ims magazine summer 2012

IMSMAGAZINESUMMERT H I N K , L E A R N , D I S C O V E R .

S t u d e n t - L e d I n i t i a t i v e

2012

GENOMIC MEDICINEON THE CUSP OF INDIVIDUALIZED PATIENT CARE

PUBLISH AND PERISH

SPIT FOR SCIENCE

Does a higher impact factor equal better science?

The Thoughts, Actions, and Genes project: exploring the genetic basis of childhood neuropsychiatric disorders

02IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE |

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TABLE OF CONTENTS

Commentary ...................................03Letter from the Editor .....................06News at a Glance ...........................07Director’s Message ........................10IMS Scientific Day Highlight ..........11Feature ............................................13Spotlight .........................................25Book Reviews .................................27Close Up ..........................................29Viewpoint .......................................31Expert Opinion ................................35Future Directions ............................37Research Highlight .........................39Ask the Experts ..............................40Past Events ......................................41Diversions .......................................42

Genomic Medicine

Expert Opinion: ProteomicsGone to the Dogs?

Our experts discuss how advances in genomic technologies will soon allow genetic insights to

aid individual patient care, and the associated challenges to consider.

By Inessa Stanishevskaya

The cover was designed to illustrate how the analysis of a person’s genome sequence could potentially play a role in the develop-

ment of individualized patient care.

Copyright © 2012 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.

The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Dr. Igor Stagljar explains translational aspects of proteomics research.

Learn how Drs. Hannes Lohi and Berge Minassian are using genomics to improve the health of purebred dogs and better understand human disease.

FEATURE

Cover Art

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MAGAZINE STAFFNatalie VenierNina BahlTetyana PekarJennifer RilstoneAllison RosenAdam SantoroMarika GaladzaKamila LearMelissa CoryLaura GreenleeMichael SoongInessa StanishevskayaAndrea ZariwnyTobi Lam, Andreea Margineanu, Merry Wang, Minyan WangCorinne DalyLaura Seohyun ParkSalvador AlcaireS. Amanda AliRickvinder BeslaDanielle DesouzaMelanie GuenetteAaron KucyiRosa MarticorenaAnna PodnosBrittany RosenbloomKarrie WongZeynep YilmazYekta Dowlati, Brett JonesLaura Feldcamp, Paulina Rzeczkowska, Mohammed Sabri

Editor-in-Chief

IN THISISSUE...

Managing EditorAssistant Managing Editors

Departmental Advisor

Advertising Manager

Magazine Committee

Design Editors

Sr. Design Editors

Photography

03 | IMS MAGAZINE SUMMER 2012 GENOMIC MEDICINE

COMMENTARYCOMMENTARY

CommentaryBy Adam Santoro, PhD student

I would like to thank Benjamin Mora for sub-mitting a thoughtful commentary in the pre-vious issue of the IMS Magazine. Mr. Mora offered a contrasting opinion to that which I presented in the Winter 2012 issue, stating that “…flourishing dialogue between science and religion in recent years is testimony to the fact that, far from being irreconcilably conflicted these two domains of human knowledge can fruitfully interact.”

Mr. Mora presented three arguments: firstly, that I was incorrect to state that scientists who are religious have not thought deeply about the issue, or are acting in a non-sci-entific manner; secondly, that my views suc-cumb to an erroneous method of thinking called scientism; and thirdly, that I can only successfully support methodological (and not philosophical) naturalism, which allows for a great number of plausible and fruitful interactions between science and religion.

As per his first argument: Mr. Mora contends that there are numerous “top-thinking” sci-entists who have thought deeply about the issue at hand. He presented a list of “top-thinkers,” presumably to illustrate how some individuals maintain a high degree of scien-tific integrity and still think about the issue deeply. To this I would simply state that an individual’s scientific prowess does not nec-essarily translate to matters not published in Science or Nature; because an individual is a leader within his scientific field, it does not necessarily follow that he maintains sufficient scientific integrity when dealing with issues outside of the published literature (especially

those that enter the realm of philosophy). Mr. Mora listed a plethora of scientists, all of whom are Christian. This is indeed curious, and raises numerous questions (i.e., why not list names of top-thinking scientists who are non-Christians?). I assume that it has to do with Mr. Mora’s theological bias, which leads me into the rest of the discussion.

As per his second and third arguments: Mr. Mora implies that scientists who support my viewpoint suffer from scientism, which states that the scientific way of knowing is the only way to discover truth. Those who share Mr. Mora’s epistemic viewpoint acknowledge that there are different ways of knowing, and theology and science are merely two of such ways. With this worldview, theological knowing can inform one about the natural world, and science can inform one about the-ology, since both ways of knowing are equally valid. There is a problem with this view. It is undoubtedly the case that a priori theologi-cal beliefs necessarily dictate those natural phenomena that can be explained by science (e.g., something inherently boring and obvi-ously un-divine as Brownian motion), and those that seemingly require theology (e.g., evolution vs. Intelligent Design). To those with this view, theology only succumbs to science when it would be to approach insan-ity to deny the scientific truth (see: the his-tory of evolution, the Heliocentric Model, etc.). Thus, it is not a simple case of comple-mentary systems of knowing that can live in harmony; all ways of knowing are apparently equal, but some are more equal than others.

Regardless, straw-men aside, I was careful to present an argument that did not depend on a single way of knowing. Instead, I (per-haps naively) assumed that scientists support methodological naturalism – a viewpoint that says all natural phenomena must be explained by science, and theology cannot dictate when it cannot. Mr. Mora should take note that the theological way of know-ing is not lost with this worldview; instead

it is limited to the knowing of non-natural things. So, much like how in some views theology often dictates the limits of science, from my perspective it is science that dictates the limits of theology. Methodological natu-ralism does not assume that the theological way of knowing is invalid or incorrect; it sim-ply states that it cannot conflict with science when dealing with the natural world. In my article I merely interpolated some conclu-sions from this viewpoint. Firstly, if theology cannot step on the toes of science on matters concerning the natural world, then nearly all theistic religions are to be rejected (since they all make naturalistic claims in some capacity, all of which conflict with scientific principles and natural laws). Second, deism is the only position a scientist/methodologi-cal naturalist can support, since this position does not contain conflicting views of natural phenomena. Thirdly, a scientist should sup-port methodological naturalism fully – to pick and choose avenues where science is to be usurped by theology is to lack scientific integrity. Thus, an individual who is properly scientific and truly accepts methodological naturalism can be a deist, at most.

As a final point, it is commonly argued that methodological naturalism can be in har-mony with theology since a theistic God can act upon the natural world in ways that we cannot detect (and hence, by their very na-ture are in tune with natural laws and can be studied with science). For example, God could drive mutations during evolution in subtle ways that we cannot detect. This is merely a logical game (you cannot prove the non-existence of the Tooth Fairy with 100% certainty). This viewpoint would seriously undermine the credibility and integrity of a “top-thinking” scientist, since the invention of ad hoc hypotheses is wonky at best.

On ‘A Reconcilable Conflict’, by Benjamin Mora (Spring 2012)All ways of knowing are equal, but some are more equal than others


COMMENTARYCOMMENTARY

@IMSMagazine

www.facebook.com/groups/imsmagazine/

By Anna Podnos, MSc student

In the last several decades, sex and gender have become widely recognized as impor-tant biological and social variables in human research, and many strategies for incorpo-rating sex in research design have been de-veloped. However, as discussed in our Sum-mer 2011 edition (see “Sexism in Biomedical Research”), stratifying experiments by sex is much rarer in animal and cell-based re-search1. Regenerative therapies, such as stem cell transplantation, are being developed based on animal and cellular models, and a fundamental component may be missing. Significant sex differences have recently been found in the regenerative properties of vari-ous stem cells. Stems cells have the unique ability to differentiate into specific cell types and self-renew, so they have the potential to treat organ failure, cancers, and degenerative diseases.

When patients’ own stem cells cannot be used therapeutically, they may require a cel-lular transplant from a donor. The success of transplantation depends on the type of donor stem cells, the characteristics of host cells, and their interactions with pathways associated with the illness2. Research using animal models has found that biological sex is an important variable in proliferation and differentiation rates of stem cells3. For exam-ple, animal studies of hematopoietic stem cell transplantation (the only stem cell therapy in standard medical practice4) have found that that the sex of both donor and recipient animals affect the transplantation outcome4. In addition, there are significant differences in the activation of mesenchymal stem cells (MSC) depending on their biological sex3. Researchers found that female stem cells produced more proliferation- and inflam-mation-promoting factors than male cells. Female muscle-derived stem cells (MDSC), which have the capacity for myocardial re-pair, were another type of stem cell found to have more regenerative capacity than male MDSC5. These sex differences may be thera-peutically relevant, but there are few studies directly comparing different cell types in dis-

References1. Beery, A., & Zucker, I. 2011. Sex Bias in Neuroscience and Biomedical Research. Neuroscience and Biobehavioral Reviews, 35 (3), 565-5722. genderedinnovations.stanford.edu3. Crisostomo, P., Markel, T., Wang, M., Lahm, T., Lillemoe, K., & Meldrum, D. 2007. In the Adult Mesenchymal Stem Cell Popula-tion, Source Gender Is a Biologically Relevant Aspect of Protec-tive Power. Surgery, 142 (2), 215-2214. Gahrton, G., Iacobelli, S., Apperley, J., Bandini, G., Björk-strand, B., Bladé, J., Boiron, J., Cavo, M., Cornelissen, J., Cor-radini, P., Kröger, N., Ljungman, P., Michallet, M., Russell, N., Samson, D., Schattenberg, A., Sirohi, B., Verdonck, L., Volin, L., Zander, A., & Niederwieser, D. 2005. The Impact of Donor Gender on Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Reduced Relapse Risk in Female to Male Transplants. Bone Marrow Transplantation, 35 (6), 609-617

Contact Us

We encourage our readers to send their feed-back -- comments, questions, corrections, and letters to the editor -- to [email protected].

ease models6.

Given that sex differences exist in stem cells, it is necessary to examine the causes of the dis-similarities, which may arise on genetic, epi-genetic or hormonal levels. Male and female cells differ genetically, and it is important to investigate the differences both between and within sexes. The hormonal environment is a key covariate to sex, because it may also reg-ulate the differentiation and proliferation of stem cells. Epigenetic differences resulting in varying gene expression levels are covariates as well. In mouse models of muscular dys-trophy, it was found that not only do female MDSC promote more regeneration than male MDSC, but also that the female recipi-ent animals undergo more regeneration than male animals do, regardless of the sex of the donor cells. However, this is not the case in immune-deficient animals, which suggests that the effect of host’s sex on the MDSC re-generative potential may be immunologically modulated, and therefore influenced by the hormonal environment.

It is challenging to appropriately incorporate sex as a variable in animal and cell-based study designs, so an interdisciplinary ap-proach is often required. Recently, Stanford University launched “Gendered Innova-tions”2 (genderedinnovations.stanford.edu), which has an abundance of information about the inclusion of sex and/or gender in engineering, science and medicine. It pro-vides practical methods and checklists for considering biological sex in basic research. The development and implementation of specific guidelines for incorporating sex in stem cell research as an informative variable, rather than just a bias, will improve regenera-tive therapies.

The Sex of Stem Cells

Disclaimer: The opinions expressed by the au-thor are in no way affiliated with the Institute of Medical Science or the University of Toronto. Comments are welcome at [email protected].

Does sex have an effect on the regen-erative potential of stem cells?

5. Deasy, B., Lu, A., Rubin, R., Huard, J., Tebbets, J., Feduska, J., Schugar, R., Pollett, J., Sun, B., Urish, K., Gharaibeh, B., & Coo, B. 2007. A Role for Cell Sex in Stem Cell-Mediated Skeletal Muscle Regeneration: Female Cells Have Higher Muscle Regen-eration Efficiency. The Journal of Cell Biology, 177 (1), 73-866. Zenovich, A., Davis, B., & Taylor, D. 2007. Comparison of Intracardiac Cell Transplantation: Autologous Skeletal Myo-blasts versus Bone Marrow Cells. In Kauser, K., & Zeiher, A. (Eds.), Bone Marrow-Derived Progenitors, pp. 117-165. Berlin: Springer Verlag

What to look for next issue:

In continuation of our Genomic Medicine fea-ture, we highlight Dr. Berge Minassian’s work in uncovering genetic causes of rare, profoundly debilitating neurological diseases.

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NEWS AT A GLANCE


early sixty years ago in a letter to Nature, Watson and Crick wrote: “We wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA). This structure has novel features which are of considerable biological interest.” This first identifi-

cation of DNA has paved the way for the field of medical genomics and, unknowingly to its discoverers at the time, has given promise of revolutionizing the diagnosis and treatment of many illnesses.

This milestone should once again remind us that a scientific discovery can open up a mul-titude of opportunities for future research. In this issue of the IMS Magazine, we guide you through a detailed timeline of the evolution of molecular medicine—from the principles of heredity, to the first discovery of genomic DNA, to the identification of novel genes of vari-ous diseases. I hope it will inspire young researchers to think about the long-term implica-tions of their research findings.

Furthermore, with the help of our experts, we hope to educate you about some of the inno-vative research surrounding genomic medicine here at the IMS. We discuss next-generation sequencing technologies, human genetic variation, pharmacogenomics, epigenomics, and important ethical considerations of its translation to patient care. We hope that this will improve your understanding of personalized medicine and inform you about the ongoing, cutting-edge science at our institute.

I also encourage you to take a look at our Viewpoint section and weigh in on our more contentious articles: we discuss the importance of understanding statistics in graduate edu-cation and controversies centered around publishing in journals with high impact factors. Be sure to also check out highlights from IMS Scientific Day, as well as our Close Up section featuring the winner of the Mel Silverman Mentorship Award, Dr. Gary Remington.

To conclude, I would like to thank Dr. Allan Kaplan and the IMS department for their ongoing support, and congratulate our newest design team on their outstanding efforts in the production of this issue. I must acknowledge the phenomenal IMS Magazine team for their creativity and dedication, and our exceptional Managing Editor, Nina Bahl, whose dedication has been integral to our production. Lastly, I strongly encourage comments and feedback letters as we continue to aspire to bring you the best of the IMS.

Enjoy!

Natalie VenierEditor-In-ChiefNatalie Venier is a third year PhD Candi-date at the Institute of Medical Science. She is currently studying prostate cancer chemoprevention at Sunnybrook Health Sciences Centre.

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Letter fromthe Editor

Natalie VenierEditor-In-Chief, IMS Magazine

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at a glance...IMS ANNOUNCEMENTS

SEPTEMBER

AUGUST

JULY

For more information on IMSSA/IMSSA-related events, please visit: http://imssa.sa.utoronto.ca

For information on IMS news and events, please see: http://www.ims.utoronto.ca

Please send your comments and suggestions to: [email protected]

28

IMS Wonderland trip

Blue Jays Game

Registration for Fall session begins

IMS Summer Undergraduate Research Day

Artists for Autism: Talent Show

IMSSA BBQ

School of Graduate Studies – Graduate Orientation for Incoming Students

IMS New Student Orientation and Reception

IMSSA Executive Elections & IMSSA Pub Night

NEWS&VIEWSIMS Scientific Day – Recap!

This year’s IMS Scientific Day was held on May 15th, 2012. The day was a great success with over 130 MSc and PhD student poster presentations, 6 Laidlaw Manuscript oral presentations, and the Bernard Langer Lecture in Health Sciences—presented by Dr. Thomas R. Insel, Director of the National Institute of Mental Health. For a glimpse of Dr. Insel’s presentation, visit our website at www.ims.utoronto.ca. Thank you to all who participated in this event. We look forward to another stimulating Scientific Day in 2013!

