IMSMAGAZINE THINK, LEARN, DISCOVER.
SPRING
2011
SNEAK-PEEK:
SCIENTIFIC DAY
Up close and personal with IMS Scientific Day keynote speaker
SPECIAL TRIBUTE Remembering Dr. McCulloch, the father of stem cell research
MULTIPLE SCLEROSIS ALSO:
An inside look into the controversial Zamboni ‘liberation’ procedure
We will never walk on the moon.
Looking back over time, history is full of triumphs, true innovations and life-altering achievements. Today, you can be part of something just as monumental. With the help of the MS Society, Canadian researchers have done the groundwork, bringing the cure for MS within reach. Let’s take this last step together.
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TABLE OF CONTENTS
IN THIS ISSUE... Letter from the Editor .....................04 News at a Glance ...........................05 Director’s Message ........................08 Scientific Day Preview ...................09 Feature ...........................................11 Special Tribute ...............................21 Spotlight .........................................23 Close Up .........................................31 Behind the Scenes .........................33 Future Directions ............................35
11
Student Life ....................................37 Module Highlight ...........................39
FEATURE
SEM Image courtesy of Jessica Hunt and Dr. Cindi Morshead, photograph by Paulina Rzeczkowska
Ask the Experts ..............................40 Past Events .....................................41 Diversions .......................................42
Multiple Sclerosis
Learn about the many different ways we are tackling the debilitating disease.
MAGAZINE STAFF Editor-in-Chief Managing Editor Assistant Managing Editor Departmental Advisor Copy Editors Advertising Manager Content Committee
Design Editors
Photography
Natalie Venier Avi Vandersluis Nina Bahl Kamila Lear S. Amanda Ali Joe Gabriel Meghna Rajaprakash Wenjun Xu Allison Rosen Aaron Kucyi Anthony Grieco Zeynep Yilmaz Samantha Bremner Minji Kim Diego Accorsi Joyce Hui Beatrice Lau Julie Man Paulina Rzeczkowska Connie Sun Mohammed Sabri
Copyright Š 2011 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.
21
Dr. Ernest McCulloch
Looking back on the life of the father of stem cell research.
30
A Taste of Summer
How the Summer Undergraduate Research Program inspired Ricky Besla to make changes.
Cover Art By Diego Accorsi MScBMC Candidate The debilitating effects of Multiple Sclerosis is due to its targeting of neurons in the Central Nervous System. The cover has been designed to illustrate the vast network of neurons in the human body. IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 02
LETTER FROM THE EDITOR
I
Letter from the Editor
am thrilled that the IMS community has graciously accepted the first edition of the IMS Magazine. It has been an absolute pleasure to create another tool that can be used to showcase the research being done by the stellar faculty and students in our department. While we focused on showcasing the students and faculty at the IMS in the inaugural edition of the IMS Magazine, as we move forward, our emphasis will be placed on research. This emphasis will be especially evident in the feature section, which, in each edition, will highlight a different disease or health issue that is currently impacting Canadian society. In this issue, we have focused our attention on multiple sclerosis (MS) - a debilitating disease that affects millions of individuals globally each year. Here at the IMS, we have several world-class scientists working to improve the lives of patients suffering from MS. With a compendium of research articles written by our very own experts, I hope you will be able to appreciate the many facets of research that go into studying complex diseases like MS and how they are all crucial to understanding disease processes and improving patient outcomes. Furthermore, we have investigated Dr. Paolo Zamboni’s new controversial cerebrospinal venous insufficiency (CCSVI) treatment strategy for MS, which has gained a considerable amount of media attention worldwide. Furthermore, with the help of our experts, particularly Dr. Paul O’Connor, Dr. Brenda Banwell and Dr. Kerry Bowman we hope to shed light on some of the challenges associated with publicizing these scientific findings.
Natalie Venier
Editor-In-Chief Natalie Venier is a second year MSc student who plans to transfer into the PhD program. She is currently studying prostate cancer chemoprevention at Sunnybrook Health Sciences Centre.
In closing, I would like to dedicate this issue of the IMS Magazine to Dr. Ernest McCulloch, one of the founding fathers of the Institute of Medical Science, who sadly passed away in January. He was an exceptional scientist whose work on stem cells changed the scientific community. He is an inspiration to all researchers who work diligently to improve the lives of others. I strongly encourage you to read about his incredible journey in our special tribute article. Once again, I would like to thank the incredible IMS Magazine Committee, our MS experts, and our extraordinary Biomedical Communications Department whose remarkable efforts were essential to the production of this issue. I hope you can take pleasure in this spring edition of the IMS Magazine and can appreciate the magnificent talent in our department. I strongly encourage feedback about our articles and magazine. We are always open to accepting any suggestions that will help us bring you the best of the IMS.
Photo by Paulina Rzeczkowska
Enjoy!
Natalie Venier Editor-In-Chief, IMS Magazine IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 04
NEWS AT A GLANCE
NEWS&VIEWS at a glance...
APRIL
14 TBA TBA
IMS STAFF ANNOUNCEMENTS
Frosh Event Career Development Series
Students in the MSc and PhD program must participate in the Alan Wu Poster Competition at least once. The Laidlaw Manuscript Competition is open to all students and everyone is strongly encouraged to participate.
Early April: Student Link (Buddy Program)
Attendance at Scientific Day counts towards completion of the IMS seminar requirement (whether in the CIP stream or the regular stream). If you cannot attend, your supervisor must submit a note to the IMS office explaining your absence.
RECENT AWARDS
MAY
3 4 19 TBA
The IMS Ernest McCulloch Scientific Day Symposium
2010/2011 CIHR Master’s Award: Frederick Banting and Charles Best Canada Graduate Scholarships: Natalie Venier Avi Vandersluis
IMS Scientific Day
2010/2011 Ontario Graduate Scholarships (OGS): Naim Panjwani Paulina Rzeczkowska Mohammed Sabri
Health Professional Workshops: Medicine Site-specific events
2010/2011 Ontario Graduate Scholarships in Science and Technology (OGSST): Leanne De Souza 2010-2012 CIHR Health Professional Award-Fellowship: Joseph Ly 2011 New Pioneers Youth Award: Jemy Joseph To read about Jemy Joseph’s award, see: http://tinyurl.com/42q7cqf
2011 Royal College Fellowship for Studies in Medical Education Award: B. Weber
JUNE
TBA TBA
All IMS Students are expected to attend IMS Scientific Day on Wednesday, May 4, 2011.
Spring Scavenger Hunt Inter-departmental Boat Cruise
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: theimsmagazine@gmail.com
05 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
2011 Vesalian Scholar Award – Vesalius Trust for Visual Communication in the Health Sciences: Enid Hajderi Joyce Hui Banting and Best Diabetes Centre – University Health Network Graduate Award: Naim Panjwani Cervical Spine Research Society Award: David W. Cadotte CIHR Canada Graduate Scholarship Doctoral Research Award (3 years): Zeynep Yilmaz CIHR Institute of Gender and Health Travel Award: Emily Glazer Harry Jerome Award in Academics: Michelle McFarlane
For more about Michelle McFarlane’s award, please read: http://tinyurl.com/4yp6ngh
Parkinson Society Canada Graduate Student Award: Y. Koshimori
NEWS AT A GLANCE
STUDENT FUNDING OPPORTUNITIES, SCHOLARSHIPS & AWARDS Laidlaw Manuscript Competition
Top rated students submitting manuscripts for the Laidlaw competition will be invited to give an oral presentation at IMS Scientific Day. Awards conferred at that time will be: Clinical Science - $750 Basic Science - $750 Honourable Mention - $400
Alan Wu Poster Competition
The Alan Wu Poster Prizes are presented to the most outstanding basic science and clinical science abstracts and poster presentations. Alan Wu Poster Prize – Clinical Science – $250 + IMS Academic Development Award Alan Wu Poster Prize – Basic Science – $250 + IMS Academic Development Award An IMS Academic Development Award, valued at $500, is awarded to each finalist. The purpose of the IMS award is to encourage students to attend national or international conferences by partially covering travel/academic expenses, with supervisors covering the remainder of the cost.
The Mel Silverman Mentorship Award
In 1991, Dr. Mel Silverman took on the Directorship of the IMS. As Director, Dr. Silverman raised the academic standards of the IMS, expanded the curriculum, and increased student enrolment and faculty appointments. During his tenure, the IMS added its first professional degree program - the Master of Science in Biomedical Communications. He was integral in encouraging clinical chairs to emulate the surgical scientist model and introduce their own departmental programs. This led to the creation of clinician scientist streams within most clinical departments. Together with Dr. Bernie Langer, he helped found the University of Toronto Royal College of Physicians and Surgeons Clinician Investigator Program (CIP). The Mel Silverman Mentorship Award is presented to an IMS graduate faculty member who has served as an outstanding mentor and role model for graduate students, and who has contributed in a significant way to the IMS graduate program.
Siminovitch-Salter Award
The Siminovitch-Salter Award was established in 1995 to honour the contributions of Dr. Lou Siminovitch and Dr. Robert Salter to the Institute of Medical Science. It is awarded annually to a graduating IMS doctoral student who has made outstanding scholarly contributions. The endowment represents contributions by Mount Sinai Hospital, the University of Toronto Department of Surgery, and the Institute of Medical Science.
Whiteside Award
The Whiteside Award was established in 2003 to honour the contributions of Dr. Catharine Whiteside to the Institute of Medical Science. It is awarded annually to a graduating IMS Master of Science student who has made outstanding scholarly contributions. It is awarded based on the recommendation of the IMS Graduate Coordinators, Associate Director, and Director.
Roncari Book Prize
The Roncari Book Prize was established in 1995 to honour the memory of Dr. Daniel Roncari. It is presented to an IMS student who has made significant contributions to the academic experience of graduate students, based on the recommendation of the IMS Graduate Coordinators, Associate Director, and Director.
Student Honours and Award
Congratulations to Diana Choi, this year’s winner of the Gordon Cressy Student Leadership Award. For more information, visit: http://uoft.me/x8 Dr. Aristotle Voineskos was featured in The Globe and Mail. Read the article here: http://tinyurl.com/3srphow To see Paul Cassar mentioned in The Scientist, please visit: http://tinyurl.com/42lqk5e
ANNOUNCING THE SARA AL-BADER MEMORIAL AWARD
The Sara Al-Bader Memorial Award will be announced at this year’s IMS Scientific Day. The award was established by IMS in memory of Sara who passed away suddenly this past November. Sara Al-Bader Memorial Award will be awarded to a PhD student who exhibits financial need and academic merit, with preference given to students who hold a visa status. The scholarship will be awarded in perpetuity and the first one is to be distributed in May of 2012 at IMS Scientific Day.
NEW FACULTY MEMBERS
Evdokia Anagnostou
Assistant Professor of Paediatrics, Bloorview Research Institute
Scott Beattie
Professor of Anaesthesia, Toronto General Hospital
Gabrielle Boulianne
Professor of Molecular Genetics, Hospital for Sick Children
Asim Cheema
Assistant Professor of Medicine, St. Michael’s Hospital
David Cherney
Assistant Professor of Medicine, Toronto General Hospital
Amy Cheung
Assistant Professor of Psychiatry, Sunnybrook Health Sciences Centre
Edward Chow
Professor of Radiation Oncology, Sunnybrook Health Sciences Centre
Kim Connelly
Assistant Professor of Medicine, St. Michael’s Hospital
Sharon Dell
Assistant Professor of Paediatrics, Hospital for Sick Children
Claudia dos Santos
Assistant Professor of Medicine, St. Michael’s Hospital
Lendra Friesen
Assistang Professor of Medicine, Sunnybrook Health Sciences Centre
Andrea Furlan
Assistant Professor of Medicine, Institute for Work and Health
Anna Gagliardi
Assistant Professor of Surgery, Toronto General Hospital
Rohan Ganguli
Professor of Psychiatry, Centre for Addiction and Mental Health
Arial Graff-Guerrero
Assistant Professor of Psychiatry, Centre for Addiction and Mental Health
Anne-Marie Guerguerian
Professor of Paediatrics, Hospital for Sick Children
Marc Jeschke
Associate Professor of Surgery, Sunnybrook Health Sciences Centre
Marianne Koritzinsky
Assistant Professor of Radiation Oncology, Princes Margaret Hospital
Douglas Lee
Assistant Professor of Medicine, Toronto General Hospital.
Clifford Librach
Associate Professor of Obstetrics and Gynecology
Muhamed Mamdani
Associate Professor of Health Policy, Management and Evaluation, St. Michael’s Hospital
Mary Pat McAndrews
Associate Professor of Psychology, Toronto Western Hospital
Mahesh Menon
Assistant Professor of Psychiatry, Centre for Addiction and Mental Health
Theo Moraes
Assistant Professor of Paediatrics, Hospital for Sick Children
Aleixo Muise
Assistant Professor of Paediatrics, Hospital for Sick Children
Andras Nagy
Professor of Molecular Genetics, Mount Sinai Hospital
Patricia O’Campo
Professor of Dalla Lana School of Public Health, St. Michael’s Hospital
Narinder Paul
Associate Professor of Medical Imaging, Toronto General Hospital
Teresa Petrella
Assistant Professor of medical Oncology, Sunnybrook Health Sciences Centre
Ranju Ralhan
Professor of Otolaryngology, Mount Sinai Hospital
Joel Ray
Assistant Professor of Medicine, University of Toronto
Gustavo Saposnik
Assistant Professor of Medicine, St. Michael’s Hospital
Ayal Schaffer
Associate Professor of Psychiatry, Sunnybrook Health Sciences Centre
Taufik Ali Valiante
Assistant Professor of Surgery, Toronto Western Hospital
Paul Wales
Assistant Professor of Surgery, Hospital for Sick Children
Fiona Webster
Assistant Professor of Surgery, Sunnybrook Health Sciences Centre
George Yousef
Assistant Professor of Laboratory Medicine and Pathobiology, St. Michael’s Hospital
Find out more about faculty on the IMS faculty database: http://www.ims.utoronto.ca/faculty/ directory.htm
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 06
DIRECTOR’S MESSAGE
Director’s Message The inaugural issue of the IMS Magazine was an overwhelming success. Comments about the first issue were uniformly laudatory, citing the quality of the articles, the clarity of the production and the beauty of the photos and illustrations. I would like to again congratulate Natalie Venier and her team on these successes and for putting their creative energies towards making Issue #2 a reality. This issue promises to be incredibly interesting. To address the highly controversial issue of the use of the Zamboni procedure for the treatment of Multiple Sclerosis, the production team has assembled a number of authors to provide a “360˚ view” of the problem. These include a scientist, a clinician, a student, a bioethicist and even a renowned media expert. This broad-based even-handed approach to reporting is one which I think we will come to expect from Ms. Venier and her team. It is also quite appropriate for this type of reporting to come from a graduate training department whose mission is to challenge dogma, with a view to objectively evaluating the scientific evidence and drawing conclusions based on its strength. Also in this issue is a commemorative to Dr. Ernest (Bun) McCulloch. In addition to his ground-breaking research, first published approximately 50 years ago, Dr. McCulloch is known for his contributions to the Institute of Medical Science. As the Graduate Coordinator, he was one of a small group of visionaries who took the IMS from concept to reality in the late 1960s. On May 3rd this year, the IMS will sponsor a Mini-symposium on Cancer Biology, where we will honour Dr. McCulloch’s contributions to cancer research and to the founding of the IMS. May 4th is our annual IMS Scientific Day. It will feature our Langer Lecturer, Dr. Andrew Feinberg from Hopkins, speaking on the “Epigenetic Basis of Common Human Disease.” This area of science is becoming increasingly recognized as being critically important in the regulation of gene expression. Dr. Feinberg is acknowledged as being both an excellent scientist as well as a superb lecturer. I strongly encourage you to attend.
