IMS Magazine Spring 2012

IMSMAGAZINE THINK, LEARN, DISCOVER.

SPRING

2012

THE HISTORY OF THE IMS

Looking back at the evolution of our institute

SNEAK PEEK: IMS SCIENTIFIC DAY

Up close and personal with Dr. Thomas Insel, this year’s keynote speaker

DOUBLE DOCTORS = DOUBLE TROUBLE? Are physician-scientists spreading themselves too thin?

STEM CELLS IN REGENERATIVE MEDICINE Student-Led Initiative

Zebrafish Chemical Biology & Pharmacogenomics Lectures (free attendance) • Dr. Randall Peterson, Harvard Medical School The chemical biology of the brain and behavior • Dr. Stephen Renshaw, University of Sheffield, UK Neutrophil biology and the development of zebrafish screens to identify novel anti-inflammation drugs • Dr. Calum MacRae, Harvard Medical School Genetic basis of common cardiovascular disease and disease-specific modifier screens • Dr. Robert Tanguay, Oregon State University Automated approaches to support rapid throughput regeneration and toxicity testing 8:45am - 12:10pm, June 15, 2012 LKSKI Auditorium St. Michael s Hospital 209 Victoria Street, Toronto Hosted by:

Xiao-Yan Wen, MD, PhD Director, Zebrafish Centre for Advanced Drug discovery Li Ka Shing Knowledge Institute St. Michael s Hospital & Department of Medicine, University of Toronto

Sponsors of the workshop

TABLE OF CONTENTS

IN THIS ISSUE...

Commentary ....................................03 Letter from the Editor ......................06 News at a Glance ...........................07 Director’s Message .........................10 Scientific Day Preview.....................11 Feature.............................................13 Spotlight ..........................................24 Expert Opinion .................................25 Book Reviews ..................................27 Close Up ..........................................29 Viewpoint ........................................31 Behind the Scenes...........................33 The History of the IMS.....................35 Research Highlight...........................39 Ask the Experts................................40 Past Events ......................................41 Diversions .......................................42

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FEATURE

Stem Cells in Regenerative Medicine

World-renowned scientists discuss exciting clinical applications of stem cell research while urging for additional work to ensure patient safety.

Cover Image by Merry Wang, Book Reviews image courtesy of http://www.sxc.hu/photo/1358287. Expert Opinion Photo by Laura Feldcamp

MAGAZINE STAFF Editor-in-Chief Natalie Venier Managing Editor Nina Bahl Assistant Managing Editors Tetyana Pekar Jennifer Rilstone Allison Rosen Adam Santoro Departmental Advisor Kamila Lear Design Editors Tobi Lam Andreea Margineanu Merry Wang Minyan Wang Jr. Design Editors Melissa Cory, Laura Greenlee, Michael Soong, Inessa Stanishevskaya, Andrea Zariwny Advertising Manager Corinne Daly Magazine Committee Salvador Alcaire S. Amanda Ali Rickvinder Besla Danielle Desouza Melanie Guenette Aaron Kucyi Rosa Marticorena Laura Seohyun Park Brittany Rosenbloom Zeynep Yilmaz Photography Yekta Dowlati Brett Jones Laura Feldcamp Paulina Rzeczkowska Mohammed Sabri Copyright Š 2012 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.

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

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Book Reviews: Bridging the Global Health Gap

Exclusive interview with global health advocates, Dr. Abdallah Daar and Dr. Peter Singer, authors of The Grandest Challenge.

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Expert Opinion: Subclinical Blast Exposure Dr. Andrew Baker and Dr. Eugene Park explore the neurological significance of subclinical blast exposure and its particular significance for the military.

Cover Art

By Merry Wang An interpretive visualization of mesenchymal stem cells in a fluid environment. These cells have a tremendous role in bone and cartilage repair in regenerative medicine.

IMS MAGAZINE SPRING 2012 STEM CELLS | 02

COMMENTARY

Commentary A Reconcilable Conflict A commentary on “An Irreconcilable Conflict” (Winter 2012)

By Benjamin Mora, MSc candidate A viewpoint concocted and popularized by secular thinkers at the end of the nineteenth century was that science and religion are in inevitable conflict with one another; that there exists a sort of “warfare” between the two, in the words of Andrew D. White, 1986.

Although this idea of warfare between science and religion remains widespread and popular, recent writings from historians and philosophers of science on the subject have undermined this concept of inevitable conflict. Far from an irreconcilable conflict between the two, over the last fifty years, there has existed a flourishing dialogue and alliance between science and religion1. Since the 1960’s, science and religion has been studied as an academic discipline. In 1966, the first specialist journal was founded in Chicago, Zygon: Journal of Religion and Science. In the same year, the textbook Issues in Science and Religion by the British physicist and theologian Ian Barbour was published.

Since then, numerous societies have arisen to promote this dialogue, including the European Society for the Study of Science and Theology, the Science and Religion Forum, the Berkeley Center for Theology and Natural Science, and so on. There are even established academic posts devoted specifically to the study of science and religion at both Oxford and Cambridge2.

The thriving conversation over recent years between science and religion in academic journals and institutions should suggest to us that not all scientists who are religious are not genuine scientists, or have not sat down to think hard about the compatibility between the two. Indeed, there are top-ranking, practicing scientists who actively promote and discuss the interaction and synergy between their religious beliefs and science, including Francis Collins, noted for his leadership of the Human Genome Project3; John Polking03 | IMS MAGAZINE SPRING 2012 STEM CELLS

horne, theoretical physicist and theologian at Cambridge4; and John Lennox, professor of mathematics and science and religion at Oxford5, just to name but a few. Surely these individuals, and scientists of a similar mindset, have thought very carefully about the relationship between science and religion, and failed to arrive at the conclusion of irreconcilable conflict and warfare. To underscore how science and religion can possibly harmoniously coexist, it would be worthwhile to briefly discuss the limits of science, potential models for integration between science and theology, and lastly, some philosophy of science.

Ever since the dawning of the scientific revolution, there have been scientists who have believed that science is the only paradigm of truth and rationality, and that if something does not line up with currently established scientific beliefs, if it is not within the domain of entities appropriate for scientific investigation, or if it is not amenable to scientific methodology, then it is not true or rational. This method of thinking has been termed scientism, according to which, everything outside of science is a matter of mere belief and subjective opinion. What is striking though is that the (hypothetical) proposition that: some proposition or theory is true and rational to believe if and only if it is a scientific proposition or theory, is itself not a proposition of science, but a second-order proposition of philosophy about science, and is thus a self-refuting and nonsensical statement. One must realize that a self-refuting proposition (e.g. there are no truths) is not such that it happens to be false but could have been true, but rather is necessarily false, and it is impossible for it to be true. Furthermore, it can be easy to overlook the fact that science itself presupposes a number of non-scientific, substantive philosophical theses, which must be assumed if science is ever even to begin in the first place6. The conclusions of science cannot be more certain than the presuppositions they rest on. Some of the philosophical presuppositions of science include: the existence of a theory-independent, exter-

nal world; the orderly nature of the external world; the knowability of the external world; the existence of truth; the laws of logic; the reliability of our cognitive and sensory faculties to serve as truth gatherers and as a source of justified beliefs in our intellectual environment; the adequacy of language to describe the world; the existence of values used in science (e.g. testing theories fairly and reporting results honestly); the uniformity of nature and induction; and the existence of numbers.

Much more can be said here, but the point is there are legitimate domains of knowledge that must exist outside and independent of science. Without providing any reasons for thinking so, it can at least be said that it is possible that one such domain of knowledge that exists outside of science includes theology. But how exactly could science and religion understand and relate to one another?

A number of possible models exist for integrating science and theology: 1) they focus on two distinct, non-overlapping areas of investigation; 2) they involve two different, complementary approaches to and descriptions of the same reality from different perspectives; 3) science can fill out details in theology or help to apply theological principles and vice versa; 4) theology provides the metaphysical and epistemological foundation for science by justifying or, at least, helping to justify the necessary presuppositions of science; 5) science provides the boundaries within which theology must work; and 6) science and theology involve descriptions that can directly interact with each other in mutually reinforcing or competing ways7.

Evaluation of these models cannot here be

COMMENTARY philosophical naturalism, and the two should not be confused. In the case of miracles, if one has good, rational reasons to believe that God(s) exist outside of the natural world, there is no reason why presuppositions of methodological naturalism should exclude the possibility of supernatural intervention into the natural order.

The flourishing dialogue between science and religion in recent years is testimony to the fact that, far from being irreconcilably conflicted, these two domains of human knowledge can fruitfully interact. Let us not stifle free inquiry and thoughtful exploration, but encourage it.

The Creation of Adam by Michelangelo, c. 1511

discussed, but they are simply mentioned to highlight the numerous possibilities for interaction and integration.

Lastly, it would be important to say a word about science, methodology and the supernatural. The goal of natural science is to explain contingent natural phenomena strictly in terms of other contingent natural phenomena. Scientific explanations should refer only to natural objects and events and not to the personal choices and actions of human and divine agents. In science, we should adopt methodological naturalism, according to which answers to questions are sought within nature, within the contingent created order. Philosophical naturalism, on the other hand, is the philosophical doctrine that the natural world is all there is and that God, angels and the like do not exist. Science presupposes methodological naturalism but not

Disclaimer: The opinions expressed by the author are in no way affiliated with the Institute of Medical Science or the University of Toronto. Comments are welcome at theimsmagazine@gmail. com.

References 1. Kurtz, Paul, Barry Karr and Ranjit Sandhu. Science and Religion: Are They Compatible? Amherst: Prometheus Books, 2003.

2. Dixon, Thomas. Science and Religion: A Very Short Introduction. New York: Oxford University Press, 2008.

3. Collins, Francis S. The Language of God: A Scientist Presents Evidence For Belief. Simon and Schuster, 2007.

4. Polkinghorne, John. Science and Religion in Quest of Truth.

Yale University Press, 2011.

5. Lennox, John C. God’s Undertaker: Has Science Buried God? England: Lion, 2009.

6. Medawar, P B. The Limits of Science. New York: Harper & Row, 1984.

7. Moreland, J P and William Lane Craig. Philosophical Foundations for a Christian Worldview. Downers Grove: IVP Academic, 2003.

Dear Editor, Sincere congratulations to you and your staff for a great Winter 2012 issue of the IMS Magazine. The concentration on sports injuries provided your readers with very useful information about concussions in sports.

Research shows that there is insufficient knowledge about concussions among health care professionals including medical doctors, nurses and therapists, and so the magazine issue is doing important public health work.

Indeed, the public health aspect of concussion was the topic of the thoughtful article written by Adam Santoro and Sherene Chinfatt. These authors and your readers will be interested to know that on March 6, 2012, the government of Ontario introduced concussion legislation, the first government in our country to do so. The new legislation covers all Ontario elementary and high schools and mandates concussion education for students, teachers, and parents. It also legislates improved concussion management for these kids and youths. The government has wisely heeded the opinion of Adam and Sherene who wrote that “the impact of sports related concussions is too profound and pervasive to ignore.”

Yours sincerely, Charles Tator CM, MD, PhD, FRCSC Professor of Neurosurgery, University of Toronto

What to look for next issue: A brief look into Med 2.0 and its impact on the field of medicine. Applications, services, and tools are examined in the growing approach to the health field.

Contact Us

Photo by Connie Sun

We really appreciate all of the encouraging comments and messages we have received since the release of the IMS Magazine’s inaugural issue. We encourage our readers to send their feedback -- comments, questions, corrections, or letters to the editor -- to theimsmagazine@gmail.com www.facebook.com/groups/imsmagazine/ @IMSMagazine

IMS MAGAZINE SPRING 2012 STEM CELLS | 04

NEWS AT A GLANCE

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LETTER FROM THE EDITOR

O

Letter from the Editor

ne of the most fascinating things about scientific research is its unpredictable nature. Though this capricious aspect of science, admittedly, often generates a great deal of frustration for the struggling graduate student, it offers an opportunity to generate an entirely new set of, potentially, thought-provoking research questions. One of my favourite examples of such unpredictability is when a hematologist and biophysicist were studying the effects of injecting bone marrow cells into irradiated mice; they noticed the development of visible nodules in their spleens in direct proportion to the number of bone marrow cells they had injected. They referred to these nodules as ‘spleen colonies’, and speculated that each nodule arose from a single marrow cell—perhaps a stem cell. These curious scientists were Dr. James Till and Dr. Ernest (Bun) McCulloch, the founding fathers of stem cell research—and integral members of the Institute of Medical Science.

Nearly half a century later, the world of stem cell research has grown immensely. The applications of stem cells are studied in a number of disease processes—from retinal degeneration and cardiovascular disease, to diabetes and cancer. In this issue of the IMS Magazine, we take you on a journey through the labs of several world-renowned researchers studying clinical applications of stem cells in regenerative medicine here at the IMS. Through this collection of articles, I hope you can appreciate the path that has been paved by stem cells’ founding fathers, and the exciting possibilities arising from this area of research.

In addition to our outstanding feature, I strongly encourage every member of the IMS to read through the captivating “History of the IMS” article. With the help of our former directors, Salvador Alcaire and Tetyana Pekar have pieced together the evolution of our institute. Definitely a fascinating read—especially as we are in the midst of the IMS’ Strategic Planning. I also highly recommend reading our exclusive interview with this year’s IMS Scientific Day Speaker, Dr. Thomas Insel, the Director of the National Institute of Mental Health in the USA.

Natalie Venier

Editor-In-Chief Natalie Venier is a third year PhD Candidate at the Institute of Medical Science.

She is currently studying prostate cancer chemoprevention at Sunnybrook Health Sciences Centre.

In summary, I would like to thank Dr. Allan Kaplan and the IMS department for their on-going support, and the incredibly talented and creative IMS Magazine Team, whose contributions are invaluable to the IMS Magazine. I would like to send a special thank you to our Managing Editor, Nina Bahl, whose dedication and efforts have been integral to our production. Lastly, I encourage comments and feedback, as we continue to aspire to bring you the best of the IMS.

Photo by Paulina Rzeczkowska

Enjoy!

Natalie Venier Editor-In-Chief, IMS Magazine IMS MAGAZINE SPRING 2012 STEM CELLS | 06

NEWS AT A GLANCE

NEWS&VIEWS APRIL 13 TBA TBA 26

IMS ANNOUNCEMENTS IMS Scientific Day – Mark your Calendars!

Casino Night IMSSA hosts Toronto Blue Jays Outing IMSSA Site Specific Events Career Development Series

10/24

TBA

All IMS students are expected to attend IMS Scientific Day. 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.

The Institute of Medical Science is extremely pleased to announce a few changes in the IMS Office.

IMS Scientific Day Career Development Series IMSSA Spring Apartment Crawl

JUNE 15

This year’s IMS Scientific Day will be held on Tuesday, May 15, 2012. It will feature Bernard Langer keynote lecturer Dr. Thomas R. Insel, Director of the National Institute of Mental Health (NIMH).

IMS Office Staff

MAY 15

at a glance...

Career Development Series: Scientific Writing

Feedback: Please send your comments and suggestions to: theimsmagazine@gmail.com For information on IMS news and events, please see: http://www.ims.utoronto.ca For more information on IMSSA/IMSSA-related events, please visit: http://imssa.sa.utoronto.ca

Kaki Narh Blackwood has accepted the position of Student and Faculty Affairs Coordinator at the IMS. Kaki will be responsible for the administration of awards, faculty appointments, and courses. She can be reached at sf.medscience@utoronto.ca and by telephone at 416946-7143.

Marika Galadza has accepted the position of Program Assistant at the IMS. Marika will be responsible for the administration of student defense examinations and monitor student progress. She can be reached at pa.medscience@utoronto.ca and by telephone at 416978-6696.

We congratulate both Kaki and Marika on their well-deserved promotions and wish them every success in their new positions.

Recruitment efforts are underway to hire a replacement for the Departmental Assistant position. In the interim, the IMS hired Cassandra Wysochanskyj to temporarily assume the role of Departmental Assistant. Cassandra will be responsible for the reception area, general inquiries, Summer Undergraduate Research Program, room bookings, and provide general administrative support. She can be reached at dir.medscience@utoronto.ca and by telephone at 416-946-8286.