IMS Office Staff

Dr. Karen Davis has completed her 10-year term as Associate Director at the IMS. Among her most lasting contributions are the establishment of ethical training modules and development of the IMS Oath recited annually at September’s student orientation. Dr. Davis is currently the Head of the Division of Brain, Imaging & Behaviour Systems at the Toronto Western Research Institute and will continue her involvement with the IMS through student supervision and as Professor of Surgery. Her vision and leadership will be greatly missed.

Dr. Carol Westall has completed her term as Graduate Coordinator at the IMS. Outside academia, Dr. Westall is a registered clinical optometrist and Director of the Visual Electrophysiology Unit at SickKids. She served as a Graduate Coordinator at IMS for 3 years. Dr. Westall’s sense of humour and tireless devotion to IMS students was much appreciated. We wish them all the best in their future endeavours!

Dr. Mingyao Liu has accepted the position of Associate Director at the IMS effective July 1, 2012. Dr. Liu has many years of experience with the IMS, acting as a member of the IMS faculty since 1997 and Graduate Coordinator between 2000 and 2005. Dr. Liu will work closely with IMS Director, Dr. Allan S. Kaplan, to oversee faculty appointments and spearhead the new IMS Strategic Plan Initiative slated for roll-out in fall of 2012.

We also welcome Dr. Cindi Morshead and Dr. Vasundara Venkateswaran as Graduate Coordinators effective summer 2012. Both have served as active IMS faculty members for over 5 years and will be a vibrant addition to our current roster.

Interim Staff Appointments

Michelle Rosen will be serving as the Interim Faculty and Student Affairs Coordinator. Michelle will be responsible for administering awards, faculty appointments, and courses. She will be covering Kaki Narh Blackwood, who is on medical leave until further notice.

Tania DaSilva has joined us as Interim Departmental Assistant. Tania worked at the IMS last summer, and will assume the role of Summer Undergraduate Research Program Assistant until July 27th, 2012. She will be responsible for general inquiries, room bookings, reception and student document pick-up and drop-off.

Please join us in extending a warm welcome to all new staff and faculty members at the IMS—we wish them a smooth transition in the months to come.

We would also like to take this opportunity to thank Cassandra Wysochanskyj for doing an excellent job as former Interim Departmental Assistant. We wish Cassandra a safe journey as she embarks on volunteer work in Eastern Europe.

NEWS AT A GLANCE

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IMSSA ANNOUNCEMENTS

New Faculty Members

Jeffrey Cheung, MSc student; Stephane Paquette, PhD student; Tetyana Pekar, MSc student

Faizal Aminmohamed Haji

Kimberly Blom, Melanie Burger, Fernando Caravaggio, Jill Cates, Jeffery Cheung, Charles de Mestral, Joana Dida, Laura Feldcamp, Gagandeep Fervaha, Erin Gibson, Fervaha Haji, Marvin Hsiao, Stuart Jantzen, Salima Jiwani, David Kepecs, Ammar Khairullah, Alex Laliberte, Tristram Lett, Biao Li, Jonathan Lipszyc, Anton Mihic, Tetyana Pekar, Rachel Rabin, Natasha Radhu, Sofia Raitsin, Meghna Rajaprakash, Grace Shen-Tu, Kevin Shield, Ivonne Suridjan, Weining Yang, Nima Zamiri, Boris Zevin

AWARDS & SCHOLARSHIPS

NSERC AWARD RECIPIENTS

2012/2013 CIHR Banting and Best Master’s Award Recipients

2012/2013 ONTARIO GRADUATE SCHOLARSHIPS RECIPIENTS

Daniel BlumbergerAssociate Member,

Centre for Addiction and Mental Health

Sam DoesburgAssociate Member,

The Hospital for Sick Children

David FismanMember, University of Toronto,

Dalla Lana School of Public Health

Caitlin GillanAssociate Member (Non-Supervisor),

ELLICSR, Toronto General Hospital

Christian HendershotAssociate Member,


Andrea LevinsonAssociate Member,

Centre for Addiction and Mental Health, Queen Street Site

Daniela LoboAssociate Member,


Jack GoodmanMember, Faculty of Kinesiology

and Physical Education

Rachel WaldAssociate Member,

Toronto General Hospital

Tom SchweizerMember,

St. Michael’s Hospital

Find out more about faculty on the IMS fac-ulty database at http://www.ims.utoronto.

ca/faculty/directory.htm.

The annual IMS Talent Show Fundraiser, Artists for Autism, will be held on Thursday, August 16th, 6-10pm (Debates Room, Hart House) featuring emcee Ori Rotstein. Acts will include piano and guitar performances, dancing, and more. Proceeds will be donated to Unity for Autism. $15 ticket includes admission, free pizza and drink. Please contact [email protected] to reserve your ticket!

Come out on Saturday, July 28th to Cherry Beach, downtown Toronto, to hang out with fellow IMS students for a Corn roast/BBQ beach day. There will be games, delicious food, great weather, and awesome people—mark your calendars! For further details, please contact [email protected].

A new academic year is around the corner, so please come out and join us at the 2012-2013 IMSSA Executive Council Elections in late September. We will be holding elections for all positions, and immediately afterwards, we will be hosting a FREE pub night for all IMS students! We strongly encourage registered IMS students of all years and degree programs to run for a position. If you have ideas for new initiatives and events for your fellow students, this is your chance to carry them out and have a meaningful impact on your student community! E-mail [email protected] for details.

NEWS AT A GLANCE

Welcome Dr. Liu, Dr. Morshead, and Dr. Venkateswaran!

Translational research and interdisciplinary graduate education that advances human health

2012 Undergraduate and International Summer Research Program

RESEARCH DAY Wednesday, August 15, 2012, 9:00 a.m. – 3:40 p.m.Medical Sciences Building, 1 King’s College Circle

9:00 am

9:05 am

9:15 am

10:00 am

10:30 am

12:00 pm

1:00 pm

3:30 pm

3:40pm

Welcome and Introduction – Macleod Auditorium, Room 2158Dr. Allan S. Kaplan, Director, Institute of Medical Science

Introduction of Keynote SpeakerDr. Vasundara Venkateswaran, Director, IMS Summer Undergraduate Research Program

Keynote Address: Dr. Freda MillerProfessor, Department of Molecular Genetics and Senior Scientist, Developmental & Stem Cell Biology, Sick Kids Hospital“Stem Cells: Building and Rebuilding the Nervous System”

Coffee Break – Macleod Auditorium Lobby, Room 2158

Student Oral Presentations – Room 2158

Lunch – Macleod Auditorium Lobby, Room 2158

Poster Presentations – Stone Lobby, Room 2171 and Student Lounge (next to Starbucks)

Concluding Remarks - Macleod Auditorium, Room 2158Dr. Mingyao Liu, Associate Director, Institute of Medical Science

Award Presentations – Macleod Auditorium, Room 2158

We thank the presenters of our 2012 Seminar SeriesDr. Nick Wooldridge, Program Director, Associate ProfessorDr. Michael Szego, Fellow in Clinical and Organizational Ethics Joint Centre for Bioethics, University of TorontoDr. Moloo Badru, Director, Animal Resources Centre, University Health NetworkDr. Neil Winegarden, Head of Operations, Microarray Centre, University Health NetworkDr. Katalin Szaszi, Scientist, Associate Professor Department of Surgery, Univer-sity of TorontoDr.Xiao-Yan Wen, Assistant Professor, Department of Medicine, University of TorontoDr. Art Petronis, Professor and Tapscott Chair, University of TorontoDr. Uri Tabori, Scientist, Staff NeuroOncologist, Associate Professor of Pediatrics, University of TorontoDr. Moody, Radiologist-in-Chief Department of Medical Imagining, Sunnybrook Health Science Centre

We Thank Our Generous BenefactorsUHN centre for research


SPOTLIGHT


Allan S Kaplan MD FRCP(C)Director, Institute of Medical Science

he IMS Magazine continues to be the showcase publication of the Institute of Medical Science student body. It has received rave reviews locally and from those internationally who have seen it, including Dr. Thomas Insel, Director of the National Institute of Mental

Health, who was interviewed in the last issue of the magazine in anticipation of his Plenary Address at IMS Research Day on May 15. Congratulations and thanks to Natalie Venier and her staff for all their hard work, as well as to Kamila Lear for her ongoing assistance with this project.

This seventh issue of the magazine focuses on the important and related areas of genomic medicine, epigenetics, and pharmacogenetics. These areas of research represent innovative work of our faculty that is very much in keeping with the IMS’ strategic initiative related to translational research.

Recently, there have been a number of departmental leadership changes that I would like address. First, Dr. Karen Davis and Dr. Carol Westall have finished their terms of service as Associate Director and Graduate Coordinator, respectively. We at the IMS owe a great deal of gratitude and thanks for their tireless efforts. As of July 1, Dr. Mingyao Liu will take over as the IMS Associate Director, and Dr. Cindi Morshead will assume the role of Graduate Coordinator. In the next few weeks, the IMS will also launch its first-ever Strategic Plan, which will guide us for the next five years. The Plan is entitled “From Cell to Society: Becoming the Global Leader in Graduate Education to Improve Human Health through Translational Research.” As we move forward with the Plan, our new tagline underscores the five-year vision of the IMS: Translational research and interdisciplinary graduate education that advances human health. Our plan has five themes that will support us in making this vision as vibrant as possible: Uniqueness, Connectedness, Presence, Belonging and Engagement. I look forward to working with our deeply committed faculty and students to bring our vision to life.

Best wishes for a restful and enjoyable summer.

Sincerely,

Director’sMessage

Allan S Kaplan, MSc, MD, FRCP(C)Director, IMS

Allan S. Kaplan, MSc, MD, FRCP(C), became the IMS Director in July 2011. He is currently the Chief of Clinical Research at the Centre for Addiction and Mental Health (CAMH), Vice Chair for Research in the Department of Psychiatry, and Professor of Psychiatry in the Faculty of Medicine. He is also a Senior Scientist at both CAMH and the Toronto General Hospital Research Institute. He was the inaugural holder of the Loretta Anne Rogers Chair in Eating Disorders at the University Health Network from 2002 to 2010.

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DIRECTOR’S MESSAGE


IMS SCIENTIFIC DAY HIGHLIGHT

Laidlaw Manu-script Competition

Grand prize Clinical Science Christopher Tran Basic Science Brian Ballios

Honourable mentionsClinical Science Ann Montgomery

Basic Science Nabilah Chowdhury Marko ŠkrtićNadia Sachewsky Ph

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IMS SCIENTIFIC DAY AWARD WINNERSCompiled by Karrie Wong and Anna Podnos

Honourable mentionsClinical Science Ann MontgomerySean BarbourLeigh ChristopherSandeep DhillonRaymond ChangAyesha Malik Laura ParkTejas Sankar

Honourable mentionsBasic Science Siba Haykal Ana Konvalinka Jeff ManStephane PaquetteSally Yu ShiVanessa Zannella

Alan Wu Poster Competition & Academic Development Award

Grand prizeClinical Science Seham Chaker

Grand prizeBasic Science Amanda Ali


IMS SCIENTIFIC DAY HIGHLIGHT

From the winners“My time spent with the IMS so far has been challenging yet very en-joyable. I am always amazed at the high quality of research being done around me.”

“It has been very enlightening for me to interact with so many fellow stu-dents who are doing work in many diverse areas of biomedical research. The interdisciplinary nature of these interactions, as well as of the semin-ar series and courses offered through the IMS, has helped me to think be-yond the narrow questions around which my research is focused.”

“I feel lucky to be a part of the IMS, which really fosters a wide range of research. IMS Scientific Day really reflected this, [and] I was able to meet fellow students and see their work in topics completely different from my own.”

“Thank you IMS administration, faculty, and students.”

“It was an honour to be afforded the opportunity to present my research at IMS Scientific Day - an event which showcases the amazing breadth of biomedical and clinical science re-search across the department. All of the speakers highlighted their cutting-edge research, while emphasizing the translational potential of their work.”

“I am so grateful to the IMS for almost every academic opportunity I have received in the last two years. As a graduate student here, I have been granted access to mentors, publications, and scholarships.”

“Sharing new ideas and scientific dis-course is at the heart of IMS Scientific Day, and is a testament to the depart-ment’s continued success at attracting first-class investigators and trainees, who are working to transform the fu-ture of healthcare.”


FEATURE


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FEATURE


FEATURE

n 2000, one of the most significant milestones in genomics was achieved: the first draft of the human genome

was completed1. The genomic sequence was based on DNA samples pooled from several individuals and it established a reference ge-nome for future sequencing projects. At the press conference announcing this achieve-ment, Bill Clinton proclaimed that the com-pleted genome sequence would “revolution-ize the diagnosis, prevention and treatment of most, if not all, human disease”2. Francis Collins, who led the effort to complete the human genome project, may have been try-

ing to manage expectations when he suggest-ed that a complete transformation of thera-peutic medicine would take up to 15 to 20 years2. One of the biggest hurdles that needed to be overcome before Clinton’s claims could be realized was the ability to sequence indi-vidual genomes. This feat required techno-logical advances in sequencing and a drastic reduction in sequencing costs.

Since 2000, whole genome sequencing (WGS) of individual genomes has been de-veloped, enabling the identification of new gene variants associated with disease that can subsequently be used for genetic test-ing in the clinical context3. The WGS is still cost prohibitive with its use and is limited to select research projects; however, its cost is decreasing rapidly and will soon be cheaper than currently employed genetic tests that as-sess one gene at a time. The development of affordable WGS may be the catalyst for the transformation that Dr. Collins predicted and the “revolution” that Clinton anticipated.

Since WGS has the potential to unlock every person’s unique disease risk profile4, it may be one of the most significant technological breakthroughs in history. Therefore, WGS deserves special consideration from an eth-ics perspective. In this short article, I will focus on two key ethical topics with respect to WGS that are found in both research and clinical settings, that is (1) informed consent and, (2) return of results.

Informed consent

The principle of informed consent is recog-nized as a main pillar in the practice of ethi-cal research and medicine. For consent to be informed within the general research con-text, the research subject must be informed of the purpose for the research, its poten-tial applications, the methods that will be employed, and any anticipated benefits and risks5,6. However, many of these criteria are Ph

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Ethics and Challenges of DeliveringGenomic Medicine

unrealistic when applied to genomic research specifically. At the time a DNA sample is taken from the research subject, all possible future research, its applications, and methods are usually not known. One main risk/ben-efit associated with most genomic research projects is the potential identification of in-cidental findings. For instance, the disclosure of a pathogenic variant that is clinically ac-tionable which is identified over the course of research is an example of a potential benefit, while possible genetic discrimination is an example of a potential risk. However, the ac-tual risks and benefits are not known before-hand because they depend on the research subject’s genomic sequence and the scientific knowledge at the time the analysis.

In order for genomic research to be per-formed, the traditional informed consent process has been modified to include broad consent. In the broad consent model, partici-pants consent to a range of possible research activities7. Under this paradigm, research subjects are educated about genomic re-search to ensure they understand the general risks and benefits. Consequently, they can make the most informed decision possible, even though the actual risks may not be com-pletely known.