Photo by Connie Sun
This will be my last IMS Scientific Day as Director, as the search process for a new director moves forward. The University of Toronto policy generally limiting a Chair/Director term to two five-year terms is one of the strengths of our institution, as it ensures that our leadership and Institutional direction are regularly refreshed. Obviously, I will have some reflections of my time as Director in my annual State-of-the-Union address. This will include a thanks to the many individuals with whom I have worked over the years. However, I would like to specifically recognize Dr. Mary Seeman who will be retiring from her position as Graduate Coordinator this summer. Mary’s expert knowledge of graduate training rules, her clarity of thought, her even-handedness and her kindness have been ever-present in our office since I can remember. We have all benefitted immensely from her dedication to the IMS, its staff and students. Hopefully, she will visit regularly. In closing, I would like to congratulate Natalie and her team on another great issue. It is packed with interesting and worthwhile information. See you at the May 3rd Cancer Symposium and also at IMS Scientific Day the following day.
Ori D. Rotstein, MD
Director, IMS Dr. Ori Rotstein has been the Director of the IMS since 2000. He is also the Surgeon-in-Chief of the Department of Surgery and Division of General Surgery at St. Michael’s Hospital. In addition, he is a scientist in the Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital and a professor in the Department of Surgery at the University of Toronto.
Ori D. Rotstein, MD Director, Institute of Medical Science University of Toronto IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 08
SCIENTIFIC DAY PREVIEW
From
Curiosity to
Conclusions
Up close and personal with this year’s IMS Scientific Day keynote speaker: Dr. Andrew Feinberg By Nina Bahl
G
iven that Dr. Andrew Feinberg is a ground-breaking researcher in the field of epigenetics, it may not be all-too-surprising that scientific curiosity and passion for discovery have permeated his life from a young age. Currently grappling with the potential ways in which epigenetic changes impact normal development and disease, Dr. Feinberg’s admiration of the scientific process remains consistent – and very evident.
Following graduation from high school, Dr. Feinberg enrolled in the Directed Studies program at Yale University, which allowed him to continue his scientific education while also engaging in the humanities for the first time. In his second year of college, rather serendipitously, Dr. Feinberg happened upon Johns Hopkins University School of Medicine while visiting a friend in Baltimore. Unsure of a definitive career path until this point, he quickly became enamoured with the idea of pursuing his medical degree; it seemed a perfect marriage of his interests. “[I decided] to become a neuroscientist-physician to fulfill my earlier dream about understanding the brain, while also nourishing my 09 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
Photo courtesy of Dr. Andrew Feinberg
Growing up in rural Pennsylvania, a young Dr. Feinberg was first exposed to the world of science by his family: a science-teaching father, and an aunt who fortified his early interests by taking him to Philadelphia’s Franklin Institute – a science and technology museum named after Benjamin Franklin – and often sending him science projects from their gift shop. Surprisingly, Dr. Feinberg’s academic curiosity evolved from a fascination for mathematics – notably due to its simple requirements of a paper and pencil to complete – to a more biologically-oriented science when he worked at an IBM research facility one summer in high school. “There was a sign in every office that said ‘Think,’ and I started to wonder how we actually do that,” explains Dr. Feinberg. “Namely, what is the basis for the biological computing that our brains perform?”
SCIENTIFIC DAY PREVIEW Yale-inspired humanistic longings,” recalls Dr. Feinberg. And so he did, by completing Hopkins’ accelerated MD program. But during a neuroscience postdoctoral fellowship at the University of California, San Diego, Dr. Feinberg shifted his research interests to developmental biology. “I came to the conclusion that we – or at least I – would not really understand the brain as a computer any time soon,” he says. “I completed my fellowship…studying cell fate decisions in primitive eukaryotes.” At the age of 26, Dr. Feinberg found himself with a whole lot of education but rather confused as to how to proceed with it all – his career path was no longer as distinct as it once seemed. He fulfilled more of his humanitarian ambitions by working in an urban poverty clinic in Baltimore for a year, during which time many of the doctors with whom he worked encouraged his return to Hopkins to complete a Master of Public Health. And thus, Dr. Feinberg’s scholarly journey continued with his MPH; he studied systems biology to try to find a mathematical niche for his biological interests, and simultaneously began training in medical genetics. Another fortuitous encounter prompted his next career resolve; this time, it was one that would remain with him and define much of his livelihood. A lecture about cell fate decisions in cancer prompted an “aha!” moment for Dr. Feinberg, who suggested to his lecturer that cancer cells undergo the same kind of cell fate decisions he had observed in normal cells at UCSD. Impelled to transform his budding ideas about epigenetics and disease to tangible research, Dr. Feinberg completed a for-credit thesis proposing the epigenetic hypothesis of cancer.
“[I decided] to become a neuroscientist-physician to fulfill my earlier dream about understanding the brain, while also nourishing my Yale-inspired humanistic longings,” Epigenetics refers to the study of cellular memory other than the DNA sequence itself; that is, the chemical alterations affecting gene expression that can remain in subsequent cellular divisions and also across generations, such as DNA methylation and gene imprinting. In normal physiological development,
the epigenome – the overall pattern of these non-genetic changes – explicates cellular differentiation, and specifically, how diverse cell types can exist despite their identical genetic information. For Dr. Feinberg, the potential link between cancer and epigenetic disruptions seemed reasonable. Indeed, working alongside Dr. Bert Vogelstein at Hopkins in 1983, he discovered altered DNA methylation patterns of genes in human cancers. Acknowledged as one of his most striking research accomplishments, this novel finding revealed tumour progression to be mediated not solely by genetic abnormalities, but anomalous epigenetic mechanisms as well. In the next seven years as a Hughes investigator, widely known for their creativity and productivity, Dr. Feinberg and his team at the University of Michigan built upon this information. “My lab discovered the first causal evidence for an epigenetic role in cancer,” remarks Dr. Feinberg. “Namely, the increased risk [for tumours in Beckwith-Wiedemann syndrome] caused by the constitutional loss of imprinting of insulin-like growth factor 2.” As knowledge in the field of epigenetics has progressed, so too have Dr. Feinberg’s everevolving research aims. Since returning to Hopkins once again in 1994, his group has shown that common epigenetic changes precede and predispose cells to cancer, and that aberrant signaling pathways mediate this risk. In another of Dr. Feinberg’s significant achievements, his lab has recently found that specific epigenetic alterations to stem cells confer a selective advantage on oncogenic mutations, implicating an epigenetic progenitor origin of human cancer. Beyond its role in a single disease process, Dr. Feinberg believes epigenetic mechanisms are fundamental to understanding both normal physiology and a broader scope of pathology. Accordingly, Dr. Feinberg and an interdisciplinary team created the world’s first disease-focused epigenome centre eight years ago to investigate epigenetic contributions to general pathology. Here, the group has pioneered methods to analyze DNA methylation genome-wide, and is developing tools to investigate other epigenetic variants that are applicable to disease generally. The future of epigenetic research for Dr. Fein-
berg appears rooted in these more expansive biological implications. “I am sure that we cannot understand normal development and disease – and therefore, ourselves – without integrating epigenetics within the framework of genetics and the environment,” he positions. “Indeed, epigenetics is the bridge between the two.” Dr. Feinberg specifically hopes to investigate his recent idea that stochastic epigenetic plasticity may be linked to development and disease. “Such mechanisms might be necessary to explain even the complex processes that give rise to the thinking brain,” contemplates Dr. Feinberg, bringing him right back to his initial scientific inklings as a teenager.
“How lucky they are to be beginning this wonderful adventure, with many decades of discovery in front of them.” His unrelenting scientific curiosity makes it easy to see that Dr. Feinberg’s research endeavours are far from over. Beyond conveying his personal work to the IMS community when he visits in May, what does he hope to communicate to his eager audience? “How lucky they are to be beginning this wonderful adventure, with many decades of discovery in front of them.” A fitting goal for a palpably dedicated scientist. Relevant publications: Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash JB, Sabunciyan S, Feinberg AP. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-86. Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet. 2009 Feb;41(2):246-50. Feinberg AP, Irizarry RA. Evolution in health and medicine Sackler colloquium: Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1757-64. Feinberg AP, Irizarry RA, Fradin D, Aryee MJ, Murakami P, Aspelund T, Eiriksdottir G, Harris TB, Launer L, Gudnason V, Fallin MD. Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med. 2010 Sep 15;2(49):49ra67. Ji H, Ehrlich LI, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K, Rossi DJ, Inlay MA, Serwold T, Karsunky H, Ho L, Daley GQ, Weissman IL, Feinberg AP. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature. 2010 Sep 16;467(7313):338-42.
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 10
FEATURE
Multiple ScleroSiS PATHOPHYSIOLOGY OF MS
cell body nucleus axon
damaged oligodendrocyte myelin sheath
macrophage phagocytosis
exposed axon
damaged myelin
lymphocytes
synaptic bulbs
11 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
Multiple Sclerosis
Multiple sclerosis is a degenerative disease affecting the central nervous system. It occurs when these neurons are attacked by the body’s immune system (i.e. white blood cells, leukocytes, macrophages, etc.). This immune response damages/ destroys the myelin around the nerve fibers – demyelination – in the brain and spinal cord. This damage causes scarring called ‘sclerosis’.
Damaged myelin can form lesions that can attenuate or prevent the transmission of nerve signals. Depending on the location of these lesions, various symptoms can occur throughout the body. Although many lesions are not associated with clinical symptoms, some lesions can cause significant morbidities.
Illustration by Lucy Zhang
Normal
In healthy individuals, neurons in the central nervous system (CNS) act to transmit signals throughout the brain and body. The fatty tissue surrounding the nerve fibers is called myelin, and it is essential for fostering the transmission of nerve signals throughout the brain and body.
FEATURE
global median = 30
880 0
PREVALENCE IN CANADA
UTSHOEUATSHTEAASSIAT ASIA SO8 0.30A .3A 8 . . 22 FR FR IC IC
A
global median = 30
A
Global Median Global Median
Fatigue
Visual disturbances Visual disturbances Balance Balance
Bladder and bowel Bladder and bowel Pain
Pain Cognitive/behavioral problems Cognitive/behavioral problems Sexual dysfunction Sexual dysfunction
5 5
WEST E R N PAC IFIC WESTE R N P AC IFIC
Fatigue
S ICA ER AM CAS I ER AM
Sensory problems
50% 50% 40% 40% 40% 40% 31% 31% 22% 22% 18% 18% 15% 15% 10% 10% 10% 10%
EAST EAST M M E E D I T E RD RAITNERRAN EAN EAN
SYMPTOMS
Motor weakness dysfuntion/spasticity Motor weakness dysfuntion/spasticity Sensory problems
8.38.3
SYMPTOMS
Infographic by Beatrice Lau
141.94.9
REGIONAL REGIONAL PREVALENCE PREVALENCE PER 100,000 PER 100,000
133 PREVALENCE IN CANADA
EU RO P EU E RO PE
Canada ranks #5 in countries Canada ranks with #5 inhighest countries prevalence with highest per 100,000 prevalence
per 100,000
GENDER DIFFERENCES GENDER DIFFERENCES
Women are twice asare likely Women to get as MSlikely than men. twice to get MS than men.
MOST AT RISK
AVERAGE AGE OF ONSET
15-40 15-40 MOST AT RISK
29.2 29.2
AVERAGE AGE OF ONSET
years of age years of age
TYPES OF MULTIPLE SCLEROSIS
years years
5% PRMS 5% PRMS
TYPES OF MULTIPLE SCLEROSIS Progressive-Relapsing • Steady worsening from disease onset •Progressive-Relapsing Distinct relapses with or without recovery • Disease continues from to progress between attacks (in contrast to Steady worsening diseaseeven onset with RRMS) nowithout true remission period • patients Distinct relapses with– or recovery • Disease continues to progress even between attacks (in contrast to patients with RRMS) – no true remission period
10% PPMS 10% PPMS
Primary-Progressive • Patients experience gradual worsening of neurologic function; no distinct attack episodes or remission periods – slow accumulation of Primary-Progressive • disability Patients experience gradual worsening of neurologic function; no • Variations in progression – sometimes, plateaus or of distinct attack episodes orrates remission periodsthere – sloware accumulation temporary disability improvements in function • Variations in progression rates – sometimes, there are plateaus or temporary improvements in function
85% RRMS 85% RRMS
Relapsing-Remitting • Patients experience episodes of acute worsening called flare-ups, attacks or exacerbations Relapsing-Remitting • Subsequent periodsepisodes of remission with worsening partial or complete recovery Patients experience of acute called flare-ups, to pre-attack function; no disease progression during this time attacks or exacerbations • Time between attacks variable; with can be months or even years Subsequent periods ofisremission partial or complete recovery to pre-attack function; no disease progression during this time • Time between attacks is variable; can be months or even years
50% SPMS of RRMS patients SPMS 50%
Secondary-Progressive • Initial period of RRMS, then steady worsening characteristic of SPMS of RRMS Secondary-Progressive • Distinct relapses and remissions become less apparent over time patients • Can flare-ups, remissions, or plateaus Initialinclude periodoccasional of RRMS, then steadyminor worsening characteristic of SPMS • Again, to accumulating disability Distinctleads relapses and remissions become less apparent over time • Can include occasional flare-ups, minor remissions, or plateaus • Again, leads to accumulating Sources: disability2008 Atlas of Multiple Sclerosis, MS Society of Canada, National MS Society Sources: 2008 Atlas of Multiple Sclerosis, MS Society of Canada, National MS Society
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 12
Multiple Sclerosis An Overview
By Dr. Brenda Banwell MD, FAAP, FRCPC Dr. Brenda Banwell is the Director of the Paediatric Multiple Sclerosis Clinic, a multidisciplinary clinic dedicated to children with MS and other acquired demyelinating diseases. She is also a staff neurologist at the Hospital for Sick Children, a senior associate scientist in the Neurosciences & Mental Health program of the SickKids Research Institute, and an associate professor in the Paediatrics Department at the University of Toronto.
