IMS Magazine Spring 2013

Student-Led Initiative

INSTITUTE OF MEDICAL SCIENCE PRESENTS TUESDAY MAY

28 2013 · CHESTNUT CONFERENCE CENTRE

89 CHESTNUT STREET · ALL SESSIONS IN COLONY GRANDE BALLROOM

8:15 9:00 9:05 10:40 11:00

Registration, Breakfast and Poster Set-up Welcome and Introduction Student Talks: Laidlaw Prize Competition Award Presentations Poster Competition

12:30 Lunch · Giovanni Room 2:00 Siminovitch-Salter Lecture 2:30 Director’s Report 3:00 Award Presentations 3:30 Bernard Langer Lecture in Health Sciences

Jeffrey Mogil, PhD

E. P. Taylor Professor of Pain Studies and Canada Research Chair in the Genetics of Pain, Department of Psychology, McGill University

4:30 Reception · Giovanni Room

www.ims.utoronto.ca Poster Design by: K.S.Ho, E.Kenzie, M-S.Ma, C.Song, A.Q.Tran

TABLE OF CONTENTS

Cover design by Andrea Zariwny; Photo of Dr. Gillian Einstein by Chung Ho Leung; Viewpoint Photo courtesy of www.stockvault.net; ID # 135411.

IN THIS ISSUE...

Commentary ....................................

Letter from the Editor.......................

News at a Glance ...........................

Director’s Message .........................

Feature.............................................

Spotlight ..........................................

Book Reviews ..................................

Close Up...........................................

Viewpoint ........................................

Expert Opinion..................................

Special Tribute.................................

Future Directions .............................

In The News ....................................

Ask the Experts ...............................

Past Events ......................................

Diversions .......................................

03 08 09 12 13 24 25 27 29 33 35 37 39 40 41 42

13 FEATURE

Drug Rescue and Repurposing

Our experts discuss how established drugs are being reinvestigated for potential new therapeutic applications.

MAGAZINE STAFF Editor-in-Chief Natalie Venier Nina Bahl Managing Editor Assistant Managing Editors S. Amanda Ali Tetyana Pekar Adam Santoro Brittany Rosenbloom Marika Galadza Departmental Advisors Mary Seeman Melissa Cory Design Editors Laura Greenlee Michael Soong Inessa Stanishevskaya Andrea Zariwny Laura Seohyun Park Advertising Manager Salvador Alcaire Magazine Committee Anna Badner Rickvinder Besla Nancy Butcher Jill Cates Josephine D’Abbondanza Danielle DeSouza Yekta Dowlati Aaron Kucyi Rosa Marticorena Benjamin Mora Anna Podnos Zeynep Yilmaz Chung Ho Leung Photography Laura Feldcamp Brett Jones Paulina Rzeczkowska

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Expert Opinion: Sex and Immunity Dr. Gillian Einstein and student Anna Podnos discuss the importance of biological sex in immune responses.

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Viewpoint: Vis Medicatrix Naturae or Medicine?

Benjamin Mora presents an evaluation of naturopathy and the healing power of nature from his scientific standpoint.

Cover Art

Copyright © 2011 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.

Cover design by Andrea Zariwny.

This cover focuses on the recycling/repurposing of a beta-blocker drug called propranolol. It was initially only used to treat high blood pressure but is undergoing research to be repurposed to treat psychiatric cases for posttraumatic stress disorder.

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 02

COMMENTARY

COMMENTARY

WHAT OUR READERS ARE SAYING

Dear Editor, My article “MD/PhD = Double Doctors = Double Trouble” appeared in the Spring 2012 issue of the IMS Magazine and posed the question: “Are physician-scientists spreading themselves too thin?” The article was purposefully titled as a question – and not a statement – to provoke useful discussion about the challenges physician-scientists face, and to stimulate critical thinking that may lead to improved physician-scientist training and career success.

And discussion was provoked. I received feedback in person and through the IMS Magazine from across the University of Toronto (U of T): from the MD/PhD Program Director, Dr. Norman Rosenblum, to the MD/PhD Class Council, to the U of T and IMS communities at large. A recent gradu-

My informal sampling of U of T’s medical and scientific community revealed disagreement as to whether physician-scientists are “spread too thin.” The division is reflected in the magazine’s online discussion forum at www. imsmagazine.com, where issues surrounding time distribution (“Why not get an MBA and do a 33%-33%-33% split?”) and definitions of success are under debate. I originally asked whether physician-scientists are spread too thin, and this question can be answered by examining the relative success of physicianscientists to their single-discipline peers.

our magazine highlighted the pitfalls of assigning excessive value to high-impact publications (see “Publish and Perish,” Fall 2012). I previously discussed a model from the Association of American Medical Colleges which categorizes personal and organizational factors that contribute to the career success of physician-scientists.1 The model highlights the need for more comprehensive metrics to evaluate the success – both extrinsic (workrelated) and intrinsic (life satisfaction) – of physicians, scientists, and physician-scientists. As Dr. Dugani mentioned himself, “Double Doctors” have “Double Responsibility,” so surely this extra responsibility has some effect on overall success in the lab, in the clinic, and at home.

As many do, Dr. Dugani offered publication record and award history as evidence of the success of MD/PhD trainees. This evidence assumes a limited definition of success, and

‘Conflicting demands’ constitute one of the organizational factors which influence the career success of physician-scientists.1 Scientists are skeptical about theories and phy-

ate of U of T’s MD/PhD program, Dr. Sagar Dugani, offered his opinion in a Letter to the Editor, published in the Fall 2012 issue.

Follow our online discussion...

RE: Letter to the Editor (by Dr. Sagar Dugani, Fall 2012) This is a good response, but I still don’t understand how it can defend against a very simple argument: a person devoting 100% of their time towards a single task will be “better” than another equally capable person spending 50% of their time on the task. That, I believe, is the core of Ali’s argument from the past issue. MD/PhD students are indeed extraordinary and do accomplish a lot, but where do you draw the line? Why not get an MBA and do a 33%-33%-33% split?

- Comment 1, Anonymous 1 I don’t think Dr. Dugani was arguing that a “person devoting 100% of their time towards a single task will be ‘better’ than another equally capable person spending 50% of their time on the task.”

Every person’s career (be it clinician-scientist, clinician or scientist) is unique because of differences in specialty, research field, and countless other personal and professional factors. Sweeping statements about MD/PhD’s being “spread too thin” as a whole ignore this individual variability and are

03

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COMMENTARY sicians are authoritative on diagnoses, and these traits serve both professionals extremely well in the different worlds they inhabit.

But skepticism and certainty are antonymous, as are many of the characteristics that are expected of scientists versus physicians.

The memorization that is required to be an efficient physician is in stark contrast to the imagination that is required to be a productive scientist. Although these opposing ways of thinking are not mutually exclusive, it is very unlikely that one individual can truly master both.