Informed consent is a different process with-in clinical medicine as compared to research. In the clinical genetic testing context, pa-tients must be told the nature of the diagnos-tic test, the expected risks and benefits of the test, and any alternative tests for consent to be informed. When WGS is used as a clinical genetic test, the nature of the diagnostic test and any alternative tests are known and can be described to the patient. Current standards of care for clinical genetic testing include pa-tient counseling about the risks and benefits and potential outcomes of the proposed ge-netic test. However, current genetic tests can examine one or a handful of genes, making counseling more straightforward than coun-

Michael Szego, PhD, MHSc

Clinical Ethicist,Centre for Clinical Ethics (A joint venture of Providence Healthcare, St. Joseph’s Health Centre, and St. Michael’s Hospital),The University of Toronto Joint Centre for Bioethics

Research Ethics Consultant,The Centre for Applied Genomics, The Hospital for Sick Children, The University of Toronto McLaughlin Centre for Molecular Medicine


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seling on a WGS test, which examines over 20,000 genes and many of which have known pathogenic variants. That said, counseling is critically important within the WGS context; however, the information needs to be more general in nature, analogous to the research setting. Healthcare providers need to educate patients about genomic testing using theory and case-based examples, identify any likely clinical implications of WGS, and discuss the general risks and benefits of undergo-ing WGS in order for patients to make an informed decision as to whether they want their genome sequenced.

Return of results

Whether researchers have a duty to return individual research results in genetic studies has been the subject of much debate. Should research be purely for research sake? This de-bate is especially important within the WGS context since the likelihood of identifying pathogenic variants is high. Fortunately, a consensus is emerging. The World Health Organization has identified three conditions to be met before disclosure should occur: (1) the data should be clinically beneficial; (2) disclosure should avert or minimize signifi-cant harm; and (3) there is no indication that the individual in question would prefer not to know8. Consistent with this approach, Ca-nadian research ethics guidelines outline an obligation to disclose any material incidental findings or unanticipated discoveries made during the course of research that are inter-preted as having a significant welfare impli-cation for the participant9.

Different strategies have been suggested to manage the return of clinically relevant re-search results in the WGS context. One ap-proach would categorize human genes ac-cording to clinical parameters10. In such a scheme, all gene mutations that are medi-cally actionable are labeled as “Bin 1” genes and would trigger an automatic return of the result. “Bin 2” genes are defined as gene mu-tations associated with human disease that could not be acted upon medically. Finally, “Bin 3” contains all other genes whose associ-ation with human disease is unknown. It has been estimated that there are currently only 100 “Bin 1” genes in the human genome10.

The ClinSeq project at the National Insti-tutes of Health (NIH) has taken a different

approach that is more research-subject-cen-tered and engages research subjects to de-termine the type and extent of information they would find useful11. In the NIH project, all pathogenic variants can be returned to re-search subjects, provided consent is obtained for disclosure. Additionally, they have set up an independent panel to periodically review any new evidence linking variants to human disease and to determine if the evidence is sufficient to warrant disclosure.

With all the effort spent on identifying vari-ants associated with human disease, new clinically relevant variants will no doubt be identified in the future. This reality neces-sitates a long-term plan to deal with stored sequences. Researchers returning individual research results could implement software that can reanalyze past genomes and flag new clinically relevant data. Alternatively, if such a measure was not possible, research subjects should be informed during the informed consent process that reanalysis will not occur and that any results returned would only re-flect current knowledge.

It is generally understood that test results are returned to patients, however, it is unclear what should be returned to patients when WGS is used as a genetic test. While any re-sults that inform the original differential di-agnosis seem appropriate to disclose, many other variants of known and unknown signif-icance may also be detected that have noth-ing to do with the original query. A “binning” mechanism or a patient-guided approach may be borrowed from the research context described above. Lastly, the issue of clinical reanalysis was addressed in a recent article by the head of the NIH clinical sequencing project mentioned previously, Leslie Bieseck-er describes WGS as a resource not a genetic test12. As such, a WGS dataset can be “inter-rogated by the patient and clinician in situ-ations where it could be of potential use to the patient, when both agree to this use”12. This type of integration would also solve the issue of reanalysis. If treated as a one off test, the physician who ordered it would not have a legal or ethical obligation to periodically reanalyze each of her patient’s genome for any new medical information. If comprehen-sively integrated into primary care, a patient’s whole genome could be part of the transfor-mation of healthcare Francis Collins and Bill Clinton predicted over a decade ago.

1. Lander ES, et al. Initial sequencing and analysis of the human genome. Nature. 2001; 409(6822): 860-921.2. Wade NA. Decade Later, Genetic Map Yields Few New Cures, in New York TImes.2010: New York.3. Tucker TM, et al. Massively parallel sequencing: the next big thing in genetic medicine. Am J Hum Genet. 2009; 85(2): 142-54.4. Tabor HK et al. Genomics really gets personal: how exome and whole genome sequencing challenge the eth-ical framework of human genetics research. Am J Med Genet A. 2011; 155A(12): 2916-24.5. Human T.-C.P.S.E.C.f.R.I. 1998 Aril 9, 2009]; Avail-able from: http://pre.ethics.gc.ca/eng/index/.6. Beauchamp TL and Childress JF. Principles of bio-medical ethics. 6th ed. 2009, New York: Oxford Univer-sity Press. xiii, 417.7. Singer PA and Viens AM. The Cambridge textbook of bioethics. 2008, Cambridge ; New York: Cambridge University Press. xvi, 538 p.8. Organization, W.H. Genetic databases: assessing the benefits and impact on human and patient rights. 2003 [cited 2009 December 15]; Available from: http://www.law.ed.ac.uk/ahrb/publications/online/whofinalreport.doc.9. Canadian Institutes of Health Research, N.S.a.E.R.C.o.C.a.S.S.a.H.R.C.o.C., Tri-Council Policy Statement: Ethical Consult for Research Involving Humans, 2010.10. Evans JP and Rothschild BB. Return of results: not that complicated? Genet Med. 2012; 14(4): 358-60.11. Biesecker LG et al. The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine. Genome Res. 2009; 19(9): 1665-74.12. Biesecker LG. Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project. Genet Med. 2012; 14(4): 393-8.

References

Concluding remarksWhile it is still unclear exactly how informed consent and return of results are going to look in the future context of WGS, many of the research projects employing WGS have an integrated ethics component, which in-cludes research subject engagement. As such, I am confident we will establish ethi-cal best practices when it comes to WGS in clinical and research settings. Furthermore, as WGS is exploited clinically, opportunities and challenges will be created for researchers and clinicians. Clinical WGS datasets could provide a rich source of data for researchers, provided that appropriate informed consent and privacy safeguards are put in place. This environment would represent a paradigm shift in which clinical medicine and research could occur using the same platform, facili-tating knowledge exchange.


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lizing medications, essentially coining the term “pharmacogenetics.” Prof. Kalow and I trained students in my laboratory, and be-fore he passed away, he saw the fruits of these labours with the delivery of genetic tests for characterizing drug metabolism. Another Toronto researcher, Dr. Victor Ling, discov-ered the role of drug transporter proteins, for which there are now DNA-based tests to determine their variation across individuals. Given this powerful history in pharmaco-genetics at the University of Toronto, I was inspired to carry the science forward using the developments in the human genome and genetic testing technology.

What are some of the clinical applications of pharmacogenetics in psychiatry?We have a number of patented genetic dis-coveries making their way into the clinic, in-cluding a test using dopamine system genes to predict risk for tardive dyskinesia (un-controlled muscle movements) as a result of prolonged use of antipsychotic medications. We also have a genetic test that identifies de-pressed patients who are at risk for develop-ing mania as a result of their antidepressant treatment. We have just published an impor-tant paper showing the role of the melano-cortin 4 receptor (MC4R) gene in determin-ing the risk for antipsychotic-induced weight gain. The newer antipsychotic medications have the side effect of substantial weight gain; some patients will gain more than 100 lb dur-ing one year of treatment and often go on to develop diabetes and heart disease. After the initial finding of this gene’s effect in the first sample, we replicated the exact same result in three independent samples.

It is now possible for the physician to see a patient in the morning, for the patient to have a quick sampling of their saliva using a swab, and this sample to be shipped off to a specialized lab where the genotyping of the relevant genetic variants for common medi-cations can be done overnight. The results are emailed to the physician the next day, and the physician writes a prescription on the ba

going through the entire disappointing se-quence of non-response. We need to move beyond trial-and-error prescription of medi-cations. With pharmacogenetics, we can help predict which patients will not respond to a particular medication, and also predict the best choice of medication on the basis of their genotype and psychiatric condition.

How did you become interested in pharma-cogenetics?I became interested in pharmacogenetics when I witnessed many patients suffer while receiving the standard textbook dose of an antidepressant or antipsychotic medication. I saw the answer was in the power of new DNA technology for testing patients to determine their combination of genetic variants and whether a given patient metabolized the medication quickly or slowly. I had also read seminal papers by Prof. Werner Kalow from his work here at the University of Toronto in the late-1950s and 1960s. He was the first to point out that people were genetically predis-posed to having different rates for metabo-

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r. James L. Kennedy is the Direc-tor of the Neuroscience Research Department at the Centre for Ad-

diction and Mental Health and the Co-Direc-tor of the Brain and Therapeutics Division in the Department of Psychiatry, University of Toronto. Dr. Kennedy has an extensive, and unique combination of training in psychia-try, genetics, and neuroscience. As a profes-sor and full-member of IMS, he has super-vised well over a hundred trainees, including undergraduate and graduate students, post-doctoral fellows, and visiting scientists.

What is pharmacogenetics, and why is it important to study?Pharmacogenetics is the science of linking a person’s DNA sequence with their response to medication. Because DNA provides its own unique blueprint of the body, we can make specific predictions as to the right drug and its correct dosage for a particular patient. We hope to prevent patients from continu-ing for weeks on ineffective medication and then having to switch to another medication,

Psychiatric PharmacogeneticsMaximizing Benefits While Minimizing Side EffectsBy Zeynep Yilmaz, PhD candidate

James L. Kennedy, MD, MSc, FRCP(C)


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How do you predict the future of pharma-cogenetics?As we move into the future, I see many ben-efits arising from pharmacogenetic testing in the population. It is easy to imagine the substantial healthcare savings when we can prevent non-response or debilitating side ef-fects from medication treatment. If patients are prescribed the right drug from the start, they should have fewer doctor visits and stay compliant with their medication. Currently, under our large pharmacogenetic initia-tive funded by the Ministry of Economic Development and Innovation to test 20,000 patients, Ontario stands to be the leader, as the largest single geographic region offering pharmacogenetic testing in the world. Per-sonalized medicine with pharmacogenet-ics is estimated to save Ontario at least $88 million in health care costs over the next 5 years. Pharmacogenetics is a very exciting area benefiting from rapid increases in DNA-based information, and computer-based al-

gorithms combining information from mul-tiple gene variants together to create more powerful methods to define an individual’s tailor-made treatment.

One of our recent projects is an innovative treatment for anorexia nervosa. We believe that one of the medications that has a calming effect in schizophrenia patients, but causes weight gain, may be helpful in anorexia ner-vosa by reducing anxiety associated with eat-ing. It will be interesting to see if MC4R gene variation can predict those individuals that, in this case, gain weight in a helpful way. The fact that MC4R is expressed in the appetite centre of the brain may help demonstrate its value in predicting the patients that would get the most benefit from this medication.

sis of the patient’s genetic profile. There is lit-tle delay in starting treatment, and the choice of medication is precise and targeted to avoid side effects and achieve the best response.

On which psychiatric disorders are you conducting pharmacogenetic studies?I expect that pharmacogenetic informa-tion will apply to virtually every psychiat-ric disorder. Over the 20 years that I have been doing research here at CAMH/UofT, I have overseen the collection of more than 24,000 DNA samples for disorders including schizophrenia, bipolar disorder, obsessive compulsive disorder, attention-deficit/hy-peractivity disorder, addictions, eating dis-orders, suicidality in teenagers treated with antidepressants, as well as severe depression in young children. Unfortunately, not all of these patients have been characterized in terms of medication response. These studies are difficult because they require a patient to be followed over an extended period of time. Nonetheless, we have several thousand DNA samples from psychiatric patients with drug response and side effect information – one of the largest collections in the world.

The human brain is the most complicated feature of the human body, and it presents many unique challenges to genomics research. The best, and perhaps only, effective approach to understanding the genetics of brain structure is to combine data from multiple research sites to conduct studies with very large and diverse population samples.

In the largest MRI study of the brain to date, re-searchers from several sites around the world reported new links between specific gene vari-ants and total brain volume, intracranial vol-ume, and hippocampal volume. The study was

A column by Aaron KucyiPick Your Brain...

possible because investigators in North America, Europe, and Australia combined brain imaging and genetics data from over 21,000 human subjects in a “crowdsourcing” project. Some findings—such as that of a strong link between hippocampal volume and the rs7294919 variant—were not in agreement with previous smaller studies. Because hippocampal and other brain volume measures have relevance to neuropsychiatric disorders, including Alzheimer’s dis-ease, schizophrenia, and depression, the new find-ings may lead to personalized genomic approaches to therapy.

The study highlights the usefulness of, and need for, further large-scale multinational collabora-tions in the field of brain imaging genetics. The 200+ authors of the study caution that their work is just a preliminary step and that the findings need to be confirmed and extended before this type of work can lead to targeted treatments for neuro-psychiatric disorders.

Reference:Stein et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet. 2012;44(5):552-561.

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A Population-based Genetic Study of Childhood Attention Deficit Hyperactivity Dis-order and Obsessive Compulsive Disorder

ould you like to spit for sci-ence?”

“SPIT! Why would I do THAT?” shouted the 10-year-old boy with both excitement and disgust. As I explained to him that his spit could contribute to science and help other people, the boy was quick to agree to partici-pate. Our setup at the Ontario Science Centre (OSC) looked like an arcade with computers, game controllers, and toy prizes--but actu-ally, it was the scene of cutting-edge research.

I had the pleasure of being a part of the Thoughts, Actions and Genes project (TAG), a ground-breaking study exploring the ge-netic basis of attention-deficit hyperactivity disorder (ADHD)1,2 and obsessive-compul-sive disorder (OCD)3,4,5. Led by Dr. Russell Schachar, Dr. Jennifer Crosbie and Dr. Paul Arnold from the Department of Psychiatry at the Hospital for Sick Children, and in part-nership with the OSC, over 17,000 children and adolescents (7-17 years of age) partici-pated in TAG. Each participant completed a behavioural questionnaire, a cognitive task

called the Stop Signal Task (SST), and do-nated a saliva sample. In a recent interview with the investigators behind TAG, the IMS Magazine learned about the project’s novel and creative approach to study complex psy-chiatric disorders.

Q What led you to conduct a research proj-ect like TAG?

Schachar: Psychiatric conditions are highly influenced by genetic risk factors as seen in twin and family studies of affected indi-viduals. Thus far, candidate gene studies and genome-wide association studies (GWAS) have generated suggestive findings but either with difficulty to replicate, or nothing that is ‘significant genome-wide’, respectively. While global collaboration among scientists is a

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Spit for Science:By Laura Seohyun Park


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1. Neale BM, et al. Meta-analysis of Genome-wide As-sociation Studies of Attention-Deficit/Hyperactiv-ity Disorder. J Am Acad Child Adolesc Psychiatry. 2010;49:884-897.2. Crosbie J, et al. Validating Psychiatric Endopheno-types: Inhibitory Control and Attention Deficit Hyper-activity Disorder. Neurosci Biobehav Rev. 2008;32:40-55. 3. Pauls DL. The Genetics of Obsessive Compulsive Dis-order: A Review of the Evidence. Am J Med Genet C Se-min Med Genet. 2008;148:133-139.4. Boileau B. A Review of Obsessive-Compulsive Disor-der in Children and Adolescents. Dialogues Clin Neuro-sci. 2011;13:401-4115. Menzies L, et al. Neurocognitive Endophenotypes of Obsessive-Compulsive Disorder. Brain. 2007;130:3223-3236. 6. Gottesman II, Gould TD. The Endophenotype Con-cept in Psychiatry: Etymology and Strategic Intentions. Am J Psychiatry .2003;160:636-645.7. Schachar RJ, et al. Heritability of response inhibition in children. J Int Neuropsychol Soc. 2011; 17(2):238-47.8. Liu DJ, Leal SM. A Unified Framework for Detecting Rare Variant Quantitative Trait Associations in Pedigree and Unrelated Individuals via Sequence Data. Hum Hered. 2012;73:105-122.

necessary strategy for collecting sufficiently large psychiatric patient samples for genetic analysis, they can introduce new problems such as the imprecision in measuring psychi-atric “phenotypes”. It is not clear that ADHD or any other psychiatric disorder is assessed and diagnosed in exactly the same way in Brazil as it is in the Netherlands. Moreover, global studies collect DNA from very di-vergent ethnic groups. It is entirely possible that the genetic risks for a common disease may not be identical in every ethnic group. Based on these limitations, it was clear to us that novel methods were needed to break this impasse.