13 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
M
A key component of MS onset during childhood relates to its effect on the developing brain. Unlike adults, children with MS experience their disease during the fundamental period of education and during key periods of brain myelination. Recent studies have identified that approximately 50% of children and adolescents with MS experience some degree of cognitive dysfunction. Reduced process-
ing speed is most commonly observed early in the disease and can impact overall efficiency of cognitive functioning. Impairments are also observed in complex attention (i.e. simultaneously attending to multiple stimuli), visual-spatial abilities, expressive language (e.g. naming), and executive functions (e.g. shifting attention back and forth between two stimuli, planning and organizing). These deficits become particularly notable in high school when the education model expects students to learn from didactic lectures and to be able to organize multiple tasks concurrently. Individual variability in the pattern and degree of cognitive dysfunction is important to highlight. Not all children and adolescents show cognitive problems, and in some individuals, cognitive changes are subtle and may not be recognized readily by the patient, family members, or health care professionals. Other individuals may develop mild to severe cognitive decline relative to baseline, resulting in significant learning difficulties and disability in daily activities. While cognitive deficits progress over time, it is difficult to predict decline on the basis of clinical factors – such as disease duration, frequency or number of relapses, or physical disability – alone. Studies in childhood MS show no or minimal correlation between cognitive deficits and physical disability, suggesting that cognitive dysfunction can be present in the absence of physical disability.
Photo courtesy of Dr. Brenda Banwell
in Children
ultiple sclerosis (MS) is a chronic inflammatory degenerative disorder of the central nervous system (CNS). While historically considered a disease of young adulthood, it is now estimated that 3-10% of individuals with MS experience their first symptoms prior to age 181-4. MS has a relapsing-remitting course in over 95% of children5,6. During a relapse, children may experience symptoms such as weakness, sensory changes, visual problems, unsteady gait, and bowel or bladder dysfunction. While most children recover well from their initial relapses, some are left with neurological impairments. Over time, the chance of residual deficits increases such that approximately 60% of paediatric-onset MS patients will require cane or wheelchair support by age 40-50 years. Fatigue, cognitive changes, and mood disorders, such as depression, may be present. All of these aspects of MS affect daily function and quality of life, leaving patients requiring multidisciplinary care.
Cognitive impairment links with brain changes on MRI – loss of normal ageexpected brain size and loss of normal brain tissue integrity can be seen in children with the greatest degree of cognitive impairment. It is believed that the impact of MS on cognitive functioning is accentuated in youth with MS compared with that observed in adult-onset MS because the widespread damage occurs during the maturation of important pathways involved in cognition, particularly with respect to white matter, which is a primary target of MS.
Illustrations by Diego Accorsi
In addition to cognitive symptoms, the onset of MS during the key formative years of development may also contribute to difficulties in psychosocial and behavioural function. Explanations for emotional disturbances and behavioural problems in youth with MS involve a combination of psychological factors related to both having a chronic illness as well as to the impact of the disease on brain networks underlying emotional and behavioural regulation. Coping with a rare disease in childhood, along with a dependence on long-term treatment, may contribute to a heightened sense of social isolation in youth with MS. Currently, there are six approved therapies for MS in adults. All therapies involve frequent needles – none yet come in an oral formulation. Although a new oral medication has just been released in the USA and
Europe, it is still under review in Canada. While the commonly used therapies (interferon and glatiramer acetate) reduce the relapse rate by approximately 30%, medications such as tysabri are more effective. But with greater efficacy comes greater risk of toxicity – and the balance between safety and benefit is of even greater concern in children (reviewed in Banwell et al, Nat Rev Neuroscience)7. The care of children with MS and their families requires appreciation of this complex disease and its many facets. Children must learn how to live with an unpredictable disorder, must cope with injections, laboratory tests, and other investigations that remove them from the normal life of a child or teenager. All patients and families require support and information to help them cope. A multidisciplinary, comprehensive approach to care is important to address all of their needs. In addition to the neurologist, this includes nurses, social workers, neuropsychologists, psychiatrists and rehabilitation therapists. Research into childhood MS offers these children and their families hope and an opportunity to better understand and treat the disease. The national demyelinating disease program involves 23 sites – including all paediatric health care facilities in Canada. Research focuses on immunology, genetics, MRI, and clinical aspects.
References: 1. Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 1997;3:43-46. 2. Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D. Early onset multiple sclerosis: a longitudinal study. Neurology 2002;59:1006-1010. 3. Duquette P, Murray TJ, Pleines J, et al. Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr 1987;111:359-363. 4. Simone I, Carrara D, Tortorella C. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology 2002;59:1922-1928. 5. Banwell B, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol 2007;6:887902. 6. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007;6:773-781. 7. Banwell B, Bar-Or A. et al, New and Emerging Therapies for Multiple Sclerosis: immunological and neurodevelopmental considerations in the pediatric patient. Nat Rev Neuroscience 2010, epub ahead of print.
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FEATURE
MRI in Multiple Sclerosis Case Study An 11-year old girl presents to the Emergency Room with complaints of “double vision,” persisting for three days. Neurological examination demonstrates impairment in conjugate lateral gaze, suggestive of an internuclear ophthalmopegia (INO), which results from dysfunction of the medial longitudinal fasciculus—a densely myelinated brainstem tract. Magnetic resonance imaging (MRI) shows an inflammatory lesion centered in the brainstem (Figure 1). Corticosteroid therapy leads to rapid improvement in symptoms. On a three-month follow-up MRI, multiple clinically silent inflammatory brain lesions are present. After consultation with the neurologist, a diagnosis of multiple sclerosis (MS) is confirmed.
M By Leonard H Verhey Leonard Verhey is currently a PhD Candidate at the IMS, conducting his doctoral research under the mentorship of Dr. Brenda Banwell. Verhey’s research focuses on the use of MRI as a predictive tool for multiple sclerosis in children at risk. Upon completion of his doctoral studies, Verhey intends to continue working towards a career as a clinician-scientist with a focused research interest in imaging as it relates to multiple sclerosis.
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ri has become widely available in the clinical setting as a diagnostic tool as well as a means to non-invasively monitor disease progression and treatment. It plays an indispensible role in the diagnosis and management of patients with MS. The classic diagnosis of MS relies on the confirmation of two acute demyelinating attacks involving multiple regions of the central nervous system (CNS) (“dissemination in space”) and separated in time by at least 28 days (“dissemination in time”) (Poser, 1983). With the widespread implementation of MRI, these criteria have been modified: (i) to identify individuals with acute inflammatory demyelination whose MRI features are strongly predictive of a future MS diagnosis (“dissemination of lesions in a pattern consistent with MS”), and (ii) to include MRI findings of new lesions as confirmatory of “dissemination in time” (Polman, 2005). Very recent modifications to the international MS diagnostic criteria now permit an MS diagnosis at the time of a first attack, provided that MRI demonstrates two or more clinically silent lesions, as well as enhancement of one lesion (indicative of lesion acuity) (Polman, epub ahead of
Figure 1. Axial FLAIR image of an 11year old girl with an INO, demonstrating a midline pontine lesion (arrow).
print). The ability to confirm MS diagnosis very early in the disease course has important ramifications for patients. Treatment can be offered earlier, and evidence suggests that this favourably influences disease course. Importantly, the MRI criteria were developed for adult-onset MS, and have lower sensitivity and specificity when applied to MRI scans of children with MS. A recent publication by our group proposed new MRI criteria that distinguish pediatriconset MS from other non-demyelinating diseases (Callen, 2009). It is now important to determine whether these pediatric-specific criteria—or modifications to them—can predict which children will be diagnosed with MS when considered in the context of a child who has undergone the first clinical attack. Given that 30-40% of children experiencing a first demyelinating attack will be later diagnosed with MS, MRI criteria to identify these children is very important. The primary aim of my research is to develop an MRI algorithm for prediction of MS risk in children with acute demyelination. We are currently following an
Photo by Mohammed Sabri
A Window into the Brain of the Youngest Patients
FEATURE
MRIs courtesy of Leonard H Verhey
incidence cohort of 300 children with acute CNS demyelination enrolled from 23 pediatric hospitals across Canada in the Canadian Pediatric Demyelinating Disease Program (PI: Dr. Brenda Banwell, Pediatric Neurologist, Hospital for Sick Children). MRI scans have been acquired at baseline and at three standard serial time-points for each child according to a research protocol (N=1200 scans). I am evaluating each scan using a 16-parameter scoring tool, developed in the first phase of my work. Time-to-event models and a recursive partitioning technique will be used to identify MRI criteria present at time of acute CNS demyelination that predict a future MS diagnosis. The clinical application of these predictive criteria will enable counseling of families, consideration of prompt treatment initiation of MS-targeted therapies for children at high risk for MS, and the ability to re-assure families of children at low risk for a future MS diagnosis. While MRI criteria for MS focus primarily on lesions in the brain, MS also affects the spinal cord. In our recent detailed analysis of spinal cord lesions in pediatric MS patients (Verhey, 2010), we found two lesion types (Figure 2). Involvement of the spine can have devastating clinical consequences: paralysis of the limbs, inability to control bladder and bowel function, and even inability to breathe if the lesion involves the upper spinal cord and brainstem. Long-term disability also correlates with spinal cord involvement, and thus, the use of MRI to better appreciate spinal cord pathology in MS has relevance to patient care. Apart from its role in MS diagnosis, MRI has applications in monitoring treatment response and in aiding understanding of the underlying disease pathobiology. MRI evaluation of microstructural changes in
pre-lesional and normal-appearing brain matter and measurement of regional and global brain atrophy will provide important information regarding MS diagnosis and disease progression. These MRI metrics will serve as surrogate indices of treatment response. The application of MRI techniques that evaluate intra- and extralesional remyelination will provide insight into the robustness of endogenous repair capacity in children with MS, where primary myelination and maturation is ongoing.
References
Callen DJ, Shroff MM, Branson HM, et al. MRI in the diagnosis of pediatric multiple sclerosis. Neurology 2009; 72:961-7. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the “McDonald Criteria.” Ann Neurol 2011; epub ahead of print. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005; 58:840-6. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227-31. Verhey LH, Branson HM, Makhija M, et al. Magnetic resonance imaging features of the spinal cord in pediatric multiple sclerosis: a preliminary study. Neuroradiology 2010; 52:1153-62.
Figure 2. Sagittal T2-weighted images of the cervico-thoracic spinal cord in two children with MS demonstrating: A) two focal lesions (arrows) and B) a longitudinally-extensive lesion (bounded by two arrows). Images from Verhey, et al. 2010.
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FEATURE
The Neuropsychiatry of
Multiple Sclerosis
By Dr. Anthony Feinstein, MBBCh, MRCPsych, MPhil, PhD, FRCPC
Dr. Anthony Feinstein
MBBCh, MRCPsych, MPhil, PhD, FRCPC Dr. Anthony Feinstein is the Director of the Neuropsychiatry Program at Sunnybrook Health Sciences Centre, a professor in the Department of Psychiatry at the University of Toronto, and an associate scientist in the Imaging – Brain Sciences Program at the Sunnybrook Research Institute. His research focuses on the neuropsychiatry of MS, the neuropsychiatry of traumatic brain injury (TBI), post-traumatic stress disorder, and on developing self-report rating scales to assess psychological illness.
Behavioural research in MS can be divided into two broad categories, namely those of mood and cognition. To begin with the former, it is now known that rates of major depression are high in MS patients with a lifetime prevalence approaching 50%. MRI work done in my lab at Sunnybrook has shown that depressed MS patients are more likely to have brain atrophy involving anterior temporal and medial frontal regions together with an increased lesion load in the medial frontal areas as well. More recently, using diffusion tensor imaging, we have shown that depressed MS patients have more subtle abnormalities involving normal appearing white and grey brain matter. These findings provide unequivocal evidence of a link between the presence of depression and pathological brain changes, but by themselves cannot give all the answers as to why the rate of clinically significant depression is so high in this disease. Psychosocial factors are clearly important as well. Major depression is but one of a constellation of disorders involving changes in mood and affect in MS. Pseudobulbar affect (PBA), although less common, is of considerable interest given a clinical presentation in which patients laugh when not feeling happy or cry when not feeling sad. Once more, MRI work has been particularly informative in teasing out how this syndrome develops. Given the
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absence of causative psychosocial factors in the etiology of PBA, MRI delineated brain changes can account for close to 80% of the variance in explaining the syndrome. Currently, the most active area of neuropsychiatric research pertains to cognitive changes in MS. Depending on the course of the disease, 40-60% of MS patients will show impairments. The hallmark cognitive deficits are slowed information processing speed and difficulties in working memory which have been robustly linked to brain changes such as generalized atrophy, selective atrophy of regions such as the thalamus and, as with the depression data, subtle changes occurring in normal appearing white and grey matter. Work done in our lab has shown that cognitive dysfunction is not linked to the presence of the APOe4 allele as it is in Alzheimer’s disease. Unfortunately, the memory enhancing drugs used in Alzheimer’s disease such as donepezil and rivastagmine are ineffective in MS. On the other hand, preliminary data suggests the interferon treatments available to patients with relapsing-remitting MS may over the long term have some cognitive benefits in addition to slowing the progression of the disease. Looking to the future, as new treatments come on the market for MS patients, and many are in the pipeline, adding cognition to the list of clinical outcome markers will be imperative. In summary, advances in technology have opened the door to interesting and clinically meaningful research relating to behavioural changes in multiple sclerosis patients. Defining brain behaviour relationships offers the promise of improving patient care through a better understanding of how deficits arise. After a slow start, the neuropsychiatry of multiple sclerosis has quickly established itself as an important sub-specialty in the study and management of a disease that remains the commonest cause of neurological disability in young and middle-aged Canadians.
Photo by Mohammed Sabri
R
esearch into the behavioural changes linked to multiple sclerosis has undergone a renaissance in the last two decades. The understanding that MS could influence the mental state is not, however, new. The great French behavioural neurologist Jean-Martin Charcot observed in the 1880’s that MS patients showed an enfeeblement of memory and slowness in thinking. For the next 100 years, however, little attention was paid to these seminal observations. It was only in 1980, with the advent of MRI, which offered an unprecedented window into the brain of MS patients, that the field came alive.
FEATURE
New Theory of Multiple Sclerosis
– Is There Hope on the Horizon?
MS. “If CCSVI is indeed present in very young paediatric patients, then our study would support CCSVI as a fundamental aspect of MS. On the contrary, if CCSVI is not detected in young MS patients, then our research would suggest that CCSVI – if it occurs – is possibly a late effect of MS,” Dr. Banwell explains. “[But] at this point, the CCSVI theory has not changed our views of MS. It remains a new idea that requires further proof.”