We would like to take this opportunity to thank Samara Carter for doing an excellent job of filling in as the Program Assistant and we wish her all the best in her future plans.

IMSSA ANNOUNCEMENTS The IMS Career Seminar Series is designed to provide graduate students with the opportunity to meet representatives from scientificrelated careers. Please RSVP (imssacareers@gmail.com) for our upcoming seminars: • Careers in Global Health/Health Policy – April 26th, 5-7pm, MaRS 4-204 • The Path to Clinical Trial Management – May 10th, 12-2pm, MaRS 4-904 • A Career in Medicine/Research – May 24th, 12-2pm, PMH 7-605 IMSSA will be leading a Teaching Assistantship Workshop on June 6th. This workshop will help you learn hands-on skills about university teaching, how to start a teaching dossier, and how to gain university teaching experience. Please e-mail us (leanne. desouza@alumni.utoronto.ca) for further details!

GOT TALENT? IMSSA is gearing up for our Annual Talent Show Fundraiser to be held this summer—come out and show off your talents for a great cause! Past acts have featured piano playing, bollywood dancing, rapping, juggling, and more! Please contact us (melanie.guenette@alumni.utoronto.ca) to inquire about performing.

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AWARDS & SCHOLARSHIPS LAIDLAW MANUSCRIPT COMPETITION Top rated students were asked to submit manuscripts for the Laidlaw competition. The following finalists were selected to give an oral presentation at IMS Scientific Day: • Ann Montgomery will present her talk on the Factor Associated with Physician Agreement and Coding Choices.

• Brian Ballios will present his talk on the Directed-differentiation of Photoreceptors from Adult Retinal Stem Cells.

• Christopher Tran will present his talk on A Family-based Association Analysis, Systematic Review and Meta-analysis of the Reading Disabilities Candidate Gen DYX1C1.

• Marko Skrtic will ˇ ´ present his talk on the Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Human Acute Myeloid Leukemia.

• Nabilah Chowdhury will present her talk on the Melanocortin-4 Receptor Gene Polymorphisms are Associated with Increased Risk of Antipsychotic Induced Weight Gain.

• Nadia Sachewsky will present her talk on the Identification and Characterization of a Novel Primitive Neural Stem Cell in the Adult Brain.

ALAN WU POSTER COMPETITION The Alan Wu Poster Prizes are presented to the most outstanding basic science and clinical science abstracts and poster presentations. An IMS Academic Development Award, valued at $500, will be 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 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. The IMS is pleased to announce that Dr. Gary Remington has been selected to receive the 2012 award.

SIMINOVITCH-SALTER AWARD The Siminovitch-Salter Award is awarded annually to a graduating IMS doctoral student who has made outstanding scholarly contributions. IMS PhD graduate, Dominique McMahon has been selected for the 2012 award. Dominique will present a lecture at IMS Scientific Day at 2:30 p.m. in the Macleod Auditorium, Medical Sciences Building.

WHITESIDE AWARD The Whiteside Award is awarded annually to a graduating IMS Master of Science student who has made outstanding scholarly contributions. IMS MSc graduate, David MacLean, has been selected for this year’s Whiteside Award. The award will be presented at IMS Scientific Day. RONCARI BOOK PRIZE The Roncari Book Prize is presented to an IMS student who has made significant contributions to the academic experience of graduate students. The IMS is very pleased to announce that MSc student, Ilyse Darwish, has been selected to receive the 2012 award.

SARA AL-BADER MEMORIAL AWARD The Sara Al-Bader Memorial Award was established by the Institute of Medical Science to honour the memory of Sara Al-Bader, an IMS PhD student whose thesis was entitled: ScienceBased Health Innovation in Sub-Saharan Africa. The award will be presented annually at Scientific Day to an international doctoral stream student who shows exceptional academic promise. We are pleased to announce that PhD student, Phan Sok, has been selected to receive the 2012 award.

GRADUATE COURSE DIRECTOR AWARD The Graduate Course Director Award recognizes excellence in the management of an IMS graduate course. The IMS is pleased to announce that Dr. Jonathan Hellmann has been selected to receive the 2012 award for his leadership in the MSC3002H – Foundations Seminar II course.

GRADUATE COURSE LECTURER AWARD The Graduate Course Lecturer Award is presented annually for a sustained contribution of three years or more to excellence in lecturing in an IMS graduate course. The IMS is pleased to announce that Dr. Lili-Naz Hazrati has been selected to receive the 2012 award for her leadership in the MSC1006H - Introduction to Anatomical Organization of the Brain.

NEWS AT A GLANCE

New Faculty Members Isabelle Caniggia Professor of Obstetrics & Gynecology, Mount Sinai Hospital Yaping Jin Assistant Professor of Ophthalmology and VisionSciences,DallaLanaSchoolofPublic Health Paul Nathan Associate Professor of Pediatrics, Hospital for Sick Children David Gladstone Assistant Professor of Medicine, Sunnybrook Health Science Centre Richard Swartz Assistant Professor of Medicine, Sunnybrook Health Science Centre Robert Wu Assistant Professor of Medicine, Toronto General Hospital Yana Yunusova Assistant Professor of Speech Language Pathology, Sunnybrook Health Science Centre Find out more about faculty on the IMS faculty database at http://www.ims.utoronto.ca/ faculty/directory.htm.

EUREKA INSTITUTE FOR TRANSLATIONAL MEDICINE The IMS has recently joined the Eureka Institute for Translational Medicine. As part of the membership, the IMS is entitled to award two students with a free registration to the International Certificate Program in Translational Medicine. This intensive 7-day program—which brings together world-class faculty and students—will be held this year in Siracusa, Italy from May 6 – May 12, 2012.

The IMS Executive Committee has nominated two exceptional trainees for the Certificate Program in Translational Medicine: PhD students David Piccin and Jeff Wilson. As part of the acceptance of this award, both students will deliver a formal presentation at the Ori Rotstein Lectureship in Translational Research Day in the fall of 2012.

For information about the certificate program, please access the following link: http://www. eurekainstitute.org/index. php/certificate-program.

IMS MAGAZINE SPRING 2012 STEM CELLS | 08

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DIRECTOR’S MESSAGE

Director’s Message This, the sixth issue of the IMS Magazine, focuses on the burgeoning area of regenerative medicine, with articles by several IMS faculty and students on their important research in this area. There are also two especially noteworthy pieces in this issue—one discusses the history of the IMS, and the second is an interview with Dr. Thomas Insel, the Director of the National Institute of Mental Health, who is the upcoming IMS Scientific Day Plenary Speaker. As noted in my previous message, IMS Scientific Day will take place on Tuesday, May 15, 2012 at the McLeod Auditorium.

The theme of this Scientific Day will be Translational Research; it is fitting that Dr. Insel, a worldrenowned translational neuroscientist, will be delivering the Plenary Address. The title of his talk is “Lost in Translation: Opportunities and Challenges for Translating Scientific Discoveries into Better Health.” Please make sure to mark this day off your calendars.

In terms of IMS news, the Annual IMS Open House was held on Saturday, February 18, 2012 and was extraordinarily successful. There were 92 students from across Ontario who attended, along with close to 20 faculty members. Congratulations to Zeynep Yilmaz, the Committee, as well as Hazel Pollard for a job well done. In addition, planning for the annual Summer Undergraduate Research Program (SURP) is well underway under the able leadership of Dr. Vasu Venkateswaran; the SURP Annual Research Day will be held on Wednesday, August 15, 2012. As well, the IMS continues to complete its extensive strategic planning initiative. We will engage the Core Team for one more meeting to develop an implementation strategy for the plan, which we hope will be completed by the end of April.

In terms of IMS staff news, we congratulate and welcome Kaki Narh Blackwood to the position of Student and Faculty Affairs Coordinator, and Marika Galadza to her new role as Program Assistant.

Finally, Dr. Karen Davis will complete her term in June as Associate Director of the IMS after almost 4 years in this role. All of us at the IMS are indebted to Karen for her tremendous contributions to our community. We will sorely miss her input, wisdom, and humour.

Congratulations once again to Natalie Venier and her incredible team for their continued hard work and collective creative energies in producing this impressive publication. Thanks as well to Kamila Lear for her ongoing assistance in this project. The IMS Magazine has been a tremendous success and is just one of the many wonderful student-initiated projects that make IMS such a very special institute. I fully support the ongoing publication of the magazine and look forward to the many opportunities it can afford us for recruitment and for publicizing the outstanding research that is being conducted by our faculty and trainees.

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

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

Photo by Mohammed Sabri

Sincerely,

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

IMS MAGAZINE SPRING 2012 STEM CELLS | 10

SCIENTIFIC DAY PREVIEW

Thomas Insel:

Shining a light on mental health

By Allison Rosen

In an interview with the IMS Magazine, Insel recalls growing up in Ohio with a father who was a doctor and a mother who worked with him as a social worker. The youngest of four sons, all of whom would one day be11 | IMS MAGAZINE SPRING 2012 STEM CELLS

In the fall of 2002, Insel was named to his current position as Director of the National Institute of Mental Health. The NIMH is the branch of the NIH that is “charged with generating the knowledge needed to understand, treat, and prevent mental disorders.” In this role, Insel directs a large number of researchers and physicians who conduct clinical trials and research regarding autism. The Institute also focuses on the role of genetics in mental illnesses.

Despite all the progress that researchers and

Photo provided by Dr. Insel

D

r. Thomas Insel, the Director of the National Institute of Mental Health (NIMH), has had a busy morning. He started the day in New York, and is now in Bethesda, Maryland. “I’m not sure where I’ll end up at the end of the day,” he jests—a theme reminiscent of his journey to become a prominent figure in the world of mental health.

come doctors—three of whom would also become scientists—Insel jokes that, “it was kind of hard to get out of the rut they had drilled for me.” Despite living in the shadow of three older brothers who “were all following pretty much the same path,” Insel quickly differentiated himself through his keen passion for learning and innovation. In the summer of 1969, an 18-year-old Insel graduated from Boston University and decided to take a year to travel around Asia. That same year, he married his wife, Debbie. In the years that followed, he would complete medical school, an internship at Berkshire Medical Center in Massachusetts, and a residency at the Langley Porter Neuropsychiatric Institute at the University of California, San Francisco. Insel became a Professor of Psychiatry at Emory University and the founding director of the Center for Behavioral Neuroscience. He was also Director of the Center for Autism Research funded by the National Institutes of Health (NIH), and the Director of the Yerkes Regional Primate Research Center in Atlanta from 1994–1999. Mental health research was a natural choice for Insel: “There’s nothing more interesting, because it gets at the very nature of who we are, and it gets at the big questions—about consciousness, about attention, about free will. These are questions about who we are, and what could be more interesting than studying that?”

SCIENTIFIC DAY PREVIEW

clinicians have enjoyed with the advent of novel technologies and a clearer understanding of disease etiology, significant challenges remain. Insel writes that combining knowledge of genetic causes and heritability, epigenetic evidence of environmental causes, and descriptions of neural circuits and their effect on various behaviours, a complex picture of mental illness is emerging. Insel notes that neural pathways seem to mediate clusters of disorders; for example, the neural basis of extinction learning is tied to “posttraumatic stress disorder, obsessive-compulsive disorder, and various phobias.” This suggests the necessity of a new classification of mental illnesses. Insel points to discrepancies between our current diagnostic methods and evidence from research on genetics and neural systems. Mental health diagnoses rely “entirely on observation, and that’s…absolutely necessary, but it’s almost never sufficient for making a precise diagnosis, or…for the most precise intervention.” Converging information points to a translational approach to mental illness: genetic, epigenetic, and neurological reports should be considered together to provide a more comprehensive view of an illness. Insel also makes the intriguing point that most mental illnesses are developmental. With a better understanding of their genetic and neurological components, treatment of mental illness in the future may focus on prevention, rather than amelioration, of symptoms.

Insel advocates for a more personalized treatment of individuals with mental illness2. He asserts that physicians should be more attuned to the specific, experiential reports of patients, despite the increasingly short times that patients spend with physicians. This is also one goal of the NIMH’s Strategic Plan.

This proposed plan resonates with the current understanding of mental illness as a complex, multidimensional process that can have various psychological and sociological implications. Putting more weight on patient reports may also enhance diagnosis, either through increasing the precision of diagnosis or by redefining classes of disorders. Insel describes how one disorder can manifest in many ways in different individuals, and touches on the

problem of multiple comorbidities and “Not Otherwise Specified (NOS)” diagnoses to substantiate his argument that an overhaul of the diagnostic system of mental illness may soon be necessary.

In 2010, Insel reviewed a series of clinical trials run by the NIMH to test the efficacy of various medications that are used to treat mental illnesses3. Insel describes the “sobering” message of the trials: that “today’s medications may be good, but they are not good enough.” The public health impact, morbidity, and mortality have not yet changed significantly from previous to current treatment options. Insel lists the development of new types of interventions as one of the most important challenges facing clinicians and researchers today. “We will have to get much more creative with the kinds of interventions that we develop. Some of them will be behavioural, some will be cognitive, and some will be pharmacological. Some might be with tools we haven’t yet come up with. We have to…recognize that within the realm of pharmacology, we are long overdue for some true innovation.”

Insel’s influence on the mental health field continues as Acting Director of the new National Center for Advancing Translational Science (NCATS). The goal of this NIH centre is to improve patient care through “shorten[ing] the time for research-based interventions to be implemented in patient care.” Insel explains the value of this institute: “what we’ve been missing are not only the treatments themselves, but the appropriate process to get to those treatments.” The mission of the institute, Insel describes, is to “reengineer the pipeline for drug discovery and for biomarker discovery.” The tools designed in this centre can be adopted at the research and drug discovery stages, by academic centres, and by the pharmaceutical industry alike.

Reflecting on his position as Director of the NIMH, Insel comments, “It’s very busy—but it’s never boring and never entirely predictable, which is good. Sometimes, you even feel like you’re really making a difference, which

makes it all worthwhile.” Looking back at his career trajectory, Insel reveals that he has faced uncertainty. “You know, I never quite figured out what I wanted to do,” he says.

“I’ve done a lot of different things I had never considered doing before, and I don’t know what I’ll do next.” When asked for advice for current students, Insel explains the importance of excitement and enjoyment. “It’s so hard to make progress, and there are so many frustrations in whatever we do these days, so it’s really important to be passionate about it; to think of it not as a job, but as a calling—as an opportunity to make a difference.”

The IMS Magazine asked Insel how he remains grounded with such a fast-paced career. He cites his two grandchildren, each three years old: “they are absolutely authentic.” He also explains that his wife is an important support as well. “It’s been said that the key to having a very creative artistic life is having a very boring home life—and that’s actually pretty good advice. I have been married to the same person for 42 years, and having that long term, very stable, very happy relationship is extremely helpful for a job that has lots of pressure and unforeseen demands.” Insel shares that this support has been particularly important in a career where he has had some “extraordinary disappointments,” including once being fired from a job at the very institute he now directs. “There are just so many things that you can’t predict, but that’s okay. That’s what makes this all so fascinating. A lot of success, especially for us in science, depends on being able to cope with failure.” Talk of failure seems a distant memory from Insel’s current position, but his words reveal a wisdom that has clearly been important in making his name one of the most prominent in the world of mental health.

References 1. Insel, T.R., Wang, P.S. 2010. Rethinking mental illness.

JAMA 303, 1970-1971 2. Cuthbert, B., Insel, T. 2010. The data of diagnosis: new approaches to diagnostic classification. Psychiatry 73, 311-314 3. Wang, P.S., Insel, T.R. 2010. NIMH-funded pragmatic trials: moving on. Neuropsychopharmacology 35, 2489249

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Stem Cells

AN OVERVIEW

What is Regenerative Medicine?

What are Stem Cells?

• The stimulation of bodily tissue and organ renewal, or the restoration of function, through natural and biov means

• Possess two key properties: 1. the ability to self-renew 2. the ability to differentiate into mature cell types

A special thanks to Kristina Nagy for her contributions to this section.