Crosbie: Endophenotypes6, which are objec-tive, quantitative, and heritable “interme-diate phenotypes” or “biological markers”, provide increased power to genetic studies by pointing to a more homogeneous genetic group of individuals and measuring a pro-cess that is closer to the underlying genetic mechanism. There is evidence that response inhibition, which refers to the ability to stop a speeded motor response and can be mea-sured by the SST, is a valid endophenotype for ADHD based on the results of clinical, family, functional imaging and preliminary genetic investigations (response inhibition influenced by the genetic risk factors that in-fluence ADHD)2,7.

Arnold: The general population-based de-sign of TAG provided a quick and cost-effec-tive way to collect a large sample of children using a single and uniform assessment of behavioural (ADHD, OCD, and other condi-tions through questionnaire), cognitive (re-sponse inhibition measured by SST) and ge-netic (saliva DNA) traits. With this data, we are able to draw from the full range of varia-tion in our traits of interest, and use an ex-treme trait approach8 to conduct a genome-wide association study comparing children in the upper and lower extremes of specific behavioural and cognitive traits.

Q What are the objectives of TAG?

Arnold: Once we have performed our GWAS and identified interesting risk vari-ants, we intend to genotype these variants in our entire sample and clinical samples. By taking our results to clinical samples, we can test if the identified variants [in the gen-eral population] are also found in ADHD or

OCD patients, and also look for associations with interesting phenotypes we can’t measure in the general population (e.g. neuroimag-ing). Another future direction is to look for other genetic variations beyond the common “single nucleotide polymorphisms” surveyed in GWAS. For example, we will analyze copy number variants and relatively rare but func-tional single nucleotide variants found in coding regions of genes.

Schachar: At that point, we will also generate animal models and learn more about the pro-teins that these genes play a role in.

Q How will this study contribute to the field of psychiatric genetics?

Schachar: There is a great deal of enthusiasm about the use of cognitive endophenotypes or biomarkers in psychiatric genetic research. Ours will be one of the first to be completed. If it proves to be useful in identifying genetic risks for inhibition and for these disorders, the field will move rapidly.

Crosbie: With this potential to point to new candidate genes of interest for ADHD and OCD, the study may provide us with novel information about the etiology and molecu-lar pathways of these disorders, as well as further our understanding of other neuro-psychiatric disorders.

Arnold: Our approach with TAG is consis-tent with previous work suggesting that we should be thinking of neuropsychiatric dis-orders as continuous rather than categorical traits. If we are successful in identifying risk variants for psychiatric disorders, others may want to adopt a similar strategy of studying large general population samples rather than focusing solely on clinic-based populations.

Jennifer Crosbie, PhD, CPsych

Paul Arnold, MD, PhD

Russell Schachar, MD, FRCP(C)


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Darci Butcher, PhD, Postdoctoral Fellow

Program in Genetics and Genome Biology,Hospital for Sick Children

enome sequencing initiatives have been unable to identify the genetic causes or phenotypic mod-

ulators of many of disorders seen in clini-cal medicine. Layered on top of the DNA sequence is epigenetic information, defined as a “stably heritable phenotype resulting from changes in a chromosome without al-terations in the DNA sequence”1. Identifying the epigenetic marks and characterizing how they are read to regulate the expression of the primary genomic sequence is necessary for our understanding of human development and disease. Multiple epigenetic mecha-nisms including DNA methylation at cyto-sine residues in CpG dinucleotides, covalent modifications of histone proteins, regulatory non-coding RNAs, including small interfer-ing RNA (siRNA), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) par-ticipate in regulating gene expression and chromatin architecture. Disruption of these mechanisms is associated with a variety of diseases with behavioural, endocrine or neu-rologic manifestations and disorders of tissue growth, including cancer. The involvement of epigenetic alterations in many diseases has been known for some time, but only recently has it begun to be useful for clinical practice to diagnose and monitor disease progression.

In the Weksberg laboratory we determine genome-wide differential DNA methylation, gene expression and histone modifications for a number of disorders that have known or suspected aberrations in their epigenomic patterns. Many of these projects are collab-orative efforts between the research labora-tory and clinicians at the Hospital for Sick Children and around the world. We are iden-tifying genes and pathways that have altered DNA methylation to determine their contri-bution to the overall disease phenotype. The projects in the laboratory can be separated into those related to growth, including ge-nomic imprinting and intrauterine growth

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EpigenomicsBeyond Genomic Sequencing

restriction and those related to neurodevel-opment including autism spectrum disorders (ASD) and other paediatric neuropsychiatric disorders.

A number of disorders are caused by aber-rant genomic imprinting resulting from un-equal contributions of maternal and pater-nal alleles to the offspring2. Imprinted genes typically function in growth regulation and neurodevelopment, and the corresponding disease phenotypes are due to genetic or epi-genetic aberrations in these genes often re-sult in abnormalities of intrauterine growth or post-natal cognition and behavior. These disorders include Beckwith-Wiedemann (BWS), Silver-Russell (SRS), Prader-Willi (PWS) and Angelman syndromes (AS).

The molecular and epigenetic causes of Beckwith-Wiedemann syndrome have been studied in depth in the Weksberg laboratory3. This disorder is a rare, often sporadic, het-erogeneous congenital overgrowth disorder which has many features including somatic overgrowth, large tongue, abdominal wall defects, ear creases and pits, kidney malfor-mations and neonatal hypoglycemia, as well as in increased risk of embryonal tumours. BWS is caused by epigenomic and/or genom-ic alterations in the imprinted gene clusters on chromosome band 11p15.54 can be sub-divided into two distinct imprinted domains. Most cases of BWS are due to epigenetic le-sions: either a gain of CpG methylation at an imprinting control region on the maternal al-lele of the H19 upstream differentially meth-ylation region (DMR), which silences H19 and activates expression of the growth pro-moting gene insulin growth factor 2 (IGF2), or a loss of methylation at another imprinting control region of the KCNQ1intronic DMR, which silences the growth suppressor gene CDKN1C plus several nearby maternally ex-pressed genes. Identifying specific molecular defects in imprinting disorders provides im-

Rosanna Weksberg, MD, PhD

Staff Physician, Clinical and Metabolic GeneticsCo-Director and Staff Geneticist, Cancer Genetics ProgramThe Hospital for Sick Children

Professor,Molecular and Medical GeneticsUniversity of Toronto


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portant information for patient management and for estimating recurrence risk. Molecular diagnostic testing for abnormal DNA meth-ylation in the relevant imprinted domains can be done for a number of imprinting dis-orders and is already widely applied in PWS/AS and BWS/SRS. The majority of molecular alterations within imprinting domains can be identified by alterations in DNA methylation in the respective imprinting control regions. A few retrospective studies have shown an in-creased incidence of epigenetic abnormalities causing both BWS and AS following the use of assisted reproductive technologies (ART). Although the increased relative risk is small for these DNA methylation errors these data highlight the importance of understanding the mechanisms behind genomic imprinting.

The number of imprinted genes in human and mouse is currently just over 100 imprint-ed transcripts. Approximately 63 of these have been identified in humans. We designed experiments using uniparental tissues and DNA methylation at known imprinted genes to identify new imprinted genes5. We took ad-vantage of two uniparental tissues; complete androgenetic hydatidiform moles (CHMs) and mature cystic ovarian teratomas. CHMs have two copies of each paternal chromo-some and no maternal chromosomes. Mature cystic teratomas, on the other hand, have two copies of the maternal genome. Analyzing the genome-wide DNA methylation patterns in these tissues and comparing them to nor-mal biparental tissue we identified a number of candidate imprinted genes and validated one of those genes both mouse and humans5. An expanded set of known imprinted genes could lead to the identification of the molec-ular cause of disorders of unknown etiology.

The laboratory is also interested in the epi-genetic contribution to intrauterine growth restriction (IUGR), a heterogeneous disorder in which babies are born with a birthweight less than the 10th centile for gestational age. IUGR has been associated not only with sig-nificant maternal and fetal/neonatal mortal-ity and morbidity but also with adult-onset disorders such as hypertension, coronary artery disease, and type 2 diabetes. DNA methylation alterations have been shown to drive increased or decreased placental and fetal growth. By determining DNA meth-ylation patterns in the placenta of children born small for gestational age, we identified that gain of methylation in WNT2 was sig-nificantly associated with reduced WNT2 expression in placenta and with low birth-weight percentile in the neonate6. This gene has been demonstrated to have important function in mouse placental development. These data suggest that WNT2 expression can be epigenetically downregulated in the placenta by DNA methylation of its promot-er and that high WNT2 promoter methyla-tion is an epigenetic variant that is associated with reduced fetal growth potential6. We ex-pect that future studies of the epigenome will elucidate other candidate genes that undergo epigenetic dysregulation and negatively im-pact placental and fetal health.

The second focus in the Weksberg labora-tory is the investigation of DNA methyla-tion alterations in paediatric neurodevel-opment and neuropsychiatric disorders. A number of neuropsychiatric disorders have been described with mutations or deletions in genes that are important for maintain-ing normal epigenetic regulation. Loss of function of these genes can disrupt normal establishment, maintenance, or reading of epigenetic marks, thereby resulting in altered chromatin structure and gene expression. In most disorders of this type, we still do not understand precisely how the mutation is re-lated to the phenotype of the human disease. Many of these disorders are associated with intellectual disability (ID), as well as addi-tional features including various congenital anomalies. The identification of alterations in DNA methylation associated with mutations in specific genes that function in epigenetic regulation will teach us more about what the responsibility of each epigenetic modifier is in the normal patterning of the epigenome. Other paediatric disorders we are investigat-

1. Berger, S.L., Kouzarides, T., Shiekhattar, R. & Shilati-fard, A. An operational definition of epigenetics. Genes & development 23, 781-3 (2009).2. Weksberg, R. Imprinted genes and human disease. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 154C, 317-320.3. Choufani, S., Shuman, C. & Weksberg, R. Beckwith–Wiedemann syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 154C, 343-354.4. Weksberg, R., Smith, A.C., Squire, J. & Sadowski, P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Human molecular genetics 12 Spec No 1, R61-8. (2003).5. Choufani, S. et al. A novel approach identifies new dif-ferentially methylated regions (DMRs) associated with imprinted genes. Genome research 21, 465-76.6. Ferreira JC, C.S., Keating S, Chitayat D, Grafodatskaya D, Shuman C, Kingdom J, and Weksberg R. WNT2 pro-moter methylation in human placenta is associated with low birthweight percentile in the neonate. Epigenetics (2011).7. Bernstein, B.E. et al. The NIH Roadmap Epigenomics Mapping Consortium. Nature biotechnology 28, 1045-8.8. Eckhardt, F., Beck, S., Gut, I.G. & Berlin, K. Future po-tential of the Human Epigenome Project. Expert review of molecular diagnostics 4, 609-18 (2004).

References

ing include autism spectrum (ASD), obses-sive compulsive (OCD) and attention deficit hyperactivity (ADHD). For each of these dis-orders there have been genetic factors identi-fied which explain a small proportion of such cases. We have proposed that epigenetic fac-tors also contribute to the etiology of these disorders. These studies are all in the initial stages but we already have a number of inter-esting and encouraging results. We are cur-rently investigating a number of candidate genes and pathways that may be relevant to these disorders.

The field of epigenetics is generating exciting discoveries in parallel to genome sequencing initiatives. The NIH Roadmap Epigenom-ics Mapping Consortium was launched to produce a public resource of human epig-enomic data to catalyze basic biology and disease oriented research7. Parallel initiatives include the NIH Epigenomics of Health and Disease Roadmap Program and CIHR Ca-nadian Epigenomic Mapping Centres. These initiatives interface with the International Human Epigenomics Consortium, which was established to accelerate and coordinate epigenomics research worldwide8. This is an exciting time for all researchers involved in epigenetic research as we work towards deci-phering the language of the epigenome at an exponential rate.

“Identifying the epigene-tic marks and character-izing how they are read to regulate the expression of the primary genomic sequence is necessary for our understanding of human development and disease.”


FEATURE SPOTLIGHT

In this new and rapidly developing field, it is challenging to stay on top of research findings and innovations in technology. An important part of the McLaughlin Cen-tre’s mandate is to develop tools and da-tabases that will be continuously updated with new information available in the liter-ature about genes and genetic diseases. An equally important component is educating clinicians, nurses, and healthcare profes-sionals (as well as scientists both in and outside of the field) to access and properly interpret this data.

The breadth and calibre of McLaughlin Centre scientists is truly remarkable. The accelerator grants that were funded in 2011 have already led to exciting new findings. Dr. Danielle Andrade’s research on the ge-netics of juvenile myoclonic epilepsy iden-tified a causative mutation in the CLN6 gene; this work is currently in press in the Pediatric Neurology journal. Dr. Anne Bas-sett’s work has identified rare copy number variants that could play an important role in the development of a common heart de-fect, the tetralogy of Fallot; these findings are soon to be reported in PloS Genetics.

Other studies funded by the McLaughlin Centre include investigating how alterna-tive splicing may contribute to Alzheimer’s disease (Dr. Blencowe); development of a service to centralize clinical pharmaco-genetic information and counseling (Dr. Koren); examining the impact and integra-tion of genetic technologies in adult and pediatric care (Dr. Shuman); as well as re-search identifying disease-causing genes in immunoglobin A neuropathy (Dr. Pei) and renal diseases (Dr. Paterson), to name a few. “[The] McLaughlin Centre is a unique experiment, and it’s going incredibly well.”

The IMS Magazine agrees, and awaits with excitement the novel findings and techno-logical breakthroughs that are sure to come to fruition from McLaughlin Centre scien-tists.

ou may not have yet heard about it – and you certainly won’t find it on the map – but McLaugh-

lin Centre scientists and collaborators are making scientific breakthroughs, de-veloping new diagnostic tests, and mak-ing a lasting impact on clinical manage-ment in Toronto and internationally.

The McLaughlin Centre derives its name from the founder of General Motors of Canada, Colonel Robert Samuel McLaugh-lin, “an entrepreneur and a brilliant man” in the words of Dr. Stephen Scherer, the Director of the McLaughlin Centre. “When he passed away, he put a large portion of his money into a foundation and said to dissolve it in 50 years, because no one will remember who he is in 50 years.” And so the Foundation ran a competition and University of Toronto put in an application and won. The original 50 million dollar investment, which is protected, was lever-aged to 200 million by the university, gov-ernment, and partner hospitals.

For about two years now, the McLaughlin Centre has been focused on advancing the field of genomic medicine.