Some argue that physician-scientists are predominantly physicians or predominantly scientists. This may be an attempt to reconcile conflicting demands. Preference for either science or medicine emerges through a physician-scientist’s division of time; if one “opts for an 80-20 split,” then the individual reveals preference for one endeavor over the other.

Throughout a career, time demand may override preference, but the elected distribution of “protected time” still reflects an individual’s priorities. When that priority is established, it can be expected that the physicianscientist will achieve greater success in the preferred discipline, at the expense of success in the other. A 20% commitment is insulting to any endeavour and will inevitably result in compromised performance.

Another organizational factor that influences the career success of physician scientists is the institution in which they are based.1 U of T may be better able to provide physicianscientists with the resources and support

necessary for success in both the clinic and the lab, whereas newer and smaller institutions may place higher demands on individual physician-scientists. Conversely, during training, newer and smaller programs may offer modern approaches which facilitate success. For example, Queen’s University is launching Canada’s first “Accelerated Route to Medical School” where high-school students are selected for a 2-year undergraduate degree program followed by a 4-year degree program in the Queen’s School of Medicine.

As one strategy for reducing the cost and time commitment of medical training, this represents the kind of improvement that is possible with progressive thinking.

U of T’s faculty and students are among the best of forward thinkers, and this is evidenced by the critical assessment of clinicianscientist training undertaken by Dr. Norman Rosenblum in Fall 2011. A Task Force on Physician Scientist Education was established to survey current U of T MD/PhD Program and Clinical Investigator Program trainees. This action demonstrates awareness that there is room for improvement, as Dr. Rosenblum points out in the Spring 2012 edition of the MD/PhD Newsletter Pair O Docs, “In many ways, the educational model for physician scientist training has been static for decades.

It is time for a careful review.”2 According to survey results, the vast majority of trainees do not regret their decision to be in these dual programs, and intend to pursue careers as physician-scientists. Nevertheless, trainees did voice concerns that support the

need for scrupulous appraisal of the existing model. As Dr. Rosenblum summarized, “Results also indicate that MD/PhD students are concerned by lack of integration between the medical and PhD curricula during their training, the length of time it takes to complete undergraduate and postgraduate training, how their career will be configured to include clinical activity and research, the sustainability of a physician scientist career and eventual career ‘burn out.’”2 With a response rate of 82%, Dr. Dugani can rest assured that these are not but one student’s comments.

The need for physician-scientists is undeniable, but so are the challenges they encounter.

This is profound justification for constructive review of current paradigms. Success exists along a spectrum, so we can always be better.

As said by Thomas A. Edison, “Discontent is the first necessity of progress.” My views are my own and everyone (students, clinicians, and scientists) can contribute to a meaningful discussion on this topic – but only if it is being discussed.

Shabana Amanda Ali PhD Candidate

References 1. Rubio DM, Primack BA, Switzer GE, Bryce CL, Seltzer DL, Kapoor WN. A comprehensive career-success model for physician-scientists.

Acad Med. 2011 Dec;86(12):1571- 6.

2. Rosenblum N. A Critical Assessment of Clinician-Scientist Training. University of Toronto; 2012 [cited 2013 January]; Available from: http://mdphd.utoronto.ca/wp-content/uploads/2012/04/MDPhD-Newsletter-2012.pdf.

unfounded. Let each person define success for his/herself. If there is a useful way to combine an MBA, MD and PhD into a single career, and someone is capable of doing so productively and effectively, then why not?

- Comment 2, Anonymous 2 I agree fundamentally, but being “spread too thin” is an objective statement implying some sort of objective measure. Defining success subjectively is in my, and I imagine your opinion, ultimately correct - but it can still render a person less “capable” at a single task than someone devoting their full time to it. I think this conclusion is the correct one, even though it might differ from a given individual’s definition of success.

- Comment 3, Anonymous 1 If being “spread too thin” is proposed to be an objective measure, then at the bare minimum it should be operationally defined, and evidence should be provided to indicate that this variable differs between MD/PhD’s and other careers. Neither was provided in the original article.

The overarching point, which I think resonates with Dr. Dugani’s piece, is that you cannot directly compare different careers in terms of ‘time devoted to a particular task’ and then conclude that one is better/more effective than the other. There are too many other factors to consider, including the fact that MD/PhD’s can use clinical experiences to their advantage when forming research questions.

- Comment 4, Anonymous 2

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COMMENTARY Dear Editor, Thoughtful and incisive, the recent IMS Magazine article on science and journalistic ethics was much needed (see “Science Fact vs. Fiction,” Fall 2012 edition). In contrast, the opinion piece on Internet use and its effects on social skills (see “Social Ineptitude,” Fall 2012 edition) would perhaps have been better placed in another publication and not a science-focused one. Opinion needs no grounds; it is simply opinion. When associated with science, though, it should have some foundation.

At the core of the opinion piece is the assumption that a heavy-Internet user’s pragmatics—their social use of language in the context of nonverbal communication—becomes impaired from lack of practice. I know of no empirical evidence for that, though it too is an empirical question. Existing findings convey quite the opposite and I quote just a taste of those findings below.

Health science investigators vary in their awareness that social science findings can be reliable and valid. (Meanwhile, distinctions between physical, health, and social sciences are now crumbling, due to findings in the physics of self-organizing systems.) Regardless of a researcher’s estimation of the social sciences, its findings are empirical. There is assuredly more recent work than what I

quote here from “Psychological Predictors of Internet Social Communication” (Birnie & Horvath, 2002), but this is a start: “Overall, the findings supported the implications of social network theory in that online social communication appeared to complement or be an extension of traditional social behavior rather than being a compensatory medium for shy and socially anxious individuals. With relation to uses and gratifications theory, however, shyness was associated with increased intimate socializing over the Internet, indicating that traditional and Internet communication are not functionally equivalent.”

Of course, since then, we have also had to consider the Internet’s social effects in the context of safety and child-teen boundary distortions. As examples, Amanda Todd’s death and The Supreme Court of Canada case of cyber-abused teen girl AB represent one side of this issue. The other side pertains to the clinically presenting problem for those of us in child and adolescent clinical and school psychology: cyber self-exposure of various kinds.

Other implications of the Internet on social skills include: (a) A transitional learning opportunity for persons with autism and Asperger disorder (www.mnsu.edu/comdis/ kuster4/part103.html); (b) Distorted Boundaries: An inquiry into the effects of Internet use on social skills (socserv2.mcmaster.ca/

soc/courses/stpp4C03/ClassEssay/socialskills.htm). Additionally, right here at U of T, Prof. Barry Wellman (http://homes.chass. utoronto.ca/~wellman/) is a leading authority on the Internet’s effects on society and has authored the book, Networked: The new social operating system (http://mitpress.mit. edu/books/networked).