By Meghna Rajaprakash
The Theory
A new, controversial theory hypothesizing that multiple sclerosis (MS) originates from venous malformations has received a tremendous amount of attention from the media and the scientific community. Developed by Dr. Paolo Zamboni of Italy, the chronic cerebrospinal venous insufficiency (CCSVI) theory suggests that MS stems from impaired venous drainage of the brain and spinal cord. In support of the CCSVI hypothesis, Dr. Zamboni reported that all of the 65 patients in his 2008 study, one of whom was his own wife, had obstructions in their azygous and internal jugular veins, while non-MS patients showed no such abnormalities. He theorized that these venous malformations lead to a buildup of blood and iron in the brain, contributing to the central nervous system inflammation and damage seen in MS. Scientists, however, have become skeptical of Dr. Zamboni’s results after a number of follow-up studies contradicted these findings. “A lot of people believe that it is an established fact that there is an association between vein abnormalities and MS. And nothing could be further from the truth,” says Dr. Paul O’Connor, neurologist and Director of the MS clinic at St. Michael’s Hospital in Toronto. “There have been studies from Germany, Sweden, England, and Holland, all of which have reported that venous drainage of the brain in MS patients is no different from that of non-MS patients.” A recent blinded, controlled study of 500 participants at the University of Buffalo, which has yet to be published, also showed different findings from the initial work of Dr. Zamboni. Dr. Robert Zivadinov’s study indicated that while 56% of MS patients exhibited narrowing of extracranial veins, 22.4% of healthy patients also showed evidence of narrowed veins, as did 45% of patients with other neurological diseases.
Illustratrion by Merry Wang
Despite these variable results, the CCSVI theory is not entirely inconsistent with the traditional view that MS is an autoimmune disorder, in which the immune system attacks the nervous system tissue. “[Dr. Zivadinov] has suggested that the vein abnormalities are more common in older MS patients who have more advanced disease. If this is true, it may imply that the vein abnormalities are not a cause, but a consequence of having a brain that is shrunken from the MS and from which less blood is draining,” states Dr. O’Connor. Most MS scientists, including Dr. Zamboni himself, are calling for more research into CCSVI. In Canada, seven large-scale projects are being conducted to address various aspects of the theory. Dr. Brenda Banwell, paediatric neurologist and the Director of the MS program at SickKids Hospital, is leading the Toronto-based study to determine whether vein abnormalities are present in children diagnosed with
This anatomical sketch details the the major veins involved in the Chronic Cerebrospinal Venous Insufficiency (CCSVI) theory.
The Treatment
Despite the inconclusive evidence for the CCSVI phenomenon, MS patients are flocking to foreign countries to receive Dr. Zamboni’s new “liberation” procedure – currently not performed in Canada – in which a surgical angioplasty technique is used to open the narrowed veins. From a patient perspective, the procedure offers hope and potential freedom from an incapacitating condition for which there is currently no cure. However, not all of the patients receiving the surgery have shown neurological improvements, and in some cases, it has led to complications and even death. “I’ve seen quite a few patients from my own practice who have gone and had the procedure done. None of them have had a major response in terms of [neurological improvement]. Many have said that they have less fatigue and their limbs feel warmer. But it’s hard to evaluate what this means,” explains Dr. O’Connor. In view of the lack of evidence, many neurologists are warning patients about the “liberation” procedure and its potential risks. “All therapies require careful evaluation. To date, neither Dr. Zamboni nor others have reported on long-term treatment effectiveness,” cautions Dr. Banwell.
The Ethics
The “liberation” procedure and CCSVI theory raise a number of ethical questions for the medical and scientific communities. Physicians are currently faced with the ethical dilemma of whether to support a
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 18
FEATURE treatment that is not fully validated. The situation becomes even more complex when doctors are asked to treat patients who suffer from complications after undergoing the treatment in foreign countries. “No medical person should make judgments about why patients got into their situation. Having said that, if the physician does not understand exactly what has been done or how it has been done, there is a very strong argument for why he or she would not want to intervene,” says Dr. Kerry Bowman, bioethicist at the Joint Centre for Bioethics and clinical ethicist at Mount Sinai Hospital. On the other hand, Dr. O’Connor suggests that “physicians owe a duty of care to their patients, irrespective of whether they approve of their having had this procedure or not.” He has been asked by the Ontario Minister of Health, Deborah Matthews, to co-chair a committee working on treatment guidelines related to the post-procedure care of pa-
When Science Goes Public By Allison Rosen
The possibility of a medical breakthrough is exciting for researchers, clinicians, and patients alike. Many researchers in medical science can only dream of making a discovery that would dramatically improve the lives of patients. However, scientists are also familiar with the arduous research process, necessary but time-consuming safety checks, and the rounds of obligatory clinical trials before the medical community accepts a new treatment. After Dr. Paolo Zamboni’s initial article on the “liberation” treatment was published online in April of 2009, the media coverage of his potentially life-changing and paradigm-shifting procedure began. In November of that year, the Globe and Mail published the first Canadian article on the subject, outlining the facts: a new theory regarding the pathogenesis of MS had been proposed, a treatment method based on this theory had been proposed, and an initial non-blinded trial showed
tients with MS who have undergone “liberation” procedures in other jurisdictions. For the scientific community, questions arise about the government’s prioritization of research in this area and the availability of funds for related clinical trials. “In the Canadian system, we work for the public, we are funded by the public, we have universal health care; yet, patients actually have very little social or community input into how research priorities are struck,” explains Dr. Bowman. At the crux of the problem is the large divide between a patient’s need for a quick, simple solution for MS and the complex, time-consuming process of medical research. “Evidence-based medicine and the reality of the illness process for patients are two different worlds. We need to find some common ground,” suggests Dr. Bowman.
positive results. Scientists quoted were optimistic, but recognized the need for more research. The article also featured anecdotes from patients who had undergone the vein-opening procedure abroad and subsequently experienced relief from some of their MS symptoms. This article was published on a Saturday. By the following Monday, Yves Savoie – the president of the MS Society of Canada – spoke out to vow that the society would fund further research into the treatment, primarily due to an overwhelming public response to the story. The society maintained, however, that there was “insufficient evidence” to definitively link chronic cerebrospinal venous insufficiency (CCSVI) to MS; Savoie urged patients to continue their current course of treatment, while also issuing an open call for grant proposals to begin research on CCSVI. Following these major reports, media coverage increased rapidly. Skeptical scientists and physicians urging caution and more research were accused of dashing the hope many patients had gained from Dr. Zamboni’s study. Patients claimed that scientists were not giving proper consideration to the new findings, and some even suggested that such perceived biases were due to pressure from pharmaceutical companies who were afraid of losing money if current treatments were abandoned. Nov 23
timeline
Nov 20-21
MS society vows to fund CCSVI research.
Canadian media involvement begins: The first article, “Researcher’s labour of love leads to MS breakthrough” is published on the front page of the Saturday edition of the Globe and Mail. A W5 program on CCSVI aired the night before.
2009
Apr
Dr. Paolo Zamboni’s original paper linking CCSVI to MS is published in the Journal of Neurology, Neurosurgery and Psychiatry.
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2010 Dec
Dr. Zamboni’s open label treatment study is published in the Journal of Vascular Surgery.
FEATURE In February of 2010, a study from Dr. Robert Zivadinov’s group in Buffalo reported that levels of venous obstruction were high in both MS patients and healthy controls. Another study by Dr. Florian Doepp’s team in Germany corroborated these results in August; no significant difference in venous occlusion was found between MS patients and controls. The MS Society reported in June of 2010 that it would put $2.4 million into seven studies across Canada and the US to investigate the proposed link between MS and CCSVI occurrence. On August 26, an expert panel recruited by the Canadian Institutes of Health Research (CIHR) and the MS Society recommended against initiating clinical trials of the “liberation” procedure until the results of the seven ongoing studies had been reported. Accordingly, Federal Health Minister Leona Aglukkaq announced the government would not proceed with interventional studies at that time. Patients reacted with such vitriol that Aglukkaq was forced to issue a clarifying statement two weeks later, in which she also accused the media of misrepresenting her original message. She stated that the government is indeed open to funding clinical trials, but results from the seven ongoing studies are still required to determine if the procedure is worth examining. The ongoing story of “liberation” treatment and CCSVI illustrates several important points regarding the way scientific progress is relayed to the public. Karen Owen, health reporter with CTV, writes about the Internet’s role in shifting a passive news audience to an active one that exerts influence over news content. Online groups and forums on which patients can organize and share personal anecdotes are key in the process of allowing individuals to come together and rally for governmental or charity-funded research or treatment provision in large, vocal groups that are hard to ignore. André Picard, health reporter with the Globe and Mail, suggests that the mainstream media is just one part of why the story has generated so much hype in the public and with patient groups. He notes that although the media has a responsibility to present information as thoroughly and as accurately as possible, another important factor came into play with the CCSVI story that made this process challenging. “I can tell you that one of the real difficulties in covering
Feb 10
Dr. Zivadinov’s group releases the preliminary results of their ongoing trial to determine the prevalence of CCSVI in MS patients compared to the general population. Results are mixed.
JuN
Canadian and American MS Societies put $2.4 million into seven two-year studies to determine the link between CCSVI and MS.
this story was that a lot of researchers and clinicians who had doubts (and more) about the Zamboni theory refused to talk on record. They didn’t want to give the theory more legitimacy and they didn’t want to be in confrontation with their patients. That made it harder to present balanced coverage.” The CCSVI story is far from over. On October 19, 2010, Mahir Mostic, a Canadian MS patient, died from complications of the “liberation” procedure performed on him in Costa Rica. This tragedy elicited very different reactions: doctors and researchers believed this demonstrated that the treatment was potentially dangerous and needed more study, while patients stressed that this death would not have occurred had the procedure been available in Canada. In January of this year, the MS Society reported a preliminary update of its seven Canadian-American trials: all studies have received approval from research ethics boards and have proceeded with patient recruitment. Findings will be reported every six months until the research is concluded. The CCSVI story has captured the attention of a large number of us in Canada, which has one of the highest rates of MS in the world. It is an emotional topic about which many people are, understandably, extremely passionate. Dr. Paul Hébert, editor-in-chief of the Canadian Medical Association Journal, reflects on the government’s role in allocating funds to research the “liberation” treatment. “Good health policy decisions should not be based on hope and desperation,” he cautions. Without following these guidelines, Dr. Hébert foresees our society setting a dangerous precedent. “It will leave our academic institutions and research community repeatedly at the mercy of advocacy campaigns and decisions based on political expediency and opportunism,” he concludes. This certainly is a strong incentive to learn how to better walk the fine line between patient satisfaction and clinical equipoise under the changing culture of health reporting – both to preserve scientific integrity and to provide the best possible care for patients.
Aug
A German study by Doepp et al. reports no difference in venous occlusion in patients compared to controls.
oct 19
Canadian patient Mahir Mostic dies after complications from the procedure that was performed on him in Costa Rica.
2011
Sep 1
Canadian Health Minister Leona Aglukkaq declines to fund interventional clinical trials based on CIHR recommendations. MS patients speak out angrily in media.
JAN 31
Sep 15
Aglukkaq issues a statement clarifying her previous report. She claims the media distorted her original message to the public.
MS Society reports progress of their seven two-year trials.
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 20
SPECIAL TRIBUTE
The Passing Dr. Ernest McCulloch: 1926-2011 By Avi Vandersluis
A staggeringly intellectual man, Dr. McCulloch was born on April 21, 1926 in Toronto. After attending high school at Upper Canada College, he went to the University of Toronto, where he earned his MD degree in 1948. He spent the following year at the Lister Institute in London, England, where he started his research career before returning to Toronto for 21 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
his clinical training at the Toronto General Hospital and Sunnybrook Health Sciences Centre. In 1954, Dr. McCulloch joined U of T’s Department of Medicine, and by 1959, he held a graduate appointment with the Department of Medical Biophysics. Significantly, upon the official opening of the Ontario Cancer Institute (OCI) as Princess Margaret Hospital’s research division in 1958, he was appointed to the scientific staff, a position he retained even after his retirement in 1991. It was there, on Sherbourne Street, that he met Dr. Till, forming a friendship and a scientific partnership that would last a lifetime. In addition to his research activities and teaching, Dr. McCulloch was extremely involved in the administrative side of both the academic and scientific worlds, holding numerous key positions in universities and research institutes in Canada and around the world. In fact, feeling that the basic science sector was too rigid and structured, and realizing the need for collaboration between the existing clinical and basic science departments at U of T, Dr. McCulloch, alongside Dr. Jack Laidlaw, was one of the IMS’ founding fathers. Despite facing widespread scepticism, Drs. McCulloch and Laidlaw established the IMS as a graduate unit of the School of Graduate Studies in the summer of 1967. The following September, they received approval from the Ontario Council of Graduate Studies. As the first Graduate Secretary – a position now termed Graduate Coordinator – and as the second Director, Dr. McCulloch was an integral part of the IMS’ early years, setting in motion the development process that has led the department to its current status as one of the most prestigious programs in the School of Graduate Studies. Moreover, he was responsible for initiating the Summer
Photo courtesy of the IMS office
H
ow significant is the number 50? In our society, one’s 50th birthday is often a grand celebration. A 50th wedding anniversary is referred to as the “golden anniversary.” But the value we place on the number 50 is not new. Indeed, the number 50 has held sacred value dating back to ancient history. According to the Pythagoreans and ancient Hindus, the number 50 was the holiest and most natural of numbers, for it is equal to the sum of the squares of the numbers 3, 4, and 5, which make up the sacred triangle of Pythagoras. René Allendy, a French homeopathic doctor and psychoanalyst who lived in the late 19th century, believed that the number 50 was “a favorable number marking a grace, a kindness, [and] a regeneration.” To Karl von Eckartshausen, a German Catholic mystic, author, and philosopher in the 1700s, 50 was the number of “the spiritual ascension to the intuition, the number of the illumination.” It is therefore perhaps noteworthy, or at least in some way uncanny, that on the eve of January 19th, 2011, a mere two weeks before the 50th anniversary of his and colleague Dr. James Edgar Till’s breakthrough discovery of stem cells, Dr. Ernest Armstrong “Bun” McCulloch, one of the University of Toronto and the Institute of Medical Science’s brightest and most respected scientists and professors emeritus, passed away peacefully at the age of 84.