“When I became the Director, we refocused on the concept of using genomewide data to try to identify risk genes for particular diseases, and equally importantly, to move those into the hospital diagnostic setting,” says Scherer. Their goal is to fund science that will not only impact the patients and their families, but will also generate in-formation and data that will be used for things like drug development.

The McLaughlin Centre runs an open com-petition and funds approximately 10 grants a year, all in the area of genomic medicine. Funding research, however, is just one part of its mandate.

One of the McLaughlin Centre’s goals in the next 5–10 years is to ensure that Toron-to becomes a leader in genomic medicine. The IMS Magazine asked Dr. Scherer how the centre plans to achieve this goal.

“The short answer: training programs, funding research projects… and bringing a community of scientists together.”

Scherer emphasizes that “close to 25 per-cent of the funding is applied to education, training, investing in the MD/PhD pro-gram; and many of these students are do-ing their PhDs in the IMS.” The McLaugh-lin Centre also supports projects that are investigating the downstream effect of genetic information, supporting genetic counselling programs, and determining the best way to collect data and deliver it to the patient.

“[The] McLaughlin Centre is a unique experiment, and it’s going incredibly well.” A unique feature of the centre is the Ac-celerator Grant program. “[Currently] if you have a new idea, it is hard to get money right away to explore that.” The accelerator program provides scientists with the op-portunity to get seed funding for a year to get preliminary data and see whether the project will be fruitful. Scientists can then apply to receive funding to complete the project.

Finally, the third goal is to bring a commu-nity of scientists together. Scherer points out that this is a new field, and having crit-ical mass of clinicians and scientists will create momentum for research in genomic medicine and lead to more innovations and breakthroughs. Indeed, collaboration is a requirement in the grants that McLaugh-lin funds: “there need[s] to be two or more partner institutions involved.”

Y

Advancing Genomic Medicine in TorontoAn Interview with Stephen W. Scherer, PhD

The McLaughlin CentreAdvancing Genomic Medicine

By Tetyana Pekar


FEATURE SPOTLIGHT

cherer is a highly influential and very successful scientist. In ad-dition to serving as the Director of

the McLaughlin Centre and The Centre for Applied Genomics (TCAG), he is also a Se-nior Scientist at the Hospital for Sick Chil-dren, a Professor at the University of To-

ronto, as well as a scientist who never stays far away from the public eye–often making appearances on TV, news, and radio.

The IMS Magazine wanted to find out more about Scherer’s career trajectory and the key to his success. Scherer completed his PhD in the Molecular Genetics Depart-ment at the University of Toronto, with Professor Lap-Chee Tsui (discoverer of the Ph

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cystic fibrosis gene). Together, they found-ed TCAG, which houses all of the latest genomic technologies to enable research studies. Scherer estimates that TCAG fa-cilitates well over 1000 laboratories in a given year.

During his PhD, he made a pioneering dis-covery: the identification of genomewide copy number variations (CNVs) as an im-portant source of genetic variation in hu-mans. His lab continues to investigate the role of CNVs in autism, as well as other disorders, through collaborations.

“You have to be persis-tent, and you have to want to do it yourself, because no one is going to do it for you.”Scherer’s job requires him to assume many different roles and responsibilities – from running his lab to running two very dif-ferent centres – so, is there an aspect of his many roles that he most enjoys?

“I’m the ‘idea’ guy. I have to kind of set the vision of where I think things should be five or ten years down the road and … figure out how to get there – [the challeng-ing part]. I have a job that allows me to capitalize on my strengths. It took a long time to get here, but I get to use my brain – people pay me to think about new things.”

Finally, I asked if he had any advice for incoming graduate students. What advice would have benefited him at the start of his graduate career? He laughed, and said that’s a very easy question: learn statistics. “What we are seeing over and over and over again is that we need to have more bi-ologists who have a strong statistical back-ground. You should be taking statistical classes, it is the one thing that will benefit you the most … [it is] absolutely critical.” (See Allison Rosen’s article on page 33.)

But, he warns, it takes more than just a good grasp of statistics to succeed in grad-uate school. “You have to be persistent, and you have to want to do it yourself, be-cause no one is going to do it for you.”

SDr. Stephen W. Scherer The “Idea” Guy


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SPOTLIGHT

the trip, at the end of the trip I felt as though my mind was recharged. I came back with a new perspective and more ready for the chal-lenges and potential frustrations ahead.” Not that Xu has ever really minded the chal-lenges of science in the first place: “I love basic science because it answers fundamental ques-tions.” Having completed her undergraduate degree in forensic science at the University of Toronto, Xu chose to pursue graduate stud-ies at the IMS rather than a CSI-style career. In particular, she was fascinated by regenera-tive medicine and stem cell research. “I took a course that focused a lot on stem cells and biotechnology, and after that course there was no turning back – I was determined to take part in stem cell research,” Xu recalls. That opportunity arrived when she met with her now supervisor, Dr. Cindi Morshead, an expert in neural stem cells whose energy and passion for science Xu found inspiring. Xu has been a happy member of the Morshead lab ever since.

Now in the third year of her PhD studies, Xu is involved in two distinct projects. She is exploring the activation and mobilization of endogeneous spinal cord stem cells in spi-nal cord injury by infusion of cyclosporine A; at the same time, she is investigating a novel adult neural stem cell population that expresses markers of pluripotent stem cells in mice. Xu finds her involvement in these two simultaneous projects both challenging and satisfying, as they allow her exposure to both translational and basic science.

Despite her strong commitment to research, Xu is also determined to find the time in her schedule to continue to gain inspiration out-side of the laboratory through her work with VIDA. She is currently working to organize another volunteer trip that is planned for next year. With her efforts, she hopes that more graduate students will be inspired to get involved and take part in the unforget-table experience (for more information on VIDA, please contact Xu at [email protected]).

Asked when she expects to finish her PhD, Xu smiles, “Hopefully in about three years.” Undoubtedly, the next three years for Xu will be as stimulating and exciting as the past three have been.

t is no secret that the world of science can be a frustrating one in which every successful experiment is

preceded by numerous experimental failures. Whenever frustration threatens to spoil her day in the lab, Wenjun Xu – a PhD student in the IMS – simply reminds herself of a differ-ent world that she experienced during a vol-unteering trip to Nicaragua and Costa Rica last year. “I think of how people there make the most out of what little they have every day, and how in comparison my problems can all be overcome.”

The two-week long trip, which Xu organized through VIDA (a non-profit organization that facilitates volunteer-based public health

services in Central America), is a highlight of Xu’s graduate experience. Along with 15 students from various graduate departments within the Faculty of Medicine, Xu and her peers traveled through remote regions in the two Central American countries, stayed in local homes, visited orphanages and AIDS centres, worked with local medical person-nel, and helped to set up mobile clinics. It was long hours of hard work every day under smothering heat, but the group’s efforts were returned in the form of warm smiles and appreciation from the local communities. When asked how the experience had influ-enced her research and outlook on graduate school in general, she offered: “Although we were physically exhausted every day during

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By Karrie Wong

Wenjun XuThe best of both worlds

STREAM PhD studentSUPERVISOR Dr. Cindi Morshead


SPOTLIGHT

Cindy LauBrain games

STREAM MSc Biomedical Communications SUPERVISOR Michael Corrin

proached me with the problem. Michael Cor-rin also really encouraged this—especially because it’s a tool that might actually be used by students in a practical, and hopefully help-ful way.”

A demo of the game reveals a sleek inter-face, an engaging method of learning, and remarkable visuals, including the ability to examine the spinal cord at individual verte-bral levels. The objective is to build a neural pathway between the brain and body region of interest, as chosen by the user from avail-able cases. “It’s a game in the sense that if you build an incorrect pathway, you lose—but we also try to mimic the temporal element of nervous signal propagation,” comments Lau. “The game is as much about accuracy as it is about time: can you build the correct neural pathway so that the nervous signal propa-gates without interruption?”

Of her scholarship, Lau relays her gratitude for the guidance and support she has received from both her advisors and peers. “I feel real-ly lucky to have been the recipient,” she con-tinues. “There is a relatively small circle of us in the biomedical communications commu-nity, so it’s quite an honour to be recognized among a group of really talented individuals.”

As she nears graduation from BMC, Lau doesn’t lose sight of her goals: “I am deter-mined to finish this project to the best of my ability—not just for the sake of finish-ing, but to really create a tool that achieves its intended goals. Especially in light of the Vesalius Trust scholarship, I want to give it my absolute best.”

otivated by a steadfast inter-est in both biology and art, Cindy Lau found her professional niche

when she discovered the Biomedical Com-munications (BMC) program two years after completing her undergraduate biomedical engineering degree. This past year, the sec-ond-year MSc BMC student was awarded the prestigious Alan W. Cole Scholarship in the Vesalius Trust’s 2012 scholarship competi-tion—an honour that undoubtedly reflects her enthusiasm for her work.

The Trust was established by a professional organization of medically-trained visual communicators—the Association of Medi-cal Illustrators—to support education and research programs in the field. Specifically, competitive research scholarships are award-ed annually to students enrolled in accred-ited North American medical illustration programs, with the Alan W. Cole scholarship granted to the top scholar across all insti-tutions. Applicants are evaluated based on background, education, project concept, de-sign, and production plan.

M Lau received the award for her master’s re-search project “NeuroPath: Creating Neural Pathways In Play and In Mind,” an interac-tive computer game designed to help medical students learn neural pathways. Supervised by BMC advisor Michael Corrin and con-tent expert Dr. Barbara Ballyk, who teaches neuroanatomy as part of the medical school curriculum, Lau is eager to make the highly visual and complex content as understand-able as possible.

“Learning how electrical signals travel from the brain to motor segments, or from sensory nerves to the brain—it can be fairly compli-cated to learn because many pathways cross over at different levels [of the nervous sys-tem],” explains Lau. “It’s challenging to learn just through rote memorization and reading textbooks.”

Lau credits her supervisors for prompting her involvement in the project. “Dr. Bal-lyk encourages her students to draw out the pathways as they learn them. She sees the difficulty they can have firsthand, so she ap- By Nina Bahl

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will be able to construct neural pathways (right) from a selection of different patient cases (left).


Jeff Brown and Mark Fenske, with Liz NeporentThe Winner’s Brain: 8 Strategies

Great Minds Use to Achieve SuccessDa Capo Press, 2011; 240 pages

Book Reviews

n the creative collaboration be-tween clinical psychologist Jeff Brown and cognitive neuroscientist Mark Fenske, the

book The Winner’s Brain: 8 Strategies Great Minds Use to Achieve Success combines cutting-edge neuroscientific research with well-established cognitive-behavioural psychological strategies to reveal how highly successful brains function. The authors give practical guidance to enhance cognitive performance and to allow the reader to achieve unique, personal ideas of success.

The Winner’s Brain starts by taking the reader through an engaging tour of the history of neu-roscience and a brief overview about what we currently know about the inner workings of the human brain.

The authors then reveal the importance of neu-roplasticity, which is defined in the book as the neurocircuitry changes that occur with every ex-perience, and using this to take control of your brain “in order to position yourself to achieve your goals and dreams.” According to Fenkse, in a recent communication with the IMS Magazine, “The saying ‘old dogs can’t learn new tricks’ is ob-viously wrong.”

The Winner’s Brain outlines five “Brain Power Tools” that all Winning Brains have in common: the Opportunity Radar (knowing which opportu-nity will lead to success and which will not), the Optimal Risk Gauge (calibrating a risk threshold to decide whether or not a chance is worth tak-ing), the Goal-Laser (intentionally and deliber-ately taking steps to accomplish important goals), the Effort Accelerator (keeping motivated), and the Talent Meter (knowing your strengths and weaknesses). All of these Brain Power Tools can be strengthened by strategies termed “Win Fac-tors,” which include Self-Awareness, Motivation, Focus, Emotional Balance, Memory, Resilience, Adaptability, and Brain Care.

These tools and strategies are derived from highly complex concepts in neuroscience and cognitive-behavioural psychology that are not easily trans-lated into a language accessible for individuals out-side of these fields. However, Brown and Fenske, ably assisted by health-writer Liz Neporent, mas-ter this feat of knowledge translation with playful and clear writing that offers an adequate founda-tion in science (highlighting applicable pieces of information), step-by-step instructions on how to master change, and interviews conducted with individuals with a range of real-life success sto-ries. Some inspirational stories of success include interviews from Trisha Meili (also known as the Central Park Jogger), Kerri Strug (gymnastics Olympian), Kevin Clash (Sesame Street’s ‘Elmo’), Andy (a London Black Cab driver), Camille Mc-Donald (Bath & Body Works’ President of Brand Development), and one of Fenske’s most inspira-

tional interviews, B.B. King (Blues guitar legend).

Fenske states that when he and his colleagues were writing the book, they wanted to include “real world examples of people and the science in action, exemplifying the science and research be-hind each [particular Win Factor].” Fenske went on to tell us about his interview with B.B. King, in which B.B. King “talked about humble begin-nings, being very poor, and how being a black artist was full of challenges when he started out.” Fenske heard the “resilience and dedication of [B.B. King] pushing through time after time, and how he had the mental strategies at [the beginning of his career] that he still uses as a performing art-ist, such as practicing and constantly and continu-ally working on himself and what he does.”

As this book is about translating the complex concept of neuroplasticity into easily accessible terms for many audiences, B.B. King’s interview, amongst many others, “illustrates how the brain is constantly changing and that each of us can be proactive by taking part in how our brain changes over the course of a lifetime.” Fenske reflected on what he has come to know about neuroscience and said, “This is a message of hope…We don’t just have to settle with what we are or what we can do at any point in time.”

The Winner’s Brain is a valuable combination of expertise of neuroscience and clinical practice. And Fenske added, “The book benefitted tremen-dously from interactions with students, which fa-cilitated discussion and helped in brainstorming ways that [this knowledge] can be translated into a language that anyone can use.” Fenske cleverly pointed out that there are “more than just scien-tists who can use this new knowledge to increase their Brain Power in their day-to-day lives.”

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Worth missing a day at the lab Try to squeeze in between experiments Wait for the weekend Wait until degree is completeExcellent Very Good Good Average

Column by Brittany N. Rosenbloom

BOOK REVIEWS


What are you reading?Aaron Kucyi, PhD candidate, recommends Free Will by Sam Harris

“The concept of free will has taken a beating in light of recent neuroscience discoveries. Harris offers no mercy in his succinct set of essays—he had no choice—but convincingly argues that de-terminism is not all awful: rather, accept-ing your ‘biochemical puppet’ status can be both humbling and awe-inspiring.”

Brett Jones, MSc candidate, recommends The Head Master’s Wager by Vincent Lam

“The Head Master’s Wager is the third book written by U of T lecturer, physician, and award-winning author of Bloodlet-ting and Miraculous Cures, Vincent Lam. Set during the Vietnam/American war, Lam tells a story of the compulsive gam-bling, womanizing Percivel Chen, who is the head master of the most prestigious English school in Saigon. This story of Percivel Chen, a fictional character based on Lam’s own grandfather, is a wonderful work of fiction on love, betrayal, and sac-rifice.”