In summary, science is science. We run terrible risks when we artificially carve it up into

University of Toronto Trauma Application – Best Practices in Trauma Care Louridas, M., Strickland M., Bakanisi B., Nathens AB. The U of T Trauma Protocols app, launched this winter, was developed to help trauma teams in Toronto’s hospitals offer their patients the best possible care.

The management of an injured patient is a complex, multidisciplinary, team effort where standardizing protocols is imperative to reduce errors and straying from best practice. Over the years, many of the city’s hospitals have individually developed and implemented set procedures for situations like cervical spine injuries or when massive amounts of blood must be given to a patient. Now, through input and leadership from physicians in the Departments of Surgery and Emergency Medicine, the University of Toronto is unifying these protocols.

Ensuring that physicians, resident doctors, nurses, and medical students are using the standards is an entirely different challenge. Given how commonly smartphones are used around the hospitals and in the day-to-day life of medical professionals, creating an app seemed like an ideal way to reach this target audience. Now, staff can download the program for Android, iOS, or as a web app and conveniently access the information as needed and where needed. With over 2000 downloads already, it is clear that the U of T Trauma Protocols app is garnering attention outside of just Toronto’s hospitals as well.

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| IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING

COMMENTARY I myself have dealt with this for several years but only was recently diagnosed. Thankfully, my doctor was able to diagnose it and prescribed me an antifungal medication. However, many people who have this condition are not even aware of it.

Before making such strong statements, it would be advisable to do one’s research on things like this. People might take it the wrong way and be hurt or offended—just a recommendation.

Anonymous

Dear Editor,

competing factions and wave flags for them as physical, or health, or social.

Yours in health and development, Ken McCallion MA CPsych Assoc

I really enjoyed your last issue. It was informative and gave me a good understanding of the trauma research going on at the IMS. As an undergraduate student in Human Biology, I feel inspired to join the IMS and contribute!

Sincerely, Samantha Rodriguez

Dear Editor, Dear Editor, The magazine looks great! I do have one comment I’d like to add: One of your writers made a comment about individuals with persistent bad breath as a marker of social ineptitude (see “Social Ineptitude,” Fall 2012)—I might add that individuals reading this who suffer from the medical condition known as oral candidasis might be offended by this statement. This is a very difficult fungal infection that immunocompromised individuals (e.g. people with AIDS, etc.) must endure on a regular basis. People with diabetes, as well as the older population, also have to deal with this condition. One of the problems with having a nasopharyngeal fungus infection is the smell that is associated with it. This is, in turn, connected to bad breath—but very few people actually know the cause. It is not due to a lack of hygiene, it is because the immune system can’t fight a fungus that lives in our bodies.

Having suffered extensive injuries in a car accident many years ago, I read your trauma edition with great interest. I am thoroughly impressed by the dedicated research efforts of the many scientists in this field. Thanks very much for also including a patient perspective piece - I hope it provides added insight into the harsh realities of traumatic injury to those working to improve urgent patient care.

Call for Articles The IMS Magazine is looking for scientific content to post on the IMS Magazine website. Whether you are a current blogger looking to cross-post your scientific musings, or are just looking to get your ideas out there on our platform, your submissions are welcome. Submissions are expected to be approximately 800 words in length (with considerable leeway) and priority will be given to individuals who comment and report on IMS specific issues (i.e. research in the department, conferences, general scientific issues that affect the IMS faculty and students, etc.) although viewpoints and commentaries are also welcome. Send an email to theimsmagazine@gmail.com for more information.

Contact Us We encourage our readers to send their feedback -- comments, questions, corrections, and letters to the editor -- to theimsmagazine@ gmail.com.

Come join our discussion on the newly designed www.imsmagazine.com. Engage in dialogue with fellow IMS students and faculty, and even post your own article to our website. We are always looking for IMS student journalists to contribute to our content, whether they wish to discuss new research around the IMS, or wish to comment on a controversial topic in science and scientific training.

Sincerely, C.L.

Disclaimer: The opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Comments are welcome at theimsmagazine@ gmail.com.

www.facebook.com/groups/imsmagazine/ @IMSMagazine

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 06

LETTER FROM THE EDITOR

Letter from the Editor R

esearch questions are essential to the scientific method. The multi-disciplinary environment here at the IMS can prompt the development of interesting research questions from different research perspectives. For example, a basic scientist may come across an interesting finding after performing a large-scale gene array analysis, an epidemiologist can encounter a noteworthy trend in a population study, or a clinician may a come across a remarkable patient observation in clinic—all of which may spark novel investigative questions that can potentially impact medical research as a whole. I believe this is one of the exquisitely unique aspects of translational research, which is of tremendous importance in delivering the most effective patient care.

The feature for this issue of the IMS Magazine focuses on the rescue and repurposing of drugs. In understanding this process, it is remarkable to realize the many different ways scientists have uncovered that a drug once used to treat a specific disease can also have beneficial effects on a completely different condition. From using established diabetes drugs to treat cancer, to using established schizophrenia drugs for anorexia nervosa, we hope to give you a birds-eye view of the rescue and repurposing initiatives taking place here at the IMS. As you read through these interesting articles, I hope you will be inspired to think about new research questions at the bench, bedside, and beyond!

Are we training PhD students for jobs that don’t exist? Recent IMS graduate, Tetyana Pekar, addresses a concern amongst many graduate students in her Viewpoint article. In addition, Benjamin Mora provides an evaluation and the healing power of nature in his perspective article, Vis Medicatrix Naturae or Medicine? I strongly encourage commentary articles and feedback letters about these controversial topics.

Natalie Venier

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

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

I would also encourage you to read through our special tribute article on Dr. Karen Davis, former Associate Director and Graduate Coordinator, who helped shape the IMS into the institution it is today. Also, as a prelude to our next issue, Laura S. Park weighs in on the misattribution of mental health in the media in our brand new In the News section.

Furthermore, I would like to thank Dr. Allan Kaplan and the IMS department for their ongoing support, and welcome our official new “expert,” Dr. Mary Seeman, who has graciously taken on the task of responding to questions in our Ask the Experts section. She brings her experience as graduate coordinator and faculty for many years at the IMS. Lastly, once again, I would like to congratulate our team on their outstanding efforts in the production of this fabulous edition of the IMS Magazine. I hope you enjoy this issue, and I strongly encourage comments and feedback letters 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 2013 DRUG RESCUE AND REPURPOSING | 08

NEWS AT A GLANCE

NEWS&VIEWS at a glance...

APRIL 12

Final day to hold MSc or PhD defense to be eligible for June 2013 convocation

22

Online registration for May courses offered by the Office of English Language and Writing Support (ELWS)

IMS ANNOUNCEMENTS

MAY 28

IMS Scientific Day - mark your calendars!

