in</strong> young children. Unfortunately, not all <strong>of</strong><br />
these patients have been characterized <strong>in</strong><br />
terms <strong>of</strong> medication response. These studies<br />
are difficult because they require a patient to<br />
be followed over an extended period <strong>of</strong> time.<br />
Nonetheless, we have several thousand DNA<br />
samples from psychiatric patients with drug<br />
response and side effect <strong>in</strong><strong>format</strong>ion – one <strong>of</strong><br />
the largest collections <strong>in</strong> the world.<br />
How do you predict the future <strong>of</strong> pharmacogenetics?<br />
As we move <strong>in</strong>to the future, I see many benefits<br />
aris<strong>in</strong>g from pharmacogenetic test<strong>in</strong>g<br />
<strong>in</strong> the population. It is easy to imag<strong>in</strong>e the<br />
substantial healthcare sav<strong>in</strong>gs when we can<br />
prevent non-response or debilitat<strong>in</strong>g side effects<br />
from medication treatment. If patients<br />
are prescribed the right drug from the start,<br />
they should have fewer doctor visits and stay<br />
compliant with their medication. Currently,<br />
under our large pharmacogenetic <strong>in</strong>itiative<br />
funded by the M<strong>in</strong>istry <strong>of</strong> Economic<br />
Development and Innovation to test 20,000<br />
patients, Ontario stands to be the leader, as<br />
the largest s<strong>in</strong>gle geographic region <strong>of</strong>fer<strong>in</strong>g<br />
pharmacogenetic test<strong>in</strong>g <strong>in</strong> the world. Personalized<br />
medic<strong>in</strong>e with pharmacogenetics<br />
is estimated to save Ontario at least $88<br />
million <strong>in</strong> health care costs over the next 5<br />
years. Pharmacogenetics is a very excit<strong>in</strong>g<br />
area benefit<strong>in</strong>g from rapid <strong>in</strong>creases <strong>in</strong> DNAbased<br />
<strong>in</strong><strong>format</strong>ion, and computer-based algorithms<br />
comb<strong>in</strong><strong>in</strong>g <strong>in</strong><strong>format</strong>ion from multiple<br />
gene variants together to create more<br />
powerful methods to def<strong>in</strong>e an <strong>in</strong>dividual’s<br />
tailor-made treatment.<br />
One <strong>of</strong> our recent projects is an <strong>in</strong>novative<br />
treatment for anorexia nervosa. We believe<br />
that one <strong>of</strong> the medications that has a calm<strong>in</strong>g<br />
effect <strong>in</strong> schizophrenia patients, but causes<br />
weight ga<strong>in</strong>, may be helpful <strong>in</strong> anorexia nervosa<br />
by reduc<strong>in</strong>g anxiety associated with eat<strong>in</strong>g.<br />
It will be <strong>in</strong>terest<strong>in</strong>g to see if MC4R gene<br />
variation can predict those <strong>in</strong>dividuals that,<br />
<strong>in</strong> this case, ga<strong>in</strong> weight <strong>in</strong> a helpful way. The<br />
fact that MC4R is expressed <strong>in</strong> the appetite<br />
centre <strong>of</strong> the bra<strong>in</strong> may help demonstrate its<br />
value <strong>in</strong> predict<strong>in</strong>g the patients that would<br />
get the most benefit from this medication.<br />
Pick Your Bra<strong>in</strong>...<br />
A column by Aaron Kucyi<br />
Illustration by Andreea Marg<strong>in</strong>eanu.<br />
The human bra<strong>in</strong> is the most complicated feature<br />
<strong>of</strong> the human body, and it presents many unique<br />
challenges to genomics research. The best, and<br />
perhaps only, effective approach to understand<strong>in</strong>g<br />
the genetics <strong>of</strong> bra<strong>in</strong> structure is to comb<strong>in</strong>e data<br />
from multiple research sites to conduct studies<br />
with very large and diverse population samples.<br />
In the largest MRI study <strong>of</strong> the bra<strong>in</strong> to date, researchers<br />
from several sites around the world<br />
reported new l<strong>in</strong>ks between specific gene variants<br />
and total bra<strong>in</strong> volume, <strong>in</strong>tracranial volume,<br />
and hippocampal volume. The study was<br />
possible because <strong>in</strong>vestigators <strong>in</strong> North America,<br />
Europe, and Australia comb<strong>in</strong>ed bra<strong>in</strong> imag<strong>in</strong>g and<br />
genetics data from over 21,000 human subjects <strong>in</strong> a<br />
“crowdsourc<strong>in</strong>g” project. Some f<strong>in</strong>d<strong>in</strong>gs—such as<br />
that <strong>of</strong> a strong l<strong>in</strong>k between hippocampal volume<br />
and the rs7294919 variant—were not <strong>in</strong> agreement<br />
with previous smaller studies. Because hippocampal<br />
and other bra<strong>in</strong> volume measures have relevance to<br />
neuropsychiatric disorders, <strong>in</strong>clud<strong>in</strong>g Alzheimer’s disease,<br />
schizophrenia, and depression, the new f<strong>in</strong>d<strong>in</strong>gs<br />
may lead to personalized genomic approaches<br />
to therapy.<br />
The study highlights the usefulness <strong>of</strong>, and need<br />
for, further large-scale mult<strong>in</strong>ational collaborations<br />
<strong>in</strong> the field <strong>of</strong> bra<strong>in</strong> imag<strong>in</strong>g genetics. The<br />
200+ authors <strong>of</strong> the study caution that their work is<br />
just a prelim<strong>in</strong>ary step and that the f<strong>in</strong>d<strong>in</strong>gs need<br />
to be confirmed and extended before this type <strong>of</strong><br />
work can lead to targeted treatments for neuropsychiatric<br />
disorders.<br />
Reference:<br />
Ste<strong>in</strong> et al. Identification <strong>of</strong> common variants associated with human<br />
hippocampal and <strong>in</strong>tracranial volumes. Nat Genet. <strong>2012</strong>;44(5):552-561.<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 18
FEATURE<br />
Spit for Science:<br />
A Population-based Genetic Study <strong>of</strong> Childhood Attention Deficit Hyperactivity Disorder<br />
and Obsessive Compulsive Disorder<br />
By Laura Seohyun Park<br />
Would you like to spit for science?”<br />
“SPIT! Why would I do THAT?” shouted the<br />
10-year-old boy with both excitement and<br />
disgust. As I expla<strong>in</strong>ed to him that his spit<br />
could contribute to science and help other<br />
people, the boy was quick to agree to participate.<br />
Our setup at the Ontario Science Centre<br />
(OSC) looked like an arcade with computers,<br />
game controllers, and toy prizes--but actually,<br />
it was the scene <strong>of</strong> cutt<strong>in</strong>g-edge research.<br />
I had the pleasure <strong>of</strong> be<strong>in</strong>g a part <strong>of</strong> the<br />
Thoughts, Actions and Genes project (TAG),<br />
a ground-break<strong>in</strong>g study explor<strong>in</strong>g the genetic<br />
basis <strong>of</strong> attention-deficit hyperactivity<br />
disorder (ADHD) 1,2 and obsessive-compulsive<br />
disorder (OCD) 3,4,5 . Led by Dr. Russell<br />
Schachar, Dr. Jennifer Crosbie and Dr. Paul<br />
Arnold from the Department <strong>of</strong> Psychiatry<br />
at the Hospital for Sick Children, and <strong>in</strong> partnership<br />
with the OSC, over 17,000 children<br />
and adolescents (7-17 years <strong>of</strong> age) participated<br />
<strong>in</strong> TAG. Each participant completed a<br />
behavioural questionnaire, a cognitive task<br />
called the Stop Signal Task (SST), and donated<br />
a saliva sample. In a recent <strong>in</strong>terview<br />
with the <strong>in</strong>vestigators beh<strong>in</strong>d TAG, the <strong>IMS</strong><br />
<strong>Magaz<strong>in</strong>e</strong> learned about the project’s novel<br />
and creative approach to study complex psychiatric<br />
disorders.<br />
Q What led you to conduct a research project<br />
like TAG?<br />
Schachar: Psychiatric conditions are highly<br />
<strong>in</strong>fluenced by genetic risk factors as seen<br />
<strong>in</strong> tw<strong>in</strong> and family studies <strong>of</strong> affected <strong>in</strong>dividuals.<br />
Thus far, candidate gene studies and<br />
genome-wide association studies (GWAS)<br />
have generated suggestive f<strong>in</strong>d<strong>in</strong>gs but either<br />
with difficulty to replicate, or noth<strong>in</strong>g that is<br />
‘significant genome-wide’, respectively. While<br />
global collaboration among scientists is a<br />
TAG photos courtesy <strong>of</strong> Laura S. Park<br />
19 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
FEATURE<br />
necessary strategy for collect<strong>in</strong>g sufficiently<br />
large psychiatric patient samples for genetic<br />
analysis, they can <strong>in</strong>troduce new problems<br />
such as the imprecision <strong>in</strong> measur<strong>in</strong>g psychiatric<br />
“phenotypes”. It is not clear that ADHD<br />
or any other psychiatric disorder is assessed<br />
and diagnosed <strong>in</strong> exactly the same way <strong>in</strong><br />
Brazil as it is <strong>in</strong> the Netherlands. Moreover,<br />
global studies collect DNA from very divergent<br />
ethnic groups. It is entirely possible<br />
that the genetic risks for a common disease<br />
may not be identical <strong>in</strong> every ethnic group.<br />
Based on these limitations, it was clear to us<br />
that novel methods were needed to break this<br />
impasse.<br />
Crosbie: Endophenotypes 6 , which are objective,<br />
quantitative, and heritable “<strong>in</strong>termediate<br />
phenotypes” or “biological markers”,<br />
provide <strong>in</strong>creased power to genetic studies<br />
by po<strong>in</strong>t<strong>in</strong>g to a more homogeneous genetic<br />
group <strong>of</strong> <strong>in</strong>dividuals and measur<strong>in</strong>g a process<br />
that is closer to the underly<strong>in</strong>g genetic<br />
mechanism. There is evidence that response<br />
<strong>in</strong>hibition, which refers to the ability to stop<br />
a speeded motor response and can be measured<br />
by the SST, is a valid endophenotype<br />
for ADHD based on the results <strong>of</strong> cl<strong>in</strong>ical,<br />
family, functional imag<strong>in</strong>g and prelim<strong>in</strong>ary<br />
genetic <strong>in</strong>vestigations (response <strong>in</strong>hibition<br />
<strong>in</strong>fluenced by the genetic risk factors that <strong>in</strong>fluence<br />
ADHD) 2,7 .<br />
Paul Arnold, MD, PhD<br />
Russell Schachar, MD, FRCP(C)<br />
Schachar: At that po<strong>in</strong>t, we will also generate<br />
animal models and learn more about the prote<strong>in</strong>s<br />
that these genes play a role <strong>in</strong>.<br />
Q How will this study contribute to the<br />
field <strong>of</strong> psychiatric genetics?<br />
Schachar: There is a great deal <strong>of</strong> enthusiasm<br />
about the use <strong>of</strong> cognitive endophenotypes or<br />
biomarkers <strong>in</strong> psychiatric genetic research.<br />
Ours will be one <strong>of</strong> the first to be completed.<br />
If it proves to be useful <strong>in</strong> identify<strong>in</strong>g genetic<br />
risks for <strong>in</strong>hibition and for these disorders,<br />
the field will move rapidly.<br />
Crosbie: With this potential to po<strong>in</strong>t to new<br />
candidate genes <strong>of</strong> <strong>in</strong>terest for ADHD and<br />
OCD, the study may provide us with novel<br />
<strong>in</strong><strong>format</strong>ion about the etiology and molecular<br />
pathways <strong>of</strong> these disorders, as well as<br />
further our understand<strong>in</strong>g <strong>of</strong> other neuropsychiatric<br />
disorders.<br />
Arnold: Our approach with TAG is consistent<br />
with previous work suggest<strong>in</strong>g that we<br />
should be th<strong>in</strong>k<strong>in</strong>g <strong>of</strong> neuropsychiatric disorders<br />
as cont<strong>in</strong>uous rather than categorical<br />
traits. If we are successful <strong>in</strong> identify<strong>in</strong>g risk<br />
variants for psychiatric disorders, others may<br />
want to adopt a similar strategy <strong>of</strong> study<strong>in</strong>g<br />
large general population samples rather than<br />
focus<strong>in</strong>g solely on cl<strong>in</strong>ic-based populations.<br />
Investigator photos by Brett Jones<br />
Arnold: The general population-based design<br />
<strong>of</strong> TAG provided a quick and cost-effective<br />
way to collect a large sample <strong>of</strong> children<br />
us<strong>in</strong>g a s<strong>in</strong>gle and uniform assessment <strong>of</strong><br />
behavioural (ADHD, OCD, and other conditions<br />
through questionnaire), cognitive (response<br />
<strong>in</strong>hibition measured by SST) and genetic<br />
(saliva DNA) traits. With this data, we<br />
are able to draw from the full range <strong>of</strong> variation<br />
<strong>in</strong> our traits <strong>of</strong> <strong>in</strong>terest, and use an extreme<br />
trait approach 8 to conduct a genomewide<br />
association study compar<strong>in</strong>g children<br />
<strong>in</strong> the upper and lower extremes <strong>of</strong> specific<br />
behavioural and cognitive traits.<br />
Q What are the objectives <strong>of</strong> TAG?<br />
Arnold: Once we have performed our<br />
GWAS and identified <strong>in</strong>terest<strong>in</strong>g risk variants,<br />
we <strong>in</strong>tend to genotype these variants<br />
<strong>in</strong> our entire sample and cl<strong>in</strong>ical samples.<br />
By tak<strong>in</strong>g our results to cl<strong>in</strong>ical samples, we<br />
can test if the identified variants [<strong>in</strong> the general<br />
population] are also found <strong>in</strong> ADHD or<br />
Jennifer Crosbie, PhD, CPsych<br />
OCD patients, and also look for associations<br />
with <strong>in</strong>terest<strong>in</strong>g phenotypes we can’t measure<br />
<strong>in</strong> the general population (e.g. neuroimag<strong>in</strong>g).<br />
Another future direction is to look for<br />
other genetic variations beyond the common<br />
“s<strong>in</strong>gle nucleotide polymorphisms” surveyed<br />
<strong>in</strong> GWAS. For example, we will analyze copy<br />
number variants and relatively rare but functional<br />
s<strong>in</strong>gle nucleotide variants found <strong>in</strong><br />
cod<strong>in</strong>g regions <strong>of</strong> genes.<br />
References<br />
1. Neale BM, et al. Meta-analysis <strong>of</strong> Genome-wide Association<br />
Studies <strong>of</strong> Attention-Deficit/Hyperactivity<br />
Disorder. J Am Acad Child Adolesc Psychiatry.<br />
2010;49:884-897.<br />
2. Crosbie J, et al. Validat<strong>in</strong>g Psychiatric Endophenotypes:<br />
Inhibitory Control and Attention Deficit Hyperactivity<br />
Disorder. Neurosci Biobehav Rev. 2008;32:40-<br />
55.<br />
3. Pauls DL. The Genetics <strong>of</strong> Obsessive Compulsive Disorder:<br />
A Review <strong>of</strong> the Evidence. Am J Med Genet C Sem<strong>in</strong><br />
Med Genet. 2008;148:133-139.<br />
4. Boileau B. A Review <strong>of</strong> Obsessive-Compulsive Disorder<br />
<strong>in</strong> Children and Adolescents. Dialogues Cl<strong>in</strong> Neurosci.<br />
2011;13:401-411<br />
5. Menzies L, et al. Neurocognitive Endophenotypes <strong>of</strong><br />
Obsessive-Compulsive Disorder. Bra<strong>in</strong>. 2007;130:3223-<br />
3236.<br />
6. Gottesman II, Gould TD. The Endophenotype Concept<br />
<strong>in</strong> Psychiatry: Etymology and Strategic Intentions.<br />
Am J Psychiatry .2003;160:636-645.<br />
7. Schachar RJ, et al. Heritability <strong>of</strong> response <strong>in</strong>hibition<br />
<strong>in</strong> children. J Int Neuropsychol Soc. 2011; 17(2):238-47.<br />
8. Liu DJ, Leal SM. A Unified Framework for Detect<strong>in</strong>g<br />
Rare Variant Quantitative Trait Associations <strong>in</strong> Pedigree<br />
and Unrelated Individuals via Sequence Data. Hum<br />
Hered. <strong>2012</strong>;73:105-122.<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 20
FEATURE<br />
Epigenomics<br />
Beyond Genomic Sequenc<strong>in</strong>g<br />
Darci Butcher, PhD, Postdoctoral<br />
Fellow<br />
Program <strong>in</strong> Genetics and Genome Biology,<br />
Hospital for Sick Children<br />
Rosanna Weksberg, MD, PhD<br />
Staff Physician, Cl<strong>in</strong>ical and Metabolic<br />
Genetics<br />
Co-Director and Staff Geneticist, Cancer<br />
Genetics Program<br />
The Hospital for Sick Children<br />
Pr<strong>of</strong>essor,<br />
Molecular and Medical Genetics<br />
University <strong>of</strong> Toronto<br />
Genome sequenc<strong>in</strong>g <strong>in</strong>itiatives<br />
have been unable to identify the<br />
genetic causes or phenotypic modulators<br />
<strong>of</strong> many <strong>of</strong> disorders seen <strong>in</strong> cl<strong>in</strong>ical<br />
medic<strong>in</strong>e. Layered on top <strong>of</strong> the DNA<br />
sequence is epigenetic <strong>in</strong><strong>format</strong>ion, def<strong>in</strong>ed<br />
as a “stably heritable phenotype result<strong>in</strong>g<br />
from changes <strong>in</strong> a chromosome without alterations<br />
<strong>in</strong> the DNA sequence” 1 . Identify<strong>in</strong>g<br />
the epigenetic marks and characteriz<strong>in</strong>g how<br />
they are read to regulate the expression <strong>of</strong> the<br />
primary genomic sequence is necessary for<br />
our understand<strong>in</strong>g <strong>of</strong> human development<br />
and disease. Multiple epigenetic mechanisms<br />
<strong>in</strong>clud<strong>in</strong>g DNA methylation at cytos<strong>in</strong>e<br />
residues <strong>in</strong> CpG d<strong>in</strong>ucleotides, covalent<br />
modifications <strong>of</strong> histone prote<strong>in</strong>s, regulatory<br />
non-cod<strong>in</strong>g RNAs, <strong>in</strong>clud<strong>in</strong>g small <strong>in</strong>terfer<strong>in</strong>g<br />
RNA (siRNA), microRNAs (miRNAs)<br />
and long non-cod<strong>in</strong>g RNAs (lncRNAs) participate<br />
<strong>in</strong> regulat<strong>in</strong>g gene expression and<br />
chromat<strong>in</strong> architecture. Disruption <strong>of</strong> these<br />
mechanisms is associated with a variety <strong>of</strong><br />
diseases with behavioural, endocr<strong>in</strong>e or neurologic<br />
manifestations and disorders <strong>of</strong> tissue<br />
growth, <strong>in</strong>clud<strong>in</strong>g cancer. The <strong>in</strong>volvement <strong>of</strong><br />
epigenetic alterations <strong>in</strong> many diseases has<br />
been known for some time, but only recently<br />
has it begun to be useful for cl<strong>in</strong>ical practice<br />
to diagnose and monitor disease progression.<br />
In the Weksberg laboratory we determ<strong>in</strong>e<br />
genome-wide differential DNA methylation,<br />
gene expression and histone modifications<br />
for a number <strong>of</strong> disorders that have known<br />
or suspected aberrations <strong>in</strong> their epigenomic<br />
patterns. Many <strong>of</strong> these projects are collaborative<br />
efforts between the research laboratory<br />
and cl<strong>in</strong>icians at the Hospital for Sick<br />
Children and around the world. We are identify<strong>in</strong>g<br />
genes and pathways that have altered<br />
DNA methylation to determ<strong>in</strong>e their contribution<br />
to the overall disease phenotype. The<br />
projects <strong>in</strong> the laboratory can be separated<br />