• Encompasses diverse research fields with a common focus: develop strategies to promote health and prevent disease through regeneration • Exciting field that can potentially treat incurable diseases (e.g. diabetes, arthritis, paralysis) Common Strategies: • Organ transplantation • Tissue engineering • Gene therapy • Stem cell therapy Source: Canadian Institutes of Health Research

Regenerative Medicine: Stem Cell Therapy • Particularly promising because stem cells could supply replacement cells for various degenerative diseases and traumatic injuries Effective translation of stem cell therapy from bench to bedside requires: • Reliable supply of stable non-tumourigenic stem cells • Reproducible methods for directing these stem cells toward specific lineages • Establishment of clinical protocols that avoid immune rejection and enable effective cell delivery, survival, and function Source: Canadian Institutes of Health Research

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• Stem cells found in adult bodies possess additional criteria: they are quiescent until needed, present in only small numbers, and remain in the body for our entire life Source: Stem Cell Network; International Society for Stem Cell Research

Dr. Ernest McCulloch and Dr. James Till: U of T’s very own co-discoverers of stem cells • The researchers didn’t start out trying to discover stem cells. In a 2005 Quirks and Quarks interview, McCulloch revealed that their famous 1960’s findings “came about, as so often happens, as an incidental result of an experiment done for a completely different reason.”

The team was attempting to determine the number of injected marrow cells required to rescue irradiated mice—a line of thought made relevant through the atomic bomb and resulting radiation-induced deaths— when they discovered nodules of cells in the spleens of recovered animals.

• The team not only proved the existence of stem cells, but demonstrated two key properties: self-renewal and differentiation.

• Both Dr McCulloch and Dr. Till were made Officers of the Order of Canada in 1998 and 1994, respectively.

• Dr. McCulloch’s death in 2011 was mourned by scientists, doctors and patients worldwide. Check out our special tribute in the Spring 2011 issue of the IMS Magazine.

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Ectoderm

Oocyte and sperm Morula Totipotent

Inner cell mass

Figure adapted by Tobi Lam from “Stem Cell Facts� International Society for Stem Cell Research 2011, and Figure 1 from O’Connor TP and Crystal RG. G enetic medicines: treatment strategies for hereditary disorders. Nature Reviews Genetics 7, 261-276 (2006).

Mesoderm

Blastocyst Embryonic stem cells Pluripotent

Fetal development

Stem Cell Classification

Endoderm Adult

Adult stem cells are multipotent cells that can produce some or all of the mature cell types found within the particular tissue or organ in which they reside. They serve to replace dead or nonfunctional cells, and have been found in several organs that need to continuously replenish themselves (e.g. skin). These stem cells can be difficult to isolate and grow in a laboratory setting because they are often deep within a given tissue and represent a very small population of cells.

Illustration by Tobi Lam

Embryonic stem cells are pluripotent cells that can give rise to any cell type in the developing embryo, but are unable to contribute to the placenta and some extra-embryonic membranes.

They are derived from the inner cell mass of the blastocyst-stage embryo that forms ~5 days after fertilization. These cells have the potential to generate every cell type in the body, and given the right conditions, can be grown and expanded in their undifferentiated state.

Induced pluripotent stem cells are somatic cells (e.g. skin cells) that have been genetically reprogrammed into a pluripotent state. They share many of the same characteristics as embryonic stem cells, but it is important to note that they are not identical. Researchers are very interested in studying these cells, in part, because pluripotent stem cell lines may now be generated specific to a disease or even to an individual patient.

Source: Stem Cell Network; International Society for Stem Cell Research

Multipotent

Adult stem cells Multipotent

Examples of germ layer differentiation

Understanding cell potency During the first few days following fertilization, all cells in the developing embryo are said to be totipotent: they can develop into any cell type in the embryo, the placenta, and extraembryonic membranes.

Somatic cells (e.g. skin cells)

Pluripotency genes

Induced pluripotent stem cells Pluripotent

As the embryo develops into the blastocyst, the cells become more restricted and inner cell mass cells become pluripotent: they can give rise to any cell type in the developing embryo, some extra-embryonic membranes, but not the placenta.

The embryo continues to develop and cells become more and more specialized, gradually losing their potency. A small proportion of cells remain multipotent: they can give rise to a limited number of cells within their host organ or tissue. Others can develop into only one or two fully differentiated cell types and are therefore labeled as bi-/uni-potent.

IMS MAGAZINE SPRING 2012 STEM CELLS | 14

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Pluripotent stem cells and cell-based therapies

Are we there yet?

ferentiated mouse, and then human skin cells, into a pluripotent stem cell state4,5. They called them induced Pluripotent Stem (iPS) cells.

Andras Nagy, PhD

Research Associate Dr. Andras Nagy’s Laboratory Mount Sinai Hospital, Samuel Lunenfeld Research Institute

Principal Investigator Mount Sinai Hospital, Samuel Lunenfeld Research Institute Professor at the Department of Gynaecology and Obstetrics, University of Toronto

T

he first derivation of Embryonic Stem (ES) cells back in 19811,2 was a breakthrough event. Suddenly, we had cells that could be propagated to virtually unlimited amounts in vitro, and at the same time, could be differentiated into any cell type found in the body. In 1998, ES cells were successfully derived from human embryos as well3, which set the stage for serious endeavours to find clinical applications to treat cell or tissue loss due to injury and degenerative diseases with stem cell based therapies. However, a serious hurdle still remained: transplants derived from ES cells would not be histo-compatible with the patients. A few years ago, Yamanaka and his student Takahashi in Kyoto succeeded with a task that, until then, was thought to be impossible; reprogramming terminally dif-

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The first iPS cell lines were created using a viral delivery method to deliver the transgenes needed to induce reprograming. Although this is a very efficient method, it has some serious drawbacks. Viruses integrate their genome into their host cells in a completely random manner. Such an event may disrupt or activate genes whose proper regulation is essential for normal physiological function and for preventing cancerous occurrences.

Secondly, the transgenes that are needed during reprogramming have to be turned off once the process has been completed, but occasionally, virally delivered transgenes can be randomly reactivated later on, possibly leading to uncontrolled proliferation of the transplanted cells. To address these short-

Photos by Yekta Dowlati

Kristina Nagy

The patient-specific nature of the iPS cells has allowed for great strides to be made in bringing cell-based therapies towards realization.

Many people immediately drew the conclusion that ES cells would no longer be needed.

Others have been more cautious; we have had decades to study ES cells, while iPS cells are relatively novel and we know very little about them. In fact, recent studies have shown that there are significant differences between the two (reviewed by Puri and Nagy 2012)6. It is, at this point, not possible to say which will be the final winner as the best source for future therapies. Preclinical trials are now initiated for the treatment of a wide array of conditions such as spinal cord injury and blindness; the hopes are high and the promises great. So why are these therapies not yet available in the clinic? Despite the urge to deliver, as quickly as possible, ready-to-apply therapies to patients who so desperately need them, research aimed to understand iPS cells in general and the reprogramming process in particular remains crucially important.

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comings, many laboratories are now working relentlessly to develop alternative methods for producing iPS cells, including the use of transposons that can be seamlessly removed once reprogramming is completed7, serial plasmid transfection, episomal transfection, RNA transduction, and protein transduction.

Another serious concern relates to the genomic changes that we know occur during reprogramming. In order to fully understand why this happens, we need to gain a much better knowledge of the nature of the molecular, genetic, and genomic changes that take place during this process. The higher the resolution of insight that can be obtained, the more detailed our understanding will be.

Image created by Merry Wang

Our laboratory has initiated an international effort to map the genetic, genomic, gene expression, and proteomic changes, as well as the complex interactions between these factors that take place during the reprogramming process. This collaboration enlists experts in the field of bioinformatics to analyze and make sense of the huge amount of data being generated. It is with high hopes that we embarked on this research endeavour, and we look forward to unravelling the fine details of the reprogramming process over the coming months and years.

We must remember that stem cells have many common attributes with cancerous cells. Many of the genes that are turned on in stem cells can also be found expressed in tumors. If ES or iPS cells are transplanted before they are properly differentiated, they do indeed form teratomas. Although these tumors are not malignant in the sense that they do not metastasize, they nevertheless are cancerous. It is, therefore, important to find appropriate safeguards to ensure that transplanted cells are truly and fully differentiated before they are grafted. However, even if we do make sure to only transplant differentiated cells, there can never be an absolute guarantee that one of them would not proliferate uncontrollably. The only way to reliably circumvent this problem is by equipping the transplanted cells with a suicide system. We are currently developing such a genetic modification that results in the death of cells that have lost control.

History has taught us that many a great solution comes from combining different approaches to solve a problem. Age-related Macular Degeneration (AMD), for example, is caused by an abnormal increase in retinal blood vessel density. The newly formed vessels are leaky and cause damage to the ret-

ina that ultimately leads to blindness. Our laboratory has a long history of studying the genetic mechanisms behind blood vessel formation and which mechanisms could be used to induce or inhibit the generation of new vessels. We are now developing stem cells that are genetically modified to produce a protein that inhibits blood vessel formation. Once transplanted into the eye of AMD patients, they would act like a drug-producing “factory� in situ.

As with all things powerful, the future of stem cell-based therapies lies in harnessing their potential for doing good, while making sure we do not let them do any harm.

References 1. Evans, MJ and Kaufman, MH (1981). Establishment in culture of pluripotential cells from mouse embryos.

Nature. 292: 154-6.

2. Martin, GR (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 78: 7634-8.

3. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998). Embryonic stem cell lines derived from human blastocysts.

Science. 282(5391): 1145-7. Erratum in: Science 282(5395): 1827.

4. Takahashi K, Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4): 663-76.

5. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5): 861-72.

6. Puri MC, Nagy A. (2011). Concise Review: ES vs. iPS Cells; the Game is on. Stem Cells. 30:10-4.

7. Woltjen, K, Michael, IP, Mohseni, P, Desai, R, Mileikovsky, M, Hamalainen, R, Cowling, R, Wang, W, Liu, P, Gertsenstein, M, Kaji, K, Sung, H-K, and Nagy, A (2009). piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458:766-70.

8. Hussein, SM, Batada, NN, Vuoristo, S, Ching, RW, Autio, R, Narva, E, Ng, S, Sourour, M, Hamalainen, R, Olsson, C, Lundin, K, Mikkola, M, Trokovic, R, Peitz, M, Brustle, O, Bazett-Jones, DP, Alitalo, K, Lahesmaa, R., Nagy, A, and Otonkoski, T (2011). Copy number variation and selection during reprogramming to pluripotency. Nature 471:58-62.

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FEATURE

Stem Cell Therapy in Cardiac Regeneration

Uswa Shahzad, BHSc MSc candidate Institute of Medical Science

Terrence M. Yau, MD, MSc Professor of Surgery, University of Toronto Angelo & Lorenza DeGasperis Chair in Cardiovascular Surgery Research

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Both pluripotent stem cells and adult stem cells have been explored as possible therapeutic options. Pluripotent stem cells include human embryonic stem cells and induced pluripotent stem cells, while adult stem cells include bone marrow-derived mononuclear cells such as mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and cardiac-resident stem cells, among others1. Pluripotent stem cells can differentiate into one of the three cardiac lineages consisting of cardiomyocytes, smooth muscle cells, and endothelial cells. In addition, fibroblasts can be reprogrammed to become pluripotent and subsequently differentiate into cardiomyocytes1.

Transplanted stem cells may act in a paracrine manner by releasing factors such as vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) that promote the growth of new blood vessels2. In addition, the transplanted stem cells may prevent further cell death of existing cardiomyocytes3 as well as activate resident cardiac stem cells2. While there is evidence to support both of the above mechanisms of action, a major unanswered question is whether stem cells differentiate into normal

cardiomyocytes after transplantation,4 fuse with the host cardiomyocytes,5 or do both.

For example, when cultured alongside cardiac cells, mesenchymal stem cells have been shown to only mimic the characteristics of cardiomyocytes6. Most of the aforementioned adult stem cell types have been shown to improve cardiac function after transplantation into infarcted hearts, but have done so without directly differentiating into cardiomyocytes1,2. There is some evidence to suggest that cardiac stem cells can differentiate into cardiomyocytes, although their endogenous effects are unknown7.

The beneficial effects of stem cell therapies have not, however, resulted in normalization of infarcted heart function. In an effort to enhance cell-based therapy, genetically enhanced stem cells that have been modified to overexpress certain growth factors such as VEGF and hepatocyte growth factor (HGF).

Overexpression of certain pro-survival genes like Akt-1 have also been utilized and have shown some promise1,8.

Despite an advanced understanding of cellbased therapy in laboratory research, in the clinical setting stem cell therapy still seems to be in its nascent stage. Major clinical trials such as BOOST9 and ASTAMI10 have demonstrated an early improvement in heart function, but found no significant differences between groups at six months. In comparison, REPAIR-AMI11 reported a small but significant improvement in cardiac function, as well as improvement in clinical outcomes such as recurrent myocardial infarction and repeat revascularization at 1 year.

While initial clinical trials have demonstrated the promise of stem cell transplantation for cardiac regeneration, there are still some issues that need to be addressed before this therapy can become widespread. Most studies have demonstrated that donor cell retention within the heart is optimal with direct intramyocardial injection12.

However, unsettled questions include the op

Photos by Yekta Dowlati. Figure image courtesy of Liao R, Pfister O, Jain M, Mouquet F

I

schemic heart disease afflicts millions of people worldwide, and accounts for at least 50% of all cardiovascular-related deaths in the developed world1.

As such, it places a significant burden on the healthcare system in terms of the cost and resources needed to manage patients with progressive to terminal cardiac dysfunction.

Myocardial infarction, commonly known as a heart attack, occurs due to a partial or complete obstruction of the arteries supplying blood to the heart, and results in the death of cardiomyocytes (heart cells). A major challenge that currently exists in treating ischemic heart disease in a clinical setting is inducing repair and regeneration in the infarcted heart. In order to address this issue, tissue engineering and stem cell transplantation (Figure 1) are being extensively investigated as cardiac regenerative strategies.

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ischemic injury

-self renewal -differentiation repair/ regeneration

-self renewal -differentiation signalling for homing

signalling for mobilization

bone marrow derived stem cells cardiac stem/progenitor cells

Figure 1. The cardiac progenitor cells normally reside in the heart and possess the ability to self-renew and differentiate into cardiomyocytes.

After ischemic injury, however, the injured myocardium releases signals to induce mobilization of stem cells from the bone marrow to augment the cardiac repair induced by cardiac progenitor cells. Cell based therapy works through this very phenomenon, as the transplanted cells respond to the homing signal released by the ischemic tissue.

Reproduced from Liao R, Pfister O, Jain M, Mouquet F: The bone marrow—cardiac axis of myocardial regeneration. Progress in Cardiovasc Diseases 50:18-30, 2007 with permission from Elsevier.

timal stem cell population and dose, whether cell therapy can be efficacious in both acute and chronic ischemic injury, the optimal timing to transplant cells, and the duration of therapy. While many of these issues have been studied in animal models, translation of those findings into a considerably more complex human population is a significant challenge. There is a need for more complex animal models that take into account the comorbidities that are characteristic of the typical patient with ischemic cardiomyopathy13.

Another issue is that the efficacy of cell transplantation is related to the number of cells that can be transplanted, engraft, and survive. Most cell therapy strategies have utilized autotransplantation in order to avoid potential problems with rejection, and the number, and perhaps, the regenerative potential of autologous donor cells is limited.

Donor cells may be expanded ex vivo to obtain greater numbers, but the longer the delay in cell preparation, the more cumbersome and less practical this process becomes in clinical application. Hence, in order to address the issue of cell survival, we have utilized cell-based gene therapy as a means to augment the survival and reparative capacity

of these cells, and also used transmyocardial revascularization (TMR) to treat the infarct zone prior to cell implantation.