IMS Scientific Day – May 28th, 2013 The Annual Scientific Day is the academic highlight of the year at the Institute of Medical Science. It is designed to highlight student achievements, provide opportunities to work on presentation skills, and encourage faculty and students to meet and mingle. All faculty and students are highly encouraged to attend.

We are delighted to announce this year’s Bernard Langer keynote lecturer as Dr. Jeffrey S. Mogil, PhD. Dr. Mogil is currently the E.P. Taylor Professor of Pain Studies at McGill University and the Canada Research Chair in the Genetics of Pain (Tier I). He is a recognized authority in the fields of sex differences in pain and analgesia, and pain testing methods in the laboratory mouse. His lecture is entitled “Mice are People Too: Translation in Pain Research from Genetics to Social Modulation.”

This year’s Scientific Day will be held on May 28th, 2013 at the Chestnut Residence and Conference Centre, 89 Chestnut St. Parking will be available on site with an early bird special for those arriving before 9am.

We look forward to celebrating your academic achievements this upcoming Scientific Day.

JUNE 5

Convocation date for PhD graduates

6

Convocation for MSc graduates

AWARDS & SCHOLARSHIPS 1. 2013-2014 Queen Elizabeth II Graduate Scholarship in Science and Technology (QEII-GSST Program) Internal Deadline: TBA 2. 2013 -2014 SGS University-Wide Awards Internal Deadline: Monday April 22, 2013 by 5pm

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

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More information can be found at: http://www.sgs.utoronto.ca/informationfor/ students/money/support/internal.htm#University%20Wide%20Awards 3. 2013 – 2014 Faculty of Medicine OSOTF and Restricted Awards Applications are submitted on-line to the Faculty of Medicine Faculty of Medicine Deadline: Wednesday, May 1, 2013 by 6pm More information can be found at: http://graduate-awards.knowledge4you.ca/ graduateawards/

NEWS AT A GLANCE

SPOTLIGHT ON IMS FACULTY From interviews in acclaimed magazines to international radio coverage, our faculty are being recognized for their impact on scientific discovery the world over.

If you’re a CBC radio morning listener, you may have caught Dr. Ian Tannock on The Current on January 14th. Dr. Tannock is a medical oncologist and senior scientist at the Princess Margaret Cancer Centre in Toronto and has been an active IMS faculty member since 1990. His segment on CBC focused on positive spin and bias in a series of drug trials for breast cancer treatment. He was joined by Dr. John Fletcher, Editor-inChief of the Canadian Medical Association Journal and Dr. An Wen Chan, scientist at Women’s College Hospital, to discuss the findings of Dr. Tannock’s research, recently published in the Annals of Oncology.

Perhaps the topic sounds familiar? In fall 2011, the IMS Magazine brought this issue

to the forefront, through an article entitled “Bias in Reporting of Randomized Clinical Trials” by Ian Tannock’s former summer undergraduate research program intern, Roman Shapiro. Check out the fall 2011 issue of the IMS Magazine for this fascinating article. Congratulations Dr. Tannock and co. for bringing this pivotal issue to the media spotlight!

Dr. Arun Ravindran, IMS Faculty member, Professor of Psychiatry, and Chief of the Division of Mood and Anxiety Disorders at CAMH, was recently featured in an editorial piece entitled “The New Normal” in the March 2013 Walrus Magazine. Dr. Ravindran weighed in on the debate over the causes of mood disorders, and appropriate patient-centered treatment. Dr. Ravindran’s research truly encapsulates the bench to bedside translational research mandate of the IMS. His research

group pursues studies on the use of both pharmacological and non-pharmacological treatments for mental illness; the latter include yoga and internet-based cognitive behavioural therapy. Along with the demands of supervising two IMS students and serving on numerous program advisory committees, Dr. Ravindran is the Director of Global Mental Health Affairs and the Office of Fellowship Training in the Department of Psychiatry at U of T. He works closely with partners in the developing world to bring scientific innovation and clinical expertise to those who may be in most need of it.

Dr. Ravindran’s dedication to enhancing mental health worldwide serves as a model for young academics in the field.

Find out more about faculty on the IMS faculty database at http://www.ims.utoronto. ca/faculty/directory.htm.

IMSSA ANNOUNCEMENTS TEDMED Day – April 19th, 2013

IMSSA’s Career Seminar Series

Join us for TEDMED Day at the University of Toronto on April 19th, 2013 at J.J.R. Macleod Auditorium (10am4pm), featuring brilliant live talks and stunning artistic performances from local faculty and students of the Institute of Medical Science. We will also be broadcasting selected presentations from the TEDMED Conference at the Kennedy Center in Washington, D.C.

Please welcome the second installment of IMSSA’s Career Seminar Series, an 8-session interdisciplinary career exploration workshop this upcoming spring; exact seminar dates TBD. Informal panel discussions will guide Master’s and Doctoral students through a multitude of unique career paths. We anticipate the following topics:

Attendees will be intellectually roused throughout the course of this fullday event, which will also include opportunities to converse with speakers, fellow students, and faculty over lunch and refreshments. This is an experience you won’t want to miss!

Limited space available. Register at www.tedmedims.com by April 18th, 2013.

Stay connected: Facebook: http://www.facebook.com/TEDMEDIMS Twitter: @imssanews

• Skills Self-Analysis for MSc/PhD Candidates • Academia and Teaching of Science • Medicine and Scientific Research • Science and Industry (including Consulting, Biotechnology, Pharmaceuticals, and Entrepreneurship • Science and Law (including Bioethics, Intellectual Property, and Health Policy) • Science and Media (including Journalism, Scientific Illustration, Biomedical Communications, and Science Literacy)

• Global and Public Health • Science and Humanities (including scientists guided by Psychology, Sociology, Anthropology, and History) Students can expect to be inspired to venture down roads less traveled, and to network with students and professionals at all levels of career development. Students affiliated with departments other than IMS are also welcome to attend. To contact the committee with any questions or suggestions, please email laura.finkelberg@mail.utoronto.ca.

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 10

NEWS AT A GLANCE

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DIRECTOR’S MESSAGE

Director’s Message T

This, the ninth issue of the IMS Magazine, focuses on the important topic of rescue and repurposing of drugs with contributions by several IMS faculty, including Dr. Aaron Schimmer and postdoctoral fellow Carolyn Goard, Dr. Ben Alman, Dr. Marianne Koritzinsky, and Dr. Freda Miller and research associate Sibel Naska.. In addition, repurposing in the realm of psychiatric illness is discussed with a research focused article from my laboratory and an ethical piece written by PhD student Nancy Butcher.