<strong>in</strong>to those related to growth, <strong>in</strong>clud<strong>in</strong>g genomic<br />
impr<strong>in</strong>t<strong>in</strong>g and <strong>in</strong>trauter<strong>in</strong>e growth<br />
restriction and those related to neurodevelopment<br />
<strong>in</strong>clud<strong>in</strong>g autism spectrum disorders<br />
(ASD) and other paediatric neuropsychiatric<br />
disorders.<br />
A number <strong>of</strong> disorders are caused by aberrant<br />
genomic impr<strong>in</strong>t<strong>in</strong>g result<strong>in</strong>g from unequal<br />
contributions <strong>of</strong> maternal and paternal<br />
alleles to the <strong>of</strong>fspr<strong>in</strong>g 2 . Impr<strong>in</strong>ted genes<br />
typically function <strong>in</strong> growth regulation and<br />
neurodevelopment, and the correspond<strong>in</strong>g<br />
disease phenotypes are due to genetic or epigenetic<br />
aberrations <strong>in</strong> these genes <strong>of</strong>ten result<br />
<strong>in</strong> abnormalities <strong>of</strong> <strong>in</strong>trauter<strong>in</strong>e growth<br />
or post-natal cognition and behavior. These<br />
disorders <strong>in</strong>clude Beckwith-Wiedemann<br />
(BWS), Silver-Russell (SRS), Prader-Willi<br />
(PWS) and Angelman syndromes (AS).<br />
The molecular and epigenetic causes <strong>of</strong><br />
Beckwith-Wiedemann syndrome have been<br />
studied <strong>in</strong> depth <strong>in</strong> the Weksberg laboratory 3 .<br />
This disorder is a rare, <strong>of</strong>ten sporadic, heterogeneous<br />
congenital overgrowth disorder<br />
which has many features <strong>in</strong>clud<strong>in</strong>g somatic<br />
overgrowth, large tongue, abdom<strong>in</strong>al wall<br />
defects, ear creases and pits, kidney mal<strong>format</strong>ions<br />
and neonatal hypoglycemia, as well<br />
as <strong>in</strong> <strong>in</strong>creased risk <strong>of</strong> embryonal tumours.<br />
BWS is caused by epigenomic and/or genomic<br />
alterations <strong>in</strong> the impr<strong>in</strong>ted gene clusters<br />
on chromosome band 11p15.5 4 can be subdivided<br />
<strong>in</strong>to two dist<strong>in</strong>ct impr<strong>in</strong>ted doma<strong>in</strong>s.<br />
Most cases <strong>of</strong> BWS are due to epigenetic lesions:<br />
either a ga<strong>in</strong> <strong>of</strong> CpG methylation at an<br />
impr<strong>in</strong>t<strong>in</strong>g control region on the maternal allele<br />
<strong>of</strong> the H19 upstream differentially methylation<br />
region (DMR), which silences H19<br />
and activates expression <strong>of</strong> the growth promot<strong>in</strong>g<br />
gene <strong>in</strong>sul<strong>in</strong> growth factor 2 (IGF2),<br />
or a loss <strong>of</strong> methylation at another impr<strong>in</strong>t<strong>in</strong>g<br />
control region <strong>of</strong> the KCNQ1<strong>in</strong>tronic DMR,<br />
which silences the growth suppressor gene<br />
CDKN1C plus several nearby maternally expressed<br />
genes. Identify<strong>in</strong>g specific molecular<br />
defects <strong>in</strong> impr<strong>in</strong>t<strong>in</strong>g disorders provides im-<br />
Photos by Brett Jones<br />
21 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
FEATURE<br />
portant <strong>in</strong><strong>format</strong>ion for patient management<br />
and for estimat<strong>in</strong>g recurrence risk. Molecular<br />
diagnostic test<strong>in</strong>g for abnormal DNA methylation<br />
<strong>in</strong> the relevant impr<strong>in</strong>ted doma<strong>in</strong>s<br />
can be done for a number <strong>of</strong> impr<strong>in</strong>t<strong>in</strong>g disorders<br />
and is already widely applied <strong>in</strong> PWS/<br />
AS and BWS/SRS. The majority <strong>of</strong> molecular<br />
alterations with<strong>in</strong> impr<strong>in</strong>t<strong>in</strong>g doma<strong>in</strong>s can be<br />
identified by alterations <strong>in</strong> DNA methylation<br />
<strong>in</strong> the respective impr<strong>in</strong>t<strong>in</strong>g control regions.<br />
A few retrospective studies have shown an <strong>in</strong>creased<br />
<strong>in</strong>cidence <strong>of</strong> epigenetic abnormalities<br />
caus<strong>in</strong>g both BWS and AS follow<strong>in</strong>g the use<br />
<strong>of</strong> assisted reproductive technologies (ART).<br />
Although the <strong>in</strong>creased relative risk is small<br />
for these DNA methylation errors these data<br />
highlight the importance <strong>of</strong> understand<strong>in</strong>g<br />
the mechanisms beh<strong>in</strong>d genomic impr<strong>in</strong>t<strong>in</strong>g.<br />
The number <strong>of</strong> impr<strong>in</strong>ted genes <strong>in</strong> human<br />
and mouse is currently just over 100 impr<strong>in</strong>ted<br />
transcripts. Approximately 63 <strong>of</strong> these<br />
have been identified <strong>in</strong> humans. We designed<br />
experiments us<strong>in</strong>g uniparental tissues and<br />
DNA methylation at known impr<strong>in</strong>ted genes<br />
to identify new impr<strong>in</strong>ted genes 5 . We took advantage<br />
<strong>of</strong> two uniparental tissues; complete<br />
androgenetic hydatidiform moles (CHMs)<br />
and mature cystic ovarian teratomas. CHMs<br />
have two copies <strong>of</strong> each paternal chromosome<br />
and no maternal chromosomes. Mature<br />
cystic teratomas, on the other hand, have two<br />
copies <strong>of</strong> the maternal genome. Analyz<strong>in</strong>g<br />
the genome-wide DNA methylation patterns<br />
<strong>in</strong> these tissues and compar<strong>in</strong>g them to normal<br />
biparental tissue we identified a number<br />
<strong>of</strong> candidate impr<strong>in</strong>ted genes and validated<br />
one <strong>of</strong> those genes both mouse and humans 5 .<br />
An expanded set <strong>of</strong> known impr<strong>in</strong>ted genes<br />
could lead to the identification <strong>of</strong> the molecular<br />
cause <strong>of</strong> disorders <strong>of</strong> unknown etiology.<br />
“Identify<strong>in</strong>g the epigenetic<br />
marks and characteriz<strong>in</strong>g<br />
how they are read to<br />
regulate the expression<br />
<strong>of</strong> the primary genomic<br />
sequence is necessary<br />
for our understand<strong>in</strong>g <strong>of</strong><br />
human development and<br />
disease.”<br />
The laboratory is also <strong>in</strong>terested <strong>in</strong> the epigenetic<br />
contribution to <strong>in</strong>trauter<strong>in</strong>e growth<br />
restriction (IUGR), a heterogeneous disorder<br />
<strong>in</strong> which babies are born with a birthweight<br />
less than the 10 th centile for gestational age.<br />
IUGR has been associated not only with significant<br />
maternal and fetal/neonatal mortality<br />
and morbidity but also with adult-onset<br />
disorders such as hypertension, coronary<br />
artery disease, and type 2 diabetes. DNA<br />
methylation alterations have been shown to<br />
drive <strong>in</strong>creased or decreased placental and<br />
fetal growth. By determ<strong>in</strong><strong>in</strong>g DNA methylation<br />
patterns <strong>in</strong> the placenta <strong>of</strong> children<br />
born small for gestational age, we identified<br />
that ga<strong>in</strong> <strong>of</strong> methylation <strong>in</strong> WNT2 was significantly<br />
associated with reduced WNT2<br />
expression <strong>in</strong> placenta and with low birthweight<br />
percentile <strong>in</strong> the neonate 6 . This gene<br />
has been demonstrated to have important<br />
function <strong>in</strong> mouse placental development.<br />
These data suggest that WNT2 expression<br />
can be epigenetically downregulated <strong>in</strong> the<br />
placenta by DNA methylation <strong>of</strong> its promoter<br />
and that high WNT2 promoter methylation<br />
is an epigenetic variant that is associated<br />
with reduced fetal growth potential 6. We expect<br />
that future studies <strong>of</strong> the epigenome will<br />
elucidate other candidate genes that undergo<br />
epigenetic dysregulation and negatively impact<br />
placental and fetal health.<br />
The second focus <strong>in</strong> the Weksberg laboratory<br />
is the <strong>in</strong>vestigation <strong>of</strong> DNA methylation<br />
alterations <strong>in</strong> paediatric neurodevelopment<br />
and neuropsychiatric disorders. A<br />
number <strong>of</strong> neuropsychiatric disorders have<br />
been described with mutations or deletions<br />
<strong>in</strong> genes that are important for ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g<br />
normal epigenetic regulation. Loss <strong>of</strong><br />
function <strong>of</strong> these genes can disrupt normal<br />
establishment, ma<strong>in</strong>tenance, or read<strong>in</strong>g <strong>of</strong><br />
epigenetic marks, thereby result<strong>in</strong>g <strong>in</strong> altered<br />
chromat<strong>in</strong> structure and gene expression. In<br />
most disorders <strong>of</strong> this type, we still do not<br />
understand precisely how the mutation is related<br />
to the phenotype <strong>of</strong> the human disease.<br />
Many <strong>of</strong> these disorders are associated with<br />
<strong>in</strong>tellectual disability (ID), as well as additional<br />
features <strong>in</strong>clud<strong>in</strong>g various congenital<br />
anomalies. The identification <strong>of</strong> alterations <strong>in</strong><br />
DNA methylation associated with mutations<br />
<strong>in</strong> specific genes that function <strong>in</strong> epigenetic<br />
regulation will teach us more about what the<br />
responsibility <strong>of</strong> each epigenetic modifier is<br />
<strong>in</strong> the normal pattern<strong>in</strong>g <strong>of</strong> the epigenome.<br />
Other paediatric disorders we are <strong>in</strong>vestigat-<br />
<strong>in</strong>g <strong>in</strong>clude autism spectrum (ASD), obsessive<br />
compulsive (OCD) and attention deficit<br />
hyperactivity (ADHD). For each <strong>of</strong> these disorders<br />
there have been genetic factors identified<br />
which expla<strong>in</strong> a small proportion <strong>of</strong> such<br />
cases. We have proposed that epigenetic factors<br />
also contribute to the etiology <strong>of</strong> these<br />
disorders. These studies are all <strong>in</strong> the <strong>in</strong>itial<br />
stages but we already have a number <strong>of</strong> <strong>in</strong>terest<strong>in</strong>g<br />
and encourag<strong>in</strong>g results. We are currently<br />
<strong>in</strong>vestigat<strong>in</strong>g a number <strong>of</strong> candidate<br />
genes and pathways that may be relevant to<br />
these disorders.<br />
The field <strong>of</strong> epigenetics is generat<strong>in</strong>g excit<strong>in</strong>g<br />
discoveries <strong>in</strong> parallel to genome sequenc<strong>in</strong>g<br />
<strong>in</strong>itiatives. The NIH Roadmap Epigenomics<br />
Mapp<strong>in</strong>g Consortium was launched to<br />
produce a public resource <strong>of</strong> human epigenomic<br />
data to catalyze basic biology and<br />
disease oriented research 7 . Parallel <strong>in</strong>itiatives<br />
<strong>in</strong>clude the NIH Epigenomics <strong>of</strong> Health and<br />
Disease Roadmap Program and CIHR Canadian<br />
Epigenomic Mapp<strong>in</strong>g Centres. These<br />
<strong>in</strong>itiatives <strong>in</strong>terface with the International<br />
Human Epigenomics Consortium, which<br />
was established to accelerate and coord<strong>in</strong>ate<br />
epigenomics research worldwide 8 . This is an<br />
excit<strong>in</strong>g time for all researchers <strong>in</strong>volved <strong>in</strong><br />
epigenetic research as we work towards decipher<strong>in</strong>g<br />
the language <strong>of</strong> the epigenome at an<br />
exponential rate.<br />
References<br />
1. Berger, S.L., Kouzarides, T., Shiekhattar, R. & Shilatifard,<br />
A. An operational def<strong>in</strong>ition <strong>of</strong> epigenetics. Genes<br />
& development 23, 781-3 (2009).<br />
2. Weksberg, R. Impr<strong>in</strong>ted genes and human disease.<br />
American Journal <strong>of</strong> Medical Genetics Part C: Sem<strong>in</strong>ars<br />
<strong>in</strong> Medical Genetics 154C, 317-320.<br />
3. Choufani, S., Shuman, C. & Weksberg, R. Beckwith–<br />
Wiedemann syndrome. American Journal <strong>of</strong> Medical<br />
Genetics Part C: Sem<strong>in</strong>ars <strong>in</strong> Medical Genetics 154C,<br />
343-354.<br />
4. Weksberg, R., Smith, A.C., Squire, J. & Sadowski, P.<br />
Beckwith-Wiedemann syndrome demonstrates a role<br />
for epigenetic control <strong>of</strong> normal development. Human<br />
molecular genetics 12 Spec No 1, R61-8. (2003).<br />
5. Choufani, S. et al. A novel approach identifies new differentially<br />
methylated regions (DMRs) associated with<br />
impr<strong>in</strong>ted genes. Genome research 21, 465-76.<br />
6. Ferreira JC, C.S., Keat<strong>in</strong>g S, Chitayat D, Grafodatskaya<br />
D, Shuman C, K<strong>in</strong>gdom J, and Weksberg R. WNT2 promoter<br />
methylation <strong>in</strong> human placenta is associated with<br />
low birthweight percentile <strong>in</strong> the neonate. Epigenetics<br />
(2011).<br />
7. Bernste<strong>in</strong>, B.E. et al. The NIH Roadmap Epigenomics<br />
Mapp<strong>in</strong>g Consortium. Nature biotechnology 28, 1045-8.<br />
8. Eckhardt, F., Beck, S., Gut, I.G. & Berl<strong>in</strong>, K. Future potential<br />
<strong>of</strong> the Human Epigenome Project. Expert review<br />
<strong>of</strong> molecular diagnostics 4, 609-18 (2004).<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 22
FEATURE SPOTLIGHT<br />
Advanc<strong>in</strong>g Genomic Medic<strong>in</strong>e <strong>in</strong> Toronto<br />
An Interview with Stephen W. Scherer, PhD<br />
By Tetyana Pekar<br />
The McLaughl<strong>in</strong> Centre<br />
Advanc<strong>in</strong>g Genomic Medic<strong>in</strong>e<br />
You may not have yet heard<br />
about it – and you certa<strong>in</strong>ly won’t<br />
f<strong>in</strong>d it on the map – but McLaughl<strong>in</strong><br />
Centre scientists and collaborators<br />
are mak<strong>in</strong>g scientific breakthroughs, develop<strong>in</strong>g<br />
new diagnostic tests, and mak<strong>in</strong>g<br />
a last<strong>in</strong>g impact on cl<strong>in</strong>ical management<br />
<strong>in</strong> Toronto and <strong>in</strong>ternationally.<br />
The McLaughl<strong>in</strong> Centre derives its name<br />
from the founder <strong>of</strong> General Motors <strong>of</strong><br />
Canada, Colonel Robert Samuel McLaughl<strong>in</strong>,<br />
“an entrepreneur and a brilliant man”<br />
<strong>in</strong> the words <strong>of</strong> Dr. Stephen Scherer, the<br />
Director <strong>of</strong> the McLaughl<strong>in</strong> Centre. “When<br />
he passed away, he put a large portion <strong>of</strong><br />
his money <strong>in</strong>to a foundation and said to<br />
dissolve it <strong>in</strong> 50 years, because no one will<br />
remember who he is <strong>in</strong> 50 years.” And so<br />
the Foundation ran a competition and<br />
University <strong>of</strong> Toronto put <strong>in</strong> an application<br />
and won. The orig<strong>in</strong>al 50 million dollar<br />
<strong>in</strong>vestment, which is protected, was leveraged<br />
to 200 million by the university, government,<br />
and partner hospitals.<br />
For about two years now, the McLaughl<strong>in</strong><br />
Centre has been focused on advanc<strong>in</strong>g the<br />
field <strong>of</strong> genomic medic<strong>in</strong>e.<br />
“When I became the Director, we refocused<br />
on the concept <strong>of</strong> us<strong>in</strong>g genomewide data<br />
to try to identify risk genes for particular<br />
diseases, and equally importantly, to move<br />
those <strong>in</strong>to the hospital diagnostic sett<strong>in</strong>g,”<br />
says Scherer. Their goal is to fund science<br />
that will not only impact the patients and<br />
their families, but will also generate <strong>in</strong><strong>format</strong>ion<br />
and data that will be used for<br />
th<strong>in</strong>gs like drug development.<br />
The McLaughl<strong>in</strong> Centre runs an open competition<br />
and funds approximately 10 grants<br />
a year, all <strong>in</strong> the area <strong>of</strong> genomic medic<strong>in</strong>e.<br />
Fund<strong>in</strong>g research, however, is just one part<br />
<strong>of</strong> its mandate.<br />
One <strong>of</strong> the McLaughl<strong>in</strong> Centre’s goals <strong>in</strong><br />
the next 5–10 years is to ensure that Toronto<br />
becomes a leader <strong>in</strong> genomic medic<strong>in</strong>e.<br />
The <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong> asked Dr. Scherer how<br />
the centre plans to achieve this goal.<br />
“The short answer: tra<strong>in</strong><strong>in</strong>g programs,<br />
fund<strong>in</strong>g research projects… and br<strong>in</strong>g<strong>in</strong>g a<br />
community <strong>of</strong> scientists together.”<br />
Scherer emphasizes that “close to 25 percent<br />
<strong>of</strong> the fund<strong>in</strong>g is applied to education,<br />
tra<strong>in</strong><strong>in</strong>g, <strong>in</strong>vest<strong>in</strong>g <strong>in</strong> the MD/PhD program;<br />
and many <strong>of</strong> these students are do<strong>in</strong>g<br />
their PhDs <strong>in</strong> the <strong>IMS</strong>.” The McLaughl<strong>in</strong><br />
Centre also supports projects that are<br />
<strong>in</strong>vestigat<strong>in</strong>g the downstream effect <strong>of</strong><br />
genetic <strong>in</strong><strong>format</strong>ion, support<strong>in</strong>g genetic<br />
counsell<strong>in</strong>g programs, and determ<strong>in</strong><strong>in</strong>g<br />
the best way to collect data and deliver it<br />
to the patient.<br />
“[The] McLaughl<strong>in</strong> Centre is<br />
a unique experiment, and it’s<br />
go<strong>in</strong>g <strong>in</strong>credibly well.”<br />
A unique feature <strong>of</strong> the centre is the Accelerator<br />
Grant program. “[Currently] if<br />
you have a new idea, it is hard to get money<br />
right away to explore that.” The accelerator<br />
program provides scientists with the opportunity<br />
to get seed fund<strong>in</strong>g for a year to<br />
get prelim<strong>in</strong>ary data and see whether the<br />
project will be fruitful. Scientists can then<br />
apply to receive fund<strong>in</strong>g to complete the<br />
project.<br />
F<strong>in</strong>ally, the third goal is to br<strong>in</strong>g a community<br />
<strong>of</strong> scientists together. Scherer po<strong>in</strong>ts<br />
out that this is a new field, and hav<strong>in</strong>g critical<br />
mass <strong>of</strong> cl<strong>in</strong>icians and scientists will<br />
create momentum for research <strong>in</strong> genomic<br />
medic<strong>in</strong>e and lead to more <strong>in</strong>novations and<br />
breakthroughs. Indeed, collaboration is a<br />
requirement <strong>in</strong> the grants that McLaughl<strong>in</strong><br />
funds: “there need[s] to be two or more<br />
partner <strong>in</strong>stitutions <strong>in</strong>volved.”<br />
In this new and rapidly develop<strong>in</strong>g field,<br />
it is challeng<strong>in</strong>g to stay on top <strong>of</strong> research<br />