SPECIAL TRIBUTE
of a Legend Undergraduate Research Program, a program that continues to thrive today. In 1979, after more than 12 years with the IMS, Dr. McCulloch left to become the Assistant Dean of the School of Graduate Studies. Having trained as a biologist, Dr. McCulloch’s initial research at the OCI centred on the viral etiology of cancer. By the early 1960s, though, his focus had switched to blood formation and leukemia. He and Dr. Till had begun examining the effect of radiation on bone marrow in vivo, and were conducting a series of experiments involving the injection of either normal or irradiated bone marrow cells into laboratory mice. While the widespread belief at the time was that radiation targeted cancer cells alone, leaving normal cells unaffected, they had set out to verify a recent controversial finding suggesting that normal cells were just as susceptible to radiation as were cancer cells (a finding they would prove to be correct). One Sunday afternoon, however, as he was comparing morphological differences between mice in the two groups, Dr. McCulloch noticed tiny nodules – which he and Dr. Till later named “spleen colonies” – on the spleen of a mouse who had received normal bone marrow. Upon further investigation, Dr. McCulloch and Dr. Till discovered that these “spleen colonies” had not only been derived from a single cell, but were also made up of differentiating hematopoietic cells. On February 1st, 1961, their ground-breaking findings were published in the journal Radiation Research. In the decades that followed, they rigorously proved that the single cell responsible for the formation of the “spleen colonies” could self-renew and give rise to all of the different types of mature blood cells, and eventually built the scaffold through which stem cells
are currently understood. The initial results, which, as Dr. McCulloch said in 2005 during an interview with CBC Radio, “came about, as so often happens, as an incidental result of an experiment done for a completely different reason,” revolutionized both science and medicine, and laid the foundation for research into new treatments for numerous debilitating and chronic diseases. In recognition of their work, Dr. McCulloch and Dr. Till received numerous awards, including the Gairdner Foundation International Award in 1969, the Thomas W. Eadie Medal in 1991, the Albert Lasker Award for Basic Medical Research – North America’s most prestigious medical prize – in 2005, and the National Cancer Institute of Canada Diamond Jubilee Award in 2007. They were also inducted into the Canadian Medical Hall of Fame in 2004. Despite all of his accolades, which also included being appointed Officer to the Order of Canada and elected a fellow of the Royal Society of London, Dr. McCulloch was fiercely loyal to his students and colleagues. Accordingly, his passing was met with an outpouring of emotions and stories. Writes Joe Sornberger, friend of the Canadian Stem Cell Foundation and author of a 50th anniversary commemorative book on Dr. McCulloch and Dr. Till to be released later this year, in his tribute to Dr. McCulloch: “I listened to researchers say they would take a bullet for the man, that he was like a father to them, that he had shown faith in them when others had scoffed at work that would later prove to be ground-breaking.” Perpetually covered in chalk, Dr. McCulloch always stressed the importance of training medical scientists. “He always encouraged us to [have] big dreams, but he also expected us to have our two feet on the ground,” recalls Dr. Tak Mak, Direc-
tor of the Campbell Family Breast Cancer Research Institute and a former student of Dr. McCulloch. But most of all, Dr. McCulloch’s passion was meaningful research. “He wanted to do something that was worth doing, and he wanted to do it well,” Dr. Alan Bernstein, Executive Director of Global HIV Vaccine Enterprise, says, “And he had no patience, no use, for boring science, science that had no impact.”
“...while we bid thee adieu, Dr. McCulloch, this is not goodbye. You will most definitely be missed, but your legacy will live on in our hearts and minds forever.” To honour Dr. McCulloch and Dr. Till’s incredible discovery 50 years ago, in addition to the reprinting of their article in the February 2011 issue of Radiation Research, a commemorative celebration was planned at The Campbell Family Cancer Research Institute to mark the special anniversary. Upon learning of his death, however, event organizers were unclear whether they should carry through with it. But, even when faced with tragedy and sadness, life must, and always does, go on. Dr. McCulloch would have wanted nothing less. In the end, on February 1st, 2011 – exactly 50 years to the day of the publishing of their landmark paper back in 1961 – Drs. McCulloch and Till were indeed honoured for the outstanding impact their work has had, and continues to have, on the scientific community worldwide (to date, their original publication alone has been cited 3000 times and counting). So while we bid thee adieu, Dr. McCulloch, this is not goodbye. You will most definitely be missed, but your legacy will live on in our hearts and minds forever. IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 22
SPOTLIGHT
Critical Factors for Improved in vitro Fertilization
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nspired by her father, a navy physician, Dr. Crystal Chan considered a career in medicine from an early age. Now, she is a senior resident in the Department of Obstetrics and Gynecology. In addition to her love of medicine, however, Chan is also interested in research, an interest she developed while studying microbiology and genetics during her undergraduate degree at the University of British Columbia. Funding from NSERC allowed her to work in a biotechnology laboratory studying the pathogenic E. coli species, and provided her with a foundation in molecular biology. With duelling interests in both medical school and graduate school, Chan faced a dilemma that is common among undergraduates. Her eventual decision to attend medical school resulted from two factors: her childhood aspirations, and her uncertainty about which field of research she should pursue. Ultimately, this was the right choice for Chan – her medical school and residency experiences have cultivated her interest in reproductive
biology and infertility, areas she has since selected as both her clinical sub-speciality and her research field.
“The time the CIP allows in residency is valuable for defining one’s research interests as an academic clinician.” When asked about her choice to pursue obstetrics and gynecology, Chan explains that unlike many areas of medicine, this specialty typically involved healthy patients with happy outcomes. “It allows the clinician a continuous therapeutic relationship with a patient, from adolescence to pregnancy to menopause and beyond,” she says. After being exposed to in vitro fertilization (IVF) during a clinical rotation, Chan tailored her focus specifically on the treatment of infertility. Choosing this clinical sub-speciality also gave her the research focus she sought, since IVF is a relatively new and technologicallycharged technique. At the midpoint of her
residency, Chan applied to the Clinician Investigator Program (CIP) at the IMS to combine her two passions. “The IMS embraces clinicians, and the CIP offers a curriculum which builds a foundation in science and laboratory methods,” explains Chan. “The time the CIP allows in residency is valuable for defining one’s research interests as an academic clinician.” The most challenging clinical problem associated with IVF is multi-fetal pregnancy, which can result in complications such as premature birth. For couples experiencing infertility, medication is used to stimulate oocyte production in women. The oocytes are subsequently harvested, fertilized in vitro, and returned to the uterus. To compensate for the low success rate of IVF, clinicians and patients often feel compelled to transfer more than one embryo. Chan’s research goal is to reduce the rate of multiple pregnancies by improving the baseline success rate of single embryo transfer outcomes. To do this, she is using molecular techniques to identify unique markers predictive of embryo competence and viability and of uterine receptivity in humans. Co-supervised on the research front by Dr. Theodore Brown and on the clinical front by Dr. Ellen Greenblatt, Chan describes a collaborative environment, and appreciates their mutual understanding of the demands on a resident going through graduate school. Tested and rewarded by both of her endeavours, Chan finds it difficult to pick the most demanding. “Residency consists of long, intense hours, but provides immediate gratification. After delivering babies all night, you may be exhausted, but there is a sense of accomplishment,” she points out. “While graduate school generally has better hours, the self-directed learning is challenging. The drive to publish can be stressful, but the end goal is also rewarding. Science and medicine pose different challenges, but I love them both and am privileged to integrate both into my training.” Although unsure about whether to pursue a PhD, Chan envisions herself as a clinician-investigator with an academic infertility practice. What she is certain about, however, is that her future will include a mix of clinical duties and research efforts as she strives to improve IVF outcomes. Interview by S. Amanda Ali
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Photo by Paulina Rzeczkowska
Crystal Chan
STREAM MSc Clinician Investigator Program SUPERVISOR Dr. Theodore Brown and Dr. Ellen Greenblatt
SPOTLIGHT
FACULTY VIEW
Jodie Jenkinson BA, MScBMC How did Biomedical Communications enter the picture? During that period, my mother was diagnosed with breast cancer. As I learned more about the disease and experienced first-hand the frustration of trying to find appropriately designed patient education materials, I guess you could say I was “called” to this profession. I undertook a MScBMC here at U of T and I’m currently in the process of completing a PhD at OISE. What’s the best way to tackle a new design project? I start by sketching out relationships. I try to conceptualize these relationships, all the while refining this concept until I arrive at its core.
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Photo by Connie Sun
n extremely talented artist and medical illustrator, Jodie Jenkinson has developed educational tools for the Prostate Centre, Breast Matters, and Anatomia, the University of Toronto Division of Anatomy’s electronic resource used to help medical and dental students learn the complexities of the human body. She also plies her trade as an assistant professor in the Biomedical Communications Unit of the Department of Biology at UTM, where she teaches aspiring MScBMC students the inner workings of visual design and scientific communication. Jenkinson met with the IMS Magazine to answer some questions about her life in the field. After completing your undergraduate degree in art history and French literature at McMaster University, where did you go from there? Well, naturally the job prospects were great, but I resisted the urge to pursue a career waitressing or telemarketing, opting instead to join an animation studio. It was there that I gained invaluable experience in traditional animation and production.
Where do you draw your inspiration from? I’m inspired by my surroundings. When I get stuck, I turn to other designers for inspiration. I love Swiss design. Josef MüllerBrockmann’s work makes me feel positively weak-kneed. Let’s switch gears a bit and talk about what you like to do when you’re not working. I have a fondness for chocolate and British tabloids. Don’t ask me why, but I find them both very satisfying. You’re also the outdoorsy-type, isn’t that right? Yes, I really enjoy the outdoors, which is not to say that I like “roughing” it, though. After a full day of travel and appreciation of Mother Nature’s fine work, I like to return to my beautifully appointed hotel room, crash on my king size bed and sink into the goose down duvet while channel surfing on the larger-than-life high definition TV. In addition to teaching, you’ve taken an interest in research as well. Your biography on the BMC website mentions that you focus on information visualization & perceptionbased design theory, as well as evaluating interactive health and science education tools. How did you get involved in these fields? When I first graduated from Biomedical Communications, I divided my time be-
tween research and contract work. In short order, the research won out. It gave me the opportunity to measure the impact of the visual tools we create. Often in an educational context the role that visual imagery plays in learning is either overlooked or evaluated in a perfunctory way. Research in Biomedical Communications examines the ways in which people learn from visual media. So, for me, this was a natural fit. You have been a key part of some pretty significant research projects, most of them aimed at helping people understand human anatomy. Which do think has had the greatest impact? I’m very excited about my most recent research endeavour. In collaboration with Gaël McGill, Director of Molecular Visualization at Harvard Medical School, we are examining the impact of visual complexity upon students’ understanding of molecular environments. Specifically, we are exploring the effectiveness of 3D visualization techniques in fostering students’ understanding of random motion, conformational flexibility of proteins, and molecular crowding. To date, we’ve learned that in this particular context, complexity can be very desirable and that it helps alleviate misconceptions that arise as a result of exposure to more basic representations. What’s the best part of your job? I think it’s the intellectual exchange that takes place with colleagues and students. I work with an incredibly talented and interesting group of people who provide a stimulating environment in which to incubate new ideas. It helps to love what you do. I think about design all the time – while walking down the street, riding the subway, even while driving. Okay, perhaps that’s not so wise. What is the most important piece of advice that you pass on to your students? This is a very exciting time to be starting out in biomedical communications. Our field is expanding rapidly and new grads have many opportunities to carve a niche for themselves. My advice to any graduating student is to think about what you really enjoy and where you want to be five years from now – and then focus! Interview by Avi Vandersluis
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SPOTLIGHT
Nigil Haroon
STREAM PhD SUPERVISOR Dr. Robert D. Inman
Investigating the Intricacies of Ankylosing Spondylitis
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s his career as a rheumatologist has progressed, Dr. Nigil Haroon has maintained a strong commitment to his patients and to the betterment of their health. In fact, making the choice to leave his homeland of Kerala, India in 2008 to pursue a PhD at the IMS was based on this very premise. Haroon has focused his efforts on understanding the progression of ankylosing spondylitis (AS), a rheumatic disease characterized by severe inflammation of the spine, and in some patients, eventual fusion of the vertebral bodies. From his experiences in the clinic, he has seen first-hand how disabling and painful the condition can be. “Maybe one of the worst parts [of the illness] is the fact that it predominantly affects those between 20-40 years of age, which is arguably the most productive years of life. It’s a terrible situation for some patients.” Prompted by this knowledge, Haroon im-
mersed himself in clinical immunology research during his rheumatology fellowship at the Sanjay Gandhi Postgraduate Institute of Medical Sciences in India. After receiving the Young Investigator Award at the National Conference of the Indian Rheumatology Association, he met his eventual supervisor, Dr. Robert Inman. Dr. Inman encouraged him to join his lab at Toronto Western Hospital when his fellowship was complete; for Haroon, it was an easy choice to work with a renowned leader in the field in the hopes of unraveling the fundamental mysteries of AS.
“But we haven’t been able to prevent bone formation involved in spinal fusion – once it occurs, nothing can really be done.” For the past three years, Haroon has been investigating specific genes related to the pathogenesis of ankylosing spondylitis. The condition remains enigmatic despite a strong
association with human leukocyte antigen B27 (HLA-B27), a gene that is expressed in 90% of AS patients. Its exact role in AS pathophysiology has remained unclear since its discovery over 30 years ago, but Haroon and colleagues are getting closer to solving the puzzle everyday. The team hypothesizes that two endoplasmic reticulum aminopeptidases – enzymes that trim peptides for antigen-presentation – may abnormally interact with HLA-B27 in such a way that explicates the aberrant immune response seen in AS. Haroon is hopeful about his work, particularly because he knows how limited current treatment is for the disease. “We can help control inflammatory processes and manage pain,” he explains. “But we haven’t been able to prevent bone formation involved in spinal fusion – once it occurs, nothing can really be done.” Haroon has had great success so far as a doctoral student, including being selected as a recipient for the prestigious Vanier Canada Graduate Scholarship in 2010, and more recently, having his work recognized as the best scientific paper at the International Spondyloarthritis Congress in Belgium. He continues to look to the future, however, and is intent on advancing his findings through greater collaboration and additional, more basic science-oriented, experiments. Interview by Nina Bahl
Lending an Ear
“If you take an example like India, realistically speaking, the number of highly-qualified rheumatologists is disproportionate to the 1.2+ billion people living in the country. People write in and I try to ease their minds in whatever small way I can,” he explains. Read more about Nigil and his efforts at http://www.nigilharoon.com.
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Photo by Paulina Rzeczkowska
Dr. Nigil Haroon has developed a personal website to promote education about rheumatic diseases and provide basic advice to patients by responding to their emails and posting commonly asked questions on his blog.
SPOTLIGHT
Jared Wilcox
STREAM MD/PhD SUPERVISOR Dr. Michael Fehlings
Scar Degradation Provides Hope of a Better Future for Spinal Cord Regeneration the ultimate goal of preserving and even improving the function of their front limbs. A major obstacle in the treatment of people with spinal cord injuries, especially those that are long-term, scar formation prevents damaged neurons from regenerating. “Within a month of the injury, structural cells in the spinal cord start to produce extracellular matrix to protect the tissue and prevent it from degrading further,” he explains. By injecting the scar-degrading enzyme chondroitinase into the injured area in addition to stem cells – which can help preserve surviving neurons via the replacement of myelin – Wilcox hopes to increase the effectiveness of the stem cells. “Research in scar degradation may allow us not only to help people immediately after they are injured, but also to help people who have been paralyzed for years to regain some function.”