In terms of IMS news, we are excited to announce the plenary speaker for our annual Scientific Day, which will take place on Tuesday, May 28th, 2013 at the Chestnut Residence and Conference Centre. The Bernard Langer keynote lecturer will be Jeffrey S. Mogil, PhD. Dr. Mogil is currently the E.P. Taylor Professor of Pain Studies at McGill University and the Canada Research Chair in the Genetics of Pain (Tier I). He is a recognized authority in the fields of sex differences in pain and analgesia, and pain testing methods in the laboratory mouse. His lecture is entitled “Mice are People Too: Translation in Pain Research from Genetics to Social Modulation.”

We have begun to operationalize our strategic plan, and we have now established short term (oneyear) and more long term (five-year) goals for each our five strategic initiatives. The full details of these will be announced shortly. As an example, as part of the Uniqueness initiative, we have submitted to the Provost Office a new proposal for a Professional Masters Program in Translational Research, the first of its kind in Canada. For the Presence initiative, we have received approval and have begun the interviewing process to hire a new Communications Officer who will help us develop a new website and establish an alumni database. For the Belonging initiative, IMSSA has begun planning several interesting new social/educational events in the coming year, including an IMS-sponsored TEDMED talk.

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 Marika Galadza for her ongoing assistance in this project.

The IMS Magazine has been a tremendous success and is just one of the many wonderful, studentinitiated projects that make the IMS such a very special institute. I fully support the ongoing publication of the magazine and look forward to the many opportunities it affords us 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 2013 DRUG RESCUE AND REPURPOSING | 12

Illustrations by Michael Soong.

FEATURE

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FEATURE

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 14

FEATURE

Investigating the Potential for Tigecycline in Acute Myelogenous Leukemia Treatment

Staff Physician and Senior Scientist Princess Margaret Cancer Centre, Ontario Cancer Institute Associate Professor, University of Toronto

Carolyn A. Goard, PhD Postdoctoral Fellow Princess Margaret Cancer Centre, Ontario Cancer Institute

What drug are you investigating for its repurposing potential?

Ongoing projects in our lab are investigating the repurposing of several FDA-approved drugs with favourable pharmacokinetic and toxicological properties for use as novel anticancer agents. One of these drugs is tigecycline, a broad-spectrum antimicrobial drug.

To identify well-tolerated drugs with novel anti-leukemic activity, we compiled and screened an in-house library of over 300 well-characterized drugs for their ability to reduce the viability of AML cell lines with leukemic stem cell-like features. One of our top hits was tigecycline, which we recently described in Cancer Cell.2

What are the research findFor what new purpose is the ings?

Our position in a multidisciplinary cancer drug being studied? centre allowed us to evaluate tigecycline in Acute myelogenous leukemia (AML) is the most common type of acute leukemia seen in adults. Despite treatment predominantly with chemotherapy, the 5-year survival rate of AML patients ranges from approximately 50% in patients 20 to 49 years old to 5% in those aged 65 years and older.1

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established AML cell lines and mouse models, along with primary cells extracted from patient samples. We were encouraged by our observation that tigecycline was selectively and potently toxic to AML cells. Tigecycline also impeded the ability of AML cells (but not normal cells) from patient samples to

Photos by Yekta Dowlati.

Aaron D. Schimmer, MD, PhD, FRCPC

FEATURE

repopulate the immune system of immunocompromised mice, supporting a preferential effect on the AML stem cell population.

To probe the anti-leukemic mechanisms of action of this drug, we were fortunate to participate in a cross-disciplinary collaboration with Drs. Guri Giaever and Corey Nislow at the Donnelly Centre for Cellular and Biomolecular Research, who work with yeast as a model system for understanding drug activity. Using haploinsufficiency profiling, where yeast strains lacking one copy of each yeast gene were treated with tigecycline, we identified proteins and cellular functions sensitive to tigecycline inhibition. These cell biology techniques complemented our translational research approaches, revealing that tigecycline affected processes involving the mitochondrial ribosome. Returning to our AML cell lines and patient samples, we subsequently used chemical and genetic approaches to highlight inhibition of mitochondrial translation as a novel therapeutic strategy for AML.

What do you hope is the future of the drug in this field?

We are now evaluating the tolerability of escalating doses of tigecycline in patients with relapsed or refractory AML in a Phase I clinical trial (NCT01332786). Our hope is that this trial will provide rapid proof-of-principle to support the development of inhibitors of mitochondrial translation as a therapeutic strategy for this disease.

This work also provided mechanistic insight

into how mitochondrial dysfunction may lead to therapeutically-targetable metabolic vulnerabilities in AML cells, which has stimulated several ongoing initiatives in the lab.

What do you think is the future of drug rescue and repurposing?

Through the use of advanced genetic sequencing technology, we are rapidly gaining an improved understanding of the genetic basis of cancer. These studies have demonstrated novel genetic mutations and dysregulated pathways in primary tumor cells. These studies have also revealed shared genetic mutations or dysregulated biological pathways between diverse types of cancer or even other conditions such as metabolic or inflammatory diseases.3 By understanding these molecular mechanisms of disease along with mechanisms of drug action, we may be able to rationally evaluate known drugs for new indications.

Additional Reading 1. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012.

CA Cancer J Clin. 2012;62(4):220-241.

2. Skrtic M, Sriskanthadevan S, Jhas B, et al.

Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell. 2011;20(5):674-688.

3. Hirsch HA, Iliopoulos D, Joshi A, et al. A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell.

2010;17(4):348-361.

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 16

FEATURE

Investigating the Potential for Nefopam in Fibromatosis Treatment

What are the research findings?

Benjamin Alman, BA, MD, FRCSC A.J. Latner Professor and Chair of Orthopaedics Vice Chair Research, Department of Surgery, University of Toronto Head, Division of Orthopaedics and Senior Scientist, Program in Developmental & Stem Cell Biology Hospital for Sick Children

What drug are you investigating for its repurposing potential?

Nefopam was developed in the 1960s and is widely used in Europe for its analgesic properties. Part of the benzoxazocine chemical class, it is an alternative to opioids for relief of moderate to severe pain, with effects stronger than aspirin.1

For what new purpose is the drug being studied?

Our lab has investigated the use of Nefopam in fibroproliferative processes to inhibit cell proliferation and reduce tumor growth and scar size. As a key mediator of canonical Wnt signaling, β-catenin levels have been shown

In a series of follow-up experiments, Nefopam was found to inhibit cell proliferation in cultures of aggressive fibromatosis tumors and hypertrophic skin wounds. It demonstrated the ability to target canonical Wnt signaling and reduce β-catenin protein levels.

In a mouse model of aggressive fibromatosis, Nefopam treatment reduced the number of tumors that developed. In skin wounding experiments, mice treated with Nefopam had scar diameters half that of control mice.4

What do you hope is the future of the drug in this field?

Because it is already used in patients and has a strong safety record, Nefopam can be quickly brought to the clinic for new uses.