f<strong>in</strong>d<strong>in</strong>gs and <strong>in</strong>novations <strong>in</strong> technology.<br />
An important part <strong>of</strong> the McLaughl<strong>in</strong> Centre’s<br />
mandate is to develop tools and databases<br />
that will be cont<strong>in</strong>uously updated<br />
with new <strong>in</strong><strong>format</strong>ion available <strong>in</strong> the literature<br />
about genes and genetic diseases. An<br />
equally important component is educat<strong>in</strong>g<br />
cl<strong>in</strong>icians, nurses, and healthcare pr<strong>of</strong>essionals<br />
(as well as scientists both <strong>in</strong> and<br />
outside <strong>of</strong> the field) to access and properly<br />
<strong>in</strong>terpret this data.<br />
The breadth and calibre <strong>of</strong> McLaughl<strong>in</strong><br />
Centre scientists is truly remarkable. The<br />
accelerator grants that were funded <strong>in</strong> 2011<br />
have already led to excit<strong>in</strong>g new f<strong>in</strong>d<strong>in</strong>gs.<br />
Dr. Danielle Andrade’s research on the genetics<br />
<strong>of</strong> juvenile myoclonic epilepsy identified<br />
a causative mutation <strong>in</strong> the CLN6<br />
gene; this work is currently <strong>in</strong> press <strong>in</strong> the<br />
Pediatric Neurology journal. Dr. Anne Bassett’s<br />
work has identified rare copy number<br />
variants that could play an important role<br />
<strong>in</strong> the development <strong>of</strong> a common heart defect,<br />
the tetralogy <strong>of</strong> Fallot; these f<strong>in</strong>d<strong>in</strong>gs<br />
are soon to be reported <strong>in</strong> PloS Genetics.<br />
Other studies funded by the McLaughl<strong>in</strong><br />
Centre <strong>in</strong>clude <strong>in</strong>vestigat<strong>in</strong>g how alternative<br />
splic<strong>in</strong>g may contribute to Alzheimer’s<br />
disease (Dr. Blencowe); development <strong>of</strong> a<br />
service to centralize cl<strong>in</strong>ical pharmacogenetic<br />
<strong>in</strong><strong>format</strong>ion and counsel<strong>in</strong>g (Dr.<br />
Koren); exam<strong>in</strong><strong>in</strong>g the impact and <strong>in</strong>tegration<br />
<strong>of</strong> genetic technologies <strong>in</strong> adult and<br />
pediatric care (Dr. Shuman); as well as research<br />
identify<strong>in</strong>g disease-caus<strong>in</strong>g genes <strong>in</strong><br />
immunoglob<strong>in</strong> A neuropathy (Dr. Pei) and<br />
renal diseases (Dr. Paterson), to name a<br />
few. “[The] McLaughl<strong>in</strong> Centre is a unique<br />
experiment, and it’s go<strong>in</strong>g <strong>in</strong>credibly well.”<br />
The <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong> agrees, and awaits with<br />
excitement the novel f<strong>in</strong>d<strong>in</strong>gs and technological<br />
breakthroughs that are sure to come<br />
to fruition from McLaughl<strong>in</strong> Centre scientists.<br />
23 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
FEATURE SPOTLIGHT<br />
cystic fibrosis gene). Together, they founded<br />
TCAG, which houses all <strong>of</strong> the latest<br />
genomic technologies to enable research<br />
studies. Scherer estimates that TCAG facilitates<br />
well over 1000 laboratories <strong>in</strong> a<br />
given year.<br />
Dur<strong>in</strong>g his PhD, he made a pioneer<strong>in</strong>g discovery:<br />
the identification <strong>of</strong> genomewide<br />
copy number variations (CNVs) as an important<br />
source <strong>of</strong> genetic variation <strong>in</strong> humans.<br />
His lab cont<strong>in</strong>ues to <strong>in</strong>vestigate the<br />
role <strong>of</strong> CNVs <strong>in</strong> autism, as well as other<br />
disorders, through collaborations.<br />
“You have to be persistent,<br />
and you have to want<br />
to do it yourself, because<br />
no one is go<strong>in</strong>g to do it for<br />
you.”<br />
Scherer’s job requires him to assume many<br />
different roles and responsibilities – from<br />
runn<strong>in</strong>g his lab to runn<strong>in</strong>g two very different<br />
centres – so, is there an aspect <strong>of</strong> his<br />
many roles that he most enjoys?<br />
“I’m the ‘idea’ guy. I have to k<strong>in</strong>d <strong>of</strong> set<br />
the vision <strong>of</strong> where I th<strong>in</strong>k th<strong>in</strong>gs should<br />
be five or ten years down the road and …<br />
figure out how to get there – [the challeng<strong>in</strong>g<br />
part]. I have a job that allows me to<br />
capitalize on my strengths. It took a long<br />
time to get here, but I get to use my bra<strong>in</strong> –<br />
people pay me to th<strong>in</strong>k about new th<strong>in</strong>gs.”<br />
Photo by Yekta Dowlati<br />
Dr. Stephen W. Scherer<br />
The “Idea” Guy<br />
Scherer is a highly <strong>in</strong>fluential<br />
and very successful scientist. In addition<br />
to serv<strong>in</strong>g as the Director <strong>of</strong><br />
the McLaughl<strong>in</strong> Centre and The Centre for<br />
Applied Genomics (TCAG), he is also a Senior<br />
Scientist at the Hospital for Sick Children,<br />
a Pr<strong>of</strong>essor at the University <strong>of</strong> Toronto,<br />
as well as a scientist who never stays<br />
far away from the public eye–<strong>of</strong>ten mak<strong>in</strong>g<br />
appearances on TV, news, and radio.<br />
The <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong> wanted to f<strong>in</strong>d out<br />
more about Scherer’s career trajectory and<br />
the key to his success. Scherer completed<br />
his PhD <strong>in</strong> the Molecular Genetics Department<br />
at the University <strong>of</strong> Toronto, with<br />
Pr<strong>of</strong>essor Lap-Chee Tsui (discoverer <strong>of</strong> the<br />
F<strong>in</strong>ally, I asked if he had any advice for<br />
<strong>in</strong>com<strong>in</strong>g graduate students. What advice<br />
would have benefited him at the start <strong>of</strong><br />
his graduate career? He laughed, and said<br />
that’s a very easy question: learn statistics.<br />
“What we are see<strong>in</strong>g over and over and<br />
over aga<strong>in</strong> is that we need to have more biologists<br />
who have a strong statistical background.<br />
You should be tak<strong>in</strong>g statistical<br />
classes, it is the one th<strong>in</strong>g that will benefit<br />
you the most … [it is] absolutely critical.”<br />
(See Allison Rosen’s article on page 33.)<br />
But, he warns, it takes more than just a<br />
good grasp <strong>of</strong> statistics to succeed <strong>in</strong> graduate<br />
school. “You have to be persistent,<br />
and you have to want to do it yourself, because<br />
no one is go<strong>in</strong>g to do it for you.”<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 24
SPOTLIGHT<br />
Wenjun Xu<br />
The best <strong>of</strong> both worlds<br />
I<br />
t is no secret that the world <strong>of</strong><br />
science can be a frustrat<strong>in</strong>g one <strong>in</strong><br />
which every successful experiment is<br />
preceded by numerous experimental failures.<br />
Whenever frustration threatens to spoil her<br />
day <strong>in</strong> the lab, Wenjun Xu – a PhD student <strong>in</strong><br />
the <strong>IMS</strong> – simply rem<strong>in</strong>ds herself <strong>of</strong> a different<br />
world that she experienced dur<strong>in</strong>g a volunteer<strong>in</strong>g<br />
trip to Nicaragua and Costa Rica<br />
last year. “I th<strong>in</strong>k <strong>of</strong> how people there make<br />
the most out <strong>of</strong> what little they have every<br />
day, and how <strong>in</strong> comparison my problems<br />
can all be overcome.”<br />
The two-week long trip, which Xu organized<br />
through VIDA (a non-pr<strong>of</strong>it organization<br />
that facilitates volunteer-based public health<br />
STREAM PhD student<br />
SUPERVISOR Dr. C<strong>in</strong>di Morshead<br />
services <strong>in</strong> Central America), is a highlight<br />
<strong>of</strong> Xu’s graduate experience. Along with 15<br />
students from various graduate departments<br />
with<strong>in</strong> the Faculty <strong>of</strong> Medic<strong>in</strong>e, Xu and her<br />
peers traveled through remote regions <strong>in</strong> the<br />
two Central American countries, stayed <strong>in</strong><br />
local homes, visited orphanages and AIDS<br />
centres, worked with local medical personnel,<br />
and helped to set up mobile cl<strong>in</strong>ics. It<br />
was long hours <strong>of</strong> hard work every day under<br />
smother<strong>in</strong>g heat, but the group’s efforts were<br />
returned <strong>in</strong> the form <strong>of</strong> warm smiles and<br />
appreciation from the local communities.<br />
When asked how the experience had <strong>in</strong>fluenced<br />
her research and outlook on graduate<br />
school <strong>in</strong> general, she <strong>of</strong>fered: “Although we<br />
were physically exhausted every day dur<strong>in</strong>g<br />
the trip, at the end <strong>of</strong> the trip I felt as though<br />
my m<strong>in</strong>d was recharged. I came back with a<br />
new perspective and more ready for the challenges<br />
and potential frustrations ahead.”<br />
Not that Xu has ever really m<strong>in</strong>ded the challenges<br />
<strong>of</strong> science <strong>in</strong> the first place: “I love basic<br />
science because it answers fundamental questions.”<br />
Hav<strong>in</strong>g completed her undergraduate<br />
degree <strong>in</strong> forensic science at the University <strong>of</strong><br />
Toronto, Xu chose to pursue graduate studies<br />
at the <strong>IMS</strong> rather than a CSI-style career.<br />
In particular, she was fasc<strong>in</strong>ated by regenerative<br />
medic<strong>in</strong>e and stem cell research. “I took<br />
a course that focused a lot on stem cells and<br />
biotechnology, and after that course there<br />
was no turn<strong>in</strong>g back – I was determ<strong>in</strong>ed to<br />
take part <strong>in</strong> stem cell research,” Xu recalls.<br />
That opportunity arrived when she met with<br />
her now supervisor, Dr. C<strong>in</strong>di Morshead, an<br />
expert <strong>in</strong> neural stem cells whose energy and<br />
passion for science Xu found <strong>in</strong>spir<strong>in</strong>g. Xu<br />
has been a happy member <strong>of</strong> the Morshead<br />
lab ever s<strong>in</strong>ce.<br />
Now <strong>in</strong> the third year <strong>of</strong> her PhD studies,<br />
Xu is <strong>in</strong>volved <strong>in</strong> two dist<strong>in</strong>ct projects. She<br />
is explor<strong>in</strong>g the activation and mobilization<br />
<strong>of</strong> endogeneous sp<strong>in</strong>al cord stem cells <strong>in</strong> sp<strong>in</strong>al<br />
cord <strong>in</strong>jury by <strong>in</strong>fusion <strong>of</strong> cyclospor<strong>in</strong>e<br />
A; at the same time, she is <strong>in</strong>vestigat<strong>in</strong>g a<br />
novel adult neural stem cell population that<br />
expresses markers <strong>of</strong> pluripotent stem cells <strong>in</strong><br />
mice. Xu f<strong>in</strong>ds her <strong>in</strong>volvement <strong>in</strong> these two<br />
simultaneous projects both challeng<strong>in</strong>g and<br />
satisfy<strong>in</strong>g, as they allow her exposure to both<br />
translational and basic science.<br />
Despite her strong commitment to research,<br />
Xu is also determ<strong>in</strong>ed to f<strong>in</strong>d the time <strong>in</strong> her<br />
schedule to cont<strong>in</strong>ue to ga<strong>in</strong> <strong>in</strong>spiration outside<br />
<strong>of</strong> the laboratory through her work with<br />
VIDA. She is currently work<strong>in</strong>g to organize<br />
another volunteer trip that is planned for<br />
next year. With her efforts, she hopes that<br />
more graduate students will be <strong>in</strong>spired to<br />
get <strong>in</strong>volved and take part <strong>in</strong> the unforgettable<br />
experience (for more <strong>in</strong><strong>format</strong>ion on<br />
VIDA, please contact Xu at wenjun.xu@utoronto.ca).<br />
Asked when she expects to f<strong>in</strong>ish her PhD,<br />
Xu smiles, “Hopefully <strong>in</strong> about three years.”<br />
Undoubtedly, the next three years for Xu will<br />
be as stimulat<strong>in</strong>g and excit<strong>in</strong>g as the past<br />
three have been.<br />
By Karrie Wong<br />
Photo by Brett Jones<br />
25 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
SPOTLIGHT<br />
C<strong>in</strong>dy Lau<br />
Bra<strong>in</strong> games<br />
STREAM MSc Biomedical Communications<br />
SUPERVISOR Michael Corr<strong>in</strong><br />
proached me with the problem. Michael Corr<strong>in</strong><br />
also really encouraged this—especially<br />
because it’s a tool that might actually be used<br />
by students <strong>in</strong> a practical, and hopefully helpful<br />
way.”<br />
A demo <strong>of</strong> the game reveals a sleek <strong>in</strong>terface,<br />
an engag<strong>in</strong>g method <strong>of</strong> learn<strong>in</strong>g, and<br />
remarkable visuals, <strong>in</strong>clud<strong>in</strong>g the ability to<br />
exam<strong>in</strong>e the sp<strong>in</strong>al cord at <strong>in</strong>dividual vertebral<br />
levels. The objective is to build a neural<br />
pathway between the bra<strong>in</strong> and body region<br />
<strong>of</strong> <strong>in</strong>terest, as chosen by the user from available<br />
cases. “It’s a game <strong>in</strong> the sense that if you<br />
build an <strong>in</strong>correct pathway, you lose—but we<br />
also try to mimic the temporal element <strong>of</strong><br />
nervous signal propagation,” comments Lau.<br />
“The game is as much about accuracy as it is<br />
about time: can you build the correct neural<br />
pathway so that the nervous signal propagates<br />
without <strong>in</strong>terruption?”<br />
Of her scholarship, Lau relays her gratitude<br />
for the guidance and support she has received<br />
from both her advisors and peers. “I feel really<br />
lucky to have been the recipient,” she cont<strong>in</strong>ues.<br />
“There is a relatively small circle <strong>of</strong> us<br />
<strong>in</strong> the biomedical communications community,<br />
so it’s quite an honour to be recognized<br />
among a group <strong>of</strong> really talented <strong>in</strong>dividuals.”<br />
Photo by Laura Feldcamp<br />
Motivated by a steadfast <strong>in</strong>terest<br />
<strong>in</strong> both biology and art, C<strong>in</strong>dy<br />
Lau found her pr<strong>of</strong>essional niche<br />
when she discovered the Biomedical Communications<br />
(BMC) program two years after<br />
complet<strong>in</strong>g her undergraduate biomedical<br />
eng<strong>in</strong>eer<strong>in</strong>g degree. This past year, the second-year<br />
MSc BMC student was awarded the<br />
prestigious Alan W. Cole Scholarship <strong>in</strong> the<br />
Vesalius Trust’s <strong>2012</strong> scholarship competition—an<br />
honour that undoubtedly reflects<br />
her enthusiasm for her work.<br />
The Trust was established by a pr<strong>of</strong>essional<br />
organization <strong>of</strong> medically-tra<strong>in</strong>ed visual<br />
communicators—the Association <strong>of</strong> Medical<br />
Illustrators—to support education and<br />
research programs <strong>in</strong> the field. Specifically,<br />
competitive research scholarships are awarded<br />
annually to students enrolled <strong>in</strong> accredited<br />
North American medical illustration<br />
programs, with the Alan W. Cole scholarship<br />
granted to the top scholar across all <strong>in</strong>stitutions.<br />
Applicants are evaluated based on<br />
background, education, project concept, design,<br />
and production plan.<br />
Lau received the award for her master’s research<br />
project “NeuroPath: Creat<strong>in</strong>g Neural<br />
Pathways In Play and In M<strong>in</strong>d,” an <strong>in</strong>teractive<br />
computer game designed to help medical<br />
students learn neural pathways. Supervised<br />
by BMC advisor Michael Corr<strong>in</strong> and content<br />
expert Dr. Barbara Ballyk, who teaches<br />
neuroanatomy as part <strong>of</strong> the medical school<br />
curriculum, Lau is eager to make the highly<br />
visual and complex content as understandable<br />
as possible.<br />
“Learn<strong>in</strong>g how electrical signals travel from<br />
the bra<strong>in</strong> to motor segments, or from sensory<br />
nerves to the bra<strong>in</strong>—it can be fairly complicated<br />
to learn because many pathways cross<br />
over at different levels [<strong>of</strong> the nervous system],”<br />
expla<strong>in</strong>s Lau. “It’s challeng<strong>in</strong>g to learn<br />
just through rote memorization and read<strong>in</strong>g<br />
textbooks.”<br />
Lau credits her supervisors for prompt<strong>in</strong>g<br />
her <strong>in</strong>volvement <strong>in</strong> the project. “Dr. Ballyk<br />
encourages her students to draw out the<br />
pathways as they learn them. She sees the<br />
difficulty they can have firsthand, so she ap-<br />
As she nears graduation from BMC, Lau<br />
doesn’t lose sight <strong>of</strong> her goals: “I am determ<strong>in</strong>ed<br />
to f<strong>in</strong>ish this project to the best <strong>of</strong><br />
my ability—not just for the sake <strong>of</strong> f<strong>in</strong>ish<strong>in</strong>g,<br />
but to really create a tool that achieves<br />
its <strong>in</strong>tended goals. Especially <strong>in</strong> light <strong>of</strong> the<br />
Vesalius Trust scholarship, I want to give it<br />
my absolute best.”<br />
A still from the current NeuroPath demo: users<br />
will be able to construct neural pathways (right)<br />
from a selection <strong>of</strong> different patient cases (left).<br />
By N<strong>in</strong>a Bahl<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 26
BOOK REVIEWS<br />
Book Reviews<br />
Excellent Very Good Good Average<br />
Worth miss<strong>in</strong>g a day at the lab Try to squeeze <strong>in</strong> between experiments Wait for the weekend Wait until degree is complete<br />
Jeff Brown and Mark Fenske, with Liz Neporent<br />
The W<strong>in</strong>ner’s Bra<strong>in</strong>: 8 Strategies<br />
Great M<strong>in</strong>ds Use to Achieve Success<br />
Da Capo Press, 2011; 240 pages<br />
In the creative collaboration between<br />
cl<strong>in</strong>ical psychologist Jeff Brown and<br />
cognitive neuroscientist Mark Fenske, the<br />
book The W<strong>in</strong>ner’s Bra<strong>in</strong>: 8 Strategies Great M<strong>in</strong>ds<br />
Use to Achieve Success comb<strong>in</strong>es cutt<strong>in</strong>g-edge<br />
neuroscientific research with well-established<br />
cognitive-behavioural psychological strategies<br />
to reveal how highly successful bra<strong>in</strong>s function.<br />
The authors give practical guidance to enhance<br />
cognitive performance and to allow the reader to<br />
achieve unique, personal ideas <strong>of</strong> success.<br />
The W<strong>in</strong>ner’s Bra<strong>in</strong> starts by tak<strong>in</strong>g the reader<br />
through an engag<strong>in</strong>g tour <strong>of</strong> the history <strong>of</strong> neuroscience<br />
and a brief overview about what we<br />
currently know about the <strong>in</strong>ner work<strong>in</strong>gs <strong>of</strong> the<br />
human bra<strong>in</strong>.<br />