In our previous studies, we have shown in a rat infarct model that transfection of bone marrow cells (BMCs) with proangiogenic factors, such as VEGF, prevents donor cell death and induces angiogenesis14. Furthermore, BMCs transfected with VEGF and bFGF augmented angiogenesis and resulted in significantly increased vascular density15.

We have also shown that stem cell factor (SCF) overexpressing MSCs can mobilize endothelial progenitor cells and promote angiogenesis, resulting in increased perfusion to surviving cardiac tissue16.

On the other hand, TMR has been used clinically in the treatment of refractory angina, and uses a laser to create channels in the ischemic myocardium. The two currently accepted mechanisms by which TMR works are denervation, which results in relief of the pain associated with angina, followed by de velopment of new blood vessels in the ischemic tissue through angiogenesis.

We have demonstrated that pretreatment of an infarct zone by TMR enhances the effects of mesenchymal stem cell transplantation. In a rat infarct model, TMR performed prior to transplantation of MSCs or MSCs overexpressing VEGF, bFGF, and insulin-like growth factor-1 (IGF-1) resulted in significantly increased angiogenesis and restoration of ventricular function17. In the TMR group, donor MSC survival three days after transplantation was four times greater than in the control group. Our recent work has shown that TMR induces engraftment of circulating MSC via the c-kit-SCF and CXCR4-SDF-1 signaling axes. These findings are another step towards understanding the specific mediators that play a role in survival of the transplanted stem cells and their interaction with endogenous myocardial repair mechanisms. In addition, this shows that TMR can potentially be used clinically as an adjunct to MSC transplantation to improve outcomes.

While still in development, stem cell therapy holds great promise as a treatment for ischemic heart disease. Great strides have been made in understanding how stem cells work in the infarcted heart, and clinical trials have shown that stem cell therapy is remarkably

safe and may improve the function and perfusion of infarcted hearts. The magnitude of this reparative effect is still modest in complex patients with multiple comorbidities, but ongoing research to elucidate the interaction of implanted stem cells with the host myocardium and bone marrow, as well as to augment the reparative capacity of each donor cell, suggest that more efficacious stem cell therapies for cardiac repair will be devised in the near future.

References 1. Mazhari R, Hare JM: Advances in cell-based therapy in structural heart disease. Progress in Cardiovasc Diseases 49:387-395, 2007 2. Liao R, Pfister O, Jain M, Mouquet F: The bone marrow—cardiac axis of myocardial regeneration. Progress in Cardiovasc Diseases 50:18-30, 2007 3. Uemura R, Xu M, Ahmad N, Ashraf M: Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. 98(11):1414-21, 2006 4. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, et al: Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 73(6):1919-25, 2002 5. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, et al: Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428(6983):664-8, 2004 6. Xu W, Zhang X, Qian H, Zhu W, Sun X, Hu J, et al: Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp Biol Med 229(7):623, 2004 7. Chimenti I, Smith RR, Li T, Gerstenblith G, Messina E, Giacomello A, et al: Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res 106:971–980, 2012 8. Van Poll D, Parekkadan B, Borel Rinkes HM, Tilles AW, Yarmush ML: Mesenchymal stem cell therapy for protection and repair of injured vital organs. Cell and Mol Bioeng 1:42–50, 2008 9. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, et al: Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141-148, 2004 10. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, et al: Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 355:1199-1209, 2006 11. Schachinger V, et al: Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210-1221, 2006 12. Li SH, Lai TYY, Sun Z, Han M, Moriyama E, Wilson B, et al: Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery. J Thorac Cardiovasc Surg 137:12251233, 2009 13. Denglar TJ, Katus HA: Stem cell therapy for the infarcted heart (“Cellular Cardiomyoplasty”). Herz 27:598–610, 2002 14. Yau TM, Kim C, Ng D, Li G, Zhang Y, Weisel RD, et al: Increasing transplanted cell survival with cell-based angiogenic gene therapy. Ann Thorac Surg 80:1779-1786, 2005 15. Yau TM, Kim C, Li G, Zhang Y, Fazel S, Spiegelstein D, et al: Enhanced angiogenesis with multimodal cell-based gene therapy. Ann Thorac Surg 83:1110-1119, 2007 16. Fazel S, Chen L, Weisel RD, Angoulvant D, Seneviratne C, Fazel A, et al: Cell transplantation preserves cardiac function after infarction by infarct stabilization: Augmentation by stem cell factor. J Thorac Cardiovasc Surg 130:1310-1310.e10, 2005 17. Spiegelstein D, Kim C, Zhang Y, Li G, Weisel RD, Li R, et al: Combined transmyocardial revascularization and cell-based angiogenic gene therapy increases transplanted cell survival. Am J Physiol Heart Circ Physiol 293:H3311-H3316, 2007

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FEATURE

Harnessing the potential

of neural stem cells for neural regeneration

Cindi M. Morshead, PhD Associate Professor and Chair, Division of Anatomy Department of Surgery Department of Rehabilitation Science Institute of Biomaterials and Biomedical Engineering

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Adult brain neural stem cells reside in a very well defined periventricular region lining the lateral ventricles3-4. Similar to other stem cells found throughout the body, neural stem cells comprise a rare population of cells in the brain and they proliferate to give rise to a more abundant population of progenitor cells. In the adult brain, the progeny of adult brain stem cells contribute to neurogenesis, the formation of new neurons, throughout life. The newly born neurons migrate to the olfactory bulb where they integrate into the neural circuitry and play a role in the sensation of smell5-6. These rare neural stem cells can be dissected from the periventricular region and placed in culture in the presence of growth factors, where they proliferate to form clonally derived, free-floating colonies of cells consisting of stem and progenitor cells (together termed “precursor cells”).

When exposed to differentiation conditions, the cells within the colonies give rise to the mature neurons and glia that make up the

central nervous system1. The ability to isolate and expand the population of stem cells and their progeny provide an excellent source of cells for transplantation.

When considering transplantation as a strategy for cell replacement, a number of hurdles need to be overcome. For instance, the survival of transplanted cells is exceedingly low (<5%)7. With the goal of enhancing cell survival, we have developed combinatorial strategies including the co-delivery of cells in biomaterials that promote their survival7, and the co-delivery of cells with factors that promote neural precursor cell survival and differentiation8. The exciting, collaborative efforts with bioengineers and neurosurgeons alike have demonstrated success in rodent models of spinal cord injury, a devastating injury with major social and economic implications, where injured rodents have shown some functional improvement and new tissue formation8. Keeping in mind the ultimate goal of therapeutic application, ongoing studies in our lab are examining the effects of drugs already used in a clinical setting, to enhance the cell transplantation efforts. In this regard, we have demonstrated that the commonly used immunosuppressant molecule, Cyclosporin A, has direct effects on neural precursor cells and promotes their survival without modifying their proliferation kinetics9-10. We are now testing the co-delivery of cells and Cyclosporin A in models of spinal cord injury.

Some of the most exciting work we are pursuing is the activation of resident neural precursor cells to enhance the “self-repair” mechanisms in the injured brain. Previous studies have demonstrated that injury alone is able to activate the resident neural precursor cells, inducing them to proliferate and undergo limited migration towards the injury site11-12. However, it is clear that this response to injury is insufficient to promote repair. Towards the goal of facilitating selfrepair, it is essential that we understand the mechanisms and factors that regulate neu-

Photo by Brett Jones

T

he discovery of neural stem cells in the adult brain in 19921 had a profound impact on the way that we think about repairing the damaged nervous system. The dogma of the time was that there was no way to replace lost neurons following injury or disease, so therapies were based on the development of neuroprotective strategies—to save the cells from dying. The existence of neural stem cells, first in the adult brain and soon thereafter in the spinal cord2, opened the door for the development of cellbased therapies to replace lost and damaged cells. Much excitement has been generated regarding two distinct stem cell based therapeutic interventions; (1) neural stem cell transplantation following their isolation and expansion in culture, and (2) stimulation of resident neural stem cells and their progeny to get them to contribute to neural repair following injury or disease. Our lab is interested in utilizing both of these strategies to promote tissue repair and functional recovery in animal models of injury including stroke and spinal cord injury.

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ral precursor cell behaviour including their survival, proliferation, migration and differentiation. All of these behaviours need to be exploited when developing activation strategies. For instance, an expansion of the rare fraction of precursor cells will permit a larger population of cells to contribute to the repair and the neural precursor cells must migrate from their periventricular niche to the injury site where they will differentiate to replace the lost cells. To understand the regulation of these behaviours, we first look to tissue culture; what we learn from the dish, we then apply to animal models. Using this strategy, we successfully demonstrated that the same factors that promote neural precursor cell proliferation, survival and differentiation into neurons in a dish (namely epidermal growth factor, Cyclosporin A and erythropoietin), are able to stimulate cells in the adult brain to induce tissue regeneration and functional recovery following a stroke injury13-14. These compelling findings were just the beginning and we have since applied our activation strategy to different models of stroke, in both rats and mice, with similar promising outcomes. Most important, we have discovered that a number of therapeutically relevant drugs currently used in the clinical setting are able to activate resident neural precursor cells, taking us one step closer to moving this regenerative strategy to the clinic.

These compelling findings also form the basis for some of our current work exploring the effects of aging on the regenerative capacity of the brain. Indeed, stroke is more prevalent in the aged population, making an examination of the neural precursor cell pool an important consideration when moving stem cell based therapies towards the clinic.

To date, little work has been done using oldage animals and we are just now beginning to understand the fundamental biology of neural stem and progenitor cells in the old-age brain. The regenerative capacity of the aged brain was thought to be compromised by the fact that there appeared to be a significant loss of neural stem cells with age15. Again,

starting in the dish, we have learned that factors from the young brain can dramatically enhance the survival of old age stem cells, and that these “young” factors can activate the neural stem cell pool when delivered directly to the brain of old-age mice. What this tells us is that neural precursor cells in the aged brain need an extra “push” to become activated. This finding has enormous implications for developing clinically relevant neuroregenerative strategies.

To enhance the efficacy of any cell replacement approach to neural repair, it is critical that neural precursor cells migrate to the site of injury. Accordingly, we have been developing novel approaches to enhance the directed and rapid migration of neural precursors cells. Based on previous studies reporting that electric fields play a critical role in the development of the central nervous system16, as well as cell migration during wound healing17, we asked whether externally applied direct current electric fields would be an effective way to promote adult derived neural precursor cell migration. Using time-lapse imaging microscopy to visualize the behavior of neural precursor cells when exposed to a physiologically relevant direct current electric field, we demonstrated that undifferentiated precursors, but not differentiated cells, migrated rapidly and directly towards the cathode. Moreover, if the direction of the cathode was changed during the cell migration, the cells would quickly respond and reverse their direction. This dramatic effect of migration is observed in virtually 100% of the precursor cells and did not change the proliferation kinetics of the cells or induce cell death18. We are currently examining this phenomenon in brain slices with the ultimate goal of applying these physiologically relevant electric fields to resident neural precursor cells in the brain to thereby promote self-repair.

Understanding the fundamental biology of neural precursor cells is an essential first step to harnessing the potential of adult neural

precursor cells and ultimately utilizing these cells in regenerative medicine strategies.

References 1. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707-1710 2. Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC, Reynolds BA. (1996) Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci. 16:7599-609 3. Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, van der Kooy D (1994) Neural stem cells in the adult mammalian forebrain: A relatively quiescent subpopulation of subependymal cells. Neuron 13(5): 1071-1082 4. Doetsch F, García-Verdugo JM, Alvarez-Buylla A. (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci. 17:5046-61.

5. Craig CG, D’Sa R, Morshead CM, Roach A, van der Kooy D (1999) Migrational analysis of the constitutively proliferating subependymal cells in the adult forebrain. Neurosci 93(3): 1197-1206 6. Livneh Y, Mizrahi A. (2011) Experience-dependent plasticity of mature adult-born neurons. Nat Neurosci.15:26-8.

7. Cooke MJ, Vulic K, and Shoichet MS (2010) Design of biomaterials to enhance stem cell survival when transplanted into the damaged central nervous system. Soft Matter 6: 4988-4998.

8. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead CM, Fehlings MG (2006) Delayed transplantation of adult neural stem cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci 26(13): 3377-89.

9. Hunt J, Cheng A, Hoyles A, Jervis E, Morshead CM (2010) Cyclosporin A has direct effects on adult neural precursor cells.

J. Neurosci, 30:2888-2896 10. Hunt J, Morshead CM (2010) Cyclosporin A enhances cell survival in neural precursor populations in the adult central nervous system. Mol Cell Pharmacol, 2(3):80-88.

11. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963-970 12. Zhang RL, Zhang ZG, Wang L, Wang Y, Gousey A, Zhang L, Ho KL, Morshead C, Chopp M (2004) Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab 24:441-448 13. Kolb B, Morshead C, Gonzalez C, Kim M, Gregg C, Shingo T, Weiss S (2007) Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab 27:983-997 14. Erlandsson A, Lin CHA, Yu F, Morshead CM (2010) Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury.

Exp Neurol doi:10.1016/j.expneurol.2010.05.018 15. Piccin D, Morshead CM (2010) Potential and pitfalls of stem cell therapy in old age, Dis Model Mech, 3:421-425 16. Hotary KB, Robinson KR (1992) Evidence of a role for endogenous electrical fields in chick embryo development. Development 114:985-996 17. Zhao M (2009) Electrical fields in wound healing-An overriding signal that directs cell migration. Semin Cell Dev Biol 20:674-682 18. Babona-Pilipos R, Droujinine IA, Popovic MR, Morshead CM. (2011) Adult subependymal neural precursors, but not differentiated cells, undergo rapid cathodal migration in the presence of direct current electric fields. PLoS One, 6:e238-8.

IMS MAGAZINE SPRING 2012 STEM CELLS | 20

FEATURE

Seeing is believing

Stem cells and retinal regeneration

Brian G. Ballios, BScE MD/PhD Candidate

Derek van der Kooy, PhD Professor, Molecular Genetics

T

he eyes are the gateway to our most striking memories of the world. The process of visualizing our world is as amazing as it is complex.

Light entering the eye is projected onto a light sensing tissue, the retina, at the back of the eye. The retina is actually an outgrowth of the brain that develops early in the formation of the human central nervous system.

And like other parts of the brain and spinal cord, it is exquisitely sensitive to injury. Once damaged, the adult human retina shows no ability to regenerate itself: vision loss is permanent.

Vision loss is devastating for both patients and their families. Polls conducted by the Gallup Organization reveal that blindness is the second most feared disease by Americans

after cancer. As arguably one of the most important sensory modalities, loss of vision can take a significant toll on quality of life and the psychosocial well being of patients. In our society, the primary causes of degenerative vision loss span the age spectrum. Agerelated macular degeneration (AMD) is the most common cause of irreversible blindness affecting seniors over 651. The macula is the part of the central retina responsible for high acuity vision. With our aging baby-boomer population, rates of newly diagnosed AMD are expected to rise in the coming decade2.

Retinitis pigmentosa (RP) affects primarily children and young adults, and is the leading cause of inherited retinal degeneration3.

What most forms of retinal degeneration have in common is the irreversible loss of

Photos of Dr. van der Kooy and Brian Ballios by Yekta Dowlati. Photo of Dr. Molly Shoicet by Darryl Augustine.

Professor, Chemical Engineering and Applied Chemistry Canada Research Chair in Tissue Engineering

Institute of Medical Science Collaborative program in Neuroscience Supervisors: Dr. Derek van der Kooy & Dr. Molly Shoichet

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Molly S. Shoicet, PhD, FRSC, O.Ont.

FEATURE

photoreceptors—the light sensitive cells in our retina that convert light into electrical signals. We are born with only a finite number, and they are literally irreplaceable. Current drug therapies for these conditions can slow the progression of disease, but are not curative.

Cell transplantation is an alternative strategy that holds promise for restoring lost vision to patients. The goal is to replace the lost photoreceptors with new donor photoreceptors.

But in approaching the design of this therapy, there are two critical questions that need to be asked. (1) What are the best cell types to transplant to replace lost retinal cells? (2) What is the optimum way to deliver these cells to ensure they distribute, survive, and integrate after transplant into the damaged retina to restore function?