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Photo by Paulina Rzeczkowska
ared Wilcox is not a typical PhD student. Neither is he a typical medical student. Wilcox is enrolled in the MD/ PhD program with the IMS, a rigorous 8-year program in which a full PhD is sandwiched between four years of medical school. Passion is essential for success in this program, Wilcox admits. “I would recommend my program for anyone interested in medicine who definitely knows they want to do research.” Now in his third year of the program – and second year of PhD work – Wilcox began in 2008, after obtaining his MSc from the University of Guelph. Attracted by the large number of supervisors conducting translational research, the IMS was a natural choice. “I liked that the IMS is more research-based,
rather than course-based. For me, getting hands-on experience conducting research is much more valuable, so the program is a great fit.” But when asked how he found his current supervisor, neurosurgeon Dr. Michael Fehlings, Wilcox’s enthusiasm for the medical field shines through. “I didn’t know who my supervisor would be until eight months into med school,” he recalls. “The first day we met, he was in surgery, so he was half an hour late. He came down in scrubs and asked me if I wanted to go to the operating room to watch. Obviously I said yes! And that was it – after seeing him do surgery, there was no chance of me saying no. I was going to be in his lab. It was official.” Wilcox’s research focuses on minimizing scarring in rats after spinal cord injury, with
How important is this research? Wilcox provides some perspective on the matter. “If someone is injured at the C5 level, his or her shoulders, arms, and hands are all affected, and this person may be on a ventilator. The employment rate of someone with this injury is close to zero,” he claims. “But if the injury is just one segment lower at C6, the employment rate jumps to 50%, since hand use is improved. At C7, it’s back up to almost 100%. So the difference a very small length of spinal cord makes is huge. That is all we need to change people’s lives dramatically. That’s the real goal of what we’re doing.” With multiple scholarships and publications already under his belt, the future looks bright for Wilcox. Not only does his research show promise, but he already has his foot in the door when it comes to a career as a clinicianscientist. “The IMS is an extremely good training program,” he professes. When asked about his plans for the future, Wilcox replies with a smile. “I’ve got the surgical bug. I absolutely love it. There’s a really good chance I’ll be a neurosurgeon…that this is what I’ll be doing in twenty years.”
Interview by Allison Rosen
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 26
SPOTLIGHT
B
y no means can Leanne De Souza’s journey to the IMS be considered direct. But the skills and understanding she picked up along the way makes it all worth it. Beginning in the final year of her undergraduate degree at the University of Toronto, Mississauga Campus, she completed a thesis project with Dr. Glenn Morris, studying bio-acoustic communication in animals. Although her research career was just beginning, it was already apparent that De Souza would be a successful researcher. Not only did she receive an award for her work, but she was and still is recognized for her undergraduate research, as her findings were just recently published in a peer-reviewed scientific journal. Success aside, however, De Souza realizes how important her undergraduate thesis experience was, as it enhanced both her communication and critical-thinking abilities. These skills have proven invaluable not only in her current research, but in her everyday life as well.
Leanne De Souza
STREAM PhD SUPERVISOR Dr. Joel Ray
Experience Pays Off in Hunt for Metabolic Factors Underlying Type 2 Diabetes Mellitus
“To be part of the biggest and the best opens doors and gives you a window into something that you [would] otherwise never achieve.”
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Dr. Ray and a co-supervisor. De Souza’s research focuses on Type 2 Diabetes Mellitus (T2DM), modeled through gestational diabetes mellitus (GDM) – otherwise known as diabetes obtained during pregnancy. De Souza studies the events that precipitate T2DM, as metabolic dysregulation in early pregnancy and during GDM can lead to development of T2DM later in life for both mothers and their children. Her work centres on Filipino women, who have a very high incidence of metabolic dysregulation, thus often suffering from its associated complications. De Souza’s interest in her field spans well beyond her PhD work, however; she is currently writing a book chapter about metabolic syndrome and metabolic dysregulation, with IMS professor, Dr. Ravi Retnakaran. Additionally, she is writing a paper on
disability rates within the American Filipino population. In recognition of her impactful research, De Souza was rewarded an IMS entrance scholarship, and currently holds an OGSST award. De Souza recognizes the need for collaboration between non-clinicians and clinicians. Despite the sheer size of the IMS, De Souza acknowledges that there are endless opportunities to form productive relationships with fellow scientists, and feels lucky to be able to work with both well-established and up-andcoming scientists. “It is a position of privilege to be part of the IMS,” she says. “To be part of the biggest and the best opens doors and gives you a window into something that you [would] otherwise never achieve.” Interview by Anthony Grieco
Photo by Paulina Rzeczkowska
Seeking real-world experience to supplement her undergraduate education, De Souza also joined the pharmaceutical company GlaxoSmithKline (GSK) as a summer student. While there, she honed her basic science skills and, upon continuing on as a co-op student, was eventually exposed to clinical and epidemiological research. Her research success continued while at GSK, where she and her mentor, Dr. Nigel Rawson, published a paper about the Canadian perspective of epidemiology within the field of pharmacology. De Souza went on to pursue a Master’s degree in clinical research in the Department of Nutritional Sciences at the University of Toronto, with Dr. Vladimir Vuksan, before being hired by the Department of Obstetrics & Gynecology at St. Michael’s Hospital as a clinical research coordinator, where she was able to apply the vast knowledge and experience she had acquired in her previous positions to women’s health research. Fortuitously, it was here that De Souza met Dr. Joel Ray, a clinical endocrinologist and internist. Realizing that an amazing research opportunity was within her grasp, she joined the IMS and is currently completing her PhD under
SPOTLIGHT
Q & A with...
Dr. Dina Brooks PhD, MSc, BScPT single day. But I was also able to carefully watch a physiotherapist – one of the few in Lebanon at the time – work with war-injured patients. Her work was so important to me, even as an 11 year old girl, since I could see, first-hand, what a difference “physiotherapy” could make in people’s lives. That was how I chose my career.
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he physiotherapist, mother of two, and “official” hockey mom talks about how she turned her war-filled past into a bright future for chronic heart disease patients. AV: Tell me a little bit about yourself. How did you get to where you are today? DB: I was born in Lebanon. When I was just a girl, maybe 7 or 8, war broke out there. It lasted for many years, continuing even after we left when I was 15. Life was very difficult: living in man-made bomb shelters, hiding between walls, counting the explosions of nearby bombs, seeing men and women shot and dropping to the ground in front of you as you walked to school, having limited food, clothing, and supplies to survive, lacking power, water and electricity for days and nights on end. When I was 11 years old, I began to volunteer at the American hospital in Beirut during periods of calm. I was exposed to dozens of victims of war every
AV: How did you get involved in research? DB: When I became a physiotherapist, I realized that there is a real need for evidence to support what we do, which drove me into the academic world. AV: How has your training as a physiotherapist helped you become a successful researcher? DB: Because of my physiotherapy background, I can ask important clinical questions that have direct implication to practice. AV: Describe your research focuses. What are you currently working on? DB: My present research focuses on the role of exercise in the management of disease in individuals with chronic conditions like heart and cardiac disease. Exercise really is the perfect “drug.” It is cheap and incredibly effective in managing illness. AV: What is the recipe for an effective exercise rehabilitation program?
DB: There are many guidelines on how we should exercise (number of minutes per day, number of times per week). However, there are still a lot of questions unanswered. Is this prescription right for everyone or should it be more individualized? How should this prescription be different in those with illnesses? How do we change human behaviour so people do exercise? AV: What are the greatest challenges that you face in your area of research and how do you overcome those challenges? DB: Rehabilitation and exercise is not a cure. Although it has an impact on quality of life and life satisfaction, it does not eradicate the disease. Thus, it is not an area that is easy to get funding for. The current funding environment is very challenging. AV: Where do you see the field heading in the future? DB: I really see exercise as “the solution” to many of the health issues we face. Exercise is a solid part of prevention and recovery from illness. The focus of the future will be on changing behaviour so more individuals take part in exercise. AV: What do you like to do outside the office? DB: I have many passions that include long distance running and reading. I have two boys – 12 and 14 – and I am an official hockey mom. Interview by Avi Vandersluis
Pick Your Brain
Social Networks and the Brain
Photo by Mohammed Sabri
By Aaron Kucyi
The IMS is a large, complex, and diverse community. Anyone who has navigated through the network of faculty members, students, and administrators can tell you that it is challenging to keep track of everyone. A growing field of research in human cognitive neuroscience is exploring how processes such as maintaining a social network are linked to brain structure and function. A recent study by Lisa Feldman Barrett and colleagues in Boston found that the size of an individual’s social network is linked to the size of their amygdala, a brain structure associated with emotion processing. Over 500 worldwide news outlets reported on the study, published in Nature Neuroscience. The study does not establish a causal link
between amygdala volume and social network size, but it does raise the question of whether, and how, a person can learn, for example, to understand the social dynamics of a large university department. Nicholas Rule, an assistant professor of psychology at the University of Toronto and Canada Research Chair in Social Perception and Cognition, called the study “a great example of the progress being made in human cognitive neuroscience, particularly as it integrates with other sub-fields of psychology, such as social psychology.” He adds, “[t]he findings are very thought-provoking and will likely stimulate further research... [A]n interesting future direction would be to examine how connections between the amygdala and higher-order cortical structures might also be related to variables like social network size.” So one question remains: how big is your social network?
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SPOTLIGHT
Maryam Hamidi
STREAM PhD SUPERVISOR Dr. Angela M. Cheung
Developing a Taste for Bone Research
“Driven to achieve happiness and success, and a firm believer in the value of clinical research for helping those in need, she knew that studying and advocating health and well-being would be the perfect choice.” 29 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
For her PhD, Hamidi has been leading three projects, each one examining a different aspect of the relationship between dietary factors and bone health among postmenopausal women. The first study looked at the effect of overall diet quality, using a dietary index, on bone turnover markers. She then went on to systematically review the association between fruit and vegetable intake and bone health. Finally, Hamidi assessed the effects of vitamin E on bone health. Her hard work has culminated in multiple conference presentations and publications. When asked how she decided on postmenopausal nutrition as her area of focus, Hamidi passionately describes her lifelong passion for health. Driven to achieve happiness and success, and a firm believer in the value of clinical research for helping those in need, she knew that studying and advocating health and well-being would be the perfect choice. Now in the last year of the PhD program, and preparing for her final defense, Hamidi reflects on her five years in the program. Not
only was she able to learn and contribute to clinical research, but her PhD training also helped her to improve her social and communication skills. Summarizing the challenges she faced along the way, Hamidi says, “I did not know what a panic attack was until I started my PhD.” However, she remarked that overcoming such difficulties are a part of graduate studies and what you gain in return is priceless. Looking back at her experiences at the IMS, Hamidi strongly recommends the program to anyone considering graduate school. She considers the department’s focus on research and productivity to be a great strength. Hamidi is also grateful to all the staff in the IMS office and to the graduate coordinators, who were especially helpful throughout her years. Being a part of the IMS community has helped her grow as a researcher, and Hamidi hopes to continue studying and advocating health in the future. Interview by Minji Kim
Photo by Paulina Rzeczkowska
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orn and raised in Iran, Maryam Hamidi considers her immigration to Canada to be the single best thing to have happened to her. Under the supervision of Dr. David Jenkins, she obtained her MSc, studying the effect of diet on cholesterol and cardiovascular disease in the Department of Nutritional Sciences at the University of Toronto. Afterwards, while working as a research nutritionist and study coordinator in the area of osteoporosis and postmenopausal health, Hamidi observed that many dietary factors lacked extensive study in postmenopausal women. She decided to pursue her interest in this research field by applying to the PhD program at the IMS under the supervision of Dr. Angela M. Cheung.
SPOTLIGHT
“D
etermination, motivation, and persistence,” answers Rickvinder Besla. He is responding to a question about the most important qualities he learned during his time in the IMS Summer Undergraduate Research Program (SURP). “Science doesn’t always go as planned. But the unexpected findings are sometimes the most gratifying.” Intrigued by scientific research since he spent his first few summers of undergrad volunteering in laboratories – including one summer with Dr. Yeni Yucel – Besla, a human biology major, took part in the SURP in 2010 under the supervision of Dr. Vasundara Venkateswaran. Inspired by the experience, he decided to continue his project – investigating a combination of compounds for the prevention of prostate cancer – towards a thesis, which he is currently completing.
Photo by Paulina Rzeczkowska
Besla’s decision to apply to the SURP was not unusual. “I was looking for a way to apply some of the theories that I had learned in my courses,” he explains, commenting that he learned of the program from Dr. Yucel, an associate professor at the IMS. “He encouraged me to sit in on the research seminars, despite not being in the program,” Besla says, referring to the mandatory weekly lecture series. “I found the program really interesting, as it included a variety of diverse topics.” Eager to develop and grow as a scientist, Besla approached Dr. Venkateswaran, who had been a guest lecturer in one of his classes. “Her research was very appealing because prostate cancer is a global health issue. As environmental factors can influence prostate cancer risk and progression, changes in diet and lifestyle may be one of the factors involved with rising incidence.” Having commenced the three-month summer program in June, Besla recalls his thoughts at the time. “I was really excited. It was my first opportunity to work on a project of my own, something I can’t do in my courses,” he claims. Additionally, working with world-class scientists, fellows and graduate students provided Besla with any help or encouragement he needed. “They taught me so much. I really got a good understanding of what it’s like to work in a research lab.” Importantly, his time in the program enabled Besla to hone many useful laboratory techniques and strategies about which he had only scratched the surface in class.
Rickvinder Besla Going Beyond the Textbook
“At school, you learn about the theory behind the techniques, but you rarely get to use them more than once. In the lab, however, I was able to perfect my skills – especially my Western Blots!” Besla adds. And although his wet-lab experiences were crucial, so too were the other aspects of the program. “I looked forward to attending seminars each Wednesday. Being lectured by experts on a different topic each week was really amazing.” On a different note, Besla was also thrilled about the opportunity to present his work in front of his colleagues and supervisors at the IMS Summer Student Research Day, one of the highlights of the SURP. “After spending the entire summer working on my project, it was nice to be able to showcase all my hard work,” he acknowledges. Undergraduate studies are often a very unsettling time for many students; unclear of their future, they are striving for academic achievement and trying to gain valuable experience for their future, all while working on a super-tight budget. But for Besla, overcoming these challenges is just part of the experience. “That’s just the way it is,” he notes. After taking part in the SURP, though, Besla is now at least clear about his immediate future goals. Upon his upcoming graduation in June, Besla is hoping to pursue a Master’s degree at the IMS come September. “My summer experience really helped me realize my passion for research.”
Summer Undergraduate Research Program (SURP) Participants in the IMS SURP spend the summer working on a research project. They are encouraged to participate in individual laboratory meetings, data analysis sessions, journal clubs, and/or appropriate clinical research rounds at the affiliated teaching hospitals. In addition, a weekly lecture series is given to complement the students’ research. The lecture series includes research presentations by IMS faculty, graduate studies information sessions, and practical skills workshops. In mid-August, students will present their work either orally or as a poster in front of their colleagues and supervisors at a research day, which also includes a keynote speaker and a reception. Upon completion of the entire IMS Summer Undergraduate Research Program, each participant will be given a certificate of completion. See http://uoft.me/imssurp for details on the methods of participation and requirements.