The authors then reveal the importance <strong>of</strong> neuroplasticity,<br />
which is def<strong>in</strong>ed <strong>in</strong> the book as the<br />
neurocircuitry changes that occur with every experience,<br />
and us<strong>in</strong>g this to take control <strong>of</strong> your<br />
bra<strong>in</strong> “<strong>in</strong> order to position yourself to achieve<br />
your goals and dreams.” Accord<strong>in</strong>g to Fenkse, <strong>in</strong><br />
a recent communication with the <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong>,<br />
“The say<strong>in</strong>g ‘old dogs can’t learn new tricks’ is obviously<br />
wrong.”<br />
The W<strong>in</strong>ner’s Bra<strong>in</strong> outl<strong>in</strong>es five “Bra<strong>in</strong> Power<br />
Tools” that all W<strong>in</strong>n<strong>in</strong>g Bra<strong>in</strong>s have <strong>in</strong> common:<br />
the Opportunity Radar (know<strong>in</strong>g which opportunity<br />
will lead to success and which will not), the<br />
Optimal Risk Gauge (calibrat<strong>in</strong>g a risk threshold<br />
to decide whether or not a chance is worth tak<strong>in</strong>g),<br />
the Goal-Laser (<strong>in</strong>tentionally and deliberately<br />
tak<strong>in</strong>g steps to accomplish important goals),<br />
the Effort Accelerator (keep<strong>in</strong>g motivated), and<br />
the Talent Meter (know<strong>in</strong>g your strengths and<br />
weaknesses). All <strong>of</strong> these Bra<strong>in</strong> Power Tools can<br />
be strengthened by strategies termed “W<strong>in</strong> Factors,”<br />
which <strong>in</strong>clude Self-Awareness, Motivation,<br />
Focus, Emotional Balance, Memory, Resilience,<br />
Adaptability, and Bra<strong>in</strong> Care.<br />
These tools and strategies are derived from highly<br />
complex concepts <strong>in</strong> neuroscience and cognitivebehavioural<br />
psychology that are not easily translated<br />
<strong>in</strong>to a language accessible for <strong>in</strong>dividuals outside<br />
<strong>of</strong> these fields. However, Brown and Fenske,<br />
ably assisted by health-writer Liz Neporent, master<br />
this feat <strong>of</strong> knowledge translation with playful<br />
and clear writ<strong>in</strong>g that <strong>of</strong>fers an adequate foundation<br />
<strong>in</strong> science (highlight<strong>in</strong>g applicable pieces <strong>of</strong><br />
<strong>in</strong><strong>format</strong>ion), step-by-step <strong>in</strong>structions on how<br />
to master change, and <strong>in</strong>terviews conducted with<br />
<strong>in</strong>dividuals with a range <strong>of</strong> real-life success stories.<br />
Some <strong>in</strong>spirational stories <strong>of</strong> success <strong>in</strong>clude<br />
<strong>in</strong>terviews from Trisha Meili (also known as the<br />
Central Park Jogger), Kerri Strug (gymnastics<br />
Olympian), Kev<strong>in</strong> Clash (Sesame Street’s ‘Elmo’),<br />
Andy (a London Black Cab driver), Camille Mc-<br />
Donald (Bath & Body Works’ President <strong>of</strong> Brand<br />
Development), and one <strong>of</strong> Fenske’s most <strong>in</strong>spirational<br />
<strong>in</strong>terviews, B.B. K<strong>in</strong>g (Blues guitar legend).<br />
Fenske states that when he and his colleagues<br />
were writ<strong>in</strong>g the book, they wanted to <strong>in</strong>clude<br />
“real world examples <strong>of</strong> people and the science <strong>in</strong><br />
action, exemplify<strong>in</strong>g the science and research beh<strong>in</strong>d<br />
each [particular W<strong>in</strong> Factor].” Fenske went<br />
on to tell us about his <strong>in</strong>terview with B.B. K<strong>in</strong>g,<br />
<strong>in</strong> which B.B. K<strong>in</strong>g “talked about humble beg<strong>in</strong>n<strong>in</strong>gs,<br />
be<strong>in</strong>g very poor, and how be<strong>in</strong>g a black<br />
artist was full <strong>of</strong> challenges when he started out.”<br />
Fenske heard the “resilience and dedication <strong>of</strong><br />
[B.B. K<strong>in</strong>g] push<strong>in</strong>g through time after time, and<br />
how he had the mental strategies at [the beg<strong>in</strong>n<strong>in</strong>g<br />
<strong>of</strong> his career] that he still uses as a perform<strong>in</strong>g artist,<br />
such as practic<strong>in</strong>g and constantly and cont<strong>in</strong>ually<br />
work<strong>in</strong>g on himself and what he does.”<br />
As this book is about translat<strong>in</strong>g the complex<br />
concept <strong>of</strong> neuroplasticity <strong>in</strong>to easily accessible<br />
terms for many audiences, B.B. K<strong>in</strong>g’s <strong>in</strong>terview,<br />
amongst many others, “illustrates how the bra<strong>in</strong><br />
is constantly chang<strong>in</strong>g and that each <strong>of</strong> us can be<br />
proactive by tak<strong>in</strong>g part <strong>in</strong> how our bra<strong>in</strong> changes<br />
over the course <strong>of</strong> a lifetime.” Fenske reflected on<br />
what he has come to know about neuroscience<br />
and said, “This is a message <strong>of</strong> hope…We don’t<br />
just have to settle with what we are or what we can<br />
do at any po<strong>in</strong>t <strong>in</strong> time.”<br />
The W<strong>in</strong>ner’s Bra<strong>in</strong> is a valuable comb<strong>in</strong>ation <strong>of</strong><br />
expertise <strong>of</strong> neuroscience and cl<strong>in</strong>ical practice.<br />
And Fenske added, “The book benefitted tremendously<br />
from <strong>in</strong>teractions with students, which facilitated<br />
discussion and helped <strong>in</strong> bra<strong>in</strong>storm<strong>in</strong>g<br />
ways that [this knowledge] can be translated <strong>in</strong>to<br />
a language that anyone can use.” Fenske cleverly<br />
po<strong>in</strong>ted out that there are “more than just scientists<br />
who can use this new knowledge to <strong>in</strong>crease<br />
their Bra<strong>in</strong> Power <strong>in</strong> their day-to-day lives.”<br />
Column by Brittany N. Rosenbloom<br />
27 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
BOOK REVIEWS<br />
John Robb<strong>in</strong>s<br />
Healthy at 100: The Scientifically Proven<br />
Secrets <strong>of</strong> the World’s Healthiest and<br />
Longest-Lived Peoples<br />
Random House Publish<strong>in</strong>g, 2007; 348pages<br />
Where <strong>in</strong> the world do people<br />
<strong>of</strong>ten live to be over 100? That<br />
is the question that beg<strong>in</strong>s this<br />
<strong>in</strong>terest<strong>in</strong>g and well-referenced book. The answer<br />
is <strong>in</strong>tricately described by John Robb<strong>in</strong>s,<br />
heir to the Bask<strong>in</strong>-Robb<strong>in</strong>s ice cream corporation,<br />
though ironically, a firm advocator <strong>of</strong><br />
healthy lifestyles. In search for answers, he takes<br />
the reader on a tour <strong>of</strong> four diverse and isolated<br />
regions: Abkhasia <strong>in</strong> the Caucasus region <strong>of</strong> Russia,<br />
the Hunza region <strong>of</strong> Pakistan, Vilcabamba<br />
<strong>in</strong> Ecuador, and the island <strong>of</strong> Ok<strong>in</strong>awa <strong>in</strong> Japan.<br />
These dispersed and unconnected regions have<br />
one th<strong>in</strong>g <strong>in</strong> common: some <strong>of</strong> the healthiest<br />
and oldest liv<strong>in</strong>g people on the planet. Dur<strong>in</strong>g<br />
the readers’ literary journey from place to place,<br />
Robb<strong>in</strong>s illustrates that it is a complex aggregate<br />
<strong>of</strong> factors that enable these populations to have<br />
more centenarians than <strong>in</strong> the Western world.<br />
Firstly, while geographically, ethnically, and<br />
culturally dist<strong>in</strong>ct, these populations have<br />
similar plant-based and meat-less diets. And <strong>of</strong><br />
course, they are free <strong>of</strong> processed-food. Equally<br />
important, exercise is <strong>in</strong>corporated <strong>in</strong>to their<br />
daily life, allow<strong>in</strong>g these populations to stay lean<br />
and active <strong>in</strong> late life. Secondly, these communities<br />
are socially healthy; they foster a strong<br />
sense <strong>of</strong> spirituality and social support. Elders<br />
are highly respected <strong>in</strong> these communities, and<br />
as <strong>in</strong>dividuals age, they ga<strong>in</strong> more stature and<br />
become revered for their wisdom and knowledge.<br />
This is <strong>in</strong> stark contrast to the common<br />
mentality <strong>in</strong> Western societies where older citizens<br />
can be seen as a burden.<br />
Strik<strong>in</strong>g, as well, is the longevity <strong>of</strong> these populations<br />
compared to the mental and physical deterioration<br />
that occurs <strong>in</strong> Western societies, and<br />
<strong>in</strong> particular, the high <strong>in</strong>cidence <strong>of</strong> old-age diseases.<br />
Communities <strong>in</strong> these regions rema<strong>in</strong> vibrant,<br />
healthy, and free <strong>of</strong> disease; remarkably,<br />
they do not have an abundance <strong>of</strong> cancers, neurological<br />
diseases, and the host <strong>of</strong> cardiovascular<br />
diseases that plague our society. A doctor<br />
would be unneeded there!<br />
Robb<strong>in</strong>s is thorough <strong>in</strong> his analysis <strong>of</strong> the literature.<br />
He considers the similarities and differences<br />
between these populations and our<br />
culture carefully, down to the level <strong>of</strong> genes and<br />
hormones. He emphasizes the l<strong>in</strong>k between animal-based<br />
foods – dairy, meat and eggs – and<br />
cancers, cardiovascular diseases and diabetes,<br />
with strong primary research articles. Moreover,<br />
he <strong>in</strong>vestigates the l<strong>in</strong>k between white<br />
foods – sugars, rice, and breads – with health<br />
abnormalities, <strong>in</strong>clud<strong>in</strong>g dental de<strong>format</strong>ions<br />
and decay.<br />
F<strong>in</strong>ally, the third section <strong>of</strong> his book is the “how<br />
to”: how to adopt and learn skills and lifestyles<br />
from these populations while balanc<strong>in</strong>g the realities<br />
and demands <strong>of</strong> our society (sounds too<br />
good to be true). He delves <strong>in</strong>to the research <strong>of</strong><br />
the m<strong>in</strong>d and body and the benefits <strong>of</strong> regular<br />
exercise, and <strong>in</strong>terest<strong>in</strong>gly, designates an entire<br />
chapter to love and healthcare – the benefits <strong>of</strong><br />
be<strong>in</strong>g <strong>in</strong> healthy and lov<strong>in</strong>g relationships (and<br />
the negative effects <strong>of</strong> ‘toxic’ relationships).<br />
Overall, an <strong>in</strong>terest<strong>in</strong>g and important read!<br />
Robb<strong>in</strong>s makes mean<strong>in</strong>gful claims about health<br />
and well-be<strong>in</strong>g, backed by solid scientific evidence.<br />
Robb<strong>in</strong>s is conv<strong>in</strong>c<strong>in</strong>g because he not<br />
only presents the scientific evidence, but also<br />
analyzes the studies’ strengths, weaknesses, limitations<br />
and possible <strong>in</strong>terpretations.<br />
And if you’re wonder<strong>in</strong>g whether Robb<strong>in</strong>s currently<br />
bears the torch to the Bask<strong>in</strong>-Robb<strong>in</strong>s<br />
corporation, the answer, as you may have<br />
guessed, is a firm no. He decl<strong>in</strong>ed that <strong>of</strong>fer.<br />
Column by Salvador Alcaire<br />
What are you read<strong>in</strong>g?<br />
Aaron Kucyi, PhD candidate, recommends Free<br />
Will by Sam Harris<br />
“The concept <strong>of</strong> free will has taken a<br />
beat<strong>in</strong>g <strong>in</strong> light <strong>of</strong> recent neuroscience<br />
discoveries. Harris <strong>of</strong>fers no mercy <strong>in</strong><br />
his succ<strong>in</strong>ct set <strong>of</strong> essays—he had no<br />
choice—but conv<strong>in</strong>c<strong>in</strong>gly argues that determ<strong>in</strong>ism<br />
is not all awful: rather, accept<strong>in</strong>g<br />
your ‘biochemical puppet’ status can<br />
be both humbl<strong>in</strong>g and awe-<strong>in</strong>spir<strong>in</strong>g.”<br />
Brett Jones, MSc candidate, recommends The<br />
Head Master’s Wager by V<strong>in</strong>cent Lam<br />
“The Head Master’s Wager is the third<br />
book written by U <strong>of</strong> T lecturer, physician,<br />
and award-w<strong>in</strong>n<strong>in</strong>g author <strong>of</strong> Bloodlett<strong>in</strong>g<br />
and Miraculous Cures, V<strong>in</strong>cent Lam.<br />
Set dur<strong>in</strong>g the Vietnam/American war,<br />
Lam tells a story <strong>of</strong> the compulsive gambl<strong>in</strong>g,<br />
womaniz<strong>in</strong>g Percivel Chen, who is<br />
the head master <strong>of</strong> the most prestigious<br />
English school <strong>in</strong> Saigon. This story <strong>of</strong><br />
Percivel Chen, a fictional character based<br />
on Lam’s own grandfather, is a wonderful<br />
work <strong>of</strong> fiction on love, betrayal, and sacrifice.”<br />
Tetyana Pekar, MSc candidate, recommends<br />
The Trouble with Physics by Lee Smol<strong>in</strong><br />
“A def<strong>in</strong><strong>in</strong>g feature <strong>of</strong> a good theory is<br />
that it makes testable and unique predictions.<br />
In this book, Lee Smol<strong>in</strong>, a theoretical<br />
physicist at the Perimeter <strong>Institute</strong>,<br />
argues that this feature is lack<strong>in</strong>g <strong>in</strong><br />
str<strong>in</strong>g theory. Smol<strong>in</strong> cogently lays out<br />
the problems with str<strong>in</strong>g theory, why it is<br />
a dead-end, and how the theory’s popularity<br />
is detrimental to progress <strong>in</strong> fundamental<br />
physics. Best <strong>of</strong> all, it is easy to<br />
read, passionate, critical and <strong>in</strong>sightful.”<br />
If you are an <strong>IMS</strong> faculty member or student<br />
and would like to have your book<br />
review published <strong>in</strong> a future issue <strong>of</strong> the<br />
<strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong>, please send a 50-word review<br />
to theimsmagaz<strong>in</strong>e@gmail.com.<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 28
CLOSE UP<br />
Interview with<br />
Dr. Gary Rem<strong>in</strong>gton<br />
Renowned cl<strong>in</strong>icianscientist<br />
and unparalleled<br />
mentor<br />
By Melanie Guenette<br />
Dr. Gary Rem<strong>in</strong>gton is the <strong>2012</strong><br />
recipient <strong>of</strong> the <strong>IMS</strong> Mel Silverman<br />
Mentorship Award. If you were to<br />
ask him about this momentous accomplishment,<br />
he would likely shake his head and immediately<br />
credit his students for nom<strong>in</strong>at<strong>in</strong>g<br />
him. That is just the sort <strong>of</strong> man he is: understated,<br />
humble, and selfless. I am biased<br />
<strong>of</strong> course, because he is my supervisor, but<br />
no one misses an opportunity to s<strong>in</strong>g the<br />
praises <strong>of</strong> this formidable cl<strong>in</strong>ician-scientist;<br />
the pro<strong>of</strong> lies <strong>in</strong> the half dozen letters <strong>of</strong> support<br />
that went <strong>in</strong>to his nom<strong>in</strong>ation package.<br />
Dr. Rem<strong>in</strong>gton is busy; he is the Director<br />
<strong>of</strong> the Medication Assessment Cl<strong>in</strong>ic <strong>in</strong> the<br />
Schizophrenia Program at the Centre for Addiction<br />
and Mental Health (CAMH), as well<br />
as Deputy Head <strong>of</strong> Research and Education<br />
for the same program. He is also Schizophrenia<br />
Head, Division <strong>of</strong> Bra<strong>in</strong> and Therapeutics<br />
and Pr<strong>of</strong>essor <strong>in</strong> the Department <strong>of</strong> Psychiatry<br />
at the University <strong>of</strong> Toronto. As if that<br />
were not enough, Dr. Rem<strong>in</strong>gton has been<br />
a member and graduate supervisor with the<br />
<strong>IMS</strong> for a decade, and he currently supervises<br />
seven students <strong>in</strong> his laboratory.<br />
Start<strong>in</strong>g out as an undergraduate at Waterloo<br />
Lutheran University (now Wilfred Laurier),<br />
Dr. Rem<strong>in</strong>gton met and worked with Dr.<br />
Hymie Anisman, whom he identifies as his<br />
first mentor. Their partnership lasted a number<br />
<strong>of</strong> years, as Dr. Rem<strong>in</strong>gton completed<br />
Photo by Laura Feldcamp<br />
29 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
CLOSE UP<br />
a PhD under his supervision <strong>in</strong> the area <strong>of</strong><br />
neurotransmitter development and hyperactivity.<br />
Set to undertake a post-doctoral<br />
position at the University <strong>of</strong> M<strong>in</strong>nesota, Dr.<br />
Rem<strong>in</strong>gton had a choice to make: “I was torn<br />
between the basic sciences and do<strong>in</strong>g work at<br />
the cl<strong>in</strong>ical level. I realized that if I wanted to<br />
make a career out <strong>of</strong> this work, I would have<br />
to marry the cl<strong>in</strong>ical with the basic, and to do<br />
so would require a medical degree.”<br />
Hav<strong>in</strong>g completed medical school at McMaster<br />
University, Dr. Rem<strong>in</strong>gton declared a specialty<br />
<strong>in</strong> neurology and began his residency<br />
at the University <strong>of</strong> Western Ontario. A year<br />
<strong>in</strong>to his tra<strong>in</strong><strong>in</strong>g, he was pulled aside by neurologist<br />
Dr. John Brown. “He said I’d make<br />
a better psychiatrist than neurologist,” recalls<br />
Dr. Rem<strong>in</strong>gton. “I called up the Psychiatry<br />
folks <strong>in</strong> Toronto and they accepted me over<br />
the phone.” He then began his psychiatry<br />
residency at CAMH. I ask him about what<br />
would eventually become the focus <strong>of</strong> his<br />
career—schizophrenia—and Dr. Rem<strong>in</strong>gton<br />
says the fasc<strong>in</strong>ation was <strong>in</strong>stant. “I had never<br />
seen anyth<strong>in</strong>g like it, nor have I s<strong>in</strong>ce.” In his<br />
second-to-last year <strong>of</strong> tra<strong>in</strong><strong>in</strong>g, Dr. Rem<strong>in</strong>gton<br />
was approached and <strong>of</strong>fered a staff position<br />
at CAMH; he has now been there almost<br />
thirty years.<br />
When asked to describe his research, Dr.<br />
Rem<strong>in</strong>gton remarks that it is a reflection <strong>of</strong><br />
why he left his post-doctoral position for<br />
medic<strong>in</strong>e. “I feel an obligation to ask a basic<br />
science question that can almost immediately<br />
be translated <strong>in</strong>to changes <strong>in</strong> cl<strong>in</strong>ical<br />
practice,” he cont<strong>in</strong>ues. Strictly speak<strong>in</strong>g,<br />
Dr. Rem<strong>in</strong>gton studies schizophrenia, but<br />
identifies one <strong>of</strong> his shortcom<strong>in</strong>gs as his “<strong>in</strong>ability<br />
to focus on a s<strong>in</strong>gle research question—someth<strong>in</strong>g<br />
that is usually preferred<br />