Stem cells for transplantation Early cell transplantation studies in humans involved the transplantation of immature (progenitor) retinal cells taken from fetal tissue. While these studies showed some subjective improvement in function, the measurable increase in retinal function was less convincing4. Many scientists agree that a population of immature retinal cells represents the most promising approach for successful transplantation. As a source of immature cells, stem cells show great promise. Human embryonic stem (hES) cells represent a potential source of therapeutic cell populations for retinal re-

pair. These cells replicate indefinitely in culture, and can be coaxed to mature (differentiate) into multiple retinal cell types5. The first report of hES-derived cell transplants into human patients represents a significant step forward in taking stem cell research from bench-to-bedside. In this study, retinal pigmented epithelium (RPE) cells derived from hES cells were transplanted into patients with forms of macular degeneration6. The RPE are the support cells of the retina, trapping light within the eye and providing metabolic support for the photoreceptors. Replacement of RPE damaged by retinal disease may help to rescue dying photoreceptors in the retina.

Early results suggest that these transplanted cells are well tolerated by the patients’ eyes, and modest visual improvement was reported in one patient. Additional detailed studies will be required to evaluate the long-term benefits of this therapy.

However, even replacement of the RPE cannot restore the vision lost by the absence of retinal photoreceptors. While numerous studies in mouse disease models have shown the potential of hES-derived retinal progenitors to integrate and differentiate into photoreceptors in host retina and restore some visual function7, the inability to purify photoreceptors from these cultures means that a mixed population of cells is transplanted, including some non-retinal cell types. Furthermore, the isolation of hES raises significant ethical issues.

Adult stem cells represent another stem cell type with potential for therapeutic translation—these cells can be isolated from adult tissue and demonstrate the ability to differentiate into multiple tissue-specific cell types.

Van der Kooy and colleagues reported the isolation of adult retinal stem cells (RSCs) in the adult mouse8 and human9 eye. These cells can differentiate into all retinal cell types, including photoreceptors. They do not differentiate into non-retinal cells, and their ability to be isolated from adult donor tissue negates the controversy around the use of fetal tissue for cell therapy. To apply these cells for retinal cell therapy, it is necessary to have control over their differentiation toward particular types of photoreceptors, and in particular, the rod photoreceptor. Rod photoreceptors are the predominant type of photoreceptor in the adult eye, and the ability to replace these cells is of critical importance as a step toward retinal cell therapy. Recently, we demonstrated that by optimizing cell culture conditions, the adult RSC could be differentiated into rod photoreceptors with unprecedented efficiency (>90% pure cultures)10. In addition, with the ability of the RSC to renew indefinitely in culture—a cardinal property of stem cells—the RSC represents a potentially unlimited source of donor photoreceptors.

Research suggests that cells committed to maturing into rods are an optimum population for rod-replacement11, and thus, adult RSC-derived rods are an ideal cell source for future therapy.

IMS MAGAZINE SPRING 2012 STEM CELLS | 22

FEATURE

Improving stem cell transplantation Three major barriers exist to the application of stem cell therapy for retinal regeneration.

These include proper distribution, survival and integration of cells after transplantation.

To overcome these barriers, an interdisciplinary approach combining an understanding of basic RSC biology and bio-engineered strategies for cell delivery are essential. Most commonly, these have included the delivery of stem cells on solid biomaterial scaffolds12.

While this represents an important advance, these solid scaffolds are not flexible and may cause damage to the sensitive retinal tissue during implantation13. In collaboration with the laboratory of Dr. Molly Shoichet (U of T, IMS), we have developed a minimally invasive, injectable and biodegradable gel for cell delivery to the retina14 called HAMC. This represents the first report of an injectable bio-engineered delivery vehicle for cell delivery to the retina. A blend of biopolymers normally found in nature, HAMC supports transplanted RSC survival and distribution across the retina, and is completely degraded within a week of injection. This delivery system may be useful in the treatment of advanced retinal disease, where large areas of retina are destroyed. The development of injectable devices represents a new dimension to therapy for retinal regeneration. Transla-

tion to the clinic will depend on improved visual function, resulting from greater cell survival and integration into host tissue.

Stem cells hold great promise for future retinal therapy. This is an exciting time for stem cell research in the eye, as advances in the laboratory are beginning to see application in clinical therapy. Innovation in stem cell therapy for retinal regeneration will depend on multidisciplinary collaboration to advance our understanding of the biology of retinal stem cells, and how they may be delivered to the diseased retina.

References 1. Kaufman, S. R. Developments in age-related macular degeneration: Diagnosis and treatment. Geriatrics 64, 16-19 (2009).

2. Congdon, N. G., Friedman, D. S. & Lietman, T. Important Causes of Visual Impairment in the World Today. Journal of the American Medical Association 290, 2057-2060 (2003).

3. Shintani, K., Shechtman, D. L. & Gurwood, A. S. Review and update: Current treatment trends for patients with retinitis pigmentosa. Optometry 80, 384-401 (2009).

4. Radtke, N. D., Aramant, R. B., Seiler, M. & Petry, H. M. Preliminary report: Indications of improved visual function after retinal sheet transplantation in retinitis pigmentosa patients. American Journal of Ophthalmology 128, 384-387 (1999).

5. Lamba, D. A., Karl, M. O., Ware, C. B. & Reh, T. A. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc. Natl. Acad. Sci. U S A 103, 12769-12774 (2006).

6. Schwartz, S. D. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713-720 (2012).

7. Lamba, D. A., Gust, J. & Reh, T. A. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell 4, 73-79 (2009).

8. Tropepe, V. et al. Retinal stem cells in the adult mammalian eye. Science 287, 2032-2036 (2000).

9. Coles, B. L. K. et al. Facile isolation and the characterization of human retinal stem cells. Proc. Natl. Acad. Sci. U S A 101, 15772-15777 (2004).

10. Ballios, B. G., Clarke, L., Shoichet, M. S. & van der Kooy, D. The adult retinal stem cell is a rare cell in the ciliary epithelium whose progeny can differentiate into photoreceptors. Biol. Open 1, doi: 10.1242/bio.2012027 (2012).

11. MacLaren, R. E. et al. Retinal repair by transplantation of photoreceptor precursors. Nature 444, 203-207 (2006).

12. Yao, J. et al. Robust cell integration from co-transplantation of biodegradable MMP2-PLGA microspheres with retinal progenitor cells. Biomaterials 32, 1041-1050 (2011).

13. Tomita, M. et al. Biodegradable polymer composite grafts promote the survival and differentiation of retinal progenitor cells. Stem Cells 23, 1579-1588 (2005).

14. Ballios, B. G., Cooke, M. J., van der Kooy, D. & Shoichet, M. S. A hydrogel-based stem cell delivery system to treat retinal degenerative diseases. Biomaterials 31, 2555-2564 (2010).

Pick Your Brain...

A column by Aaron Kucyi

Alzheimer’s disease is extremely common—it affects roughly 50% of people over 85—yet there are no available treatments that successfully prevent or change the course of the disease. Although animal research has provided insights into the pathophysiology of Alzheimer’s disease, laboratory animals do not typically exhibit the disease in a similar fashion to humans, so preclinical studies do not always have translational merit. For the first time, researchers have developed a technique to study neurons, derived directly from the tissue of human Alzheimer’s patients, in a dish.

23 | IMS MAGAZINE SPRING 2012 STEM CELLS

Lawrence Goldstein at UC San Diego and his colleagues took fibroblast cells from skin tissues from patients with Alzheimer’s disease and healthy individuals. Using a technique developed in the past few years—known as cellular reprogramming—the fibroblasts were ‘tricked’ into behaving like embryonic stem cells, which could then be converted into neurons. Studying these neurons in vitro, the researchers found that neurons derived from Alzheimer’s patients had higher levels of tell-tale disease markers, including the proteins amyloid-β and phospho-tau, relative to controls.

Since most human research on Alzheimer’s disease to date has relied upon the use of neuroimaging techniques with crude levels of resolution and the study of post-mortem tissues, the ability to study single cells of patients represents a significant advance. Although the cells from only four patients were used in this study, the proof-of-concept provided for the technique will open doors for larger investigations in the future.

Reference:

Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, et al. (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482: 216-220.vv

SPOTLIGHT

Siba Haykal MD

STREAM PhD SUPERVISOR Dr. Thomas Waddell

From Plastics to Thoracic Reconstruction require permanent artificial airways, which leads to complications with multiple infections and hospital admissions. More specifically, I am working with biological scaffolds in which a donor trachea is harvested, decellularized and recellularized with recipients’ progenitor cells before transplantation. I initially evaluated the structural integrity of these scaffolds and I am now interested in the immune response directed towards these allografts, as well as the fate of the progenitor cells.

Q Do you feel that having a medical degree has assisted in your research progress and opportunities?

A All research brings us closer to having an

A

s a 2012 Vanier Canada Graduate Scholarship recipient and current PhD candidate in the Surgeon Scientist Program at the IMS, Dr. Siba Haykal is no stranger to hard work and dedication.

After graduating as class silver medalist and valedictorian from the University of Ottawa Medical School, Haykal began her residency in plastic and reconstructive surgery at the University of Toronto in 2007. She currently conducts research in the area of regenerative medicine under the supervision of Dr. Thomas Waddell.

Between conducting tracheal transplant experiments, long hours in the laboratory, hot yoga sessions, and weekly runs, Haykal took time to sit down with the IMS Magazine to discuss her current work.

Q Why did you decide to join the Surgeon Photo by Yekta Dowlati

Scientist Program?

A I have always had an interest in basic sci-

ence research. I worked in a cell biology laboratory for three years while pursuing a biochemistry degree at the University of Ottawa.

I then worked in a neuroscience laboratory

during medical school. I enjoyed the challenging aspects of basic science and the Surgeon Scientist Program allowed me to combine the best of both worlds as I strive for a future surgical career in which I can continue to pursue my research.

As I was searching for a project, my co-supervisor, Dr. Stefan Hofer, a reconstructive microsurgeon at Toronto General Hospital, introduced me to the idea of the reconstruction of an airway. This led to meeting Dr. Waddell, chief of Thoracic Surgery at UHN and a scientist at the Latner Thoracic Surgery Laboratories. It has truly been a great opportunity for me to work with this group, as I have found great mentors and I am learning about transplantation with the hope of applying this knowledge to a better understanding of the field of composite tissue allotransplantation.

Q Can you describe your research focus?

A My area of research focuses on recon-

structing long tracheal segments, which is necessary following malignancy, traumatic injury or stenosis. Patients affected by these

impact on patients’ lives. I feel that my medical degree gives me a different perspective on tackling the current problems and allows me to focus on areas that are directly applicable to the clinic.

Q

As a winner of the Vanier award, you must be very involved. How do you make time for everything and how do you unwind?

A I try to be as organized as possible while staying flexible with my schedule, as life can be unpredictable. My family and friends help me unwind. They are my support system and have constantly encouraged me. I also believe that you can’t help anyone else if you don’t help yourself first. Fitness has also always been a big part of my life, as it allows me to maintain both physical and mental balance.

Q What advice do you have for students wanting to pursue careers in both medicine and research?

A

My advice is to stay focused, work hard and never give up. There are plenty of great opportunities for people who have that drive and are interested in lifelong learning. Both careers, although challenging, are extremely rewarding.

By Rickvinder Besla

IMS MAGAZINE SPRING 2012 STEM CELLS | 24

EXPERT OPINION

The Neurological Significance of

Subclinical Blast Exposure

E

xplosions or blasts cause trauma through exposure to thermal and chemical stress, through the blunt impact of the wind (sufficient to cause amputations), and through the impact and penetration of high velocity debris and shrapnel.

However, preceding all of these sources of trauma is the primary blast wave of overpressure. This primary blast wave is characterized by an instantaneous increase in ambient pressure, heat and density, followed by a prolonged negative pressure.

Chief, Department of Clinical Care Scientist, Keenan Research Centre Li Ka Shing Knowledge Institute St. Michael’s Hospital Professor, Departments of Anesthesia and Surgery Member, Institute of Medical Science University of Toronto

Eugene Park, PhD Research Associate Cara Phelan Centre for Trauma Research Li Ka Shing Knowledge Institute

25 | IMS MAGAZINE SPRING 2012 STEM CELLS

Blast injury results from trauma caused by explosions. During recent conflicts in Iraq and Afghanistan, improvised explosive devices have caused a large number of injuries. At the same time during these conflicts, there has been an increased frequency of identified traumatic brain injury, including concussions, and post-traumatic stress disorder (PTSD).

While armour and other barriers have reduced penetrating injuries to the body, the emergence and persistence of brain injuries has raised the question of the relationship of blast exposure to this problem. Our laboratory is particularly interested in determining the potential relevance of blast exposure to mild traumatic brain injury, or even as an organic contributor to PTSD. A common practical issue following an explosion is the triage of people exposed to blast wave. Symptoms and signs of injury to the tympanic membrane, lung or bowel—or even obvious neurologic changes—would indicate that the patient has been injured and needs careful attention. However, if there are no obvious or immediate physical injuries present, it is not clear whether there have been any neurologic implications following exposure to a blast at a distance. In short, sub-clinical or mild blast trauma could cause easily missed injuries in the brain that would ultimately manifest as symptoms and signs of

Photo by Laura Feldcamp

Andrew Baker (above), MD, FRCPC

The primary blast wave trauma is now the focus of much research internationally aimed at understanding the mechanisms, prevention and treatment strategies of injury. Primary blast waves will transfer energy and cause injury primarily at the interfaces between tissues of differing density and especially differing phase (gas, liquid, solid).

Thus, the tympanic membrane, the lung and bowel are commonly injured and characterize this trauma exposure.

EXPERT OPINION

Photo courtesy of www.istockphoto.com; ID # 17960554

either mild traumatic brain injury or organic contributors to PTSD. This raises an important question. In soldiers not otherwise affected by intense primary blast wave energy, was it possible that there were organic effects of primary blast exposure?

To examine this question further, we developed a model of primary blast injury in the laboratory. In association with the U of T Institute for Aerospace Studies, we characterized the physics of blast wave dynamics.

Rats were randomly exposed to sham or blast wave conditions. We varied the intensity until we found the minimum that would affect the lung parenchyma, and lowered this intensity by 30%. The rats were then examined with various neuropsychological tests, and their brains were examined with both imaging and electrophysiological functional studies.

This study showed that rats exposed to blast had worse coordination or concentration on the Rotarod (a rotating rod that normal rats like to run on, much like a wheel for a pet rodent). They exhibited more anxiety in open field and light/dark box studies (measuring confidence to exit their safe dark box and explore in the light exposed pen). The brains of blast-exposed rats demonstrated evidence of cytoskeletal proteolysis by twelve hours, and cell death in the corpus callosum

â&#x20AC;&#x153;In short, sub-clinical or mild blast trauma could cause easily missed injuries in the brain that would ultimately manifest as symptoms and signs of either mild traumatic brain injury or organic contributors to PTSD. â&#x20AC;&#x153; and periventricular white matter areas. There was reduced amplitude of the stimulated compound action potential in the corpus callosum.

Taken together, these results demonstrated that subclinical primary blast exposure resulted in measureable changes to the brain.

We saw evidence of axonal injury, impaired white matter function and cell death. There was evidence of impaired neuropsychological measures including anxiety and coordination or concentration. Prior to these studies, it was not clear that subclinical exposure to primary blast wave could result in measurable organic brain injury. These studies dem-

onstrated that primary blast waves, of intensity too low to injure the lung or bowel, may indeed harm neurons.

These studies have raised many questions in our minds. For example, could apparently harmless exposure to a primary blast wave actually cause organic brain injury that would result in measurable symptoms and signs? Further, if so, could this be related to the relatively high prevalence of symptoms and signs that are attributed to either mild traumatic brain injury and to PTSD? Our group is pursuing these questions in both civilian and military populations. We hope to identify the underlying mechanisms and look for prophylactic and early treatments. Finally, we hope this information will lead to more questions that will ultimately be helpful for our military personnel.