Applied daily as a cream over the course of 3 weeks, Nefopam can reduce scar formation following surgery or injury. Development and commercialization are underway in collaboration with MaRS Innovation and Novotek Therapeutics Co. Ltd., in China. Clinical trials of the compound as ‘ScarX’ are anticipated to begin this year, in Toronto.5 If this drug is approved for use as a topical agent to mitigate the common occurrence of scarring, it is more likely to be approved in an oral form to treat the rare patient with aggressive fibromatosis.

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What do you think is the future of drug rescue and repurposing?

In biomedical research where efficient translation can make the difference between success or failure of a product, drug repurposing offers the advantage of expediting the move from bench to bedside. Drugs that are already in use come with safety reports, pharmacokinetic profiles, efficacy records, and other such data which eliminate the need for extensive resource-demanding clinical trials. Drug libraries like the one we tested (MicroSource Spectrum collection) are particularly valuable for interrogating known drugs for novel applications, especially for diseases with limited therapeutic options.3 On the other hand, because these drugs are repurposed, issues around intellectual property arise and can cause concern for pharmaceutical, biotechnology, and venture capital companies.

References 1. Wang, R. I. and E. M. Waite (1979). “The clinical analgesic efficacy of oral nefopam hydrochloride.” J Clin Pharmacol 19(7): 395402.

2. Bowley, E., D. B. O’Gorman, et al. (2007).

“Beta-catenin signaling in fibroproliferative disease.” J Surg Res 138(1): 141-150.

3. Peacock, C. D., Q. Wang, et al. (2007).

“Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma.” Proc Natl Acad Sci U S A 104(10): 4048-4053.

4. Poon, R., H. Hong, et al. (2012). “A high throughput screen identifies Nefopam as targeting cell proliferation in beta-catenin driven neoplastic and reactive fibroproliferative disorders.” PLoS One 7(5): e37940.

5. Priest, L. (2012). “Canadian discovers method to radically minimize scars.” The Globe and Mail: 1, 8.

Photos provided by Dr. Ben Alman.

to regulate the number of mesenchymal cells that contribute to wound repair and scar size.

Its stabilization has also been shown to cause aggressive fibromatosis, a locally invasive soft tissue tumor consisting of mesenchymal cells with cytologic similarity to hypertrophic scars.2 Because there are limited pharmacologics to treat these β-catenin-induced disorders, we undertook a screen to identify potential therapeutics from a library of over 2,000 compounds which are naturally occurring or have been used in humans.3 From this screen, Nefopam was found to inhibit cell viability in cultures of hypertrophic wound samples and aggressive fibromatosis samples, but not in normal fibroblasts.4

FEATURE

Improving Radiotherapy Response with

Metformin

the vessels. We therefore reasoned that if we can inhibit oxygen consumption, perhaps we would be able to increase the oxygen content of the tumors and make radiation therapy more efficient. Metformin was very interesting to us in this respect, since it was already known to inhibit mitochondrial respiration.

Furthermore, it is a well-tolerated drug that has been taken by a large number of diabetics undergoing radiotherapy for cancer, so it is unlikely to cause severe side-effects when combined with radiation treatment.

What are the research findings?

Marianne Koritzinsky, PhD, MSc Assistant Professor, Department of Radiation Oncology University of Toronto Scientific Associate, Ontario Cancer Institute

What drug are you investigating for its repurposing potential?

Our work so far has focused on metformin, which is a biguanide commonly prescribed for type II diabetes. In the treatment of diabetes, metformin works by reducing gluconeogenesis in the liver. This occurs because metformin inhibits mitochondrial activity, which in turn triggers metabolic adaptation in the liver cells.

Photo by Chung Ho Leung.

For what new purpose is the drug being studied?

We are studying a specific role for metformin to enhance the response to radiotherapy during cancer treatment. We know that areas of poor oxygenation (hypoxia) in tumors limit the success of radiotherapy because hypoxic cells are radiation resistant. Hypoxia arises in part because the cancer cells close to blood vessels rapidly consume all the delivered oxygen, leaving nothing for cells further from

We have grown tumors in mice and measured hypoxia by administering specific drugs (2-nitroimidazoles) that bind and mark hypoxic cells. The markers can be detected using fluorescent antibodies either by immunohistochemistry or flow cytometry.

Markers can also be detected non-invasively

by PET imaging, a technique that is increasingly being utilized also in the clinic to identify patients with hypoxic tumors. Using all these approaches, we found that if we gave the mice metformin, there was less hypoxia in the tumors. These better oxygenated tumors also showed increased response to radiation, as we would expect. These preclinical studies have therefore provided proof-ofprinciple that metformin can help reprogram the metabolism of cancer cells to decrease tumor hypoxia and enhance the efficacy of radiotherapy.

What do you hope is the future of the drug in this field?

There is already great general interest in metformin as an anti-cancer drug. Epidemiological and retrospective studies of diabetics have suggested that metformin might protect against cancer development and enhance response to chemotherapy. Metformin might therefore be beneficial for several independent reasons, and have application as an anticancer therapeutic in different contexts.

So far, there have been many efforts in the clinic to try to increase tumor oxygenation by

supplying more oxygen. In these strategies, patients have been breathing high-oxygen or high-pressure gas during radiotherapy, or received blood transfusions or vasodilating agents. These approaches have worked to some extent, but are not very practical. The idea of patients rather taking metformin pills before or during radiotherapy is therefore very attractive.

We know that hypoxia is a poor prognostic factor in patients with head and neck, prostate and cervix cancer, so these are the sites we will pursue first. We are hoping to assess in non-diabetic patients whether metformin can decrease tumor hypoxia.

We started this project by investigating metformin, because it is such a commonly prescribed drug. However, other mitochondrial poisons could also have similar beneficial effects on tumor oxygenation. We are therefore pursuing other clinically available drug candidates that we think might be useful for this purpose.

What do you think is the future of drug rescue and repurposing?

Drug repurposing has enormous potential since it can shorten the way from laboratory to clinic substantially. This has certainly been realized in the cancer field, where large pharmacological screens are taking place across the world to identify drugs with anti-cancer properties that are currently used for other indications. Also, as we learn more about the mechanisms of action of specific drugs, we are able to expand this field in a hypothesisdriven approach. Metformin is a great example of the latter. Knowledge of its primary mechanism of action has accumulated over the last decades, although it has been known for centuries that French Lilac extracts which contains biguanides could relieve troublesome frequent urination--a symptom we recognize today as reflective of diabetes. Now we can use this mechanistic knowledge to propose novel applications for metformin in other diseases.