by scientists.” To illustrate the breadth <strong>of</strong> his<br />
work, Dr. Rem<strong>in</strong>gton and his students study<br />
an array <strong>of</strong> research questions that <strong>in</strong>clude<br />
schizotypy, the metabolic side effects <strong>of</strong> antipsychotic<br />
drugs, antipsychotic tolerance and<br />
adherence, and the manifestations <strong>of</strong> negative<br />
symptoms <strong>of</strong> schizophrenia through virtual<br />
reality techniques.<br />
Given that Dr. Rem<strong>in</strong>gton is be<strong>in</strong>g recognized<br />
for his mentorship abilities, our talk<br />
shifts to students and student supervision. I<br />
ask him how he chooses his students and he<br />
says, “It all depends on the <strong>in</strong>terview. I get a<br />
sense <strong>of</strong> whether or not the fit is right after<br />
speak<strong>in</strong>g to them.” When I ask him to describe<br />
his students, he takes a m<strong>in</strong>ute, a smile<br />
form<strong>in</strong>g on his face, and says his students are<br />
“motivated, able to work <strong>in</strong>dependently, and<br />
hopefully enjoy their research.” He adds, “I<br />
really enjoy the enthusiasm and excitement<br />
my students br<strong>in</strong>g to the laboratory every<br />
day. I rema<strong>in</strong> <strong>in</strong>spired by them.”<br />
“I f<strong>in</strong>d it stimulat<strong>in</strong>g to see the<br />
scope and quality <strong>of</strong> research be<strong>in</strong>g<br />
done by the students at the <strong>IMS</strong>. I<br />
really like see<strong>in</strong>g the passion they<br />
have for their work.”<br />
Dr. Rem<strong>in</strong>gton is known for his eloquence<br />
and candor, so when I ask him about his mentor<strong>in</strong>g<br />
style, I am <strong>in</strong>itially surprised when he<br />
pauses and says, “I don’t know how others<br />
mentor—it’s not like there’s a book for this<br />
sort <strong>of</strong> th<strong>in</strong>g.” He then cont<strong>in</strong>ues, “I mentor<br />
the way I was mentored [by Dr. Anisman]:<br />
I ensure close and regular contact with my<br />
students. I make myself available and try to<br />
provide a supportive environment, giv<strong>in</strong>g my<br />
students the resources they need to succeed.<br />
It’s noth<strong>in</strong>g fancy.” At this last po<strong>in</strong>t I laugh,<br />
know<strong>in</strong>g all too well how rare this situation<br />
can be: Gary Rem<strong>in</strong>gton is an absolutely fantastic<br />
mentor, he pours everyth<strong>in</strong>g <strong>in</strong>to his<br />
students, and they know it. So why does he<br />
do it? “I was there. Somebody did it for me.<br />
Dr. Anisman categorically changed my approach,<br />
not only to medic<strong>in</strong>e, but also to life.<br />
He was amaz<strong>in</strong>g—a role model to me. I feel<br />
I have an obligation to do that for as many<br />
people as possible mov<strong>in</strong>g forward.”<br />
Of the <strong>IMS</strong>, Dr. Rem<strong>in</strong>gton says, “I th<strong>in</strong>k it<br />
has an <strong>in</strong>novative approach to br<strong>in</strong>g<strong>in</strong>g people<br />
together from diverse backgrounds, and<br />
<strong>of</strong>fer<strong>in</strong>g them the opportunity to cross traditional<br />
research boundaries.” He adds that<br />
the challenge rema<strong>in</strong>s <strong>in</strong> “br<strong>in</strong>g<strong>in</strong>g people together<br />
from many areas and levels <strong>of</strong> expertise<br />
<strong>in</strong> an environment that rewards absolute<br />
focus on a s<strong>in</strong>gle area or research question.”<br />
Dr. Rem<strong>in</strong>gton’s <strong>in</strong>volvement <strong>in</strong> the <strong>IMS</strong><br />
doesn’t only <strong>in</strong>clude his role as a graduate<br />
supervisor; he has been on countless Project<br />
Advisory Committees (PACs) and has been<br />
a judge <strong>in</strong> both the <strong>Summer</strong> Undergraduate<br />
Research Program (SURP) and <strong>IMS</strong> Scientific<br />
Days. “I f<strong>in</strong>d it stimulat<strong>in</strong>g to see the<br />
scope and quality <strong>of</strong> research be<strong>in</strong>g done by<br />
the students at the <strong>IMS</strong>. I really like see<strong>in</strong>g<br />
the passion they have for their work.”<br />
I ask Dr. Rem<strong>in</strong>gton what he sees himself<br />
do<strong>in</strong>g <strong>in</strong> ten years: “I hope to still be com<strong>in</strong>g<br />
<strong>in</strong>to work every day. I don’t see what I do as<br />
a job. It’s a well kept secret how much I enjoy<br />
this.” Admitt<strong>in</strong>g that he sleeps about four<br />
hours a night, he adds, “I am blessed with do<strong>in</strong>g<br />
someth<strong>in</strong>g that I love so much and still<br />
want to be do<strong>in</strong>g. I am so lucky—I hope no<br />
one catches on!”<br />
For students, Dr. Rem<strong>in</strong>gton says the largest<br />
obstacle is the “<strong>in</strong>credible competition to<br />
capture a spot <strong>in</strong> this research environment.”<br />
I ask him what is key to select<strong>in</strong>g the right<br />
supervisor, to which he replies, “F<strong>in</strong>d a mentor<br />
as early on as you can. The goal is to f<strong>in</strong>d<br />
someone you respect. Respect is fundamental.”<br />
Dr. Rem<strong>in</strong>gton sees the potential <strong>in</strong> his students<br />
and treats them as valued members <strong>of</strong><br />
the scientific community. His ability to effectively<br />
guide and support his students, while<br />
always rema<strong>in</strong><strong>in</strong>g committed to their success,<br />
makes him the true def<strong>in</strong>ition <strong>of</strong> a mentor.<br />
Although he would never admit to it, I can<br />
th<strong>in</strong>k <strong>of</strong> no one more deserv<strong>in</strong>g <strong>of</strong> the Mel<br />
Silverman Mentorship Award. Congratulations<br />
Dr. Rem<strong>in</strong>gton.<br />
Student sentiments<br />
“Dr. Rem<strong>in</strong>gton is friendly, warm, and encourag<strong>in</strong>g,<br />
while rema<strong>in</strong><strong>in</strong>g entirely pr<strong>of</strong>essional.<br />
He is respectful and sensitive to the<br />
needs <strong>of</strong> his students.”<br />
- George Foussias, MD, PhD candidate<br />
“Dr. Rem<strong>in</strong>gton allows his students to<br />
demonstrate their success, easily stepp<strong>in</strong>g<br />
aside to enable personal growth and accomplishment.”<br />
- Gagan Fervaha, MSc candidate<br />
“Dr. Rem<strong>in</strong>gton sees the potential <strong>in</strong> his<br />
students and treats them as creative, <strong>in</strong>telligent,<br />
and responsible scientists.”<br />
- Laura Schulze, MSc candidate<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 30
VIEWPOINT<br />
Publish<br />
and Perish<br />
Why science takes two steps forward and one step back<br />
By S. Amanda Ali<br />
It is the dream <strong>of</strong> every scientist to<br />
publish a research article <strong>in</strong> Nature, Cell,<br />
or Science. For a graduate student work<strong>in</strong>g<br />
towards a PhD, a publication <strong>in</strong> one <strong>of</strong><br />
these prestigious journals almost guarantees<br />
a successful defense exam<strong>in</strong>ation, a reputable<br />
post-doctoral fellowship, and a subsequent<br />
tenure-track position. For a senior scientist<br />
manag<strong>in</strong>g a research lab, publications <strong>of</strong> this<br />
calibre provide an advantage <strong>in</strong> grant competitions<br />
and give greater stability <strong>in</strong> fund<strong>in</strong>g.<br />
For a research <strong>in</strong>stitution, high-impact publications<br />
draw global spotlight, attract better<br />
scientists, and earn the <strong>in</strong>stitution prestige.<br />
It therefore appears to be <strong>in</strong> everyone’s best<br />
<strong>in</strong>terest to publish <strong>in</strong> the highest impact<br />
journals possible, but this dream could be a<br />
nightmare <strong>in</strong> disguise.<br />
The higher the journal’s impact factor, the<br />
higher its retraction rate 1 . Reasons for retraction<br />
are distributed between misconduct and<br />
honest error, but the underly<strong>in</strong>g causes for<br />
these occurrences rema<strong>in</strong> largely unexam<strong>in</strong>ed.<br />
Executive editor <strong>of</strong> Science, Monica M.<br />
Bradford, defended this f<strong>in</strong>d<strong>in</strong>g <strong>in</strong> The New<br />
York Times by suggest<strong>in</strong>g that high-impact<br />
journals have a higher retraction rate because<br />
they receive more attention and are subject to<br />
more scrut<strong>in</strong>y 2 . While this may be the case, it<br />
implies that other, lower-impact journals also<br />
publish articles that violate ethical guidel<strong>in</strong>es,<br />
conta<strong>in</strong> scientific misconduct or error,<br />
or plagiarize previously published work, but<br />
that those articles go unnoticed. The end result<br />
is the same—our scientific literature is<br />
full <strong>of</strong> error, and that error is on the rise.<br />
A recent article <strong>in</strong> Nature reported that the<br />
number <strong>of</strong> retraction notices has <strong>in</strong>creased<br />
10-fold over the past decade, while publications<br />
have <strong>in</strong>creased by only 44% 3 . Although<br />
improved vigilance is a convenient and plausible<br />
explanation for this trend, there are<br />
other possible culprits. Astound<strong>in</strong>gly, 1-2%<br />
<strong>of</strong> scientists have admitted to fabricat<strong>in</strong>g, fal-<br />
sify<strong>in</strong>g, or modify<strong>in</strong>g data or results at least<br />
once 4 . A close exam<strong>in</strong>ation <strong>of</strong> the publish<strong>in</strong>g<br />
pipel<strong>in</strong>e reveals several po<strong>in</strong>ts where the<br />
pressure to publish may overwhelm an otherwise<br />
honest scientist, lead<strong>in</strong>g them to transgression.<br />
As mentioned, graduate students<br />
need to publish to build their future, and<br />
senior scientists need to publish to secure<br />
their future. This pressure to publish is compounded<br />
by the predom<strong>in</strong>ant bias to publish<br />
positive results more than negative results.<br />
(For a complete discussion <strong>of</strong> the research bias<br />
towards positive results, see “Positive Pressure,”<br />
<strong>in</strong> our Fall 2011 issue.) While only a m<strong>in</strong>ority<br />
<strong>of</strong> scientists may be will<strong>in</strong>g to fabricate or<br />
falsify results to fit their hypotheses, a majority<br />
<strong>of</strong> scientists may be <strong>in</strong>cl<strong>in</strong>ed to select data<br />
which support their hypotheses, and ignore<br />
data which do not.<br />
There lies the danger <strong>of</strong> predicat<strong>in</strong>g the success<br />
<strong>of</strong> a scientist on their publication record;<br />
the purpose for publish<strong>in</strong>g shifts toward<br />
Photo courtesy <strong>of</strong> www.istockphoto.com; ID # 16340434<br />
31 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
VIEWPOINT<br />
survival <strong>of</strong> the fittest author, and away from<br />
dissem<strong>in</strong>at<strong>in</strong>g authentic results. Scientists<br />
are <strong>in</strong>creas<strong>in</strong>gly be<strong>in</strong>g evaluated us<strong>in</strong>g metrics<br />
such as the h-<strong>in</strong>dex, which is based on<br />
number <strong>of</strong> publications and number <strong>of</strong> citations<br />
per publication 5 . Assess<strong>in</strong>g a scientist’s<br />
performance us<strong>in</strong>g such metrics creates undeniable<br />
desire, need, and pressure to publish<br />
<strong>of</strong>ten, and <strong>in</strong> highly cited journals. Countries<br />
such as Ch<strong>in</strong>a, South Korea, and Turkey <strong>of</strong>fer<br />
cash <strong>in</strong>centives to encourage local scientists<br />
to submit their manuscripts to high-impact<br />
journals 6 . Despite the low probability <strong>of</strong> success,<br />
the high volume <strong>of</strong> submissions overwhelms<br />
reviewers and congests the publish<strong>in</strong>g<br />
pipel<strong>in</strong>e. Given these circumstances, how<br />
can the literature be trusted, and how can<br />
scientific progress be made?<br />
The soar<strong>in</strong>g retraction rate observed<br />
<strong>in</strong> high-impact journals may<br />
be an accelerated manifestation <strong>of</strong><br />
the decl<strong>in</strong>e effect. Because highimpact<br />
journals publish studies<br />
with novel and dramatic results,<br />
those results are more likely to be<br />
overstated, and are less likely to be<br />
reproducible. The lack <strong>of</strong> reproducibility<br />
is unsurpris<strong>in</strong>g consider<strong>in</strong>g<br />
the tweak<strong>in</strong>g, select<strong>in</strong>g, and beautify<strong>in</strong>g<br />
<strong>of</strong> data that <strong>of</strong>tentimes precedes<br />
publication.<br />
First reported <strong>in</strong> the 1930s, an established<br />
barrier to scientific advancement is the decl<strong>in</strong>e<br />
effect, which is observed <strong>in</strong> the literature<br />
as scientifically discovered effects that<br />
dim<strong>in</strong>ish over time. Schooler suggests that<br />
“if early results are more likely to be reported<br />
when errors comb<strong>in</strong>e to magnify the apparent<br />
effect, then published studies will show<br />
systematic bias towards <strong>in</strong>itially exaggerated<br />
f<strong>in</strong>d<strong>in</strong>gs, which are subsequently statistically<br />
self-corrected” 7 . The soar<strong>in</strong>g retraction rate<br />
observed <strong>in</strong> high-impact journals may be an<br />
accelerated manifestation <strong>of</strong> the decl<strong>in</strong>e effect.<br />
Because high-impact journals publish<br />
studies with novel and dramatic results, those<br />
results are more likely to be overstated, and<br />
are less likely to be reproducible. The lack <strong>of</strong><br />
reproducibility is unsurpris<strong>in</strong>g consider<strong>in</strong>g<br />
the tweak<strong>in</strong>g, select<strong>in</strong>g, and beautify<strong>in</strong>g <strong>of</strong><br />
data that <strong>of</strong>tentimes precedes publication.<br />
Detrimentally, if the studies <strong>in</strong> high-impact<br />
journals are reach<strong>in</strong>g the widest audiences<br />
and are convey<strong>in</strong>g less-than-accurate results,<br />
the scientific field is be<strong>in</strong>g misguided.<br />
The argument can be made that science is an<br />
imperfect field, with enormous variability. In<br />
biomedical research, there are <strong>in</strong>numerable<br />
known and unknown variables that <strong>in</strong>fluence<br />
experimental outcomes, some as significant<br />
as the stra<strong>in</strong> <strong>of</strong> mouse used, some as <strong>in</strong>nocuous<br />
as the time <strong>of</strong> day an experiment is conducted.<br />
Every experiment conta<strong>in</strong>s outliers,<br />
<strong>in</strong>consistent replicates, and unexpected f<strong>in</strong>d<strong>in</strong>gs,<br />
but these are rarely reported, and perhaps<br />
that is the bigger issue. As Dr. Karen Davis,<br />
Associate Director <strong>of</strong> the <strong>IMS</strong> and Editor<br />
<strong>of</strong> Pa<strong>in</strong>, previously communicated to the <strong>IMS</strong><br />
<strong>Magaz<strong>in</strong>e</strong> (“Positive Pressure,” Fall 2011), an<br />
<strong>in</strong>complete or <strong>in</strong>correct scientific record can<br />
lead to propagation <strong>of</strong> unfounded ideas, unnecessary<br />
replication <strong>of</strong> experiments, cl<strong>in</strong>ical<br />
translation <strong>of</strong> harmful therapies, or delayed<br />
development <strong>of</strong> alternate hypotheses. Once<br />
flawed ideas are published, they can never<br />
truly be retracted. Budd et al. report that<br />
even after an article is retracted, it cont<strong>in</strong>ues<br />
to be cited, without acknowledgement <strong>of</strong> the<br />
retraction 3 . Understandably, once digital versions<br />
<strong>of</strong> articles are downloaded, researchers<br />
are unlikely to consult the orig<strong>in</strong>al source<br />
aga<strong>in</strong>, and are therefore unlikely to be aware<br />
<strong>of</strong> corrections.<br />
What is needed is a more complete account<br />
<strong>of</strong> scientific f<strong>in</strong>d<strong>in</strong>gs, be they negative or<br />
positive, consistent or <strong>in</strong>consistent, surpris<strong>in</strong>g<br />
or expected. Dur<strong>in</strong>g the <strong>IMS</strong> Scientific<br />
Day <strong>2012</strong> Bernard Langer Lecture <strong>in</strong> Health<br />
Sciences, Dr. Thomas R. Insel, MD, Director<br />
<strong>of</strong> National <strong>Institute</strong> <strong>of</strong> Mental Health, posited<br />
that if experiments are soundly designed<br />
and flawlessly executed, then those results<br />
should be dissem<strong>in</strong>ated, regardless <strong>of</strong> what<br />
they are. Furthermore, Schooler believes “we<br />
need a better record <strong>of</strong> unpublished research<br />
before we can know how well the current<br />
scientific process, based on peer review and<br />
experimental replication, succeeds <strong>in</strong> dist<strong>in</strong>guish<strong>in</strong>g<br />
grounded truth from unwarranted<br />
fallacy” 7 . He recognizes the difficulties <strong>in</strong><br />
implementation, but suggests an open-access<br />
database <strong>of</strong> research methods, which allows<br />
scientists to log their hypotheses and methodologies<br />
prior to experiments, and their<br />
published and unpublished results afterwards<br />
7 .<br />
Schooler believes “we need a better<br />
record <strong>of</strong> unpublished research<br />
before we can know how well the<br />
current scientific process, based on<br />
peer review and experimental replication,<br />
succeeds <strong>in</strong> dist<strong>in</strong>guish<strong>in</strong>g<br />
grounded truth from unwarranted<br />
fallacy.”<br />
To purify the publication pool, the current<br />
publish<strong>in</strong>g paradigm should be restructured<br />
to diffuse the pressure experienced by researchers.<br />
Among other strategies, graduate<br />
students should be given avenues to publish<br />
their negative results, and senior scientists<br />
should be evaluated on metrics other than<br />
their publish<strong>in</strong>g records. To purify the publication<br />
pool, more focus should be placed<br />
on honest account<strong>in</strong>g <strong>of</strong> data <strong>in</strong> its entirety,<br />
and less focus should be placed on polish<strong>in</strong>g<br />
<strong>of</strong> data for high-impact journals. Researchers<br />
should be m<strong>in</strong>dful <strong>of</strong> the permanence <strong>of</strong><br />
published results, and wary that embellished<br />
or modified data can significantly h<strong>in</strong>der<br />
scientific progress. To alleviate current publish<strong>in</strong>g<br />
pressures is to purify the publication<br />
pool, and move science forward.<br />
Disclaimer: The op<strong>in</strong>ions expressed by the<br />
author(s) are <strong>in</strong> no way affiliated with the <strong>Institute</strong><br />