IMS MAGAZINE SPRING 2012 STEM CELLS | 26

Book Reviews Excellent

Worth missing a day at the lab

Drs. Abdallah Daar and Peter Singer The Grandest Challenge Double Day Canada, 2011; 304 pages

G

lobal health researchers and advocates Drs. Abdallah Daar and Peter Singer have an remarkable goal—to bridge the global health gap that sees life expectancy in the developing world at almost half of what it is in developed nations such as Canada. The cover of their recent book, The Grandest Challenge, speaks straight to that point. Written for a general audience, the book promises to highlight the challenges involved in “taking life-saving science from lab to village.”

The early pages of The Grandest Challenge detail the very personal motivations of the authors, as each discovered their passion for global health and their desire to influence the future in developing nations. Later, they discuss how their research on determining the

27 | IMS MAGAZINE SPRING 2012 STEM CELLS

Very Good

Try to squeeze in between experiments

Good

Wait for the weekend

Average

Wait until degree is complete

top 10 biotechnological priorities for improving health in the developing world1 caught the eye of the Bill and Melinda Gates Foundation.

This collaboration led them to strategically identify critical barriers to improving health outcomes in the developing world—and then led to funding research that addresses them.

This project continues with the founding of Grand Challenges Canada, a Government of Canada-sponsored organization designed to bring innovation to the field of global health.

identify entry points for students and others.”

The Grandest Challenge is eye-opening and informative to basic researchers, students, and those with a genuine desire to become involved with providing aid to the developing world.

Daar and Singer provide unique insights into the challenges of communication, building trust within communities, and the critical role of commercialization. Other insights include the particular obstacles involved in preventing and treating non-communicable diseases in developing regions, beyond the recognized threat of infectious disease. Finally, the book highlights inspiring examples of biotechnological innovation stemming from within low- and middle-income countries themselves, and explains the importance of fostering growth and collaboration in these sectors.

Daar and Singer also discussed with us the role of Grand Challenges Canada, a federallyfunded organization “reinforcing Canada’s role as an innovator in global health development.”

Daar highlights the creation of the Development Innovation Fund in the 2008 Canadian Federal Budget as a “game-changing policy innovation.” This fund resulted in the creation of Grand Challenges Canada and its unique approach to research funding for Canadian innovators and those from low- and middleincome countries. Singer adds that he has “been inspired by the bold ideas of innovators in Canada and the developing world.” Their initiative has made it clear that Canada can make a difference in global health. Asked what the measure of success for the Grand Challenges endeavour will be, Singer answers, “Grand Challenges Canada wants to enable innovators with bold ideas to save and improve lives.”

“Through our book, it is possible to understand the broad sweep of global health and perhaps identify entry points for students and others.”

Calling it a “niche platform at the intersection of life sciences, global health and innovation/ entrepreneurship,” Daar discussed with IMS Magazine some motivations for presenting the Grand Challenges platform in a book accessible to the broader public. “There is tremendous demand from students to learn more about global health,” Daar shares. “Through our book, it is possible to understand the broad sweep of global health and perhaps

Beyond global health, the book offers important insights for trainees who want to see their work used for greater purpose. As Daar says, students “would benefit from paying attention to community engagement and building trust from the very beginning.” Those who don’t have direct interaction with the subjects of their research should still think ahead about how their work will translate into patient benefits.

As simple as that, The Grandest Challenge is a personable and thorough introduction to the great promise and the greater challenges of translating bench science to life-saving interventions in parts of the world that lack the infrastructure to easily do so. The reader will be left with a clearer understanding of cultural barriers, pragmatic challenges, and perhaps also a novel perspective on their own role in bridging the divide between lab and village.

Column by Jennifer Rilstone

BOOK REVIEWS of cause and effect – if event A always precedes event B, and if event B does not occur without event A, then we interpret A as having caused B. Thus, if our conscious thoughts occur before our conscious actions, and conscious actions do not occur without conscious thoughts, then our conscious thoughts must be causing our conscious actions. According to Wegner, the true cause of a ‘conscious action’ is merely an unconscious brain event. This phenomenon is nothing more than trickery. He argues that this system has evolved in the human mind and offers an advantage to the species. By thinking we are consciously willed beings, we develop notions of responsibility, personhood, etc. However, it is still trickery.

Daniel M. Wegner The Illusion of Conscious Will The MIT Press, Cambridge, 2003; 419 pages

R

ene descartes believed that humans consist of two functionally different parts: the mind (or soul), and the body. Although the immaterial mind and the material body influence each other, they are nonetheless distinct. Mind-body dualism has fallen out of fashion with modern cognitive scientists, who suggest that mental and cognitive states reduce to physical phenomena in the brain. However, the problem of consciousness – or specifically, conscious will – is difficult to reconcile under a non-dualistic framework; if cognitive processes are explained physically, then how is it possible for us to have a conscious will that supposedly usurps the physiological events in our brain? The feeling of conscious will is strong, and few people are willing to succumb to the notion that we do not consciously will our actions.

In his book The Illusion of Conscious Will, Richard Wegner not only denies any notion of mind-body dualism, but also delivers a convincing blow to the concept of conscious will.

Wegner’s hypothesis is simple: there are unconscious brain events that lead to conscious thoughts, and there are unconscious brain events that lead to conscious actions. It is only because conscious thoughts invariably precede their associated conscious actions that we feel as though conscious thoughts cause conscious actions. Our brains have a time-centric concept

Wegner offers up a number of chapters full of psychological evidence to show dissociations between conscious thoughts and conscious actions. His plan of attack is to show that we can separate conscious will from conscious action through delicate psychological experiments. If the two can be separated, then it must mean that they are not causally linked. Wegner dives through explanations of Ouija boards, spiritual possession, hypnosis, and others. All of the examples are extremely fascinating, and explained simply enough to attract the non-neuro reader.

The bulk of the book consists of explanations of events that illustrate a de-coupling of conscious will and conscious actions. It is only in the final chapter that Wegner decides to get philosophical. It is here where he renders free will as merely an emotion, and instead promotes determinism. Unfortunately, the last chapter is the weakest. Wegner’s ideas should be considered hypotheses upon which future science is guided. Although many science readers may agree with his conclusions, the evidence Wegner puts forth is not enough to finally settle the debate between free will and determinism. Wegner illustrated many anomalies of conscious will – he did not offer a framework to explain “normal” situations. Simply put, if unconscious events are the true causes of a few conscious actions (namely, those he presented), then it does not necessarily follow that conscious willing cannot cause conscious actions.

Nonetheless, The Illusion of Conscious Will is extremely interesting and offers powerful ideas that will without a doubt be central to the way we think about conscious will in the future.

Column by Adam Santoro

What are you reading?

Melanie Guenette, MSc Candidate, recommends White Coat Black Hat by Carl Elliott (2011, 1st ed) “White Coat Black Hat explores the corrupt relationship between medicine and consumerism. Elliott exposes everything from ruthless drug representatives to professional guinea pigs. If you have ever wondered what goes into getting that pill from the laboratory to your palm, this book will open your eyes to an unsettling reality.”

Allison Rosen, MSc Candidate, recommends The Checklist Manifesto by Atul Gawande (2009, 1st ed) “Gawande departs from his usual anecdote-driven style to propound the benefits of employing checklists in the medical field. The surgeon and writer talks with everyone from construction workers to pilots to describe how trivial errors can happen nearly anywhere. Fans of his earlier works need not worry; this book proves to be just as inspiring and enjoyable as those that came before. Be sure to check this book off your to-read list!”

Allison Rosen, MSc Candidate, recommends The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee (2010, 1st ed) “Mukherjee accomplishes the nearly impossible task of writing a dense, detailed book about the history of cancer that appeals to cancer researchers and lay people alike. From early theories of misbalanced humours to a moving portrayal of the efforts of philanthropists and maverick researchers to increase cancer funding in the early twentieth century, this book delivers equal parts science and history.”

If you are an IMS faculty member or student and would like to have your book recommendation published in a future issue of the IMS Magazine, please send a 50-word review to theimsmagazine@ gmail.com

IMS MAGAZINE SPRING 2012 STEM CELLS | 28

CLOSE UP

O Professor

By Laura Seohyun Park

David Mazierski 29 | IMS MAGAZINE SPRING 2012 STEM CELLS

ver a cup of coffee, I recently met with Professor David Mazierski to discuss his fascinating and unplanned journey to become an associate professor in the Division of Biomedical Communications (BMC) at the University of Toronto Mississauga campus. After beginning his undergraduate degree in art at Buffalo State College, his love for both art and science led him to Toronto. When discussing medical art, Mazierski comments, â&#x20AC;&#x153;Sometimes people pursue art or science, but get excited when they find out that they can

Photo by Laura Feldcamp

Interview with

CLOSE UP

Image courtesy of Dave Mazierski

combine the two,” — something he was able to accomplish at the University of Toronto (U of T) through the Department of Art, as applied to Medicine (then an undergraduate program, but now the BMC graduate program).

Mazierski’s passion and enthusiasm for his work were apparent throughout our conversation. His willingness to take chances led him to numerous cities during his training. In the summer of his last year at U of T, Mazierski completed a medical illustration internship at the University of British Columbia. This experience was important in itself, but also played a pivotal role in leading him to a unique work experience in Israel.

While investigating work opportunities after graduation, he unexpectedly received a letter from a veterinary hospital in Israel inviting him to come work on an atlas of camel anatomy. The director of the veterinary hospital, Professor Daniel Cohen, was looking for a medical illustrator. A colleague at UBC, who had met Mazierski that summer, forwarded Mazierski’s name. Though he had never been to Israel and did not know Cohen, Mazierski was excited by this opportunity, accepted it, and spent a year and a half working on the world’s first atlas of camel anatomy. This also gave him the chance to fulfill his childhood dream of travelling to Egypt, and to work in South Africa where he conducted scientific illustration workshops. With the completion of the camel atlas, he returned to Toronto and taught part-time at U of T while doing freelance work. Working in the Faculty of Medicine’s former medical art service department from 1988 to 1993 also led to the opportunity to contribute to the ninth edition of the Grant’s Atlas of Anatomy. These accomplishments had not been on Mazierski’s “To Do” list and he had no idea where his career would take him, but one thing that kept him going was his passion and love for visual communication. “You have to be interested, passionate and open to ideas,” he says.

While currently supervising BMC master’s degree students, Mazierski also teaches two graduate courses, undergraduate courses (including the human biology course, HMB304H1: Biomedical Visualization), and continues to do freelance work and research in two areas of interest: vertebrate paleontology and the history of medical illustration. Some of the questions that he

and his students explore include: What is the theory behind communication and how can we use and build on various techniques and methodologies to create more effective communication? How can communication be improved for a given audience? How do games work and how can this be used as a strategy to learn? With excitement, Mazierski notes, “The things we do can be applied to any subject.” Indeed, his students represent diversity in science, with research ranging from cell biology to entomology. He agrees that whether or not you are a BMC student, communication skills are essential. “How you present yourself, how you talk, how you relate to others; the basic communication is important,” advises Mazierski. The ability to communicate your ideas clearly using different methods of communication tailored to

your audience is critical — no matter what field you are in.

“Medical illustration is more than knowing how to render an accurate and aesthetically pleasing picture.

It is understanding and answering the needs of the audience and client.” — Professor David Mazierski Asking Mazierski for any advice to our readers, he replied, “Whether you know what you want to do or not, find something that interests you and don’t be afraid of following it.

Believe in what you want to do — enjoy it and be passionate about it.”

IMS MAGAZINE SPRING 2012 STEM CELLS | 30

VIEWPOINT

MD Double Doctors PhD Double Trouble Are physician-scientists spreading themselves too thin?

By S. Amanda Ali

C

The training of a physician-scientist doubles as a selection process to weed out the faint of heart. Four years of undergraduate studies, 2 to 6 years of graduate school, 2 years of postdoctoral research, 4 years of medical school, and 2 to 6 years of residency and specialization equal a lot of time, effort, and money spent on higher education. Many institutions offer a harmonized version of this training, including the University of Toronto. Their 8 to 9 year MD/PhD curriculum produces fully accredited physicians who have completed graduate work according to the PhD guidelines of the School of Graduate Studies.

This still requires a minimum of 12 years of formal and expensive education, a commitment that selects for the particularly keen.

From this extensive training, physician-scientists acquire interdisciplinary knowledge which facilitates their translational contribu31 | IMS MAGAZINE SPRING 2012 STEM CELLS

Photo courtesy of www.istockphoto.com; ID # 10364403

onsider a day in the life of a physician, whose responsibilities include examining patients, performing diagnostic and therapeutic procedures, liaising with medical and non-medical specialists to optimize patient care, teaching medical students, staying current with medical advances, serving on boards, and attending meetings. Now consider a day in the life of a scientist, whose responsibilities include conducting experiments, analyzing data, reading literature, writing grants, publishing results through the peer-review process, supervising graduate students, serving on committees, and attending conferences.

Then consider a day in the life of a physicianscientist whose responsibilities include all of the above. Excelling at either of these professions is admirable, but excelling at both is fantastical.

VIEWPOINT tions to biomedical research and patient care, but this interdisciplinarity also presents a challenge to physician-scientists. Physicians and scientists are trained in very different environments to embody very different values.

Academia is peer-oriented, with great importance placed on the peer-review process.

Medicine is patient-oriented, with doctors aiming to treat and cure individual patients.

Popular culture perpetuates stereotypes of scientists as crazy, socially-awkward nerds (The Big Bang Theory), while physicians are portrayed as attractive, level-headed experts (Grey’s Anatomy). Scientific concepts are frequently challenged by scientists, while medicine is sold to non-expert consumers.

Scientists convince disbelieving peers while physicians handle submissive patients. Academia is slow-paced, with skeptical scientists facing few hard deadlines. Medicine is fastpaced, with decisive physicians reacting to emergency situations. At the centre of these colliding worlds are physician-scientists, with their innate drive to excel and desire to gain acceptance from peers.

Recently, a survey on physician-scientist education was conducted among the students in the MD/PhD program at the University of Toronto. Regarding the balancing of clinical and research responsibilities, and performing both at a high level, one student explained, “I’m concerned about being an excellent world-class researcher and an excellent physician. The reality is that to be one or the other is already to be an exceptional person.” Some perceive a lack of respect and recognition, and feel the “additional training to become a physician-scientist often leads to…less respect from both medical professionals and researchers.” Because of their educational promiscuity, physician-scientists are frequently not accepted as “real” doctors, nor “real” scientists, so their work may be subject to more scrutiny and less recognition.

Alternatively, based on the way in which physician-scientists are revered for their unique ability to speak both science and medicine, their work may be less scrutinized and gain higher recognition than their single-discipline peers.

Evaluating the relative success of physicianscientists over their single-discipline peers is challenging because in both science and medicine, the metrics required for measuring success are severely lacking. Supposedly,

the number of articles a scientist publishes in high-impact journals, and the number of patients a doctor treats and cures reflect their skill; but current metrics do not integrate the multi-factorial responsibilities of these professionals. For example, there are no conventional methods for assessing the quality of teaching and mentorship offered by scientific supervisors in laboratories or by medical doctors in hospitals. Mentoring is an established determinant of the success of a trainee, and has been defined as “the provision, by an already successful and secure academic, of resources (but not obligations), opportunities (but not demands), advice (but not orders) and protection,” from unwarranted scrutiny1.

Therefore, the ability of a physician-scientist to mentor trainees should be considered an indicator of their career success.

But it’s not.

Physician-scientists exhibit a characteristic drive to do more, do it better, and do it faster.

As mentioned, the requisite training selects and breeds a cohort of hardworking overachievers, but surely this takes a toll. Many double doctors seem to execute their enviable multi-tasking capabilities on autopilot, with very little sleep and sustenance from the coffee and cookies at meetings. To speak negatively or criticize a physician-scientist is almost taboo because their role in bridging the gap between bench and bedside is essential for biomedical progress. This, combined with the lack of appropriate metrics, has resulted in very few studies examining the successes and failures of physician-scientists relative to their single-discipline peers. Yet the need for these studies is evident, if based solely on the fact that physician-scientists have double the responsibility of their peers. It is common to praise physician-scientists as the ultimate translators of medical research without questioning the cost at which this skill comes; but when considering the small army of subordinates, patients, and students influenced by physician-scientists, questioning becomes necessary.