Tetyana Pekar, MSc candidate, recommends The Trouble with Physics by Lee Smolin

“A defining feature of a good theory is that it makes testable and unique predic-tions. In this book, Lee Smolin, a theoreti-cal physicist at the Perimeter Institute, argues that this feature is lacking in string theory. Smolin cogently lays out the problems with string theory, why it is a dead-end, and how the theory’s popu-larity is detrimental to progress in funda-mental physics. Best of all, it is easy to read, passionate, critical and insightful.”

here in the world do people often live to be over 100? That is the question that begins this

interesting and well-referenced book. The an-swer is intricately described by John Robbins, heir to the Baskin-Robbins ice cream corpo-ration, though ironically, a firm advocator of healthy lifestyles. In search for answers, he takes the reader on a tour of four diverse and isolated regions: Abkhasia in the Caucasus region of Rus-sia, the Hunza region of Pakistan, Vilcabamba in Ecuador, and the island of Okinawa in Japan. These dispersed and unconnected regions have one thing in common: some of the healthiest and oldest living people on the planet. During the readers’ literary journey from place to place, Robbins illustrates that it is a complex aggregate of factors that enable these populations to have more centenarians than in the Western world.

Firstly, while geographically, ethnically, and culturally distinct, these populations have similar plant-based and meat-less diets. And of course, they are free of processed-food. Equallyimportant, exercise is incorporated into their daily life, allowing these populations to stay lean and active in late life. Secondly, these commu-nities are socially healthy; they foster a strong sense of spirituality and social support. Elders

are highly respected in these communities, and as individuals age, they gain more stature and become revered for their wisdom and knowl-edge. This is in stark contrast to the common mentality in Western societies where older citi-zens can be seen as a burden.

Striking, as well, is the longevity of these popu-lations compared to the mental and physical de-terioration that occurs in Western societies, and in particular, the high incidence of old-age dis-eases. Communities in these regions remain vi-brant, healthy, and free of disease; remarkably,they do not have an abundance of cancers, neu-rological diseases, and the host of cardiovascu-lar diseases that plague our society. A doctor would be unneeded there!

Robbins is thorough in his analysis of the lit-erature. He considers the similarities and dif-ferences between these populations and our culture carefully, down to the level of genes and hormones. He emphasizes the link between an-imal-based foods – dairy, meat and eggs – and cancers, cardiovascular diseases and diabetes, with strong primary research articles. More-over, he investigates the link between white foods – sugars, rice, and breads – with health abnormalities, including dental deformations and decay.

Finally, the third section of his book is the “how to”: how to adopt and learn skills and lifestyles from these populations while balancing the re-alities and demands of our society (sounds too good to be true). He delves into the research of the mind and body and the benefits of regularexercise, and interestingly, designates an entire chapter to love and healthcare – the benefits ofbeing in healthy and loving relationships (and the negative effects of ‘toxic’ relationships).

Overall, an interesting and important read! Robbins makes meaningful claims about healthand well-being, backed by solid scientific evi-dence. Robbins is convincing because he not only presents the scientific evidence, but also analyzes the studies’ strengths, weaknesses, lim-itations and possible interpretations.

And if you’re wondering whether Robbins cur-rently bears the torch to the Baskin-Robbins corporation, the answer, as you may have guessed, is a firm no. He declined that offer.

John RobbinsHealthy at 100: The Scientifically Proven

Secrets of the World’s Healthiest andLongest-Lived Peoples

Random House Publishing, 2007; 348pages

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If you are an IMS faculty member or stu-dent and would like to have your book review published in a future issue of the IMS Magazine, please send a 50-word re-view to [email protected]. Column by Salvador Alcaire

BOOK REVIEWS


DBy Melanie Guenette

Renowned clinician-scientist and unpar-alleled mentor

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CLOSE UP

r. Gary Remington is the 2012 recipient of the IMS Mel Silverman Mentorship Award. If you were to

ask him about this momentous accomplish-ment, he would likely shake his head and im-mediately credit his students for nominating him. That is just the sort of man he is: un-derstated, humble, and selfless. I am biased of course, because he is my supervisor, but no one misses an opportunity to sing the praises of this formidable clinician-scientist; the proof lies in the half dozen letters of sup-port that went into his nomination package.

Dr. Remington is busy; he is the Director of the Medication Assessment Clinic in the Schizophrenia Program at the Centre for Ad-

diction and Mental Health (CAMH), as well as Deputy Head of Research and Education for the same program. He is also Schizophre-nia Head, Division of Brain and Therapeutics and Professor in the Department of Psychi-atry at the University of Toronto. As if that were not enough, Dr. Remington has been a member and graduate supervisor with the IMS for a decade, and he currently supervises seven students in his laboratory.

Starting out as an undergraduate at Waterloo Lutheran University (now Wilfred Laurier), Dr. Remington met and worked with Dr. Hymie Anisman, whom he identifies as his first mentor. Their partnership lasted a num-ber of years, as Dr. Remington completed

Interview with Dr. Gary Remington


CLOSE UP

a PhD under his supervision in the area of neurotransmitter development and hyper-activity. Set to undertake a post-doctoral position at the University of Minnesota, Dr. Remington had a choice to make: “I was torn between the basic sciences and doing work at the clinical level. I realized that if I wanted to make a career out of this work, I would have to marry the clinical with the basic, and to do so would require a medical degree.”

Having completed medical school at McMas-ter University, Dr. Remington declared a spe-cialty in neurology and began his residency at the University of Western Ontario. A year into his training, he was pulled aside by neu-rologist Dr. John Brown. “He said I’d make a better psychiatrist than neurologist,” recalls Dr. Remington. “I called up the Psychiatry folks in Toronto and they accepted me over the phone.” He then began his psychiatry residency at CAMH. I ask him about what would eventually become the focus of his career—schizophrenia—and Dr. Remington says the fascination was instant. “I had never seen anything like it, nor have I since.” In his second-to-last year of training, Dr. Reming-ton was approached and offered a staff posi-tion at CAMH; he has now been there almost thirty years.

When asked to describe his research, Dr. Remington remarks that it is a reflection of why he left his post-doctoral position for medicine. “I feel an obligation to ask a ba-sic science question that can almost imme-diately be translated into changes in clinical practice,” he continues. Strictly speaking, Dr. Remington studies schizophrenia, but identifies one of his shortcomings as his “in-ability to focus on a single research ques-tion—something that is usually preferred by scientists.” To illustrate the breadth of his work, Dr. Remington and his students study an array of research questions that include schizotypy, the metabolic side effects of anti-psychotic drugs, antipsychotic tolerance and adherence, and the manifestations of nega-tive symptoms of schizophrenia through vir-tual reality techniques.

Given that Dr. Remington is being recog-nized for his mentorship abilities, our talk shifts to students and student supervision. I ask him how he chooses his students and he says, “It all depends on the interview. I get a sense of whether or not the fit is right after

speaking to them.” When I ask him to de-scribe his students, he takes a minute, a smile forming on his face, and says his students are “motivated, able to work independently, and hopefully enjoy their research.” He adds, “I really enjoy the enthusiasm and excitement my students bring to the laboratory every day. I remain inspired by them.”

Dr. Remington is known for his eloquence and candor, so when I ask him about his men-toring style, I am initially surprised when he pauses and says, “I don’t know how others mentor—it’s not like there’s a book for this sort of thing.” He then continues, “I mentor the way I was mentored [by Dr. Anisman]: I ensure close and regular contact with my students. I make myself available and try to provide a supportive environment, giving my students the resources they need to succeed. It’s nothing fancy.” At this last point I laugh, knowing all too well how rare this situation can be: Gary Remington is an absolutely fan-tastic mentor, he pours everything into his students, and they know it. So why does he do it? “I was there. Somebody did it for me. Dr. Anisman categorically changed my ap-proach, not only to medicine, but also to life. He was amazing—a role model to me. I feel I have an obligation to do that for as many people as possible moving forward.”

Of the IMS, Dr. Remington says, “I think it has an innovative approach to bringing peo-ple together from diverse backgrounds, and offering them the opportunity to cross tra-ditional research boundaries.” He adds that the challenge remains in “bringing people to-gether from many areas and levels of exper-tise in an environment that rewards absolute focus on a single area or research question.” Dr. Remington’s involvement in the IMS doesn’t only include his role as a graduate supervisor; he has been on countless Project Advisory Committees (PACs) and has been a judge in both the Summer Undergradu-ate Research Program (SURP) and IMS Sci-entific Days. “I find it stimulating to see the scope and quality of research being done by

the students at the IMS. I really like seeing the passion they have for their work.”

I ask Dr. Remington what he sees himself doing in ten years: “I hope to still be coming into work every day. I don’t see what I do as a job. It’s a well kept secret how much I en-joy this.” Admitting that he sleeps about four hours a night, he adds, “I am blessed with do-ing something that I love so much and still want to be doing. I am so lucky—I hope no one catches on!”

For students, Dr. Remington says the larg-est obstacle is the “incredible competition to capture a spot in this research environment.” I ask him what is key to selecting the right supervisor, to which he replies, “Find a men-tor as early on as you can. The goal is to find someone you respect. Respect is fundamen-tal.”

Dr. Remington sees the potential in his stu-dents and treats them as valued members of the scientific community. His ability to effec-tively guide and support his students, while always remaining committed to their success, makes him the true definition of a mentor. Although he would never admit to it, I can think of no one more deserving of the Mel Silverman Mentorship Award. Congratula-tions Dr. Remington.

“Dr. Remington is friendly, warm, and en-couraging, while remaining entirely profes-sional. He is respectful and sensitive to the needs of his students.”

- George Foussias, MD, PhD candidate

“Dr. Remington allows his students to demonstrate their success, easily stepping aside to enable personal growth and ac-complishment.”

- Gagan Fervaha, MSc candidate

“Dr. Remington sees the potential in his students and treats them as creative, intel-ligent, and responsible scientists.”

- Laura Schulze, MSc candidate

Student sentiments

“I find it stimulating to see the scope and quality of research being done by the students at the IMS. I really like seeing the passion they have for their work.”


t is the dream of every scientist to publish a research article in Nature, Cell, or Science. For a graduate student work-

ing towards a PhD, a publication in one of these prestigious journals almost guarantees a successful defense examination, a reputable post-doctoral fellowship, and a subsequent tenure-track position. For a senior scientist managing a research lab, publications of this calibre provide an advantage in grant compe-titions and give greater stability in funding. For a research institution, high-impact pub-lications draw global spotlight, attract better scientists, and earn the institution prestige. It therefore appears to be in everyone’s best interest to publish in the highest impact journals possible, but this dream could be a nightmare in disguise. The higher the journal’s impact factor, the higher its retraction rate1. Reasons for retrac-tion are distributed between misconduct and honest error, but the underlying causes for

these occurrences remain largely unexam-ined. Executive editor of Science, Monica M. Bradford, defended this finding in The New York Times by suggesting that high-impact journals have a higher retraction rate because they receive more attention and are subject to more scrutiny2. While this may be the case, it implies that other, lower-impact journals also publish articles that violate ethical guide-lines, contain scientific misconduct or error, or plagiarize previously published work, but that those articles go unnoticed. The end re-sult is the same—our scientific literature is full of error, and that error is on the rise. A recent article in Nature reported that the number of retraction notices has increased 10-fold over the past decade, while publica-tions have increased by only 44%3. Although improved vigilance is a convenient and plau-sible explanation for this trend, there are other possible culprits. Astoundingly, 1-2% of scientists have admitted to fabricating, fal-

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Why science takes two steps forward and one step back

sifying, or modifying data or results at least once4. A close examination of the publish-ing pipeline reveals several points where the pressure to publish may overwhelm an other-wise honest scientist, leading them to trans-gression. As mentioned, graduate students need to publish to build their future, and senior scientists need to publish to secure their future. This pressure to publish is com-pounded by the predominant bias to publish positive results more than negative results. (For a complete discussion of the research bias towards positive results, see “Positive Pressure,” in our Fall 2011 issue.) While only a minor-ity of scientists may be willing to fabricate or falsify results to fit their hypotheses, a major-ity of scientists may be inclined to select data which support their hypotheses, and ignore data which do not.

There lies the danger of predicating the suc-cess of a scientist on their publication record; the purpose for publishing shifts toward

Publish and Perish


survival of the fittest author, and away from disseminating authentic results. Scientists are increasingly being evaluated using met-rics such as the h-index, which is based on number of publications and number of cita-tions per publication5. Assessing a scientist’s performance using such metrics creates un-deniable desire, need, and pressure to publish often, and in highly cited journals. Countries such as China, South Korea, and Turkey offer cash incentives to encourage local scientists to submit their manuscripts to high-impact journals6. Despite the low probability of suc-cess, the high volume of submissions over-whelms reviewers and congests the publish-ing pipeline. Given these circumstances, how can the literature be trusted, and how can scientific progress be made?

1. Fang FC, Casadevall A. Retracted science and the re-traction index. Infect Immun. 2011;79(10):3855-3859.2. Zimmer C. A Sharp Rise in Retractions Prompts Calls for Reform. The New York Times. 2012 Apr 17;Sect. D-1.3. Van Noorden R. Science publishing: The trouble with retractions. Nature. 2011;478(7367):26-28.4. Fanelli D. “Positive” results increase down the Hierar-chy of the Sciences. PLoS One. 2010;5(4):e10068.5. Hirsch JE. An index to quantify an individual’s sci-entific research output. Proc Natl Acad Sci U S A. 2005;102(46):16569-16572.6. Stephan P. Research efficiency: Perverse incentives. Nature. 2012;484(7392):29-31.7. Schooler J. Unpublished results hide the decline effect. Nature. 2011;470(7335):437.

References

Disclaimer: The opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto. Comments are welcome at [email protected].

VIEWPOINT

Schooler believes “we need a bet-ter record of unpublished research before we can know how well the current scientific process, based on peer review and experimental rep-lication, succeeds in distinguishing grounded truth from unwarranted fallacy.”

The soaring retraction rate ob-served in high-impact journals may be an accelerated manifestation of the decline effect. Because high-impact journals publish studies with novel and dramatic results, those results are more likely to be overstated, and are less likely to be reproducible. The lack of reproduc-ibility is unsurprising considering the tweaking, selecting, and beau-tifying of data that oftentimes pre-cedes publication. First reported in the 1930s, an established barrier to scientific advancement is the de-cline effect, which is observed in the litera-ture as scientifically discovered effects that diminish over time. Schooler suggests that “if early results are more likely to be reported when errors combine to magnify the appar-ent effect, then published studies will show systematic bias towards initially exaggerated findings, which are subsequently statistically self-corrected”7. The soaring retraction rate observed in high-impact journals may be an accelerated manifestation of the decline ef-fect. Because high-impact journals publish studies with novel and dramatic results, those results are more likely to be overstated, and are less likely to be reproducible. The lack of reproducibility is unsurprising considering the tweaking, selecting, and beautifying of data that oftentimes precedes publication.

Detrimentally, if the studies in high-impact journals are reaching the widest audiences and are conveying less-than-accurate results, the scientific field is being misguided. The argument can be made that science is an imperfect field, with enormous variability. In biomedical research, there are innumerable known and unknown variables that influence experimental outcomes, some as significant as the strain of mouse used, some as innocu-ous as the time of day an experiment is con-ducted. Every experiment contains outliers, inconsistent replicates, and unexpected find-ings, but these are rarely reported, and per-haps that is the bigger issue. As Dr. Karen Da-vis, Associate Director of the IMS and Editor of Pain, previously communicated to the IMS Magazine (“Positive Pressure,” Fall 2011), an incomplete or incorrect scientific record can lead to propagation of unfounded ideas, un-necessary replication of experiments, clinical translation of harmful therapies, or delayed development of alternate hypotheses. Once flawed ideas are published, they can never truly be retracted. Budd et al. report that even after an article is retracted, it continues to be cited, without acknowledgement of the retraction3. Understandably, once digital ver-sions of articles are downloaded, researchers are unlikely to consult the original source again, and are therefore unlikely to be aware of corrections.