<strong>of</strong> Medical Science or the University <strong>of</strong> Toronto.<br />
Comments are welcome at theimsmagaz<strong>in</strong>e@<br />
gmail.com.<br />
References<br />
1. Fang FC, Casadevall A. Retracted science and the retraction<br />
<strong>in</strong>dex. Infect Immun. 2011;79(10):3855-3859.<br />
2. Zimmer C. A Sharp Rise <strong>in</strong> Retractions Prompts Calls<br />
for Reform. The New York Times. <strong>2012</strong> Apr 17;Sect. D-1.<br />
3. Van Noorden R. Science publish<strong>in</strong>g: The trouble with<br />
retractions. Nature. 2011;478(7367):26-28.<br />
4. Fanelli D. “Positive” results <strong>in</strong>crease down the Hierarchy<br />
<strong>of</strong> the Sciences. PLoS One. 2010;5(4):e10068.<br />
5. Hirsch JE. An <strong>in</strong>dex to quantify an <strong>in</strong>dividual’s scientific<br />
research output. Proc Natl Acad Sci U S A.<br />
2005;102(46):16569-16572.<br />
6. Stephan P. Research efficiency: Perverse <strong>in</strong>centives.<br />
Nature. <strong>2012</strong>;484(7392):29-31.<br />
7. Schooler J. Unpublished results hide the decl<strong>in</strong>e effect.<br />
Nature. 2011;470(7335):437.<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 32
VIEWPOINT<br />
A Numbers Game<br />
Why an article about statistics shouldn’t make you want to turn the page<br />
By Allison Rosen<br />
What do Chi-squared tests,<br />
t-tests and ANOVAs all have <strong>in</strong><br />
common? Some might contend<br />
that they are all statistical tests, but others<br />
will attest that they are all th<strong>in</strong>gs that give<br />
graduate students a headache. But why do<br />
so many students harbor negative attitudes<br />
towards statistics? These tests are there to<br />
help us—to validate our results and help our<br />
<strong>in</strong>terpretations. Right? The <strong>IMS</strong> <strong>Magaz<strong>in</strong>e</strong><br />
conducted a series <strong>of</strong> <strong>in</strong>terviews to provide<br />
a snapshot <strong>of</strong> what graduate students face<br />
when approach<strong>in</strong>g statistics.<br />
“I’m not comfortable with statistics.”<br />
<strong>IMS</strong> MSc Student Jack* pr<strong>of</strong>essed this view,<br />
and he certa<strong>in</strong>ly does not stand alone. Many<br />
graduate students <strong>in</strong>terviewed for this article<br />
confessed that they do not feel they have<br />
enough knowledge <strong>of</strong> statistics to perform<br />
the tests necessary to properly <strong>in</strong>terpret their<br />
experiments. Poor knowledge <strong>of</strong> statistics<br />
can have a big impact <strong>in</strong> graduate school.<br />
Jack expla<strong>in</strong>s, “It has made my ability to<br />
analyze and <strong>in</strong>terpret my own research data<br />
more challeng<strong>in</strong>g. I have had to teach myself<br />
th<strong>in</strong>gs along the way, or seek significant help<br />
from labmates and outside sources; it’s been<br />
… a def<strong>in</strong>ite source <strong>of</strong> frustration.” Another<br />
<strong>IMS</strong> student agreed with this sentiment: “I<br />
am only confident us<strong>in</strong>g very basic statistical<br />
tests that apply to my data,” claims Lauren*,<br />
a PhD student.<br />
“Statistical analysis is a huge part <strong>of</strong> my research.<br />
My limited knowledge on the subject<br />
<strong>of</strong>ten limits my <strong>in</strong>terpretation <strong>of</strong> my data<br />
and ability to clearly understand research articles,”<br />
Lauren elaborates. Jack confessed that<br />
although he has not yet been affected by his<br />
lack <strong>of</strong> adequate statistical knowledge, this<br />
problem will become more prom<strong>in</strong>ent as he<br />
prepares to defend his thesis. “We use a statistician,<br />
so really I just need to know how to<br />
make data look pretty <strong>in</strong> Excel.”<br />
But not all students share these negative<br />
views. Cor<strong>in</strong>ne Daly, who recently defended<br />
her MSc, and Richard Foty, currently work<strong>in</strong>g<br />
on his PhD, share their thoughts. “As an<br />
epidemiologist, I spend a good portion <strong>of</strong> my<br />
day analyz<strong>in</strong>g data or review<strong>in</strong>g articles, so<br />
over time I’ve gotten comfortable with the<br />
math. It’s the <strong>in</strong>terpretation <strong>of</strong> those results,<br />
however, that I am most <strong>in</strong>terested <strong>in</strong>. Statistical<br />
analysis is just the tool I use to get me<br />
there,” expla<strong>in</strong>s Richard. Cor<strong>in</strong>ne expands by<br />
expla<strong>in</strong><strong>in</strong>g that her familiarity with statistics<br />
has been helpful <strong>in</strong> understand<strong>in</strong>g rounds<br />
presentations, publications, and expla<strong>in</strong><strong>in</strong>g<br />
her research. “An understand<strong>in</strong>g and appreciation<br />
<strong>of</strong> statistics has been <strong>in</strong>dispensable <strong>in</strong><br />
my research career,” states MSc student Benjam<strong>in</strong><br />
Mora.<br />
Contrast<strong>in</strong>g feel<strong>in</strong>gs towards statistics aside,<br />
all <strong>of</strong> these students agree that know<strong>in</strong>g statistics<br />
is important. Amy*, an <strong>IMS</strong> student<br />
complet<strong>in</strong>g her MSc, expla<strong>in</strong>s that despite her<br />
discomfort with statistics, she understands<br />
its importance. “Better knowledge <strong>of</strong> statistics<br />
can help tremendously <strong>in</strong> understand<strong>in</strong>g<br />
papers beyond simple P-values; it allows for<br />
critical analysis, which is a skill all graduates<br />
need to learn.” Amy further elaborates on the<br />
level <strong>of</strong> statistical knowledge she believes to<br />
be necessary for graduate students. “Whether<br />
or not they complete their own analysis or<br />
send results <strong>of</strong>f to a statistician, I absolutely<br />
believe graduate students should be familiar<br />
with statistics—and I’m speak<strong>in</strong>g as someone<br />
who currently has very limited statistical<br />
knowledge. It’s difficult to gauge the exact<br />
level <strong>of</strong> knowledge needed, but I th<strong>in</strong>k it<br />
would be universally helpful to understand<br />
the various types <strong>of</strong> analyses available, and<br />
Photo courtesy <strong>of</strong> www.istockphoto.com; ID # 9015523<br />
33 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
VIEWPOINT<br />
more importantly, why they are appropriate<br />
under different circumstances.”<br />
“You can collect all the high quality data you<br />
want, but…you need to have the statistics to<br />
back it up,” Cor<strong>in</strong>ne emphasizes. However,<br />
she also concedes that the issue is more complex<br />
than that. “There is never [one] right answer<br />
<strong>in</strong> statistical methods. Most times there<br />
are a few ways <strong>of</strong> look<strong>in</strong>g at the same problem.<br />
Problem solv<strong>in</strong>g and discuss<strong>in</strong>g which<br />
method is best for a specific question is necessary<br />
sometimes.”<br />
Given that most students understand how<br />
important statistics are to their research, why<br />
do some students still feel negatively about<br />
statistics?<br />
“I personally th<strong>in</strong>k <strong>in</strong> the <strong>IMS</strong>, not enough<br />
people know much <strong>of</strong> anyth<strong>in</strong>g about statistics,”<br />
Cor<strong>in</strong>ne shares. “[This] makes me<br />
question how <strong>in</strong>dividuals read and understand<br />
other publications out there. However,<br />
I def<strong>in</strong>itely th<strong>in</strong>k it is the responsibility <strong>of</strong> a<br />
supervisor and surround<strong>in</strong>g research group<br />
to discuss common methods <strong>in</strong> their field so<br />
that graduate students can <strong>in</strong>dependently analyze<br />
their data and then consult the proper<br />
resources when necessary.”<br />
While the supervisor holds some responsibility<br />
<strong>in</strong> ensur<strong>in</strong>g a student has adequate statistical<br />
knowledge to successfully design and<br />
<strong>in</strong>terpret experiments, students also have an<br />
onus to take courses to improve their skills.<br />
Cor<strong>in</strong>ne has taken two statistics courses<br />
with<strong>in</strong> the <strong>IMS</strong>: Biostatistics for Health Scientists<br />
and Introduction to Cl<strong>in</strong>ical Biostatistics,<br />
and recommends that other graduate<br />
students follow suit <strong>in</strong> order to understand<br />
the statistics necessary for their research<br />
projects. “These courses def<strong>in</strong>itely provided<br />
a foundation for understand<strong>in</strong>g methods<br />
and theory beh<strong>in</strong>d basic and more advanced<br />
statistical methods. However, apply<strong>in</strong>g what<br />
you know…is a whole new ball game. Only<br />
through repeated practice and discussion<br />
with my research group have I learned the<br />
mean<strong>in</strong>g <strong>of</strong> statistical tests that I learned<br />
about <strong>in</strong> those courses.”<br />
While Cor<strong>in</strong>ne has already taken many<br />
courses to become familiar with statistics,<br />
most students have not. “My only formal <strong>in</strong>troduction<br />
to statistics was through a very<br />
brief component <strong>of</strong> an undergraduate biol-<br />
ogy course that touched upon biostatistics. I<br />
have never taken an entire course dedicated<br />
to statistics at either the high school or undergraduate<br />
level,” confides Amy.<br />
Enter Dr. Paul Corey. Corey has a number <strong>of</strong><br />
positions teach<strong>in</strong>g statistics with<strong>in</strong> the University<br />
<strong>of</strong> Toronto. He teaches both Biostatistics<br />
for Health Scientists and Introduction to<br />
Cl<strong>in</strong>ical Biostatistics <strong>in</strong> the <strong>IMS</strong>. “Every good<br />
researcher asks whether [an] observed difference<br />
is likely to be due entirely to chance,”<br />
Corey expla<strong>in</strong>s. However, he also recognizes<br />
that a problem does exist and shares a story<br />
<strong>of</strong> a former student who, after completed a<br />
class assignment on a paper she had published,<br />
realized “the published analysis was<br />
wrong.”<br />
Smaller, more focused courses circumvent<br />
current dilemmas <strong>in</strong>volv<strong>in</strong>g<br />
bloated statistics courses that<br />
overwhelm students.<br />
“Many students do not have a statistician on<br />
their thesis committee and some unfortunate<br />
analyses get published,” Corey expla<strong>in</strong>s.<br />
“There is enormous variation <strong>in</strong> the statistical<br />
literacy <strong>of</strong> my scientific colleagues.”<br />
Surely we do not want to lower the quality <strong>of</strong><br />
published science. But how extensive should<br />
a graduate student’s knowledge <strong>of</strong> statistics<br />
be? Corey discussed his future vision <strong>of</strong> statistics<br />
education <strong>in</strong> graduate departments. “I<br />
th<strong>in</strong>k that we are <strong>in</strong> a stage where there will<br />
be more modular courses that will enable students<br />
to choose to study only those topics <strong>of</strong><br />
use for the type <strong>of</strong> analyses they will need to<br />
do <strong>in</strong> their thesis research. This will <strong>in</strong>crease<br />
the <strong>in</strong>terest and dedication <strong>of</strong> some students.<br />
In the future, I predict that there will be more<br />
short statistics courses with fewer students <strong>in</strong><br />
each.”<br />
Smaller, more focused courses circumvent<br />
current dilemmas <strong>in</strong>volv<strong>in</strong>g bloated statistics<br />
courses that overwhelm students. Such<br />
an approach changes not only research quality,<br />
but also op<strong>in</strong>ions and attitudes towards<br />
statistics among graduate students. As Corey<br />
describes, “Many students beg<strong>in</strong> to truly<br />
appreciate the power <strong>of</strong> statistics when they<br />
have to perform the analyses on their own<br />
thesis data. A proper teach<strong>in</strong>g and under-<br />
stand<strong>in</strong>g <strong>of</strong> statistics rests on a few important<br />
and basic concepts. These concepts can only<br />
be understood by frequent repetition us<strong>in</strong>g<br />
language and logic.”<br />
Corey warns that not all students may be<br />
pleased by the changes. “Sometimes students<br />
are impatient and just want the facts. That is,<br />
they want a cookbook course. This is where<br />
the danger lies.”<br />
“Students should be able to analyze their own<br />
data with a little help from their friends,” Corey<br />
goes on to suggest, mirror<strong>in</strong>g the thoughts<br />
<strong>of</strong> many <strong>IMS</strong> students. “I generally seek help<br />
from someone <strong>in</strong> the lab when I can’t figure<br />
out how to analyze my data,” shares Lauren.<br />
Even Benjam<strong>in</strong>, who feels comfortable<br />
with statistics, agrees that “<strong>in</strong> cases where<br />
the analysis becomes more convoluted, it is<br />
helpful to receive assistance from more experienced<br />
researchers or from statisticians.”<br />
Cor<strong>in</strong>ne also stresses the importance <strong>of</strong> gett<strong>in</strong>g<br />
help: “I def<strong>in</strong>itely th<strong>in</strong>k that labs and research<br />
groups should have access to biostatistical<br />
assistance.”<br />
“Start by review<strong>in</strong>g the literature and see<br />
what k<strong>in</strong>ds <strong>of</strong> tests other scientists have used<br />
to answer similar questions,” Richard suggests.<br />
“Once you’ve come up with a few possibilities,<br />
research them thoroughly and consult<br />
a statistician if you can. F<strong>in</strong>ally, present<br />
the different methods to your supervisor and<br />
committee members and get their recommendations.”<br />
Plann<strong>in</strong>g ahead and consult<strong>in</strong>g<br />
others early on can be a big time saver.<br />
Richard advises students to “not be <strong>in</strong>timidated<br />
by statistics; they’re a useful tool. Remember<br />
that we all have to look th<strong>in</strong>gs up.<br />
If we knew exactly what we were do<strong>in</strong>g, they<br />
wouldn’t call it research.”<br />
* Names have been changed to protect the anonymity<br />
<strong>of</strong> the students <strong>in</strong>terviewed<br />
Disclaimer: The op<strong>in</strong>ions expressed by the<br />
author(s) are <strong>in</strong> no way affiliated with the <strong>Institute</strong><br />
<strong>of</strong> Medical Science or the University <strong>of</strong> Toronto.<br />
Comments are welcome at theimsmagaz<strong>in</strong>e@<br />
gmail.com.<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 34
EXPERT OPINION<br />
Interactive proteomics with MYTH:<br />
Identify<strong>in</strong>g prote<strong>in</strong> puzzles and putt<strong>in</strong>g them <strong>in</strong>to their correct cellular pathway<br />
By Igor Stagljar, PhD<br />
Every process <strong>in</strong> a cell is affected<br />
by <strong>in</strong>teractions between prote<strong>in</strong>s,<br />
which determ<strong>in</strong>e everyth<strong>in</strong>g from the<br />
cell shape to the function <strong>of</strong> a particular biochemical<br />
pathway. Just as we tailor our own<br />
conversations depend<strong>in</strong>g on sett<strong>in</strong>g, prote<strong>in</strong>s<br />
exhibit many different modes <strong>of</strong> <strong>in</strong>teraction.<br />
Long-term prote<strong>in</strong>-prote<strong>in</strong> <strong>in</strong>teractions<br />
(PPIs) result <strong>in</strong> prote<strong>in</strong> complexes, while<br />
briefer prote<strong>in</strong> liaisons may lead to a range<br />
<strong>of</strong> possible chemical modifications. Because<br />
they are so <strong>in</strong>tegral to the physiological function<br />
<strong>of</strong> any organism, PPIs are essential to<br />
many l<strong>in</strong>es <strong>of</strong> research, both basic and cl<strong>in</strong>ical.<br />
In the past decade, scientists work<strong>in</strong>g <strong>in</strong> the<br />
emerg<strong>in</strong>g field <strong>of</strong> “<strong>in</strong>teractive proteomics”<br />
have <strong>in</strong>itiated numerous projects to build<br />
comprehensive maps <strong>of</strong> all PPIs (also called<br />
“<strong>in</strong>teractomes”) <strong>of</strong> a given cell or organism<br />
with the ultimate goal <strong>of</strong> understand<strong>in</strong>g the<br />
functions <strong>of</strong> the many prote<strong>in</strong>s whose roles<br />
are not yet known (Figure 1). This is based<br />
upon the pr<strong>in</strong>ciple that if two prote<strong>in</strong>s <strong>in</strong>teract<br />
with each other they very likely partici-<br />
pate <strong>in</strong> the same or related cellular functions<br />
(the pr<strong>in</strong>ciple <strong>of</strong> “guilt by association”). In<br />
other words, clues about the function <strong>of</strong> one<br />
prote<strong>in</strong> whose role is not understood can be<br />
ga<strong>in</strong>ed by observ<strong>in</strong>g that it <strong>in</strong>teracts with another<br />
prote<strong>in</strong> whose function is known. Such<br />
an approach, when applied on a large-scale<br />
with all prote<strong>in</strong>s <strong>of</strong> a certa<strong>in</strong> organism, can<br />
result <strong>in</strong> the identification <strong>of</strong> novel components<br />
<strong>of</strong> previously known pathways, or, vice<br />
versa, one may conclude that a prote<strong>in</strong> previously<br />
known to be <strong>in</strong>volved <strong>in</strong> one biological<br />
pathway also functions <strong>in</strong> another.<br />
A special focus <strong>of</strong> our laboratory is on prote<strong>in</strong>s<br />
associated with biological membranes,<br />
also called membrane prote<strong>in</strong>s, which total<br />
approximately one third <strong>of</strong> all prote<strong>in</strong>s <strong>in</strong> any<br />
cell 1 . These prote<strong>in</strong>s mediate a wide range<br />
<strong>of</strong> fundamental biological processes such as<br />
cell signal<strong>in</strong>g, transport <strong>of</strong> membrane-impermeable<br />
molecules, cell-cell communication,<br />
and cell adhesion. Interest<strong>in</strong>gly, many<br />
<strong>of</strong> these membrane prote<strong>in</strong>s have been found<br />
to have disease-associated function, and notably<br />
most <strong>of</strong> the drugs on the market today<br />
are targeted towards membrane prote<strong>in</strong>s. As<br />
such, there is a strong demand from both<br />
academic researchers and biotech/pharma<br />
companies to ga<strong>in</strong> further <strong>in</strong>sight <strong>in</strong>to pathways<br />
and <strong>in</strong>teractions <strong>in</strong>volv<strong>in</strong>g membrane<br />
prote<strong>in</strong>s. It is therefore <strong>of</strong> utmost importance<br />
to build a comprehensive <strong>in</strong>teractome <strong>of</strong> this<br />
crucial class <strong>of</strong> prote<strong>in</strong>s. However, despite extensive<br />