So are physician-scientists spreading themselves too thin? Are they adequately equipped to fulfill their job description? Do they have the time to stay current on both medical and scientific literature? Can they review this literature in a meaningful way, so as to synthesize and apply the findings to their work?

How is their bedside manner affected? Are their experimental methods relevant? Do they make significant contributions to supervisory committees and advisory boards?

Is mentoring of medical and graduate students a priority? How well do they interact with colleagues and establish collaborations?

What is the impact on their family and quality of life?

Undoubtedly, physician-scientists will have an advantage in some areas, but a disadvantage in others. In December 2011, the Association of American Medical Colleges published a model outlining the factors involved in the career success of physician-scientists.

According to the model, personal factors such as education, personality, psychosocial milieu, and demographics, as well as organizational factors, such as institutional resources, training, mentoring/networking, and conflicting demands contribute to the extrinsic and intrinsic career success of physicianscientists. This model is meant to serve “as a conceptual framework for research into what does and does not work in efforts to develop a positive career trajectory for aspiring physician-scientists2.” The utility of such a model would be greatly improved if also applied as an evaluative tool to monitor the success of physician-scientists over the course of their careers. Doing so will begin to generate answers to the many questions about the pros and (equally important) cons of being a physician-scientist.

Disclaimer: The opinions expressed by the author are in no way affiliated with the Institute of Medical Science or the University of Toronto. Comments are welcome at theimsmagazine@gmail. com.

References 1. Sackett, D. L. (2001). “On the determinants of academic success as a physician-scientist.” Clin Invest Med 24(2): 94-100.

2. Rubio, D. M., B. A. Primack, et al. (2011). “A comprehensive career-success model for physician-scientists.”

Acad Med 86(12): 1571-6.

IMS MAGAZINE SPRING 2012 STEM CELLS | 32

BEHIND THE SCENES

Behind the Scenes:

Dr. Carol Westall

Visionary Researcher and Compassionate Mentor

33 | IMS MAGAZINE SPRING 2012 STEM CELLS

immediately feel comfortable, much as I did when she interviewed me for admission to the Institute of Medical Science almost two years ago.

We sit down to begin our interview, and Westall tells me she studies children who are

at increased risk of retinal dysfunction due to type 1 diabetes or side-effects from vigabatrin, a drug used to treat infantile spasms (a form of epilepsy). She employs cutting edge imaging techniques called multi-model adaptive optics to examine microscopic changes in the retina. “It’s the same technique used to visu-

Photo by Paulina Rzeczkowska

A

s I arrive at Dr. Carol Westall’s office, she is preparing a cup of tea, true to her British roots. There are several bicycle helmets strewn about, along with a couple of pairs of running shoes.

Seeing me notice these, she exclaims, “I love Bixi bikes!” Her energy is disarming, and I

By Melanie Guenette

BEHIND THE SCENES alize the stars!” she adds, and I can’t help but absorb her enthusiasm. Her laboratory aims to identify the early neurovisual markers that precede detectable vascular dysfunction and the markers of neuronal disease that are predictive of subsequent sight-threatening retinopathy. As she speaks, I realize how strikingly translational her research is in nature.

For example, she has the largest database of retinal findings resulting from vigabatrinuse in a pediatric cohort, and found reduced risk of retinal toxicity when the drug was used for six months or less. These data were presented to an expert panel, whose favourable vote led to the drug’s approval for infantile spasms by the US Food and Drug Association (FDA).

Westall’s exceptional academic training began at The City University in London, England, where she completed a degree in Optometry. When asked why she chose this field, her answer is simple: “I had vision problems as a child and wanted to learn more.” Shortly after graduating, busy with her practice, Westall felt compelled to shift her focus from the clinical setting to vision science research, something that had interested her throughout her undergraduate training. Thanks to the advice of her mentors in London, Westall soon found herself on a plane to Indiana, USA, where she would complete her Master’s degree in physiological optics. She studied the perceptual effects of abnormal eye movements in a disorder called amblyopia, where vision is impaired in a physically normal eye due to disruption in signal transduction from the retina to the brain. To say she had been bitten by the research bug would be an understatement: Westall went on to complete a PhD at the University of California, Berkeley, and two post-docs, this time back in the UK. “After completing my sixth year as a postdoc, it was time to find a real job,” she says, “and a letter from the Hospital for Sick Children (HSC) arrived in the mail.”

In 1991, Westall became Director of the Visual Electrophysiology Unit at the HSC, a position she still holds today. She was appointed, a mere month later, Assistant Professor in the Department of Ophthalmology and Vision Sciences at the University of Toronto. She was surprised to learn that few of her colleagues were supervising graduate students and that the position of Assistant Professor would not suffice for her own graduate supervision. Although she hoped to have

graduate students, Westall explains that she was very busy with her roles in clinic and the Visual Electrophysiology Unit, which included clinical testing, developing a pediatric database of normal values and supervising resident research projects. “I was constantly learning new skills, since my background was not in the clinical assessment of visual electrophysiology; I would not have had the time back then.”

“I really love watching the evolution of my students. I have the privilege of encouraging their academic growth and seeing them achieve great things.”

In 1996, Westall began reconsidering graduate supervision. She credits Dr. Brenda Gallie, fellow vision science researcher, with introducing her to the IMS and encouraging her to seek appointment within the department. “She was my guide and mentor,” she adds fondly. Westall had extensive experience supervising students from her post-doctoral days in the UK but was eager to train students in an official capacity within the IMS. She served on several Project Advisory Committees (PACs) before taking on her first official graduate student in 1999; she has since had more than ten students successfully complete degrees under her supervision.

Westall cannot say enough about the quality of the training offered at the IMS: “I like the structure of the program; in Europe students don’t have modules or seminars like those here.” She also adds that as a non-physician, “I feel accepted and appreciated within the administration, something that has not always been the case.” When asked what drives her to do her job, Westall says her students are the main source of her motivation. “I really love watching the evolution of my students. I have the privilege of encouraging their academic growth and seeing them achieve great things.” Westall’s current role as a member of the IMS admissions committee continues to reaffirm her dedication towards students. “I know what it’s like to worry about getting that acceptance letter, for I had pathetic scores in both English and Biology on my GRE!”

three graduate coordinators for the department. When asked why she accepted the position, she explains that on several occasions she had taken on students who had required a change of graduate supervisor. She says the department was “very open to dialogue,” regarding these students, and that this truly impressed her. For many years, she has been involved in seminars aiming to improve the student-supervisor relationship. She believes this interaction is “amongst the most important” for a student and “crucial to their success within the program and beyond.”

Because the IMS is currently undergoing an external review, I asked Westall about her wish list for the department in the years to come. “I think there is always room for improvement. The main focus should be the way students are supervised; better relationships with supervisors are key to the happiness and productivity of students.” She adds that a critical balance must be achieved in any student-supervisor dynamic: students must be properly supported in all aspects of their research, yet challenged in order to achieve their potential.

“Believe in yourself. Believe in your strength! You can achieve anything if you remain strong. And always remember to breathe.”

In Westall’s opinion, the largest obstacle faced by graduate students involves life after graduate school, “with all the cutbacks in funding, the competition, it is hard to become the next Dr. Whiteside (former IMS student, graduate coordinator and current Dean of Medicine at the University of Toronto)!” Westall’s commitment to her students is obvious to anyone who knows her. When asked what advice she has for graduate students, she quiets for a moment and says, “Believe in yourself. Believe in your strength! You can achieve anything if you remain strong. And always remember to breathe.”

In 2000, Westall became a full member of the IMS and has served, since 2009, as one of IMS MAGAZINE SPRING 2012 STEM CELLS | 34

THE HISTORY OF IMS

The History of the IMS

By Tetyana Pekar and Salvador Alcaire

Dr. Jack Laidlaw

a graduate appointment within the University if they were successful in getting crossappointments in one of the basic science departments in the Faculty of Medicine. This was only granted to a few, and even then, required commitment of extra teaching at the undergraduate level. Thus, very few clinician scientists with appointments in clinical departments had approval from the School of Graduate Studies (SGS) to supervise graduate students.

Dr. Laidlaw envisioned a new program that was tailored to training clinicians and medical students in scientific research. It had to be more flexible than the traditional graduate departments in basic sciences, provide a greater scope of research, and bring together faculty from clinical departments and nearby hospitals. The model for training of clinician scientists across the best academic medical centres typically involved a research fellowship of 3-4 years following completion of clinical training. While this model of training was extremely successful in developing leaders of biomedical research, in the words of Dr. Aubie Angel, Director of the IMS from 1983 to 1990, Dr. Laidlaw felt that research training in the health sciences area would be greatly advantaged with the introduction of standards embodied in formal graduate studies.

The creation of the IMS enabled the establishment of a common curriculum and certain standards in research training. “Whether they were doing an MSc or a PhD, they knew that they had a weekly conference, and that they were expected to report on their work

1960’s – Dissatisfied with graduate training for clinician investigators, Dr. Jack Laidlaw sees need for a more flexible and multidisciplinary approach to training clinicians interested in research.

at a yearly symposium,” says Dr. Angel. “As students, they knew that they had a thesis committee to guide them.”

Dr. Ernest (Bun) McCulloch Before the IMS, there was a huge divide along College Street, separating the basic science departments to the North (the University), and clinical research to the South (the hospitals). In the 1960’s, Dr. Jack Laidlaw joined forces with Dr. Ernest (Bun) McCulloch, who at the time was working with Dr. Lou Siminovitch, to create a multidisciplinary and collaborative program that, in the words of Dr. Mel Silverman, Director of the IMS from 1991 to 2000, “would be responsive to the needs of the clinical departments and [would] train clinician scientists.”

1969 – Dr. Claude Morin, the first IMS graduate, received his Master’s degree.

1967 – The IMS is established as a graduate department at the University of Toronto. Dr. Jack Laidlaw becomes the first Director of the IMS.

35 | IMS MAGAZINE SPRING 2012 STEM CELLS

Photos provided by the IMS Office, Courtesy of Robert Lear

T

he Institute of Medical Science (IMS) is an internationally recognized leader in training clinician scientists and basic researchers—but it wasn’t always that way. In the 1960’s, while basic science research at the University of Toronto was flourishing, research in medical science had fallen badly behind McGill University, its main competitor. Around the same time, Dr. Jack Laidlaw—at the time, Director of the Clinical Sciences Division at the Faculty of Medicine—became increasingly dissatisfied with the quality of training for clinicians interested in becoming physicianscientists. At the time, training consisted of little more than an apprenticeship-style program. Clinician scientists who held clinical appointments in hospitals could only hold

THE HISTORY OF IMS And with that, the IMS was established as a graduate unit within the SGS in the summer of 1967. “It was the genius of Jack Laidlaw… and Ernest McCulloch. They had the vision,” says Dr. Angel. “If it were not for the IMS, various clinical departments would probably have to have graduate programs of their own. We would have had a multitude of small graduate programs with varying standards.

In place of that, we had a large graduate program with a real effort to maintain standards, and the genuine opportunity to provide an interdisciplinary approach,” explained Dr. McCulloch in the 1984 Hanna History of Medicine Interview.

Photos provided by the IMS Office, Courtesy of Robert Lear

In the early 1990’s, student enrollment at the IMS was around 110, and went up to over 300 students by 2000. Currently, the IMS trains approximately 500 graduate students who come from diverse backgrounds: 30% are licensed medical doctors, residents, or fellows, 5% have international MD degrees

Dr. Daniel Roncari

but no longer practice medicine, while 65% of students are non-MDs. In 2010, there were 52 students in the Clinician Investigator Program and 58 enrolled in IMS Professional Programs.

Initially, the IMS was restricted to accepting medical students and physicians interested in becoming clinician scientists. Now, the IMS is open to all students wishing to complete a graduate degree. According to Dr. Angel, the pressure to expand came from the outside: “As the science [within] expanded, the Institute became very attractive to students who weren’t MDs, but who wanted to do medical or medically-related research. [Students] wanted to work with supervisors who dealt with human disease at the bedside, so over time, there was pressure from the outside to accept these students.” Dr. Silverman echoes this point. “The growth of IMS occurred, I think, because a lot of students wanted to have access to people whose research projects and labs were multidisciplinary.”

Furthermore, the IMS is home to the Master of Health Science in Medical Radiation Science and in Bioethics, the Biomedical Communications Program, the Clinician-Investigator Program, and the MD/PhD Program.

It was also the home of the Nursing Sciences Program before it became an independent unit within the SGS. The Surgeon Scientist Program, for example, was initiated and developed by Dr. Bernard Langer and Dr. Steven Strasburg in 1983. Their vision was to build the resources and infrastructure to allow surgeons to engage in research during their post-graduate medical education.

Initially criticized for this conceptual leap, graduates from this Master’s program performed exceedingly well in their careers and went on to hold leadership and academic appointments at the University of Toronto and elsewhere.

1975 – Dr. Ernest McCulloch, previously Graduate Secretary of the IMS, becomes the new IMS Director.

1975 – The IMS launches the Summer Undergraduate Research Program.

When Dr. Angel came to head the Institute in 1983, the IMS was a “Cinderella” program that had yet to rise to its fullest potential, but because it “was de novo from the beginning,” Dr. Angel had the opportunity to launch new initiatives and programs. The Summer Undergraduate Research Program was launched, allowing students to spend their summers doing research, and an undergraduate program enabled students to do research during their lecture-free days. Dr. Angel also helped in launching the Bioethics Program under Dr. Fred Lowy, and in the creation of the Nursing Sciences Graduate Program. He also introduced academic sections—groups of graduate students and faculty who had expertise in a particular area of research. The groups “held separate gatherings that expanded and intensified the experience for the students.”

In 1990, Dr. Angel left to become the Chair of Medicine at the University of Manitoba, and in 1991, Dr. Mel Silverman replaced the Acting Director, Dr. John Wherrett. Dr. Silverman further increased the academic standards and greatly expanded student enrollment. “I restructured the advisory and executive committees, brought in new people, and proceeded to raise the standards and reduce the number of course requirements to maximize time for research,” Dr. Silverman recalls. In addition, inspired by Dr. Bernie Langer’s creation of the Surgical Scientist Program, Dr. Silverman persuaded other clinical departments to jump on board and organize a clinician scientist program in their respective clinical specialties. These included medicine, psychiatry, pediatrics, anesthesia, ophthalmology, radiation oncology, and obstetrics and gynecology. Dr. Silverman explains, “I went around to all the clinical departments and I said, ‘See what surgery has done? You need to get on board if you want to get with it! You need to put some money into the pot to create a cohort of clinical scientists

1979 – Dr. McCulloch is appointed Associate Dean of the School of Graduate Studies, and Dr. H.B. Kedward becomes Acting Director.

1980 – Dr. Daniel Roncari becomes Director of the IMS.

IMS MAGAZINE SPRING 2012 STEM CELLS | 36

THE HISTORY OF IMS

Prior to joining the IMS as Director, Dr. Silverman had been appointed as Director of the

through this dual degree program. Dr. Silverman believed that it was important for clinician scientists to be recognized by the Royal College of Physicians (RCP), which did not formally recognize the title. It was his efforts, along with like-minded colleagues at University of Alberta—and with the support of Dr. Bernie Langer as President of the RCP in the 1990’s—that led to its recognition. Thus was born the RC Clinical Investigator Program, which was targeted to trainees during their postgraduate clinical training. Dr. Silverman recalls, “It was important for clinical scientists to have recognition for their own career.

At the University of Toronto, everyone understood what [the term] ‘clinician scientist’ meant, but at other universities, they didn’t have the infrastructure of training clinician scientists (either [through] an MD/PhD or a program like the IMS). So I went across the country to speak about the IMS, the RC Clinical Investigator Program and the MD/PhD program.” This led to seven or eight other

Dr. Aubie Angel MD/PhD program that he helped develop in the 1980’s. The University of Toronto was the first Canadian university to develop such a program, and Dr. Mel Silverman contributed to restructuring the educational curriculum and enabling aspiring clinician scientists to be trained as both physicians and scientists

1983 – Dr. Aubie Angel steps in as Director of the IMS.