What is needed is a more complete account of scientific findings, be they negative or positive, consistent or inconsistent, surpris-ing or expected. During the IMS Scientific Day 2012 Bernard Langer Lecture in Health Sciences, Dr. Thomas R. Insel, MD, Director of National Institute of Mental Health, pos-ited that if experiments are soundly designed and flawlessly executed, then those results should be disseminated, regardless of what they are. Furthermore, Schooler believes “we need a better record of unpublished research before we can know how well the current scientific process, based on peer review and experimental replication, succeeds in distin-guishing grounded truth from unwarranted fallacy”7. He recognizes the difficulties in implementation, but suggests an open-access database of research methods, which allows scientists to log their hypotheses and meth-odologies prior to experiments, and their published and unpublished results after-wards7.

To purify the publication pool, the current publishing paradigm should be restructured to diffuse the pressure experienced by re-searchers. Among other strategies, graduate students should be given avenues to publish their negative results, and senior scientists should be evaluated on metrics other than their publishing records. To purify the pub-lication pool, more focus should be placed on honest accounting of data in its entirety, and less focus should be placed on polishing of data for high-impact journals. Research-ers should be mindful of the permanence of published results, and wary that embellished or modified data can significantly hinder scientific progress. To alleviate current pub-lishing pressures is to purify the publication pool, and move science forward.


What do Chi-squared tests, t-tests and ANOVAs all have in common? Some might contend

that they are all statistical tests, but others will attest that they are all things that give graduate students a headache. But why do so many students harbor negative attitudes towards statistics? These tests are there to help us—to validate our results and help our interpretations. Right? The IMS Magazine conducted a series of interviews to provide a snapshot of what graduate students face when approaching statistics. “I’m not comfortable with statistics.”

IMS MSc Student Jack* professed this view, and he certainly does not stand alone. Many graduate students interviewed for this article confessed that they do not feel they have enough knowledge of statistics to perform the tests necessary to properly interpret their experiments. Poor knowledge of statistics can have a big impact in graduate school. Jack explains, “It has made my ability to analyze and interpret my own research data more challenging. I have had to teach myself things along the way, or seek significant help from labmates and outside sources; it’s been

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A Numbers GameWhy an article about statistics shouldn’t make you want to turn the page

… a definite source of frustration.” Another IMS student agreed with this sentiment: “I am only confident using very basic statistical tests that apply to my data,” claims Lauren*, a PhD student.

“Statistical analysis is a huge part of my re-search. My limited knowledge on the subject often limits my interpretation of my data and ability to clearly understand research ar-ticles,” Lauren elaborates. Jack confessed that although he has not yet been affected by his lack of adequate statistical knowledge, this problem will become more prominent as he prepares to defend his thesis. “We use a stat-istician, so really I just need to know how to make data look pretty in Excel.”

But not all students share these negative views. Corinne Daly, who recently defended her MSc, and Richard Foty, currently work-ing on his PhD, share their thoughts. “As an epidemiologist, I spend a good portion of my day analyzing data or reviewing articles, so over time I’ve gotten comfortable with the math. It’s the interpretation of those results, however, that I am most interested in. Statis-tical analysis is just the tool I use to get me there,” explains Richard. Corinne expands by

explaining that her familiarity with statistics has been helpful in understanding rounds presentations, publications, and explaining her research. “An understanding and appre-ciation of statistics has been indispensable in my research career,” states MSc student Ben-jamin Mora.

Contrasting feelings towards statistics aside, all of these students agree that knowing sta-tistics is important. Amy*, an IMS student completing her MSc, explains that despite her discomfort with statistics, she understands its importance. “Better knowledge of statis-tics can help tremendously in understanding papers beyond simple P-values; it allows for critical analysis, which is a skill all graduates need to learn.” Amy further elaborates on the level of statistical knowledge she believes to be necessary for graduate students. “Whether or not they complete their own analysis or send results off to a statistician, I absolutely believe graduate students should be familiar with statistics—and I’m speaking as some-one who currently has very limited statisti-cal knowledge. It’s difficult to gauge the ex-act level of knowledge needed, but I think it would be universally helpful to understand the various types of analyses available, and


more importantly, why they are appropriate under different circumstances.”

“You can collect all the high quality data you want, but…you need to have the statistics to back it up,” Corinne emphasizes. However, she also concedes that the issue is more com-plex than that. “There is never [one] right an-swer in statistical methods. Most times there are a few ways of looking at the same prob-lem. Problem solving and discussing which method is best for a specific question is nec-essary sometimes.”

Given that most students understand how important statistics are to their research, why do some students still feel negatively about statistics?

“I personally think in the IMS, not enough people know much of anything about sta-tistics,” Corinne shares. “[This] makes me question how individuals read and under-stand other publications out there. However, I definitely think it is the responsibility of a supervisor and surrounding research group to discuss common methods in their field so that graduate students can independently an-alyze their data and then consult the proper resources when necessary.”

While the supervisor holds some responsi-bility in ensuring a student has adequate sta-tistical knowledge to successfully design and interpret experiments, students also have an onus to take courses to improve their skills. Corinne has taken two statistics courses within the IMS: Biostatistics for Health Sci-entists and Introduction to Clinical Biosta-tistics, and recommends that other graduate students follow suit in order to understand the statistics necessary for their research projects. “These courses definitely provided a foundation for understanding methods and theory behind basic and more advanced statistical methods. However, applying what you know…is a whole new ball game. Only through repeated practice and discussion with my research group have I learned the meaning of statistical tests that I learned about in those courses.”

While Corinne has already taken many courses to become familiar with statistics, most students have not. “My only formal in-troduction to statistics was through a very brief component of an undergraduate biol-

Disclaimer: The opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto. Comments are welcome at [email protected].

VIEWPOINT

ogy course that touched upon biostatistics. I have never taken an entire course dedicated to statistics at either the high school or un-dergraduate level,” confides Amy.

Enter Dr. Paul Corey. Corey has a number of positions teaching statistics within the Uni-versity of Toronto. He teaches both Biostatis-tics for Health Scientists and Introduction to Clinical Biostatistics in the IMS. “Every good researcher asks whether [an] observed dif-ference is likely to be due entirely to chance,” Corey explains. However, he also recognizes that a problem does exist and shares a story of a former student who, after completed a class assignment on a paper she had pub-lished, realized “the published analysis was wrong.”

“Many students do not have a statistician on their thesis committee and some unfortu-nate analyses get published,” Corey explains. “There is enormous variation in the statisti-cal literacy of my scientific colleagues.”

Surely we do not want to lower the quality of published science. But how extensive should a graduate student’s knowledge of statistics be? Corey discussed his future vision of sta-tistics education in graduate departments. “I think that we are in a stage where there will be more modular courses that will enable stu-dents to choose to study only those topics of use for the type of analyses they will need to do in their thesis research. This will increase the interest and dedication of some students. In the future, I predict that there will be more short statistics courses with fewer students in each.”

Smaller, more focused courses circumvent current dilemmas involving bloated statis-tics courses that overwhelm students. Such an approach changes not only research qual-ity, but also opinions and attitudes towards statistics among graduate students. As Co-rey describes, “Many students begin to truly appreciate the power of statistics when they have to perform the analyses on their own thesis data. A proper teaching and under-

Smaller, more focused courses cir-cumvent current dilemmas involv-ing bloated statistics courses that overwhelm students.

standing of statistics rests on a few important and basic concepts. These concepts can only be understood by frequent repetition using language and logic.”

Corey warns that not all students may be pleased by the changes. “Sometimes students are impatient and just want the facts. That is, they want a cookbook course. This is where the danger lies.”

“Students should be able to analyze their own data with a little help from their friends,” Co-rey goes on to suggest, mirroring the thoughts of many IMS students. “I generally seek help from someone in the lab when I can’t figure out how to analyze my data,” shares Lau-ren. Even Benjamin, who feels comfortable with statistics, agrees that “in cases where the analysis becomes more convoluted, it is helpful to receive assistance from more ex-perienced researchers or from statisticians.” Corinne also stresses the importance of get-ting help: “I definitely think that labs and re-search groups should have access to biostatis-tical assistance.”

“Start by reviewing the literature and see what kinds of tests other scientists have used to answer similar questions,” Richard sug-gests. “Once you’ve come up with a few pos-sibilities, research them thoroughly and con-sult a statistician if you can. Finally, present the different methods to your supervisor and committee members and get their recom-mendations.” Planning ahead and consulting others early on can be a big time saver.

Richard advises students to “not be intimi-dated by statistics; they’re a useful tool. Re-member that we all have to look things up. If we knew exactly what we were doing, they wouldn’t call it research.”

* Names have been changed to protect the ano-nymity of the students interviewed


EXPERT OPINION

Interactive proteomics with MYTH: Identifying protein puzzles and putting them into their correct cellular pathway

pate in the same or related cellular functions (the principle of “guilt by association”). In other words, clues about the function of one protein whose role is not understood can be gained by observing that it interacts with an-other protein whose function is known. Such an approach, when applied on a large-scale with all proteins of a certain organism, can result in the identification of novel compo-nents of previously known pathways, or, vice versa, one may conclude that a protein previ-ously known to be involved in one biological pathway also functions in another.

A special focus of our laboratory is on pro-teins associated with biological membranes, also called membrane proteins, which total approximately one third of all proteins in any cell1. These proteins mediate a wide range of fundamental biological processes such as cell signaling, transport of membrane-im-permeable molecules, cell-cell communica-tion, and cell adhesion. Interestingly, many of these membrane proteins have been found to have disease-associated function, and no-tably most of the drugs on the market today are targeted towards membrane proteins. As such, there is a strong demand from both academic researchers and biotech/pharma companies to gain further insight into path-ways and interactions involving membrane proteins. It is therefore of utmost importance to build a comprehensive interactome of this crucial class of proteins. However, despite ex-tensive research in the past decade, there is a lack of in-depth understanding of PPIs as-sociated with this class of proteins because of their unique biochemical features and enor-mous complexity. This is a major obstacle for designing improved and more targeted therapies, and importantly, understanding the biology of deregulation of these integral membrane proteins which leads to numerous human diseases.

Previously, our lab developed the Membrane Yeast Two-Hybrid (MYTH) system, a pow-erful proteomic tool for identifying the in-teractors of membrane proteins in an in vivo setting using baker’s yeast as a model organ-

ism (Figure 2). Using the MYTH system, an interaction between two proteins can be con-verted into an ‘observable signal’, specifically the growth, and blue coloration, of yeast on a specialized media. A unique advantage of MYTH is that it can detect proteins associ-ated with almost any membrane protein in a high-throughput screening format, and is therefore perfectly suited for building in-teractomes of this difficult class of proteins. Since the development of MYTH, it has been applied successfully to identify both transient and stable interactions among various mem-brane proteins from yeast, plant, fly, worm, and humans2-5. It became a valuable pro-teomic tool by creating a bridge between the basics of protein biochemistry and practical applications in the field of medicine and dis-ease management. Along this notion, MYTH has recently been applied to ATP13A2, a hu-man lysosomal membrane protein involved in Kufor-Rakeb syndrome characterized by early-onset parkinsonism, neurodegenera-tion and dementia. MYTH identified dozens of ATP13A2-associated proteins many of which showed to be functionally and mecha-nistically interconnected to ATP13A26. This and other studies showed that MYTH is an interesting translational research tool, allow-ing researchers to study the interactions of a disease-associated protein of interest in both the presence and absence of drugs and ob-serve how these compounds affect the pro-tein’s interaction profile. This information, in turn, can be used to help understand how these compounds affect the physiology of diseased cells. Our lab has currently been involved in using MYTH and variations of MYTH to investi-gate various key areas of research that have direct disease relevance. For example, one large on-going project in the lab is the study of ABC transporters3, a major class of pro-teins responsible for the transport of a wide range of substances across various cellular membranes. ABC transporters are of intense clinical interest because of the key role they play in the multidrug resistance of pathogen-ic microorganisms and tumor cells, as well

very process in a cell is affect-ed by interactions between proteins, which determine everything from the

cell shape to the function of a particular bio-chemical pathway. Just as we tailor our own conversations depending on setting, proteins exhibit many different modes of interac-tion. Long-term protein-protein interactions (PPIs) result in protein complexes, while briefer protein liaisons may lead to a range of possible chemical modifications. Because they are so integral to the physiological func-tion of any organism, PPIs are essential to many lines of research, both basic and clini-cal. In the past decade, scientists working in the emerging field of “interactive proteomics” have initiated numerous projects to build comprehensive maps of all PPIs (also called “interactomes”) of a given cell or organism with the ultimate goal of understanding the functions of the many proteins whose roles are not yet known (Figure 1). This is based upon the principle that if two proteins inter-act with each other they very likely partici-

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the observation that dysfunction of these transporters is associated with a range of human diseases. Similarly, we are also work-ing on building a comprehensive interaction map between the human receptor tyrosine kinase (RTKs) and selected human G-pro-tein coupled receptors (GPCRs). These two families of membrane proteins play a crucial role in cell signaling, a process by which cells respond to cues in their internal or external environment. The finished interactomes of RTKs and GPCRs represent a robust bank of knowledge which will greatly contribute to therapeutic research and shed new light on the mechanism of natural control circuits that regulate biological systems. As an exam-ple, one of our recent findings showed that a

References1. Stagljar, I. and Fields, S. (2002) Analysis of membrane protein interactions using yeast-based technologies. Trends Biochem Sci 27, 559-563. 2. Thaminy, S., Auerbach, D., Arnoldo, A., and Stagljar, I., (2003) Identification of novel ErbB3- interacting fac-tors using the split-ubiquitin membrane yeast two-hy-brid system, Genome Res 13, 1744–1753.3. Paumi, C.M., Menendez, J., Arnoldo, A., Engels, K., Iyer, K., Thaminy, S., Georgiev, O., Barral, Y., Michaelis, S., and Stagljar, I. (2007) Mapping Protein-Protein In-teractions for the Yeast ABC Transporter Ycf1p by In-tegrated Split-Ubiquitin Membrane Yeast Two-Hybrid (iMYTH) Analysis, Mol Cell 26, 15-25.4. Gisler, S.M., Kittanakom, S., Fuster, D., Radanovic, T., Wong, V., Bertic, M., Hall, R.A., Engels, K., Murer, H., Biber, J., Markovic, D., Moe, O.W., and Stagljar, I. (2008) Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiqui-tin membrane yeast two-hybrid system, Mol Cell Pro-teomics 7, 1362-1377. 5. Deribe, Y. L., Wild, P., Chandrashaker, A., Curak, J., Schmidt, M. H., Kalaidzidis, Y., Milutinovic, N., Kratch-marova, I., Buerkle, L., Fetchko, M. J., Schmidt, P., Kit-tanakom, S., Brown, K. R., Jurisica, I., Blagoev, B., Ze-rial, M., Stagljar, I., and Dikic, I., (2009) Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6, Sci Signal 2, p. ra84. 6. Usenovic, M., Knight, A. L., Raj, A., Wong, V., Brown, K. R., Caldwell, G. A., Caldwell,K. A., Stagljar, I., Krainc, D. (2012) Identification of novel ATP13A2 interactors and their role in α-synuclein misfolding and toxicity, Hum Mol Genet, in press (PMID: 22645275).