research <strong>in</strong> the past decade, there is<br />
a lack <strong>of</strong> <strong>in</strong>-depth understand<strong>in</strong>g <strong>of</strong> PPIs associated<br />
with this class <strong>of</strong> prote<strong>in</strong>s because <strong>of</strong><br />
their unique biochemical features and enormous<br />
complexity. This is a major obstacle<br />
for design<strong>in</strong>g improved and more targeted<br />
therapies, and importantly, understand<strong>in</strong>g<br />
the biology <strong>of</strong> deregulation <strong>of</strong> these <strong>in</strong>tegral<br />
membrane prote<strong>in</strong>s which leads to numerous<br />
human diseases.<br />
Previously, our lab developed the Membrane<br />
Yeast Two-Hybrid (MYTH) system, a powerful<br />
proteomic tool for identify<strong>in</strong>g the <strong>in</strong>teractors<br />
<strong>of</strong> membrane prote<strong>in</strong>s <strong>in</strong> an <strong>in</strong> vivo<br />
sett<strong>in</strong>g us<strong>in</strong>g baker’s yeast as a model organism<br />
(Figure 2). Us<strong>in</strong>g the MYTH system, an<br />
<strong>in</strong>teraction between two prote<strong>in</strong>s can be converted<br />
<strong>in</strong>to an ‘observable signal’, specifically<br />
the growth, and blue coloration, <strong>of</strong> yeast on<br />
a specialized media. A unique advantage <strong>of</strong><br />
MYTH is that it can detect prote<strong>in</strong>s associated<br />
with almost any membrane prote<strong>in</strong> <strong>in</strong><br />
a high-throughput screen<strong>in</strong>g <strong>format</strong>, and<br />
is therefore perfectly suited for build<strong>in</strong>g <strong>in</strong>teractomes<br />
<strong>of</strong> this difficult class <strong>of</strong> prote<strong>in</strong>s.<br />
S<strong>in</strong>ce the development <strong>of</strong> MYTH, it has been<br />
applied successfully to identify both transient<br />
and stable <strong>in</strong>teractions among various membrane<br />
prote<strong>in</strong>s from yeast, plant, fly, worm,<br />
and humans 2-5 . It became a valuable proteomic<br />
tool by creat<strong>in</strong>g a bridge between the<br />
basics <strong>of</strong> prote<strong>in</strong> biochemistry and practical<br />
applications <strong>in</strong> the field <strong>of</strong> medic<strong>in</strong>e and disease<br />
management. Along this notion, MYTH<br />
has recently been applied to ATP13A2, a human<br />
lysosomal membrane prote<strong>in</strong> <strong>in</strong>volved<br />
<strong>in</strong> Kufor-Rakeb syndrome characterized by<br />
early-onset park<strong>in</strong>sonism, neurodegeneration<br />
and dementia. MYTH identified dozens<br />
<strong>of</strong> ATP13A2-associated prote<strong>in</strong>s many <strong>of</strong><br />
which showed to be functionally and mechanistically<br />
<strong>in</strong>terconnected to ATP13A2 6 . This<br />
and other studies showed that MYTH is an<br />
<strong>in</strong>terest<strong>in</strong>g translational research tool, allow<strong>in</strong>g<br />
researchers to study the <strong>in</strong>teractions <strong>of</strong> a<br />
disease-associated prote<strong>in</strong> <strong>of</strong> <strong>in</strong>terest <strong>in</strong> both<br />
the presence and absence <strong>of</strong> drugs and observe<br />
how these compounds affect the prote<strong>in</strong>’s<br />
<strong>in</strong>teraction pr<strong>of</strong>ile. This <strong>in</strong><strong>format</strong>ion,<br />
<strong>in</strong> turn, can be used to help understand how<br />
these compounds affect the physiology <strong>of</strong><br />
diseased cells.<br />
Our lab has currently been <strong>in</strong>volved <strong>in</strong> us<strong>in</strong>g<br />
MYTH and variations <strong>of</strong> MYTH to <strong>in</strong>vestigate<br />
various key areas <strong>of</strong> research that have<br />
direct disease relevance. For example, one<br />
large on-go<strong>in</strong>g project <strong>in</strong> the lab is the study<br />
<strong>of</strong> ABC transporters 3 , a major class <strong>of</strong> prote<strong>in</strong>s<br />
responsible for the transport <strong>of</strong> a wide<br />
range <strong>of</strong> substances across various cellular<br />
membranes. ABC transporters are <strong>of</strong> <strong>in</strong>tense<br />
cl<strong>in</strong>ical <strong>in</strong>terest because <strong>of</strong> the key role they<br />
play <strong>in</strong> the multidrug resistance <strong>of</strong> pathogenic<br />
microorganisms and tumor cells, as well<br />
Photo by Paul<strong>in</strong>a Rzeczkowska<br />
35 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
EXPERT OPINION<br />
In keep<strong>in</strong>g with the tradition <strong>of</strong> our research<br />
group, we are still active <strong>in</strong> develop<strong>in</strong>g new<br />
technologies which can further the field <strong>of</strong> <strong>in</strong>teractive<br />
proteomics. Recently, we have been<br />
work<strong>in</strong>g on develop<strong>in</strong>g a mammalian version<br />
<strong>of</strong> MYTH named MaMTH. The fundamentals<br />
<strong>of</strong> the yeast-based and mammalian technologies<br />
are similar, however MaMTH will<br />
allow for test<strong>in</strong>g <strong>of</strong> human membrane prote<strong>in</strong>s<br />
<strong>in</strong> the context <strong>of</strong> human cell l<strong>in</strong>es. Our<br />
<strong>in</strong>itial pro<strong>of</strong> <strong>of</strong> concept experiments were a<br />
success and we are currently <strong>in</strong> the process<br />
<strong>of</strong> upscal<strong>in</strong>g MaMTH to a high-throughput<br />
screen<strong>in</strong>g <strong>format</strong> by build<strong>in</strong>g cDNA libraries<br />
that conta<strong>in</strong> all 21,000 human Open Read<strong>in</strong>g<br />
Frames (ORFs). The groundbreak<strong>in</strong>g aspect<br />
<strong>of</strong> this technology is that it can be used to<br />
study PPIs <strong>in</strong> a drug and/or agonist dependent<br />
manner <strong>in</strong> the context <strong>of</strong> the human cell,<br />
which has the potential to change the way<br />
drug screen<strong>in</strong>g is performed <strong>in</strong> <strong>in</strong>dustry.<br />
Figure 1. Interactive proteomics is a subdiscipl<strong>in</strong>e <strong>of</strong> proteomics whose goal is to map all prote<strong>in</strong>-prote<strong>in</strong><br />
<strong>in</strong>teractions <strong>of</strong> a given cell or organism. Here, the <strong>in</strong>teractome <strong>of</strong> the 50 selected human G-prote<strong>in</strong><br />
coupled receptors is shown (recent unpublished work from the Jurisica & Stagljar lab).<br />
the observation that dysfunction <strong>of</strong> these<br />
transporters is associated with a range <strong>of</strong><br />
human diseases. Similarly, we are also work<strong>in</strong>g<br />
on build<strong>in</strong>g a comprehensive <strong>in</strong>teraction<br />
map between the human receptor tyros<strong>in</strong>e<br />
k<strong>in</strong>ase (RTKs) and selected human G-prote<strong>in</strong><br />
coupled receptors (GPCRs). These two<br />
families <strong>of</strong> membrane prote<strong>in</strong>s play a crucial<br />
role <strong>in</strong> cell signal<strong>in</strong>g, a process by which cells<br />
respond to cues <strong>in</strong> their <strong>in</strong>ternal or external<br />
environment. The f<strong>in</strong>ished <strong>in</strong>teractomes <strong>of</strong><br />
RTKs and GPCRs represent a robust bank<br />
<strong>of</strong> knowledge which will greatly contribute<br />
to therapeutic research and shed new light<br />
on the mechanism <strong>of</strong> natural control circuits<br />
that regulate biological systems. As an example,<br />
one <strong>of</strong> our recent f<strong>in</strong>d<strong>in</strong>gs showed that a<br />
prote<strong>in</strong> called HDAC6 regulates degradation<br />
<strong>of</strong> an RTK called Epidermal Growth Factor<br />
(EGFR), a receptor that is overactive <strong>in</strong><br />
several human cancers 5 . Based on this work,<br />
we are <strong>in</strong>vestigat<strong>in</strong>g the possibility <strong>of</strong> treat<strong>in</strong>g<br />
those cancers <strong>in</strong> which EGFR is <strong>in</strong>volved<br />
by us<strong>in</strong>g drugs to <strong>in</strong>hibit HDAC6, thereby<br />
speed<strong>in</strong>g up degradation <strong>of</strong> the oncogenic<br />
EGFR prote<strong>in</strong>.<br />
Figure 2. An example <strong>of</strong> a positive (upper row) and negative (lower row) <strong>in</strong>teraction detected by MYTH.<br />
Prote<strong>in</strong>s X and Y are synthesized <strong>in</strong> yeast and tested for <strong>in</strong>teraction via MYTH by assess<strong>in</strong>g their growth<br />
on specific media. The blue sta<strong>in</strong><strong>in</strong>g and growth <strong>of</strong> yeast cells on specific media are <strong>in</strong>dicative <strong>of</strong> two<br />
prote<strong>in</strong>s <strong>in</strong>teract<strong>in</strong>g <strong>in</strong> MYTH.<br />
In summary, although membrane prote<strong>in</strong>s<br />
play a very crucial role <strong>in</strong> ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g a<br />
healthy cell state, and dysfunction <strong>of</strong> membrane<br />
prote<strong>in</strong>s has been l<strong>in</strong>ked to a plethora<br />
<strong>of</strong> diseases, there are still huge gaps rema<strong>in</strong><strong>in</strong>g<br />
<strong>in</strong> our knowledge and understand<strong>in</strong>g <strong>of</strong><br />
this group <strong>of</strong> prote<strong>in</strong>s. MYTH and MaMTH<br />
can be used to fill <strong>in</strong> this gap, which <strong>in</strong> turn<br />
will have great implications <strong>in</strong> our understand<strong>in</strong>g<br />
<strong>of</strong> various diseases and how to better<br />
create effective treatments for them.<br />
References<br />
1. Stagljar, I. and Fields, S. (2002) Analysis <strong>of</strong> membrane<br />
prote<strong>in</strong> <strong>in</strong>teractions us<strong>in</strong>g yeast-based technologies.<br />
Trends Biochem Sci 27, 559-563.<br />
2. Tham<strong>in</strong>y, S., Auerbach, D., Arnoldo, A., and Stagljar,<br />
I., (2003) Identification <strong>of</strong> novel ErbB3- <strong>in</strong>teract<strong>in</strong>g factors<br />
us<strong>in</strong>g the split-ubiquit<strong>in</strong> membrane yeast two-hybrid<br />
system, Genome Res 13, 1744–1753.<br />
3. Paumi, C.M., Menendez, J., Arnoldo, A., Engels, K.,<br />
Iyer, K., Tham<strong>in</strong>y, S., Georgiev, O., Barral, Y., Michaelis,<br />
S., and Stagljar, I. (2007) Mapp<strong>in</strong>g Prote<strong>in</strong>-Prote<strong>in</strong> Interactions<br />
for the Yeast ABC Transporter Ycf1p by Integrated<br />
Split-Ubiquit<strong>in</strong> Membrane Yeast Two-Hybrid<br />
(iMYTH) Analysis, Mol Cell 26, 15-25.<br />
4. Gisler, S.M., Kittanakom, S., Fuster, D., Radanovic,<br />
T., Wong, V., Bertic, M., Hall, R.A., Engels, K., Murer,<br />
H., Biber, J., Markovic, D., Moe, O.W., and Stagljar, I.<br />
(2008) Monitor<strong>in</strong>g prote<strong>in</strong>-prote<strong>in</strong> <strong>in</strong>teractions between<br />
the mammalian <strong>in</strong>tegral membrane transporters and<br />
PDZ-<strong>in</strong>teract<strong>in</strong>g partners us<strong>in</strong>g a modified split-ubiquit<strong>in</strong><br />
membrane yeast two-hybrid system, Mol Cell Proteomics<br />
7, 1362-1377.<br />
5. Deribe, Y. L., Wild, P., Chandrashaker, A., Curak, J.,<br />
Schmidt, M. H., Kalaidzidis, Y., Milut<strong>in</strong>ovic, N., Kratchmarova,<br />
I., Buerkle, L., Fetchko, M. J., Schmidt, P., Kittanakom,<br />
S., Brown, K. R., Jurisica, I., Blagoev, B., Zerial,<br />
M., Stagljar, I., and Dikic, I., (2009) Regulation <strong>of</strong><br />
epidermal growth factor receptor traffick<strong>in</strong>g by lys<strong>in</strong>e<br />
deacetylase HDAC6, Sci Signal 2, p. ra84.<br />
6. Usenovic, M., Knight, A. L., Raj, A., Wong, V., Brown,<br />
K. R., Caldwell, G. A., Caldwell,K. A., Stagljar, I., Kra<strong>in</strong>c,<br />
D. (<strong>2012</strong>) Identification <strong>of</strong> novel ATP13A2 <strong>in</strong>teractors<br />
and their role <strong>in</strong> α-synucle<strong>in</strong> misfold<strong>in</strong>g and toxicity,<br />
Hum Mol Genet, <strong>in</strong> press (PMID: 22645275).<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 36
FUTURE DIRECTIONS<br />
Dr. Gabriella Farcas-Chan<br />
JD, PhD<br />
By Danielle D. DeSouza<br />
If dur<strong>in</strong>g her undergraduate degree<br />
you were to ask Dr. Gabriella Farcas-<br />
Chan if she could imag<strong>in</strong>e pursu<strong>in</strong>g career<br />
<strong>in</strong> law, her answer would have been an<br />
assured “no.” So how is it that this former<br />
<strong>IMS</strong> student established herself as the Vice<br />
President <strong>of</strong> Legal Affairs at a rapidly grow<strong>in</strong>g<br />
biotechnology company?<br />
Farcas-Chan started her post-secondary education<br />
at the Loyola University <strong>of</strong> Chicago<br />
where she studied biology and art history.<br />
To help with the steep costs <strong>of</strong> obta<strong>in</strong><strong>in</strong>g an<br />
undergraduate degree <strong>in</strong> the USA, she participated<br />
<strong>in</strong> a work-study program that allowed<br />
her to ga<strong>in</strong> valuable medical research<br />
experience while also earn<strong>in</strong>g an <strong>in</strong>come.<br />
Although her ma<strong>in</strong> <strong>in</strong>terest at the time was<br />
cardiac research, Farcas-Chan kept an open<br />
m<strong>in</strong>d towards other research topics; when<br />
the pr<strong>in</strong>cipal <strong>in</strong>vestigator <strong>of</strong> her choice research<br />
topic was between grants and unable<br />
to accommodate any work-study students,<br />
she was recommended to work with a group<br />
Photo by Laura Feldcamp.<br />
37 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
FUTURE DIRECTIONS<br />
that focused on quality <strong>of</strong> life research <strong>in</strong><br />
lung transplant patients. They noticed that a<br />
number <strong>of</strong> problems faced by these patients,<br />
<strong>in</strong>clud<strong>in</strong>g organ rejection, were caused by cytomegalovirus<br />
(CMV), a virus belong<strong>in</strong>g to<br />
the herpesviruses family. Farcas-Chan was<br />
fasc<strong>in</strong>ated with the literature on <strong>in</strong>fectious<br />
diseases and soon became <strong>in</strong>spired to pursue<br />
a graduate degree <strong>in</strong> the field.<br />
Under the supervision <strong>of</strong> Dr. Kev<strong>in</strong> Ka<strong>in</strong>, a<br />
cl<strong>in</strong>ician-scientist specializ<strong>in</strong>g <strong>in</strong> the diagnostics<br />
and surveillance <strong>of</strong> <strong>in</strong>fectious diseases,<br />
Farcas-Chan enrolled <strong>in</strong> the <strong>Institute</strong><br />
<strong>of</strong> Medical Science (<strong>IMS</strong>). Dur<strong>in</strong>g her studies,<br />
she was an active member <strong>of</strong> the <strong>IMS</strong><br />
Students’ Association, carry<strong>in</strong>g out two<br />
terms as president. She began her thesis<br />
work exam<strong>in</strong><strong>in</strong>g the impact <strong>of</strong> non-steroidal<br />
anti-<strong>in</strong>flammatory drugs on malaria, but her<br />
project soon took an <strong>in</strong>terest<strong>in</strong>g turn. In the<br />
midst <strong>of</strong> her studies, health <strong>of</strong>ficials declared<br />
the global epidemic <strong>of</strong> severe acute respiratory<br />
syndrome (SARS), a condition caused<br />
by a novel coronavirus (CoV). Approached<br />
by companies try<strong>in</strong>g to develop kits to diagnose<br />
SARS as early as possible, Farcas-Chan<br />
was given an excit<strong>in</strong>g research opportunity:<br />
she analyzed tissue samples from <strong>in</strong>dividuals<br />
that had died <strong>of</strong> SARS us<strong>in</strong>g real-time PCR.<br />
Us<strong>in</strong>g this method, she could assess viral load<br />
as measured by CoV RNA <strong>in</strong> different parts<br />
<strong>of</strong> the body. Her flexibility <strong>in</strong> tak<strong>in</strong>g on this<br />
unexpected project resulted <strong>in</strong> sem<strong>in</strong>al work<br />
show<strong>in</strong>g the dissem<strong>in</strong>ation <strong>of</strong> SARS-CoV<br />
throughout all major organs, not just the<br />
lungs <strong>in</strong> fatal SARS patients. 1<br />
“Students need to know<br />
what their rights are, especially<br />
<strong>in</strong> labs where<br />
there are collaborations<br />
with companies. Students<br />
need to make sure<br />
they’re not be<strong>in</strong>g taken<br />
advantage <strong>of</strong>.”<br />
After complet<strong>in</strong>g her PhD and while work<strong>in</strong>g<br />
for Fio Corporation, a privately held Canadian<br />
company work<strong>in</strong>g to develop a por-<br />
table device capable <strong>of</strong> molecular diagnosis<br />
<strong>of</strong> <strong>in</strong>fectious diseases us<strong>in</strong>g nanotechnology,<br />
Farcas-Chan participated <strong>in</strong> a young entrepreneurship<br />
program that greatly impacted<br />
her career path. She had been heavily <strong>in</strong>volved<br />
<strong>in</strong> <strong>in</strong>tellectual property (IP) searches<br />
on patent databases at Fio when she attended<br />
the Biotechnology YES (Young Entrepreneurs<br />
Scheme) competition held by the UK<br />
government. This competition, aimed at doctoral<br />
students, addressed all aspects <strong>of</strong> start<strong>in</strong>g<br />
a biotechnology company. Farcas-Chan<br />
was part <strong>of</strong> the only Canadian team that was<br />
selected to attend the week-long tra<strong>in</strong><strong>in</strong>g session<br />
<strong>in</strong> Oxford, UK. Here, she was further<br />
exposed to IP law, as she began convers<strong>in</strong>g<br />
with lawyers about the patent application<br />
process. Shortly after these discussions, Farcas-Chan<br />
applied to law school.<br />
Although her first semester at Osgoode Hall<br />
Law School at York University was a difficult<br />
transition, Farcas-Chan knew that a career<br />
<strong>in</strong> law was the right move. Her goal was to<br />
do patent management <strong>in</strong> a field where she<br />
could also apply the knowledge accumulated<br />
<strong>in</strong> her graduate degree. To Farcas-Chan, go<strong>in</strong>g<br />
to law school was a natural progression.<br />
Achiev<strong>in</strong>g her goal, Farcas-Chan is currently<br />
the Vice President <strong>of</strong> Legal Affairs at Cytodiagnostics<br />
Inc., a biotechnology company<br />
that focuses on the development and distribution<br />
<strong>of</strong> nanotechnology derived products.<br />
In speak<strong>in</strong>g about this role she said you have<br />
to be a “jack-<strong>of</strong>-all-trades,” as you need to liaise<br />
between both the scientific and the law<br />
worlds. Remarkably, she is do<strong>in</strong>g this while<br />
balanc<strong>in</strong>g family life. When I asked her how<br />
she manages to do it all, she said, “Flexibility<br />
is key. I have a hugely supportive husband<br />
and I am lucky that I have the option to work<br />
from home [to be with my son].”<br />