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 18

FEATURE

Investigating the Potential for Olanzapine in Anorexia Nervosa Treatment

Director, Institute of Medical Science Chief of Clinical Research and Senior Scientist Campbell Research Institute Centre for Addiction and Mental Health Senior Scientist, Toronto General Research Institute Vice Chair, Research, Department of Psychiatry Professor of Psychiatry

(FDA) approved drug. Olanzapine, among its other effects, has affinity for dopaminergic receptors in the brain, acting primarily to block the brain chemical, dopamine. The core disturbances in anorexia nervosa include disturbances in reward (anhedonia), activity (compulsive/excessive exercising), regulating intense negative feelings (affective regulation), and the interpretation of bodily sensations (enteroceptive awareness). All of these functions are known to be mediated by dopamine.

Which drug is being investigated for its repurposing potential?

What are the research findings?

Olanzapine (Zyprexa) is being investigated for its repurposing potential. It has Health Canada approval for the treatment of schizophrenia and bipolar disorder.

For what new purpose is the drug being studied?

The drug is being studied in the context of anorexia nervosa. Currently, there are no evidence based treatments for adults with anorexia nervosa, a serious psychiatric disorder with the highest mortality among psychiatric illnesses of approximately 15%.

Anorexia nervosa is the only psychiatric disorder for which there is no Health Canada or U.S. Food and Drug Administration

My colleagues and I are conducting a National Institute of Mental Health (NIMH)funded, multisite, randomized, placebocontrolled clinical trial evaluating the effectiveness of olanzapine compared to placebo in 200 outpatients acutely ill with anorexia nervosa. My colleagues at the Centre for Addiction and Mental Health (CAMH) Neurogenetics Laboratory and I are also conducting a pharmacogenetics study as part of this trial, examining genes that are known to predict weight gain in the subjects in this trial. In a pilot study involving 25 subjects, 13 of whom were assigned to olanzapine, there was a statistically different rate of weight gain in subjects assigned to olazanpine compared

19 | IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING

to placebo. The drug was well tolerated and no serious side effects were noted.

What do you hope is the future of the drug in this field?

With the results of the pharmacogeneti aspect of this study, the hope is that we can identify those subjects whose genetics would predict a positive response to this drug as we move to personalized medicine in psychiatry.

As such, it is hoped that olanzapine can be a useful adjunctive treatment for select patients with anorexia nervosa.

What do you think is the future of drug rescue and repurposing?

Many pharmaceutical companies are moving away from developing new central nervous system (CNS) drugs and psychiatric drugs in particular, due to the high costs of drug development, the absence of good animal models for psychiatric disorders, and low success rates in phase 3 clinical trials.

As a result, the CNS pipeline is drying up and drug repurposing becomes an important and valuable research approach to being able to develop new drug treatments in a cost effective manner窶馬ot just for psychiatry but for other areas of medicine as well.

Photo by Chung Ho Leung.

Allan S. Kaplan, MSc, MD, FRCP(C)

FEATURE

Promoting Tissue Regeneration with

Stem Cells

a brain injury model to further assess the efficacy of these drugs.

Excitingly, our data suggest that drugs that increase stem cell activity are also able to promote recovery following brain injury or skin wounds.

What do you hope is the future of the drug in this field?

Sibel Naska, PhD

Research Associate, Freda Miller’s lab Developmental and Stem Cell Biology The Hospital for Sick Children

Freda Miller, PhD

Senior Scientist, Developmental and Stem Cell Biology The Hospital for Sick Children Professor, Department of Molecular Genetics University of Toronto Canada Research Chair in Developmental Neurobiology Howard Hughes Medical Institute International Research Scholar

For example, we have shown that the widelyused type II diabetes drug metformin could activate neural precursors in vivo, and thus enhance neurogenesis and hippocampusdependent memory. Based on these results, we are now testing whether this repurposed drug can be used to recruit endogenous neural stem cells and promote brain repair.

In another study, we discovered an adult dermal stem cell—termed skin-derived precursors (SKPs)—and have shown that SKPs contribute to hair follicle formation, wound healing, and prevent skin from aging. SKPs represent a major therapeutic breakthrough and we are now developing drugs to activate these dermal cells and promote their ability to repair skin under pathological conditions.

Which drug is being investigated for its repurposing potential?

What are the research findings?

We are investigating a variety of drugs that are approved for use in humans and are being used in the clinic for a wide variety of pathologies.

Photo by Chung Ho Leung.

For what new purpose is the drug being studied?

The drugs are being investigated to increase the activity of neural or dermal stem cells with the final goal to promote tissue repair and regeneration. The idea to undertake this research developed gradually, based on previous work done in our lab or in collaboration with others.

We use both in vitro and in vivo methods to investigate the aforementioned compounds.

Particularly, we have used a high-throughput stem cell-based screening assay to identify compounds already in clinical use that activate stem cells. We then validate the most promising compounds in culture through specific assays.

For in vivo studies, we use different approaches such as drug delivery in genetically modified animals, wound healing models, as well behavioural assays. In collaboration with Dr. Cindi Morshead, we are also using

As we know, the brain does not repair itself after an injury, often times resulting in cognitive deficits and neurodegeneration. On the other hand, the skin has a remarkable capacity for regeneration; during aging or specific pathologies such as diabetes, however, this reparative capacity becomes impaired and can lead to chronic wounds and decreased quality of life. In our current market, the number of agents that have documented ability to enhance brain repair or wound healing is minimal and there is an increased need for new therapeutic approaches.

We hope to bring our drugs to the clinic as novel therapeutic candidates. In this regard, we are working closely with The Hospital for Sick Children and the Centre for Commercialization of Regenerative Medicine to make the translation of our work possible, and furthermore, to potentially move into human clinical trials for brain injury and chronic wound care.

What do you think is the future of drug rescue and repurposing?

We think drug repurposing will grow in importance over the years—primarily because it is significantly less expensive and it takes a shorter time to repurpose than to develop a drug the traditional way. For example, the drugs that we use are all drugs that are already safely being used in humans. This means we do not have to undergo toxicity tests or FDA approvals before they are released to the market.

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 20

FEATURE

Old drugs and new tricks:

By Nancy Butcher, MSc

Repurposing drugs to treat psychiatric disorders

The need for improved psychiatric treatments and better patient outcomes is substantial—one in five Canadians will experience a mental illness in their lifetime, and these illnesses come

with high personal and socioeconomic costs.2 Although some patients do respond very well to current medications, there is little evidence that our very best treatments have reduced the overall prevalence or disability associated with any major psychiatric disorder.3 Only recently have new therapeutic targets for major psychiatric disorders begun to emerge, following advances in molecular and bioinformatics research. But who is going to develop these new drugs? The major pharmaceutical companies are shutting down their neuroscience laboratories or redirecting their research programs.