EXPERT OPINION

protein called HDAC6 regulates degradation of an RTK called Epidermal Growth Fac-tor (EGFR), a receptor that is overactive in several human cancers5. Based on this work, we are investigating the possibility of treat-ing those cancers in which EGFR is involved by using drugs to inhibit HDAC6, thereby speeding up degradation of the oncogenic EGFR protein. In keeping with the tradition of our research group, we are still active in developing new technologies which can further the field of in-teractive proteomics. Recently, we have been working on developing a mammalian version of MYTH named MaMTH. The fundamen-tals of the yeast-based and mammalian tech-

nologies are similar, however MaMTH will allow for testing of human membrane pro-teins in the context of human cell lines. Our initial proof of concept experiments were a success and we are currently in the process of upscaling MaMTH to a high-throughput screening format by building cDNA libraries that contain all 21,000 human Open Reading Frames (ORFs). The groundbreaking aspect of this technology is that it can be used to study PPIs in a drug and/or agonist depen-dent manner in the context of the human cell, which has the potential to change the way drug screening is performed in industry.

In summary, although membrane proteins play a very crucial role in maintaining a healthy cell state, and dysfunction of mem-brane proteins has been linked to a plethora of diseases, there are still huge gaps remain-ing in our knowledge and understanding of this group of proteins. MYTH and MaMTH can be used to fill in this gap, which in turn will have great implications in our under-standing of various diseases and how to bet-ter create effective treatments for them.

Figure 1. Interactive proteomics is a subdiscipline of proteomics whose goal is to map all protein-protein interactions of a given cell or organism. Here, the interactome of the 50 selected human G-protein coupled receptors is shown (recent unpublished work from the Jurisica & Stagljar lab).

Figure 2. An example of a positive (upper row) and negative (lower row) interaction detected by MYTH. Proteins X and Y are synthesized in yeast and tested for interaction via MYTH by assessing their growth on specific media. The blue staining and growth of yeast cells on specific media are indicative of two proteins interacting in MYTH.


FUTURE DIRECTIONS

To help with the steep costs of obtaining an undergraduate degree in the USA, she par-ticipated in a work-study program that al-lowed her to gain valuable medical research experience while also earning an income. Although her main interest at the time was cardiac research, Farcas-Chan kept an open mind towards other research topics; when the principal investigator of her choice re-search topic was between grants and unable to accommodate any work-study students, she was recommended to work with a group

Dr. Gabriella Farcas-Chan

f during her undergraduate degree you were to ask Dr. Gabriella Farcas-Chan if she could imagine pursuing ca-

reer in law, her answer would have been an assured “no.” So how is it that this former IMS student established herself as the Vice President of Legal Affairs at a rapidly grow-ing biotechnology company?

Farcas-Chan started her post-secondary ed-ucation at the Loyola University of Chicago where she studied biology and art history.

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FUTURE DIRECTIONS

table device capable of molecular diagnosis of infectious diseases using nanotechnology, Farcas-Chan participated in a young entre-preneurship program that greatly impacted her career path. She had been heavily in-volved in intellectual property (IP) searches on patent databases at Fio when she attended the Biotechnology YES (Young Entrepre-neurs Scheme) competition held by the UK government. This competition, aimed at doc-toral students, addressed all aspects of start-ing a biotechnology company. Farcas-Chan was part of the only Canadian team that was selected to attend the week-long training ses-sion in Oxford, UK. Here, she was further exposed to IP law, as she began conversing with lawyers about the patent application process. Shortly after these discussions, Far-cas-Chan applied to law school.

Although her first semester at Osgoode Hall Law School at York University was a difficult transition, Farcas-Chan knew that a career in law was the right move. Her goal was to do patent management in a field where she could also apply the knowledge accumulated in her graduate degree. To Farcas-Chan, go-ing to law school was a natural progression.

Achieving her goal, Farcas-Chan is currently the Vice President of Legal Affairs at Cyto-diagnostics Inc., a biotechnology company that focuses on the development and distri-bution of nanotechnology derived products. In speaking about this role she said you have to be a “jack-of-all-trades,” as you need to li-aise between both the scientific and the law worlds. Remarkably, she is doing this while balancing family life. When I asked her how she manages to do it all, she said, “Flexibil-ity is key. I have a hugely supportive husband and I am lucky that I have the option to work from home [to be with my son].”

So what’s next on the horizon for Farcas-Chan? In addition to continuing her work at Cytodiagnostics Inc., she would like to be more involved in teaching and, in particu-lar, would like to be involved with the IMS. Just this past April, she was a panel member for the IMS Career Seminar Series entitled, “A Graduate Student Alumni Perspective.” In the future, she discussed the desire to de-velop courses for IMS students that integrate training in IP. She discussed the importance of bringing awareness to students about pro-tecting their property: “It’s crucial. Students

need to know what their rights are, espe-cially in labs where there are collaborations with companies. Students need to make sure they’re not being taken advantage of.” She also discussed the pros of having a patent on a grant or scholarship application and said, “You never know when you have something that somebody may be interested in purchas-ing or using.”

When I asked Farcas-Chan what advice she would give to current IMS students she said, “I think the most important thing is to know who you are and what you want. Participate in things and go to seminars and lectures and meet people who are outside of your field.” She went on to say it is in these situ-ations where you can have a seed planted in you for a new idea or career path, or when you will have the opportunity to network. She also discussed the importance of being involved in activities and groups outside of lab work. Throughout her education she did more than just her schoolwork, whether it was participating in research for her under-graduate work-study program, or serving as the president of the IMS Students’ Asso-ciation. She said, “You should get as much as you can out of the grad-school experience.” Given Farcas-Chan’s many successes, current graduate students would be wise to take this advice whole-heartedly.

that focused on quality of life research in lung transplant patients. They noticed that a number of problems faced by these patients, including organ rejection, were caused by cy-tomegalovirus (CMV), a virus belonging to the herpesviruses family. Farcas-Chan was fascinated with the literature on infectious diseases and soon became inspired to pursue a graduate degree in the field.

Under the supervision of Dr. Kevin Kain, a clinician-scientist specializing in the diag-nostics and surveillance of infectious dis-eases, Farcas-Chan enrolled in the Institute of Medical Science (IMS). During her stud-ies, she was an active member of the IMS Students’ Association, carrying out two terms as president. She began her thesis work examining the impact of non-steroidal anti-inflammatory drugs on malaria, but her project soon took an interesting turn. In the midst of her studies, health officials declared the global epidemic of severe acute respira-tory syndrome (SARS), a condition caused by a novel coronavirus (CoV). Approached by companies trying to develop kits to diag-nose SARS as early as possible, Farcas-Chan was given an exciting research opportunity: she analyzed tissue samples from individuals that had died of SARS using real-time PCR. Using this method, she could assess viral load as measured by CoV RNA in different parts of the body. Her flexibility in taking on this unexpected project resulted in seminal work showing the dissemination of SARS-CoV throughout all major organs, not just the lungs in fatal SARS patients.1

After completing her PhD and while work-ing for Fio Corporation, a privately held Ca-nadian company working to develop a por-

References1. Farcas GA, Poutanen SM, Mazzulli T, Willey BM, Butany J, Asa SL, Faure P, Akhavan P, Low DE, Kain KC. Fatal Severe Acute Respiratory Syndrome is Associated with Multiorgan In-volvement by Coronavirus. J Infect Dis. 2005;191:193-197.

“I think the most impor-tant thing is to know who you are and what you want. Participate in things and go to seminars and lectures and meet people who are outside of your field.”

“Students need to know what their rights are, es-pecially in labs where there are collaborations with companies. Stu-dents need to make sure they’re not being taken advantage of.”


RESEARCH HIGHLIGHT

aula ballak travelled to france in 2010 to pick up the puppy of her dreams—a black-and-white, wavy-

haired Barbet (French water dog) named Rocket. Like other Barbet breeders, Ballak is dedicated to reviving this rare, historical, working breed—persecuted in WWII as the national dog of France—which is no small feat considering its limited numbers and ge-netic diversity. Rocket represented a distinct genetic line to breed with her own dogs, and in the first year, he excelled as a retriever. However, just after his first birthday, Rocket began to have seizures. The seizure disorder progressed quickly, affecting his behaviour and quality of life, and was determined to probably have a genetic cause. Recently—at just over the age of 2—Rocket had to be put down after having no response to antiepilep-tic medications.

Canine epilepsy is not rare, occurring in as many as 1 –5% of purebred dogs (compared with 1% of the general human population), and up to 20% of some breeds. Considered a side effect of selective breeding, the insidi-ous condition occurs in multiple forms and with multiple genetic causes. The insight of veterinary neurologists has shown that these many varieties of canine epilepsy are remark-

ably similar to the many forms of human epi-lepsy. Beyond epilepsy, dogs and humans are physiologically similar and many canine dis-eases mimic human conditions. Researchers, therefore, have begun to study canine genetic diseases with two hopes—improving the health of purebred dogs, and gaining insights about related diseases that afflict humans.

The study of canine epilepsy to aid human health has a proud history in Toronto. Drs. Hannes Lohi and Berge Minassian at the Hospital for Sick Children discovered the first canine epilepsy gene in 2005. Mutations in this gene caused myoclonic epilepsy in the miniature wire-haired dachshund (MWHD) breed1. Mutations in the same gene were con-currently discovered to cause Lafora progres-sive myoclonic epilepsy in children. While research into the human disease continues, breeders of the MWHD dogs are now able to identify carriers of the epilepsy mutation by genetic testing. As a result of this testing and responsible breeding practices, the incidence of epilepsy has decreased and the health of the breed has improved. Dr. Lohi has since moved on to establish a canine genetic re-search laboratory at the University of Hel-sinki, where more canine disease genes have since been identified—including the gene

causing epilepsy in the Barbet’s close relative, Lagotto Romagnolo (Italian water dog)2. Bal-lak hopes that Rocket’s DNA will lead to sim-ilar success for the imperiled Barbet breed.

Amid growing controversy about the declin-ing health of purebred dogs, Lohi hopes to harness advancing genomic technologies to address health concerns and genetic diversity in all breeds. With a worldwide network of collaborating scientists, breed clubs who are passionate about the health of their dogs, and tireless veterinarians (including Dr. Fiona James, the veterinary neurologist at Ontario Veterinary College who cared for Rocket), Lohi collects health records and generates genetic data for vast pedigrees of purebred dogs. The age of genomic medicine has come not only to people, but also to the veterinary clinic. And with the promise of new insights into our own health that can be gleaned by studying canine diseases, we are again in-debted to man’s best friend.

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Genomic medicine: gone to the dogs? By Jennifer Rilstone

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References1. Lohi H, Young EJ, Fitzmaurice SN, et al. Expanded Repeat in Canine Epilepsy. Science 2005;307(5706):81.2. Seppälä EH, Jokinen TS, Fukata M, et al. LGI2 trunca-tion causes a remitting focal epilepsy in dogs. PLoS Genet 2011;7(7):e1002194.

How genomics are helping to improve the health of purebred dogs


Things Supervisors Wished Students Knew:Students should/can1. give regular, written updates regard-

ing their work2. know that it takes time to get a PAC/

exam committee together3. tell their PAC they want to transfer to

PhD/go to medical school4. refer to PAC members, other stu-

dents, lab mates, and IMSSA if they need help or advice

5. know all deadlines 6. find external funding 7. tell their supervisor if they can’t live

on the stipend amount8. tell their supervisor if the pressure

and stress is too great9. tell their supervisor if they are having

problems writing their thesis, grant applications, or papers

Student Involvement in Forming Their PACA number of decisions need to be made at the beginning of a graduate student’s stud-ies. Aside from the obvious choices, such as choosing a supervisor and a project, a critical decision that graduate students quickly face is who should serve on their Program Ad-visory Committee (PAC). As the IMS web-site indicates, PAC members should include faculty who have expertise complementing the supervisor’s research and within the stu-dents’ proposed area of research. The balance between advisors (i.e. committee members and supervisor(s)) is one that can certainly help students thrive in their studies, especial-ly by utilizing the guidance and encourage-ment from each advisor to navigate through some of the challenges that may arise during the course of each student’s research career.

As such, students not only need to feel com-fortable with their committee members (e.g. to ask research questions), but also need to make sure that PAC members are willing to be available for additional meetings as needed. To achieve this, it is imperative that students are a part of deciding who is on their own committee. This requires a series of iterative discussions between student and supervisor about project goals, the guiding expertise needed to accomplish these goals, and the best learning/teaching style that will maximize the student’s experience. A cru-cial factor to consider in this process is how much time and guidance each potential PAC member can provide.

Many newly admitted students leave this de-cision up to the supervisor, and it is common

for supervisors to choose their close col-leagues or collaborators. Therefore, students should share any potential PAC members in mind and take an active role in this process. Putting together the best-suited PAC is im-portant for students to be successful in their graduate training while having a fun and ex-citing time!

What Supervisors Expect From Their StudentsOne of the challenges for many graduate stu-dents is having a productive and meaningful relationship with their supervisors. Problems may range from inadequate communication to more serious issues such as lab bullying and ethical misconduct. Unfortunately, these difficulties do arise and it is important to real-ize them early on and to seek assistance. Both the IMS office and the IMS Students’ Asso-ciation (IMSSA) provide student-supervisor relationship advice whether one-on-one, or through workshops such as the one held last March.

Listed are some general but key pieces of ad-vice shared by Dr. Carol Westall, one of our graduate coordinators.

These are some basic points to keep in mind as a graduate student. It is likely that most supervisors will expect more from their stu-dents; it is the student’s job to fulfill more than the minimum. Also, each supervisor has their own unique mentoring style and stu-dents should apply these guidelines at their own discretion. Nevertheless, having a good student-supervisor relationship is not only in the hands of the students, but also in those of their supervisors.

Any discussion with a Graduate Coordinator will remain confidential unless you choose otherwise. Don’t shy away from asking for guidance.

Do you have a question for the experts? Please send it to [email protected]. (ATTN: Experts).

EXPERT TIP

ExpertsAskthe

Expert Tips: Enriching your Graduate ExperienceColumn By Laura S. Park & Brittany N. Rosenbloom


PAST EVENTS

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The Biomedical Com-munications Department took a field trip to the zoo! Along with having a lot of fun, students practiced drawing and photography skills. (left and right)

Can’t hide their smiles! Friends unwind dur-ing IMSSA’s Wine and Cheese event, one of the many social events hosted throughout the year for IMS students.

This year’s IMS Scientific Day again allowed students to showcase their research and learn of the diverse science being conducted across the department. Above, a student engages in discussion during the afternoon poster session.


DIVERSIONS

Passionate about your research and eager to write for the IMS Magazine? We are currently welcoming research article sub-missions from SURP students as we hope to feature at least one article in our Fall 2012 magazine edition.

What to include with your submission: title, author name, supervisor name, article text, references (10 maximum). 750 word limit not including references/title. Figures (2 maximum) are also welcome with appropriate captions and permissions wherever applicable.

Please send your complete article to [email protected] by Friday, August 17, 2012 in .doc/.docx formats only. Please feel free to email with any questions or comments. Thank you for your interest!

Down:

2. The I in IMS.3. The A in IMSSA.5. A plea, essay, speech etc., in support of something.6. A subject for composition or essay.10. A group of people gathered in answer to a summons.11. A section of the thesis.12. An act or operation for the purpose of discovering something unknown or of test-ing a principle.14. One who runs your assays.15. What every student wants, maybe in Cell or Nature.16. The interpretation of numerical facts and data.20. A supply of money or pecuniary resour-ces, as for some purpose.

Summer Student Writing Competition

CROSSWORD

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1. The charge or fee for instruction.4. The A in PAC.7. A meeting for consultation or discussion.8. A sum of money or other aid granted to a student, because of merit, need, etc., to pursue his or her studies.9. A system of moral principles.13. Your mentor, one who guides you.17. Where one runs experiments.18. Current director of the IMS (2 words).19. The kind of research done at the IMS.

http://issuu.com/imsmagazine

READ IT ONLINE

[email protected]/groups/imsmagazine/

ims magazine summer 2012

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