Interview by Natalie Venier
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CLOSE UP
An Immunological Perspective
INFECTIOUS DISEASE
Clinician-scientist Dr. Conrad Liles describes his career, his research, and his advice for future graduates. By S. Amanda Ali
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A
mong other appointments, Dr. W. Conrad Liles, MD, PhD, is the Vice-Chair of the Department of Medicine, the Director of the Division of Infectious Diseases, and a professor of medicine in the Institute of Medical Science at the University of Toronto. His research examines innate immunity, inflammation, and host responses in the pathogenesis of infectious diseases. As a clinician-scientist, Liles is acutely aware of the importance of translational medicine, and is a strong advocate for bridging the gap between medical practice and laboratory research. In addition to his impressive career (evidenced by the accreditations which follow his name), Liles makes time for an equally impressive personal life – one which could have led to Conrad Liles, the mountain guide.
Photo by Connie Sun
on
CLOSE UP
Q
Why become a clinician-scientist, instead of choosing either one or the other?
A
I never wanted to be strictly a clinician; I was always interested in research. The National Institutes of Health in the U.S. has a program to support MD-PhD training at selected medical schools, called the Medical Scientist Training Program, so that funded all my medical school and graduate school. I knew that was the direction I wanted to go, so I applied strictly to MD-PhD programs, and was fortunate enough to be accepted by the University of Washington.
Q
If you had to choose between the clinician or the scientist in you, which would it be?
A Scientist. Investigation and discovery are
what drive me. Patient care is very important, but what excites me is really discovery and innovation – things that will last beyond my lifetime. I want my research to be clinically applicable.
them in the laboratory, using our molecular techniques and pre-clinical models to try to understand the molecular pathogenesis. The insight that is gained this way allows us to design innovative interventions which can be extended back to the clinic. My interest in this process has led to my involvement with the IMS translational medicine curriculum.
Q
What factors do you think are most important for bridging the gap between scientists and clinicians, and translating findings from the bench to bedside?
A
I think the role of the MD-PhD is to fill that gap. It’s the ability to have exposure to clinical disease that allows research insight. When we treat patients, we don’t really know what’s going on – like in sepsis and multiple organ dysfunction. The bridge is formed by taking those problems back into the laboratory, coming up with new molecular insights – so called molecular medicine – and then taking that back to the clinic for novel therapeutic application.
Q Describe your research interests and in- Q volvement with the IMS.
Photo courtesy of Dr. Conrad Liles
A
My research interests have evolved over time. My PhD was in the Department of Pharmacology, which focused on molecular neuroscience at the University of Washington, and at that time I thought I wanted to be a neurosurgeon. But I became interested in innate immunity, inflammation, and host responses. These aspects are the focus of my research on infectious disease, rather than the microbiology of pathogens per se. I try to understand the molecular pathogenesis of infectious diseases and host responses. Our focus now is on sepsis, which is a major cause of morbidity and mortality in both the developed world and the developing world, and malaria, which is also a major cause of morbidity and mortality worldwide. Much of my research at the University of Toronto is conducted in collaboration with Dr. Kevin Kain. We work together on several projects in the Sandra Rotman Laboratory of the McLaughlin-Rotman Centre for Global Health located in the MaRS Building. The idea is to take major clinical problems of public health importance that are not well understood in the clinical setting and study
Do you think that immuno-modulation is a viable strategy for treating infectious disease?
A
Yes, there are already examples of broad strokes of immuno-modulation. For example, corticosteroids are used to treat certain types of tuberculosis and bacterial meningitis. We’re interested not only in immunomodulation affecting immune effector cells, but an emerging interest is on the endothelial cell, because we think that endothelial activation and dysfunction may represent a common pathway for tissue injury. Strategies that have targeted just immune effector cells – like blocking cytokines – haven’t necessarily been effective. Targeting the endothelial cells to prevent vital organ injury and dysfunction seems like a viable method, and so that’s part of the major focus right now.
sued. Some of my colleagues might say that I’ve gotten much more involved in academic administration than they think I should be. There’s no doubt that it impacts your personal productivity, but it was important for me to be involved in the mentorship process, and help other people in their careers.
Q
Do you find it difficult balancing your career and personal life?
A
I guess this wasn’t realistic, but I thought about being a mountain guide because I really like ski mountaineering – I’ve been all across Western Canada and Alaska. I like it for the exploration. If I had been born 200 years ago, I would have been attracted to exploration, and that’s how I see science, as exploration in today’s world. My wife is also a clinician-scientist, currently conducting research on HIV clinical epidemiology to complete her PhD. To have time to do activities, you have to make time. If you’re totally consumed, your work will suffer anyway.
Q
What advice would you give to a graduate student who is unsure about their next step?
A
Only do research if you’re really drawn to research, and only investigate problems that you think are really interesting and important. Research should be exciting and personally fulfilling, not a chore or a job. Never get sucked into doing something because it seems to be the easy way out. Younger investigators are often criticized because they’re not focused – I think you can be too focused. I’ve become involved in research areas that I never thought I would have – atherosclerosis, stem cells, gene therapy. If you had told me 15 or 20 years ago that I would be involved in those things, I would have said no way, but you have to keep an open mind.
Q
What is the most rewarding part of your job? And the most challenging?
A
Taking a discovery from the lab and translating it into a clinical setting is the most rewarding…and also the most challenging. If you could go back in time and change something, what would it be? I’m happy with the pathway that I’ve pur-
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 32
BEHIND THE SCENES
Keeping it
together
Dianne Fukunaga is a staple in the IMS office whose role continues to grow. By Samantha Bremner
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BEHIND THE SCENES
Recently appointed as the Student and Faculty Affairs Coordinator, Dianne Fukunaga plays a dynamic role in the IMS office. In less than three years, Fukunaga has progressed through a series of promotions.
O
riginally hired as the Departmental Assistant in June 2008 to replace a colleague on maternity leave, she was promoted to the position of Program Assistant in July of 2009 before receiving her current title. While many of Fukunaga’s duties as the Program Assistant overlap with her previous role – providing administrative support for the MSC1010/11Y seminar series, planning the annual IMS Curriculum Retreat, and participating on numerous committees, for starters – she is now additionally responsible for managing all faculty appointments and reappointments, award applications, and fee deferrals, as well as assisting with faculty development workshops and helping students with course registration.
Photos by Connie Sun
“The thesis defense and the defense process can be one of the most stressful times in a student’s academic career,” Fukunaga explains. “My goal is to help them the best I can and try not to make them cry.”
Originally from Thornhill, Fukunaga completed a Bachelor of Fine Arts degree in photography at Ryerson University. Although she still does one photo shoot a year for a friend’s dance studio, Fukunaga always knew she would work in an administrative or customer service type of position rather than pursue a career in photography. Looking for a permanent position at the University of Toronto after completing her undergraduate studies, she applied to “everything under the sun,” including the Department of Astronomy and Astrophysics, where she was hired to assist the department manager, prepare admission files for review, organize special events, and perform general office duties. By chance, Fukunaga heard about an opening at the IMS and decided to apply. “I was just lucky that things worked out so well with the IMS,” she says modestly. For Fukunaga, the social interactions are the best part of her current position with the IMS. “I like the people,” she quips, noting that she really enjoys working with the students, staff and faculty members, even during the tough times. “The thesis defense and the defense process can be one of the most stressful times in a student’s academic career,” Fukunaga explains. “My goal is to help them the best I can and try not to make them cry.” What makes it all worthwhile is seeing how appreciative the students are for her assistance. “Students have included me in the acknowledgement section of their theses. I know how important the thesis is to them, so I take that a huge compliment,” smiles Fukunaga. To new IMS students, Fukunaga has some valuable advice. “Double check deadlines for everything – awards, exams, classes, registration,” she reminds. Missing these deadlines could create stress, she explains, and could potentially have negative academic and financial outcomes. While there is much to remember, Fukunaga stresses the importance of not getting overwhelmed, admitting that she too is still learning the policies and procedures of the IMS department.
Outside of work, Fukunaga has many hobbies. She enjoys going to restaurants with her friends and “in theory, likes to bake.” She jokes that while she does not bake very often or very well, she still likes to try. She also loves spending time with her cats, Shadow and Catty, and aspires to one day travel the world. But one of her favourite hobbies is reading. Among her favourite authors is Charlaine Harris, whose series of novels formed the basis for the popular HBO television series “True Blood,” also one of Fukunaga’s favourites. Fukunaga finds her work with the IMS department to be challenging, but very rewarding. The job requires a unique mix of abilities – customer service, problem-solving, organization, event planning, and computer skills to name a few. “I’m still just learning the ins and outs of my new position,” she says. “As with any new job, the biggest challenge is learning what needs to happen when.” As she looks to the future, Fukunaga is eager to continue learning the responsibilities of her new position and interacting with the staff, students and faculty.
Insider Information Dream Car: “One that has four wheels, air conditioning, and starts and stops when it’s supposed to.” Favourite Dessert: Caramel Crunch Cake from Pickle Barrel Ideal Vacation Spot: Staying at home Favourite Band: The Weakerthans Favourite Pizza Topping: Pepperoni Favourite Store: Grocery and book stores Favourite Colour: Purple.“I recently discovered my wardrobe reflects this preference.” Favourite Animal: Penguins Favourite TV Show: True Blood Favourite Movies: “While You Were Sleeping,” “Up,” and “Amélie” Last Read: “The Hunger Games” by Suzanne Collins
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 34
FUTURE DIRECTIONS
A Brain
D
r. Jonathan Downar is not exactly what you would call your typical doctor. In the nine years since earning his PhD at the IMS, Downar has experienced an enlightening fusion of art, medicine, science and media – including a role as a screenwriter for an IMAX film. He’s now back at the Toronto Western Hospital, home of his IMS graduate training, where his diverse experiences and unwavering dedication are guiding a ceaseless effort to make scientific research relevant, meaningful, and useful.
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By Aaron Kucyi
A Toronto native, Downar always had farranging interests in writing, literature, and science. He pursued an undergraduate degree at McGill University, where he studied a combination of neuroscience, biology and anthropology. In addition to coursework, Downar was avidly involved in the arts, serving as an editor for a literary magazine that consisted of short fiction stories. It was during this time that influences from science and art converged to spark a most fundamental human question that Downar became committed to pursuing: what is consciousness?
He decided that the IMS was a good place to address this question. The problem of consciousness had long been solely a philosophical issue, but when Downar joined the IMS in 1998, people were starting to use brain imaging techniques, such as functional MRI (fMRI), to understand the intricate link between neural activity and subjective experience. Downar eagerly joined the lab of Dr. Karen Davis, who had been developing fMRI at the Toronto Western Hospital to study pain.
Photo by Paulina Rzeczkowska
Built for Translation
FUTURE DIRECTIONS ed events and highly behaviourally-relevant experiences such as pain. Together, Downar’s findings provided multiple lines of evidence pinpointing specific brain regions in the general roles of human awareness and attention. Despite the success of his projects, Downar’s research required a keen perseverance that was, at times, difficult to maintain. He describes a “formative experience” while attending a lecture by psychiatrist Dr. Shitij Kapur at the Centre for Addiction and Mental Health in Toronto. Kapur explained how brain imaging was being used to precisely measure the amount of dopamine activity in the brain that was needed to abolish symptoms of schizophrenia. For Downar, “this was beautiful, because not only was it good neuroscience that taught us something about how the mind works, but it had such direct clinical applications right there on the spot.” With the intent of applying scientific research to achieve tangible clinical outcomes, Downar attended medical school at the University of Calgary after completing his PhD. During medical training, he quickly realized that there was an astonishing amount of translational work to be done. “In the areas of medicine and neuroscience, respectively, there’s a lot of research being done,” he notes. “However, the pipeline between the two is this tiny little thing. If your PhDs are like sensory neurons and your MDs are like motor neurons, then you’ve got a lot of sensory neurons and a lot of motor neurons, but there aren’t that many interneurons.” Determined to shed light on the neural basis of conscious awareness, Downar designed his first project as a Master’s student to probe the workings of the human brain with fMRI. His study identified a network of specific brain regions that were activated by changes in the sensory environment – regardless of whether a change was visual, auditory or tactile. The findings were published in Nature Neuroscience (and the study was to become a classic in the neuroscience literature). With the momentum of his successful first project, Downar reclassified as a PhD student and conducted three follow-up studies to better understand the brain’s ability to select the bits of information in our environment that reach consciousness. These experiments explored how the brain responds to unexpect-
Downar saw great potential value in being an “interneuron,” someone who could turn the mountains of data coming out of the neuroscience field into constructive differences in the lives of patients. After completing medical school, he came back to Toronto to undertake residency training in the area of psychiatry. “Most of my residency was really a bit of a head-scratching endeavor to try to figure out what area of psychiatry could best be transformed and improved with the direct application of neuroscientific knowledge,” he recalls. An answer did not come easily, but Downar gained some insight during a postdoctoral fellowship he undertook in a world-leading neuroscience centre at Baylor College of Medicine. “They were studying three main
things: social behavior, decision-making, and emotion regulation,” Downar explains. “After being out of the field for a while, I came back to find that neuroscience is finally starting to speak the language of psychiatry… but again, how do we translate it?” According to Downar, brain stimulation with new technological devices is an answer that holds great promise. In January of this year, Downar and his colleagues opened Toronto’s first transcranial magnetic stimulation (TMS) clinic for psychiatry. “I think this has become my translational niche,” Downar suggests. He plans to combine neuroimaging studies with TMS to identify new, highly focal targets for the treatment of psychiatric disorders. “The pay-off could be huge; treatment-resistant depression affects over 100,000 people in Toronto alone.” In addition to Downar’s clinical research goals, he has been involved in separate efforts to enhance the impact of scientific research. “The other narrow pipeline is not from science into medicine, but from science into the public consciousness,” he explains. Given his backgrounds in both literary writing and science, Downar was offered an opportunity, as a medical student, to serve as scientific consultant and screenwriter for the IMAX film Wired to Win, which documented the mental willpower of Tour de France bicycle racers. He used the opportunity to branch out of the scientific community and teach the general public what we know from neuroscience about the human pursuit of abstract goals. Downar is also currently working on a number of writing projects that he hopes will gain influence beyond the scientific and medical communities. These projects include a fiction book of short stories, a popular science book, and a neuroscience textbook for nonneuroscientists. In his time back in Toronto, Downar has been very impressed with the caliber of the current IMS students he has encountered. He hopes to see others become “interneuron” translators who help build pipelines between science and medicine; and between science and the public domain. “We don’t know what our impact is going to be at the end of the day, but I suspect that doing this translational work will have a bigger impact on the world.”
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 36
STUDENT LIFE
StreSSeS
A view from the IMS Administrative Office
M
any students experience multiple stresses during their graduate training, which can be tempered by graduate administrators who understand academic, research and financial issues, are trained in conflict resolution, and are equipped to address personal and family problems. The personnel of the IMS administrative office pride themselves in being good at problem solving. This article provides an overview of some of the more common student stresses we have encountered. In describing common issues, we hope to reduce the general reluctance to discuss problems and, thereby, find solutions. This outline should also be informative for graduate supervisors, many of whom may not fully appreciate the stresses their students face.