Dr. Mel Silverman

universities starting programs to train clinician scientists, particularly after Toronto’s program—under the leadership of the IMS— was approved by the RCP in 1995. “By 1999, we were the largest clinician-scientist training centre and largest MD/PhD centre,” Dr. Silverman adds.

It became evident that IMS had reached international success when the National Institute of Health (NIH) and the American Association of Medical Colleges (AAMC) invited Dr. Mel Silverman to participate in the restructuring of the American model for training clinician scientists. Using the expertise of the IMS clinician-scientist training program, the AAMC included the IMS model as an exceptional template in their AAMC Task Force Report intended to restructure their program.

Did the IMS ever get too big? “At some point, the breadth and diversity becomes too big; but on the other hand, because the IMS is the graduate unit for all the clinical departments, by definition, it must be able to span the areas represented by the Faculty of Medicine,” Dr. Silverman continues. “The increasing size of the IMS was following in parallel with the increasing size and importance of the health sciences complex at the University.

And as basic scientists join forces with clinician investigators, the combination and flow of ideas was allowing them to tackle more complex problems.”

Initially, the IMS was in the SGS, but now it is housed within the Faculty of Medicine. This seemingly small distinction has, nonetheless, had an impact on the philosophy and future direction of the IMS. “The SGS was dedicated to the excellence of science. The Faculty of Medicine is now taking positions with respect to the role of healthcare in society,” says Dr. Angel. Translational medicine, in the last few years, has become a big priority for the

1990 – Dr. John Wherrett becomes Acting Director of the IMS.

1983 – Drs. Bernard Langer and Steven Strasburg spearhead the initiation of the Surgeon-Scientist Program. Dr. Fred Lowy launches the Bioethics Program, and Dr. James Till (of Stem Cell research fame) launches the Nursing Research Program—initiatives that led to the creation of independent graduate programs and centres at U of T.

37 | IMS MAGAZINE SPRING 2012 STEM CELLS

Photos by Brett Jones

in other departments.’ So even the smaller departments gradually bought into it, and Cathy Whiteside, then Graduate Coordinator, did a great job to lobby the Chair of the Faculty of Medicine to start the PhysicianScientist Program.” The first professional program in Biomedical Communications was also added during Dr. Silverman’s time.

1991 – Dr. Mel Silverman replaces Dr. Wherrett as IMS Director.

THE HISTORY OF IMS Faculty of Medicine, and consequently, for the IMS as well. To some extent, this priority shapes the direction of research undertaken by faculty members within the Institute.

According to Dr. Angel, the priorities were different when the Institute was under the SGS: “We were interested in training the next generation of scientists; it didn’t matter what they did…we were not directing them to an outcome in society. We were directing them to an outcome in the quality of research.”

Photo of Dr. Ori Rotstein by Paulina Rzeczkowska

Photo of Dr. Allan Kaplan by Mohammed Sabri

When it comes to thinking about the future of the Institute, the most important thing, as Dr. Angel sees it, is to maintain creative initiative and focus on developing young minds.

The IMS has to “make sure that the environments are free of misdirected pressures, so that students can understand what original thinking is, and understand the meaning, value, and ethics of original research.” Dr. Angel hopes that the pressures are not direct-

Dr. Ori Rotstein

ed toward producing a drug for the pharmaceutical industry or focusing on whether or not their work is relevant. He adds that when the “government [says] that your work is of no value unless there’s an economic return, that can be a stultifying pressure.” Dr. Angel is concerned that “graduate students will be influenced by priorities of senior granting agencies that value research only in terms of its relevance to an innovation/commercialization agenda. IMS mentors should continuously remind themselves that translational research and innovation are inextricably dependent on a robust base of discovery science and the knowledge that flows from it. I think that we’ve got to be careful there; this requires careful thought.”

In the last four decades since the IMS was established, it has grown from training a handful of students to the present enrollment of over 500 trainees, introduced many programs and initiatives, and has served as a launching pad for several graduate programs. It is not an accident that a significant portion of the biomedical and clinical research that is being done at the University of Toronto is intimately linked with IMS faculty and students.

But perhaps most importantly, the success of the IMS is reflected in the quality of the students it produces: Dr. Ori Rotstein, a graduate of the Surgeon Scientist Program, and the Dean of Medicine, Dr. Catharine Whiteside, are among its alumni. What about the future success of the IMS? It appears to lie in the Institute’s continued dedication to training the next generation of scientists and clinician investigators, attracting nationally- and internationally-renowned faculty, and producing top quality research. In many ways, the future of the IMS is in the hands of today’s students, faculty and administrators—in short, it is in good hands. With the recent initiation of the first-ever IMS Strategic Planning Process under the direction of its new Director, Dr. Allan S. Kaplan, and the current IMS Executive

Committee, the IMS will create a vision for its future that will build on its past.

Dr. Allan S. Kaplan

2011 – After Dr. Rotstein’s departure, Dr. Allan S. Kaplan become the current Director of the IMS. 2000 – Dr. Ori Rotstein takes over as Director of the IMS.

IMS MAGAZINE SPRING 2012 STEM CELLS | 38

RESEARCH HIGHLIGHT

The Canadian Sports Concussion Project

W

hile a single concussion can resolve without issue, repeated head trauma may cause grave long-term consequences, including degenerative brain disease in the most severe cases. Given the prevalence of concussions in sports—especially in high-contact games like football and hockey—this problem is especially relevant for athletes. (For a full discussion of sports-related concussions, please see our Winter 2012 edition.)

Researchers involved in the Canadian Sports Concussion Project—based at the Krembil Neuroscience Centre at Toronto Western Hospital—are investigating a potential correlation between repeated concussive incidents in athletes and late deterioration of brain function. The project’s multidisciplinary team includes neurosurgeons, neurologists, neuropathologists, and neuroradiologists, among others, allowing for a unique clinicalMRI-neuropathological research analysis of the athletes studied. Specifically, the project encompasses two main studies: a clinical research arm and a brain donation component.

Of particular interest to the group is chronic traumatic encephalopathy (CTE), a posttraumatic neurodegenerative disease first described in boxers in the 1920s that is characterized by tau protein deposits, neurofibrillary tangles, and brain atrophy. Clinically, those suffering from CTE may exhibit personality changes, disordered motor control, and a progressive loss of cognitive function, which can ultimately develop into full-blown dementia. At present, there is no effective treatment for this condition and confirmation of the disease is generally only possible upon postmortem evaluation.

Currently, the clinical study is open to former Canadian Football League (CFL) players, in which participants undergo neurological, neuropsychiatric, and neuropsychological assessments, as well as an MRI scan. “[The] brain imaging arm [examines] the possible functional and structural brain abnormalities associated with repeated concussions,” explains Dr. Karen Davis, who runs the MRI 39 | IMS MAGAZINE SPRING 2012 STEM CELLS

component of the study and is Head of Toronto Western Research Institute’s Division of Brain, Imaging and Behaviour – Systems Neuroscience. “The definition of a concussion was not clear many years ago, and this certainly impacted record keeping in the past,” cautions Dr. Davis. “It can be a challenge to determine the exact concussion history of former players because [of this].” The project’s researchers encourage CFL alumni to participate in this study even if they have never received an official concussion diagnosis, but are currently experiencing head injury-related symptoms.

The second component of the Concussion Project involves postmortem brain evaluations of professional athletes and members of the public who have suffered multiple concussions. At present, brain donations can come from family members of deceased football and hockey players, as well as living donors who agree to provide their brains upon death. All donations are completed with full, informed consent, and privacy of donors is of utmost importance to the research group.

Thus far, six former CFL players have donated their brains for study, but autopsy results suggest that the relationship between repeated head injury and neurodegenerative disease is not so clear-cut. “All [players] had sustained multiple concussions—but three had CTE, and three did not,” reveals Dr. Charles Tator, Professor and Former Chair of Neurosurgery, and one of the project’s leading concussion experts. Indeed, the study’s initial results have generated more questions than answers regarding the long-term consequences of frequent concussions.

In a 2011 UHN media release, Dr. Tator emphasized the need to determine what causes CTE to develop in some athletes and not others, and to elucidate the number of concussions or level of trauma required to trigger the degenerative disease. Through both research arms of the Concussion Project, the hope is that investigators will be able to reveal the specific pathophysiology of CTE— knowledge that will certainly have tremen-

By Nina Bahl

dous impact on athletes in the future. “We want to be able to detect CTE antemortem, and to discover effective prevention and treatment strategies,” says Dr. Tator.

Results from this project and other recent studies have confirmed that CTE can develop in a number of different athletes who are exposed to repeated brain injury, but further research is needed to determine any concrete links between frequent concussions and neural degeneration. With endorsements from the Canadian Football League Alumni Association, the Canadian Football League, and the Professional Hockey Players Association, the Canadian Sports Concussion Project is well positioned to begin disentangling this complex relationship.

To learn more about the Canadian Sports Concussion Project, please visit www.donateyourbrain.ca. To support the project, please visit the Toronto General and Western Hospital Foundation at www.tgwhf.ca/giving/donate.asp Canadian Sports Concussion Project Research Team Richard Wennberg, MD, FRCPC Charles Tator, MD, PhD, FRCSC Lili-Naz Hazrati, MD, PhD, FRCPC Anthony Feinstein, MD, PhD, FRCPC Robin Green, PhD, CPsych Karen D. Davis, PhD Michelle Keightley, PhD, CPsych Leo Ezerins, Executive Director of CFL Alumni Association David Levy, MD, DOHS, DipSM Carmela Tartaglia, MD, FRCPC Peter St. George-Hyslop, MD, PhD, FRCPC Pushpindar Saini, MA, CPsych Sophie Soklaridis, PhD J. David Cassidy, PhD, DrMedSc

References 1. University Health Network. (2012). The Canadian Sports Concussion Project at the Krembil Neuroscience Centre, Toronto Western Hospital.

2. University Health Network. (2011). Brain autopsies of four former football players reveal not all get chronic traumatic encephalopathy.

3. McKee AC, Cantu RC, Nowinski CJ, et al. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy following repetitive head injury. J Neuopathol Exp Neurol, 68(7): 709-735.

Ask the

Experts

Dear Experts, I am an associate faculty member at the IMS and I would like to take on new graduate students. When do I find out if they have been accepted or not? What if they don’t get accepted to IMS? -Waiting on Students Dear W.S., As an Associate Member of IMS, it would be a good idea to sit on one or more Program Advisory Committees (PACs) before supervising your own MSc student (you cannot supervise a PhD student until you become a Full Member). By sitting on a number of PACs, you will find out about important issues dealing with courses, timelines, and other requirements. IMS has two entry dates: Sept 1 and Jan 1 of each year. Students will usually know whether they are accepted by July (for September) and early December (for January). Occasionally there is a delay, usually because final grades are not available or a reference is missing. If the student is not accepted, he or she can make an appointment with a Graduate Coordinator to find out what can be done to improve the application for the next entry period. As the supervisor-to-be, you may wish to accompany the student and ask your own questions.

Dear Experts, I am international student in the process of writing my PhD thesis; unfortunately, my English writing is not very good. Is there somewhere or someone I can give my thesis to review before showing my supervisor and PAC members?

-Writing Worries Dear W.W., The best first step would be to show your supervisor the initial draft of your thesis and consult with him or her as to what to do.

There is help at the University and there may

be help in your supervisor’s laboratory, which is sometimes preferable for a highly technical topic. If there is time, an English writing course (several are offered at the University of Toronto) would be very useful—not only for the thesis, but for later publications as well. All students, especially those who are non-native English speakers, are encouraged to take English writing courses; they are immensely valuable for an academic career.

Dear Experts, I’m a first year PhD student. Am I able to take a vacation this summer?

-Beachy Keen Dear B.K., You are, of course, entitled to a vacation, but when it takes place is something you need to discuss with your supervisor. The requirements of your project and the contingencies of the laboratory will dictate when you can be absent. It is best to work that out many months before your planned vacation.

Dear Experts, I am in the process of finishing my first year of my Master’s degree. How do I know if I am eligible to transfer to a PhD program? When should I talk to my supervisor?

-Aspiring Academic Dear A.A., Why not talk to your supervisor about this right away? The answer may be “let’s wait and see,” but it is a good idea to let the supervisor know that you are interested in transferring. The decision should probably be made at around 15 months after you start and will depend on the nature of your project, how well it is progressing, and also on available funding. If your current supervisor is to be your PhD supervisor, he or she must have a Full Graduate School appointment.

Dear Experts, How do I talk to my supervisor about attending a conference?

-Conference Hopeful Dear C.H., The question suggests that either your supervisor is hard to talk to, money in the lab is very tight, you don’t know if you are entitled to go to a conference, or you are shy about asking. Whatever the reason, the only thing to do is to ask! Select a specific conference and ask if you can attend.

If you prepare an abstract for the conference, the likelihood of a positive answer rises. If your abstract is accepted, it rises even more. If the concern is regarding money, make sure to look into any travel awards for which you are eligible—the websites of the intended conference and the School of Graduate Studies are great starting points.

EXPERT TIP Don’t be afraid to communicate openly and honestly with your supervisor throughout your graduate degree.

Do you have a question for the experts? Please send it to theimsmagazine@gmail.com (ATTN: Experts).

IMS MAGAZINE SPRING 2012 STEM CELLS | 40

PAST EVENTS

PAST EVENTS

Prospective students learn about the opportunities offered by the IMS from current students and faculty at this year’s successful IMS Open House event.

IMS students and fellow yogis participate in the “Downward for Dogs” yoga charity fundraiser. This event helped raise funds for the Ontario Society for the Prevention of Cruelty Towards Animals, one of the largest, most responsive animal welfare organizations in the country.

Students engage in some serious pool action during IMSSA’s Apartment Crawl. This event gave students an opportunity to hang out, relax, and take a fun break from the lab.

IMS students and faculty mingle over some delicious treats at the IMS Annual Holiday Party (bottom left).

Photos courtesy of the IMS/IMSSA.

The delighted Holiday Party Committee poses for a photo at their successful event (right).

41 | IMS MAGAZINE SPRING 2012 STEM CELLS

DIVERSIONS

Messy Desk Competition Winner!

Around the laboratory

Congratulations to Rickvinder Besla, winner of the Messy Desk Competition!

CROSSWORD ACROSS: 2. An apparatus used to hatch eggs or grow microorganisms under controlled conditions.

7. An instrument used for cutting cloth, paper, and other material.

8. The movement of charged particles in a fluid or gel under the influence of an electric field.

12. A tube or pipe that is wide at the top and narrow at the bottom, used for guiding liquid or powder into a small opening.

â&#x20AC;&#x153;Piled Higher and Deeperâ&#x20AC;? by Jorge Cham www.phdcomics.com

Photo provided by Rickvinder Besla, winner of Messy Desk Competition

15. A small container, typically cylindrical and made of glass, used esp. for holding liquid medicines.

16. A machine with a rapidly rotating container that applies centrifugal force to its contents, typically to separate fluids of different densities or liquids from solids.

DOWN: 1. An instrument for preventing the flow of blood from an open blood vessel by compression of the vessel.

3. A person employed to look after equipment or do practical work in a laboratory.

4. A substance or mixture for use in chemical analysis or other reactions.

5. An implement with a broad, flat, blunt blade, used for mixing and spreading things.

6. A cup-shaped receptacle made of hard material, in which ingredients are crushed or ground, used esp. in cooking or pharmacy.

9. An appliance or compartment that is artifically kept cool and used to store food and drink.

10. To reduce to particles and disperse throughout a fluid.

11. A covering for the hand worn for protection from contamination.

13. A tube with a nozzle and piston or bulb for sucking in and ejecting liquid in a thin stream.

14. A straight-sided, optically clear container for holding liquid samples in a spectrophotometer or other instrument.

IMS MAGAZINE SPRING 2012 STEM CELLS | 42

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