So what’s next on the horizon for Farcas-<br />
Chan? In addition to cont<strong>in</strong>u<strong>in</strong>g her work<br />
at Cytodiagnostics Inc., she would like to be<br />
more <strong>in</strong>volved <strong>in</strong> teach<strong>in</strong>g and, <strong>in</strong> particular,<br />
would like to be <strong>in</strong>volved with the <strong>IMS</strong>.<br />
Just this past April, she was a panel member<br />
for the <strong>IMS</strong> Career Sem<strong>in</strong>ar Series entitled,<br />
“A Graduate Student Alumni Perspective.”<br />
In the future, she discussed the desire to develop<br />
courses for <strong>IMS</strong> students that <strong>in</strong>tegrate<br />
tra<strong>in</strong><strong>in</strong>g <strong>in</strong> IP. She discussed the importance<br />
<strong>of</strong> br<strong>in</strong>g<strong>in</strong>g awareness to students about protect<strong>in</strong>g<br />
their property: “It’s crucial. Students<br />
need to know what their rights are, especially<br />
<strong>in</strong> labs where there are collaborations<br />
with companies. Students need to make sure<br />
they’re not be<strong>in</strong>g taken advantage <strong>of</strong>.” She<br />
also discussed the pros <strong>of</strong> hav<strong>in</strong>g a patent on<br />
a grant or scholarship application and said,<br />
“You never know when you have someth<strong>in</strong>g<br />
that somebody may be <strong>in</strong>terested <strong>in</strong> purchas<strong>in</strong>g<br />
or us<strong>in</strong>g.”<br />
“I th<strong>in</strong>k the most important<br />
th<strong>in</strong>g is to know<br />
who you are and what<br />
you want. Participate <strong>in</strong><br />
th<strong>in</strong>gs and go to sem<strong>in</strong>ars<br />
and lectures and meet<br />
people who are outside<br />
<strong>of</strong> your field.”<br />
When I asked Farcas-Chan what advice she<br />
would give to current <strong>IMS</strong> students she said,<br />
“I th<strong>in</strong>k the most important th<strong>in</strong>g is to know<br />
who you are and what you want. Participate<br />
<strong>in</strong> th<strong>in</strong>gs and go to sem<strong>in</strong>ars and lectures<br />
and meet people who are outside <strong>of</strong> your<br />
field.” She went on to say it is <strong>in</strong> these situations<br />
where you can have a seed planted <strong>in</strong><br />
you for a new idea or career path, or when<br />
you will have the opportunity to network.<br />
She also discussed the importance <strong>of</strong> be<strong>in</strong>g<br />
<strong>in</strong>volved <strong>in</strong> activities and groups outside <strong>of</strong><br />
lab work. Throughout her education she did<br />
more than just her schoolwork, whether it<br />
was participat<strong>in</strong>g <strong>in</strong> research for her undergraduate<br />
work-study program, or serv<strong>in</strong>g<br />
as the president <strong>of</strong> the <strong>IMS</strong> Students’ Association.<br />
She said, “You should get as much as<br />
you can out <strong>of</strong> the grad-school experience.”<br />
Given Farcas-Chan’s many successes, current<br />
graduate students would be wise to take this<br />
advice whole-heartedly.<br />
References<br />
1. Farcas GA, Poutanen SM, Mazzulli T, Willey BM, Butany<br />
J, Asa SL, Faure P, Akhavan P, Low DE, Ka<strong>in</strong> KC. Fatal Severe<br />
Acute Respiratory Syndrome is Associated with Multiorgan Involvement<br />
by Coronavirus. J Infect Dis. 2005;191:193-197.<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 38
RESEARCH HIGHLIGHT<br />
Genomic medic<strong>in</strong>e: gone to the dogs?<br />
How genomics are help<strong>in</strong>g to improve the health <strong>of</strong> purebred dogs<br />
By Jennifer Rilstone<br />
Paula ballak travelled to france<br />
<strong>in</strong> 2010 to pick up the puppy <strong>of</strong> her<br />
dreams—a black-and-white, wavyhaired<br />
Barbet (French water dog) named<br />
Rocket. Like other Barbet breeders, Ballak<br />
is dedicated to reviv<strong>in</strong>g this rare, historical,<br />
work<strong>in</strong>g breed—persecuted <strong>in</strong> WWII as the<br />
national dog <strong>of</strong> France—which is no small<br />
feat consider<strong>in</strong>g its limited numbers and genetic<br />
diversity. Rocket represented a dist<strong>in</strong>ct<br />
genetic l<strong>in</strong>e to breed with her own dogs, and<br />
<strong>in</strong> the first year, he excelled as a retriever.<br />
However, just after his first birthday, Rocket<br />
began to have seizures. The seizure disorder<br />
progressed quickly, affect<strong>in</strong>g his behaviour<br />
and quality <strong>of</strong> life, and was determ<strong>in</strong>ed to<br />
probably have a genetic cause. Recently—at<br />
just over the age <strong>of</strong> 2—Rocket had to be put<br />
down after hav<strong>in</strong>g no response to antiepileptic<br />
medications.<br />
Can<strong>in</strong>e epilepsy is not rare, occurr<strong>in</strong>g <strong>in</strong> as<br />
many as 1 –5% <strong>of</strong> purebred dogs (compared<br />
with 1% <strong>of</strong> the general human population),<br />
and up to 20% <strong>of</strong> some breeds. Considered<br />
a side effect <strong>of</strong> selective breed<strong>in</strong>g, the <strong>in</strong>sidious<br />
condition occurs <strong>in</strong> multiple forms and<br />
with multiple genetic causes. The <strong>in</strong>sight <strong>of</strong><br />
veter<strong>in</strong>ary neurologists has shown that these<br />
many varieties <strong>of</strong> can<strong>in</strong>e epilepsy are remarkably<br />
similar to the many forms <strong>of</strong> human epilepsy.<br />
Beyond epilepsy, dogs and humans are<br />
physiologically similar and many can<strong>in</strong>e diseases<br />
mimic human conditions. Researchers,<br />
therefore, have begun to study can<strong>in</strong>e genetic<br />
diseases with two hopes—improv<strong>in</strong>g the<br />
health <strong>of</strong> purebred dogs, and ga<strong>in</strong><strong>in</strong>g <strong>in</strong>sights<br />
about related diseases that afflict humans.<br />
The study <strong>of</strong> can<strong>in</strong>e epilepsy to aid human<br />
health has a proud history <strong>in</strong> Toronto. Drs.<br />
Hannes Lohi and Berge M<strong>in</strong>assian at the<br />
Hospital for Sick Children discovered the<br />
first can<strong>in</strong>e epilepsy gene <strong>in</strong> 2005. Mutations<br />
<strong>in</strong> this gene caused myoclonic epilepsy <strong>in</strong> the<br />
m<strong>in</strong>iature wire-haired dachshund (MWHD)<br />
breed 1 . Mutations <strong>in</strong> the same gene were concurrently<br />
discovered to cause Lafora progressive<br />
myoclonic epilepsy <strong>in</strong> children. While<br />
research <strong>in</strong>to the human disease cont<strong>in</strong>ues,<br />
breeders <strong>of</strong> the MWHD dogs are now able to<br />
identify carriers <strong>of</strong> the epilepsy mutation by<br />
genetic test<strong>in</strong>g. As a result <strong>of</strong> this test<strong>in</strong>g and<br />
responsible breed<strong>in</strong>g practices, the <strong>in</strong>cidence<br />
<strong>of</strong> epilepsy has decreased and the health <strong>of</strong><br />
the breed has improved. Dr. Lohi has s<strong>in</strong>ce<br />
moved on to establish a can<strong>in</strong>e genetic research<br />
laboratory at the University <strong>of</strong> Hels<strong>in</strong>ki,<br />
where more can<strong>in</strong>e disease genes have<br />
s<strong>in</strong>ce been identified—<strong>in</strong>clud<strong>in</strong>g the gene<br />
caus<strong>in</strong>g epilepsy <strong>in</strong> the Barbet’s close relative,<br />
Lagotto Romagnolo (Italian water dog) 2 . Ballak<br />
hopes that Rocket’s DNA will lead to similar<br />
success for the imperiled Barbet breed.<br />
Amid grow<strong>in</strong>g controversy about the decl<strong>in</strong><strong>in</strong>g<br />
health <strong>of</strong> purebred dogs, Lohi hopes to<br />
harness advanc<strong>in</strong>g genomic technologies to<br />
address health concerns and genetic diversity<br />
<strong>in</strong> all breeds. With a worldwide network <strong>of</strong><br />
collaborat<strong>in</strong>g scientists, breed clubs who are<br />
passionate about the health <strong>of</strong> their dogs, and<br />
tireless veter<strong>in</strong>arians (<strong>in</strong>clud<strong>in</strong>g Dr. Fiona<br />
James, the veter<strong>in</strong>ary neurologist at Ontario<br />
Veter<strong>in</strong>ary College who cared for Rocket),<br />
Lohi collects health records and generates<br />
genetic data for vast pedigrees <strong>of</strong> purebred<br />
dogs. The age <strong>of</strong> genomic medic<strong>in</strong>e has come<br />
not only to people, but also to the veter<strong>in</strong>ary<br />
cl<strong>in</strong>ic. And with the promise <strong>of</strong> new <strong>in</strong>sights<br />
<strong>in</strong>to our own health that can be gleaned by<br />
study<strong>in</strong>g can<strong>in</strong>e diseases, we are aga<strong>in</strong> <strong>in</strong>debted<br />
to man’s best friend.<br />
References<br />
1. Lohi H, Young EJ, Fitzmaurice SN, et al. Expanded Repeat <strong>in</strong><br />
Can<strong>in</strong>e Epilepsy. Science 2005;307(5706):81.<br />
2. Seppälä EH, Jok<strong>in</strong>en TS, Fukata M, et al. LGI2 truncation<br />
causes a remitt<strong>in</strong>g focal epilepsy <strong>in</strong> dogs. PLoS Genet<br />
2011;7(7):e1002194.<br />
Photo courtesy <strong>of</strong> Jennifer Rilstone<br />
39 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
Ask<br />
Experts<br />
the<br />
Expert Tips: Enrich<strong>in</strong>g your Graduate Experience<br />
Column By Laura S. Park & Brittany N. Rosenbloom<br />
Student Involvement <strong>in</strong> Form<strong>in</strong>g Their PAC<br />
A number <strong>of</strong> decisions need to be made at<br />
the beg<strong>in</strong>n<strong>in</strong>g <strong>of</strong> a graduate student’s studies.<br />
Aside from the obvious choices, such as<br />
choos<strong>in</strong>g a supervisor and a project, a critical<br />
decision that graduate students quickly face<br />
is who should serve on their Program Advisory<br />
Committee (PAC). As the <strong>IMS</strong> website<br />
<strong>in</strong>dicates, PAC members should <strong>in</strong>clude<br />
faculty who have expertise complement<strong>in</strong>g<br />
the supervisor’s research and with<strong>in</strong> the students’<br />
proposed area <strong>of</strong> research. The balance<br />
between advisors (i.e. committee members<br />
and supervisor(s)) is one that can certa<strong>in</strong>ly<br />
help students thrive <strong>in</strong> their studies, especially<br />
by utiliz<strong>in</strong>g the guidance and encouragement<br />
from each advisor to navigate through<br />
some <strong>of</strong> the challenges that may arise dur<strong>in</strong>g<br />
the course <strong>of</strong> each student’s research career.<br />
As such, students not only need to feel comfortable<br />
with their committee members (e.g.<br />
to ask research questions), but also need to<br />
make sure that PAC members are will<strong>in</strong>g<br />
to be available for additional meet<strong>in</strong>gs as<br />
needed. To achieve this, it is imperative that<br />
students are a part <strong>of</strong> decid<strong>in</strong>g who is on<br />
their own committee. This requires a series<br />
<strong>of</strong> iterative discussions between student and<br />
supervisor about project goals, the guid<strong>in</strong>g<br />
expertise needed to accomplish these goals,<br />
and the best learn<strong>in</strong>g/teach<strong>in</strong>g style that will<br />
maximize the student’s experience. A crucial<br />
factor to consider <strong>in</strong> this process is how<br />
much time and guidance each potential PAC<br />
member can provide.<br />
Many newly admitted students leave this decision<br />
up to the supervisor, and it is common<br />
for supervisors to choose their close colleagues<br />
or collaborators. Therefore, students<br />
should share any potential PAC members <strong>in</strong><br />
m<strong>in</strong>d and take an active role <strong>in</strong> this process.<br />
Putt<strong>in</strong>g together the best-suited PAC is important<br />
for students to be successful <strong>in</strong> their<br />
graduate tra<strong>in</strong><strong>in</strong>g while hav<strong>in</strong>g a fun and excit<strong>in</strong>g<br />
time!<br />
What Supervisors Expect From Their Students<br />
One <strong>of</strong> the challenges for many graduate students<br />
is hav<strong>in</strong>g a productive and mean<strong>in</strong>gful<br />
relationship with their supervisors. Problems<br />
may range from <strong>in</strong>adequate communication<br />
to more serious issues such as lab bully<strong>in</strong>g<br />
and ethical misconduct. Unfortunately, these<br />
difficulties do arise and it is important to realize<br />
them early on and to seek assistance. Both<br />
the <strong>IMS</strong> <strong>of</strong>fice and the <strong>IMS</strong> Students’ Association<br />
(<strong>IMS</strong>SA) provide student-supervisor<br />
relationship advice whether one-on-one, or<br />
through workshops such as the one held last<br />
March.<br />
Listed are some general but key pieces <strong>of</strong> advice<br />
shared by Dr. Carol Westall, one <strong>of</strong> our<br />
graduate coord<strong>in</strong>ators.<br />
These are some basic po<strong>in</strong>ts to keep <strong>in</strong> m<strong>in</strong>d<br />
as a graduate student. It is likely that most<br />
supervisors will expect more from their students;<br />
it is the student’s job to fulfill more<br />
than the m<strong>in</strong>imum. Also, each supervisor has<br />
their own unique mentor<strong>in</strong>g style and students<br />
should apply these guidel<strong>in</strong>es at their<br />
own discretion. Nevertheless, hav<strong>in</strong>g a good<br />
student-supervisor relationship is not only <strong>in</strong><br />
the hands <strong>of</strong> the students, but also <strong>in</strong> those <strong>of</strong><br />
their supervisors.<br />
Th<strong>in</strong>gs Supervisors Wished Students Knew:<br />
Students should/can<br />
1. give regular, written updates regard<strong>in</strong>g<br />
their work<br />
2. know that it takes time to get a PAC/<br />
exam committee together<br />
3. tell their PAC they want to transfer to<br />
PhD/go to medical school<br />
4. refer to PAC members, other students,<br />
lab mates, and <strong>IMS</strong>SA if they<br />
need help or advice<br />
5. know all deadl<strong>in</strong>es<br />
6. f<strong>in</strong>d external fund<strong>in</strong>g<br />
7. tell their supervisor if they can’t live<br />
on the stipend amount<br />
8. tell their supervisor if the pressure<br />
and stress is too great<br />
9. tell their supervisor if they are hav<strong>in</strong>g<br />
problems writ<strong>in</strong>g their thesis, grant<br />
applications, or papers<br />
EXPERT TIP<br />
Any discussion with a Graduate Coord<strong>in</strong>ator<br />
will rema<strong>in</strong> confidential unless you choose<br />
otherwise. Don’t shy away from ask<strong>in</strong>g for<br />
guidance.<br />
Do you have a question for the experts? Please<br />
send it to theimsmagaz<strong>in</strong>e@gmail.com. (ATTN:<br />
Experts).<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 40
PAST EVENTS<br />
PAST<br />
EVENTS<br />
This year’s <strong>IMS</strong> Scientific Day aga<strong>in</strong> allowed students to showcase<br />
their research and learn <strong>of</strong> the diverse science be<strong>in</strong>g conducted<br />
across the department. Above, a student engages <strong>in</strong> discussion<br />
dur<strong>in</strong>g the afternoon poster session.<br />
The Biomedical Communications<br />
Department<br />
took a field trip to the<br />
zoo! Along with hav<strong>in</strong>g<br />
a lot <strong>of</strong> fun, students<br />
practiced draw<strong>in</strong>g and<br />
photography skills. (left<br />
and right)<br />
Can’t hide their smiles!<br />
Friends unw<strong>in</strong>d dur<strong>in</strong>g<br />
<strong>IMS</strong>SA’s W<strong>in</strong>e and<br />
Cheese event, one <strong>of</strong><br />
the many social events<br />
hosted throughout the<br />
year for <strong>IMS</strong> students.<br />
Photos courtesy <strong>of</strong> the <strong>IMS</strong> Office, <strong>IMS</strong>/<strong>IMS</strong>SA. & Laura E. Smith.<br />
41 | <strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE
DIVERSIONS<br />
CROSSWORD<br />
Down:<br />
2. The I <strong>in</strong> <strong>IMS</strong>.<br />
3. The A <strong>in</strong> <strong>IMS</strong>SA.<br />
5. A plea, essay, speech etc., <strong>in</strong> support <strong>of</strong><br />
someth<strong>in</strong>g.<br />
6. A subject for composition or essay.<br />
10. A group <strong>of</strong> people gathered <strong>in</strong> answer<br />
to a summons.<br />
11. A section <strong>of</strong> the thesis.<br />
12. An act or operation for the purpose <strong>of</strong><br />
discover<strong>in</strong>g someth<strong>in</strong>g unknown or <strong>of</strong> test<strong>in</strong>g<br />
a pr<strong>in</strong>ciple.<br />
14. One who runs your assays.<br />
15. What every student wants, maybe <strong>in</strong><br />
Cell or Nature.<br />
16. The <strong>in</strong>terpretation <strong>of</strong> numerical facts<br />
and data.<br />
20. A supply <strong>of</strong> money or pecuniary resources,<br />
as for some purpose.<br />
Across:<br />
1. The charge or fee for <strong>in</strong>struction.<br />
4. The A <strong>in</strong> PAC.<br />
7. A meet<strong>in</strong>g for consultation or discussion.<br />
8. A sum <strong>of</strong> money or other aid granted to<br />
a student, because <strong>of</strong> merit, need, etc., to<br />
pursue his or her studies.<br />
9. A system <strong>of</strong> moral pr<strong>in</strong>ciples.<br />
13. Your mentor, one who guides you.<br />
17. Where one runs experiments.<br />
18. Current director <strong>of</strong> the <strong>IMS</strong> (2 words).<br />
19. The k<strong>in</strong>d <strong>of</strong> research done at the <strong>IMS</strong>.<br />
<strong>Summer</strong> Student Writ<strong>in</strong>g<br />
Competition<br />
Passionate about your research and eager to write for the <strong>IMS</strong><br />
<strong>Magaz<strong>in</strong>e</strong>? We are currently welcom<strong>in</strong>g research article submissions<br />
from SURP students as we hope to feature at least<br />
one article <strong>in</strong> our Fall <strong>2012</strong> magaz<strong>in</strong>e <strong>edition</strong>.<br />
What to <strong>in</strong>clude with your submission: title, author name,<br />
supervisor name, article text, references (10 maximum). 750<br />
word limit not <strong>in</strong>clud<strong>in</strong>g references/title. Figures (2 maximum)<br />
are also welcome with appropriate captions and permissions<br />
wherever applicable.<br />
Please send your complete article to theimsmagaz<strong>in</strong>e@gmail.<br />
com by Friday, August 17, <strong>2012</strong> <strong>in</strong> .doc/.docx <strong>format</strong>s only.<br />
Please feel free to email with any questions or comments.<br />
Thank you for your <strong>in</strong>terest!<br />
“Piled Higher and Deeper” by Jorge Cham www.phdcomics.com<br />
<strong>IMS</strong> MAGAZINE SUMMER <strong>2012</strong> GENOMIC MEDICINE | 42
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