Finances
Finances are the prime source of stress. Stu37 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
dent fees continue to rise and living expenses spiral upwards while limitations are placed on student income by university regulations, fellowship requirements, ceilings on supervisors’ grants, or legal obstacles to employment for foreign students. Many students live on stipends that barely cover their costs, especially when they live independently or have a family to support. Single mothers or students with personal or family health problems are at particular risk. Students are often unaware of bursaries and financial awards they can apply for or sources of emergency funding available at the university. School fees can be deferred and budget consultants are available. Reasonably priced housing exists, as do apartment-sharing opportunities. Teaching assistant placements or other sources of part-time funding can often be arranged. However, it is essential that the time required for teaching, clinical or other part time work does not hinder the comple-
tion of the degree. The trick is to find the right balance. Financial problems and lack of resources sometimes impede the student’s ability to carry out research. This may include lack of laboratory resources (equipment, reagents, travel funds) or physical space to conduct experiments, no desk space or no computers. Such issues need to be discussed with supervisors, ideally before the start of graduate training. A graduate coordinator can help if the issues cannot be rectified within the lab. Students with disability may be able to access some of the equipment they require through disability services. Though not explicitly stated, students are expected to find external funding over the course of their graduate training. Much time and effort is needed for this, and it may be harder in some fields of study than in others. Obtaining grants is excellent for the student’s CV and provides good and necessary experience and preparation for the scientific life.
Deadlines
The pressure of deadlines is high, especially in the first year of the MSc or PhD program. There are numerous deadlines to meet – scholarship applications, coursework, ethics
Photo by Connie Sun
Graduate student
STUDENT LIFE reviews, supervisor and committee meetings, and abstract and paper submissions. There are also deadlines for various administrative issues, such as leave of absence, achievement of candidacy, and submission and defense of the thesis or transition from MSc to PhD. The pressure of deadlines weighs heavily on students. The graduate office knows where all regulations and dates can be found and can often help.
Complexity of Research Project
MSc students plan to complete their degrees in two years, which speed by very quickly. Again, with the pressure of coursework, literature reviews, new laboratory techniques, ethics submissions, subject recruitment, and meetings with the supervisory committee, there is little time to complete a research project, write a thesis, and prepare for a defense. Thus, the project for a MSc student needs to be simple and straightforward. If poorly chosen, the stress for the student is overwhelming. Some students who have excelled in their MSc work opt to transfer to the PhD program, which gives them more time. For many students, however, this is not an option. PhD students, because they have more time and are increasingly ambitious and autonomous, frequently choose complicated projects that may not always work out. Some laboratories may not want to settle for runof-the-mill projects or publish unless in Nature or Science, a strategy that can sometimes result in little to show for years of work. The graduate office can provide guidance and help with timelines and practical considerations.
Conflicts
Difficulties in personal relationships can occur in all environments, but are perhaps most common in competitive situations such as graduate school. Authorship issues, for example, are infamous for giving rise to conflicts.
Supervisor/Student Relationship
The heart of a successful graduate experience is the quality of the relationship between student and supervisor. Roughly 5% of students report difficulties in this relationship. Ideally, supervisors provide ideas that help determine the research topic and guide the student to the appropriate methodology. They
open the door to resources, equipment and expertise. They suggest a timetable for thesis completion, give prompt feedback on progress, identify critical paths for data collection, and, most importantly, make themselves available to the student. Ideal supervisors provide helpful criticism of research design, grant proposals, presentations, draft papers, draft thesis chapters, and they help with data interpretation. Good supervisors also check the student’s progress regularly, provide timely and systematic feedback and help the student plan an appropriate work schedule.
versity offers for help with English.
The ideal supervisor must also appreciate that different students learn in different ways, so teaching methods must be flexible. Students want autonomy on one hand and guidance on the other, an understandable ambivalence that needs to be resolved.
Harassment
Committee Structure
The program advisory committee (PAC) consists of the supervisor plus two other faculty members. The student and the supervisor select the members together, with the supervisor providing most of the input, although the student retains the right to change committee members. We recommend a variety of inputs for the committee e.g. a basic scientist, a clinician, an epidemiologist or a sociologist, an ethicist, a statistician, (depending on the topic). At the IMS, students meet with their PAC every 6 months. The meetings are usually relatively formal, i.e., slide presentation, questioning, written evaluation of progress, and minutes, as this is good preparation for the final defense. For some students, these meetings are extremely stressful and fearprovoking. Sometimes, out of fear, students delay the meetings indefinitely. Talking it over first with the Graduate Coordinators should desensitize students and ensure timely and useful meetings.
Learning/Teaching Styles
Some students learn best by trial and error, some by reading and re-reading, some by questioning, some by watching and imitating. A good fit between learning and teaching styles is important, but not always possible to achieve. For many students, especially those for whom English is not a first language, writing is a stumbling block. The graduate office can help direct students to the resources the uni-
Graduate students are diverse not only with respect to race, gender, economic class and nationality, but also with respect to age, employment status, number of dependents, and physical and emotional handicaps. There are diverse personal circumstances, backgrounds, and different ways of learning. As a consequence, students require different supervisory styles, ranging from paternalistic to “hands off.” The graduate office can help ensure that such diverse needs are better met.
Workplace harassment does occur and is taken seriously by the University. It includes more than sexual harassment – it is all behaviour that is bullying, offensive, unwelcome, unsolicited, repeated, intimidating, humiliating, or threatening. The University has a special office that deals with harassment and the graduate office is knowledgeable about internal grievance procedures and protocols. Students are often uncertain whether they are being oversensitive in such circumstances. Graduate coordinators can help students make sense of what they are experiencing.
Mental Health
As a result of stress and personal vulnerability, students may suffer from a variety of mental health problems during their graduate training. They can become despondent over not meeting their own or others’ standards, over their perceived burden of responsibilities, over feelings of incompetence and anxiety. They may develop somatic and emotional symptoms and run into trouble with relationships. This can manifest as “bad” behaviour (e.g., coming late, missing days in the lab, failing courses, missing deadlines). Emotional stress can, albeit rarely, lead to ethical misconduct such as plagiarism, misrepresentation, and fraud. The graduate office is an efficient triage centre to refer students to appropriate counseling and treatment. Students and supervisors are encouraged to respond to this article in person or in writing so that the Graduate Office can develop a better sense of the stresses they undergo and find ways to buffer and reverse them. Special thank you to all the graduate coordinators for their expert advice on dealing with graduate stresses.
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 38
MODULE HIGHLIGHT
Protein Mass Spectrometry: An Inside Look
The module, newly introduced this year, is organized by Dr. Thomas Kislinger, a professor in the Department of Medical Biophysics and a researcher within the Ontario Cancer Institute. Kislinger, an expert in mass spectrometry proteomics, currently conducts translational research to investigate cancer biomarkers and to model pathological processes that occur within the human heart and cardiovascular system. As he explains, this new module is an excellent opportunity for students to gain unique exposure to the fields of proteomics and mass spectrometry. “The goal of the Protein Mass Spectrometry module at the IMS is to provide graduate students with first-hand insight into all aspects of modern bio-molecular mass spectrometry,” says Kislinger. “This module should provide students with a perspective of how mass spectrometry could potentially affect their own research and also of how to interpret the current literature on proteomics and
39 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
mass spectrometry.”
learn and apply novel ideas are essential.”
The module consists of five two-hour sessions. For the first hour of each session, experts in different areas within mass spectrometry will deliver lectures, giving a broad overview of all major concepts within the field. These concepts will include the use of proteomics in neurobiology, systems biology and cancer, the use of mass spectrometry within the area of post-translational modification and the applications of mass spectrometry to protein folding. The second hour of each session will be devoted to 10-minute student presentations on the fundamentals of mass spectrometry, as well as to student-led discussions on manuscripts from the fields of mass spectrometry and proteomics that are relevant to each student’s own area of research.
Kislinger also notes that an understanding of the basic concepts of proteomics and mass spectrometry could prove useful within a wide variety of research milieus beyond analytical chemistry and protein biochemistry, including bioinformatics, translational medicine and more.
Now, fields as complex and technically-demanding as proteomics and mass spectrometry may seem daunting to some, and perhaps even wholly-inaccessible to others. But, as Kislinger emphasizes, the development of a few basic skills and attributes will go a long way for the budding proteomics researcher: “The most important advice for any student interested in proteomics would be to develop a solid foundation in basic concepts of analytical chemistry and protein biochemistry. This will help tremendously when first entering this field. Secondly, the ability to collaborate and communicate with investigators from different research areas will be very important. Finally, the curiosity and interest to
Those interested in the Protein Mass Spectrometry module should contact the IMS office for registration details. By Joe Gabriel
Protein Mass Spectrometry Facilitators Dr. Thomas Kislinger Scientist, Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, Department of Medical Biophysics. Dr. Gerold Schmitt-Ulms Assistant Professor, Tanz Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology. Objectives This course will provide a broad introduction into protein mass spectrometry, with a strong focus on translational research. Basics of mass spectrometry will be covered at the beginning of the course. Applications of mass spectrometry to disease relevant questions (i.e. biomarker research, post-translational modifications, protein-protein interactions, etc.) will be covered in the following modules. Following an introductory lecture, sessions will be divided into two parts: a 1-hour lecture and a 1-hour student-led presentation of a manuscript. Students will also elaborate on one technical aspect of mass spectrometry (i.e. Ionization, mass analyzer, scan modes, spectra interpretation, quantitation). The 1-hour lecture will be held by five different investigators and will deal with different aspects of biological mass spectrometry, emphasizing possible medical applications or translational aspects.
Photo by Mohammed Sabri
A
s a researcher, one should always strive for self-improvement. Luckily, grad student life brims with opportunities to help you expand your expertise across a number of fields. Want to improve your public speaking skills? Try sitting in on a few debates. Could your backhand drop shot need some work? Hit the squash courts at Hart House. Looking to gain an intimate understanding of how to quantify the post-translational ubiquination of your favorite proteins? Then the IMS Protein Mass Spectrometry module is for you.
Experts
Ask the
Dear Experts, When I first started my Master’s program, my supervisor would ask me to complete small tasks that were not related to my research. These tasks did not take much time, and I thought nothing of it. As time progressed, however, she continued to pile on more and more work. It is now at the point that the extra work is preventing me from focusing on my own research project. Please help me! - Overwhelmed Dear O., As you may be aware, the best first step is to speak with a graduate coordinator. The advice will probably be to discuss the matter tactfully with your supervisor and perhaps with your PAC. You may also want to refer to student-supervisor agreement (on-line). Dear Experts, I am currently enrolled in my Master’s program. I really love research, however, I also would like to pursue medical school. I have applied for medical school but have not yet heard whether or not I have been accepted. If I do not get accepted, I am keen to pursue a PhD. What should I do? - Waiting Nervously Dear W.N., Assuming you are in the final year of your MSc, you must plan to have a completed thesis by the end of June in order to begin medical school in September. So you need to complete your experiments, finish your course work, write your thesis, hold your final PAC, organize your exam committee and submit all the paperwork to the IMS by mid May. Since you do not know whether you will be accepted at a medical school and will not know until the beginning of May, you may also want to organize a transfer exam if you are still within the transfer-eligible time period. Discuss this with your supervisor. Al-
ternatively, before the end of March, you can apply for a PhD to begin in September. This gives you the option of changing supervisor and changing your project but still continuing in research should you not be accepted to medical school. Dear Experts, I am in my third year of undergraduate studies majoring in Human Biology at the University of Toronto. I do not have any research experience, but I am considering graduate school. Is there anything I can do to gain some more research experience? - Planning for Future Dear P.F., Check out the summer research opportunities (i.e. IMS SURP). Volunteering in a lab is another great way to gain some experience. Many universities offer 4th year thesis-based courses that allow you to spend some time in the lab environment. Don’t be shy in contacting potential supervisors about positions. Good luck! Dear Experts, I am an Assistant Professor at the IMS. Am I eligible to supervise a graduate student? - Eligibility Issues Dear E.I., Your professorial status is not relevant to the supervision of graduate students; it is your status within the School of Graduate Studies that matters. If you have an Associate Membership in the IMS, you can supervise Master’s students. If you have a Full Membership, you can supervise PhD students. If you have a restricted membership, depending on the terms, you probably cannot supervise students at all. If you are an Associate Member and are planning to apply for Full Membership, it is suggested you get involved with the department (i.e. join PAC committees, chair exams, judge at IMS Scientific Day, etc.)
Dear Experts, I’m a new graduate student at the IMS; do I need to provide a report prior to my PAC meetings? - All PAC’d Out Dear A.P.O., Discuss this with your supervisor. It is a good idea to make your PAC meetings relatively formal. Prepare handouts, prepare a 20 minute slide show, be ready to answer questions on what you have read, what you have accomplished, what courses you are taking, and what your next steps will be. To get the most out of your PAC committee meetings, keep progress notes and record all suggestions.
EXPERT TIP Being prepared is the key to future success. Do you have a question for the experts? Please send it to theimsmagazine@gmail.com (ATTN: Experts).
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 40
PAST EVENTS
Special thanks to sponsors of the party: Sarstedt Inc., DiaMed, RAININ, Wisent, IDT, the Integrative Health Institute, Sette Jewellery, Missbehave Boutique, Creative Touch.
Photos by Paulina Rzeczkowska
Fellow IMS students enjoy IMS’ Annual holiday party.
Photos courtesy of IMSSA
PAST EVENTS
IMS students take in the exciting Toronto Maple Leafs game at the Air Canada Centre on February 1.
IMSSA hosts an enjoyable pub night.
41 | IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS
DIVERSIONS
SUDOKU 2
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you know it’s your
LUCKY DAY
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when...
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• You arrive at a lab meeting late, but no one has arrived yet • You start an experiment and have just enough buffer to
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• You pour the exact amount of compound onto the scale • You receive an extension on an article or grant you are
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• Your noon meeting includes a free lunch • Your abstract is accepted to a conference in Hawaii, travel
complete it
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IT’S YOUR LUCKY DAY
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struggling to complete
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• You get to the bus stop just as the bus arrives • You find a coupon for a free coffee in the newspaper • Your grant application is approved for funding • All of the patients you approach consent to be in your study Please visit http://www.surveymonkey.com/s/BW2NRZ8 to vote for your favourite scenario. Look out for the poll results in the next edition!
contest
Have an It’s your lucky day scenario of your own? Send it to theimsmagazine@gmail.com (ATTN: LUCKY DAY CONTEST) by June 1st. The best scenario will be published in the next edition along with your name & photo!
“Piled Higher and Deeper” by Jorge Cham http://www.phdcomics.com
IMS MAGAZINE SPRING 2011 MULTIPLE SCLEROSIS | 42
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