Research and development (R&D) dollars are being shifted away from mental illness and into more biologically tractable disorders like cancers.1,3 The reason is simple: companies are not getting enough bang for their buck by pursuing new treatments for psychiatric illnesses. This issue is further compounded by the abundance of generic drugs now on the market, lack of novel validated targets and biomarkers, increased regulatory challenges, and the absence of valid animal models for mental illnesses.3

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As industry retreats from psychiatric drug development, we must give current translational research practices in psychiatry a sober second thought. The pipeline of drugs is running dry and there is a crisis in drug development for mental illness. Repurposing old drugs is one of many suggested alternatives but it may provide the fastest and cheapest results.1 The number of molecular pathways implicated in mental illnesses is exploding, and some may already be targeted by old medications. This could provide an unprecedented opportunity to rapidly identify, evaluate, and bring new psychiatric drugs to market and to the patients who need them.

A study published last month in Nature Communications on bipolar disorder exemplifies the promise that drug repurposing holds for rapidly advancing mental health discoveries and treatment.4 Bipolar disorder is a serious mental illness that affects approximately 1 in 100 people. Individuals with bipolar disorder experience alternating periods of mania and depression, sometimes known as “highs and lows.� Lithium has remained the gold standard

Photo courtesy of www.sxc.hu; ID# 1054533.

T

here is no question that major advances have been made in treating psychiatric illnesses over the past six decades. The serendipitous discoveries in the 1950s of the antidepressant effects of the antituberculosis drug iproniazid and the antipsychotic effects of the anaesthetic chlorpromazine ushered in a golden age of psychopharmacology. Patients previously considered untreatable were discharged from psychiatric hospitals in record numbers. Some successfully reintegrated back into the community and resumed relatively normal lives. Although others responded minimally or not at all to these new treatments, it was hoped that improved drugs would be just around the corner. After decades of research and advances in the biology underlying mental illnesses, better drugs are still desperately needed for essentially all psychiatric disorders.1

FEATURE of treatment in bipolar disorder for the last 60 years, but it is toxic at only twice the therapeutic dosage. Lithium is also known for its many unpleasant or serious side effects including tremors, weight gain, and kidney damage. To find a safer but equally effective drug, the study authors combed through the U.S. National Institutes of Health Clinical Collection—a library of drugs known to be safe with no current clinical use—to find drugs that act in similar way as lithium. Ebselen, an out of patent antioxidant originally developed for stroke patients, was identified as a good candidate for a safer alternative to lithium. Testing mice showed that ebselen does indeed act in the brain by blocking the same key enzyme as lithium. Human testing of ebselen can now quickly follow.

In addition to drugs designed for another disease, medications already tested in psychiatric disorders may be worth a careful second look.

In recent years, the primary targets of psychiatric medications and clinical endpoints have begun to dramatically shift. Medication targets are moving away from the traditional model of correcting chemical imbalances (e.g. blocking dopamine receptors to treat psychosis) to addressing dysfunctional brain circuitry.1 Previous clinical trials may have missed important but subtle improvements in patients. New measures of success including improvements in symptoms that cut across different psychiatric diagnoses such as social and working memory deficits, may help identify new roles for old or discarded candidate psychiatric drugs.

For example, early trials of baclofen in the treatment of schizophrenia were not encouraging because the study endpoint was a reduction in psychotic symptoms. The effect of the drug on the highly disabling cognitive and negative symptoms of schizophrenia, including flattened affect and social withdrawal, were not investigated. Baclofen is currently approved for muscle relaxation and spasticity but it is regaining interest as a treatment for mental illness, and not just for schizophrenia. A recent study found that baclofen improved social deficits and spatial memory in mice with brain abnormalities common to a spectrum of psychiatric disorders, including schizophrenia, intellectual disability, and autism spectrum disorders.5 Baclofen was well-tolerated by individuals with schizophrenia in the original exploratory trials, suggesting that it may be a viable new treatment for social and cognitive deficits if it proves similarly effective in new clinical studies.

“The need for improved psychiatric treatments and better patient outcomes is substantial— one in five Canadians will experience a mental illness in their lifetime.”

Although the repurposing of drugs does show promise in short-term deliverables for new treatments of psychiatric disorders, it is not without its challenges. Repurposed drugs will need to be tested carefully against current gold-standard treatments as well as against each other. Safety issues in psychiatric populations may be a concern. Intellectual property and patent issues must be resolved. Similar to currently available psychiatric medications, it is likely that not all patients will respond to treatment or even respond to the same degree.

But at this stage, should we even expect them to? Despite their distinct diagnostic classifications, there is increasing evidence that individual mental illnesses are actually a biologically heterogeneous collection of diseases. New personalized medicine approaches to treatment selection, informed by biomarkers and genetics, have the potential to dramatically increase treatment success rates. Measures of success also need to be refocused, with a new emphasis on treatment in the early stages of the disease when outcomes might be better, and a therapeutic goal of complete and not partial recovery.6 Treating complex illnesses like psychiatric disorders is not easy, but it is possible. With the potential of drug repurposing in identifying novel treatments for serious mental illnesses emerging, hope is on the horizon.

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. Insel TR. Next-generation treatments for mental disorders. Sci Transl Med. 2012; 4:1-9.

2. Health Canada [homepage on the Internet].

A Report on Mental Illness in Canada; 2002 [updated 2012 Jan 5; cited 2013 Feb 8]. Available from http://www.phac-aspc.gc.ca/publicat/miic-mmac/chap_1-eng.php.

3. Brady LS, Insel TR. Translating discoveries into medicine: psychiatric drug development in 2011. Neuropsychopharmacol. 2012; 37:281-3.

4. Singh N, Halliday A, Thomas J et al. A safe lithium mimetic for bipolar disorder. Nat Commun. 2013; 4:1332.

5. Gandal MS, Sisti J, Klook K et al. GABABmediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction. Transl Psychiatry; 2:e142.

6. Insel TR, Sahakian BJ, Voon V, et al. Drug research: a plan for mental illness. Nature 2012;483:269.

“As industry retreats from psychiatric drug development, we must give current translational research practices in psychiatry a sober second thought.”

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 22

SPOTLIGHT

FACULTY VIEW

Dr. Lucy Osborne PhD

D

Photo by Laura Feldcamp.

r. Lucy Osborne is an associate professor in the Institute of Medical Science (IMS) conducting research at the forefront of medical genetics. She is a world expert on the deletion and duplication of a small but fascinating region of the genome, 7q11.23 on chromosome 7, which contains just 25 genes. The deletion of this region on one of the pairs of chromosome 7 leads to Williams-Beuren syndrome (WBS).

WBS is a rare neurodevelopmental disorder that affects nearly every system in the body.

Individuals with WBS are often overly social and autism-like traits are common. Intellectual disability, elf-like facial features, anxiety disorders, and cardiovascular problems are also characteristics of WBS. “Studying the genes affected in WBS provides an oppor-

tunity to understand the molecular basis of symptoms that occur in WBS as well as other conditions,” Osborne explains.

Osborne began her work on WBS as a postdoctoral fellow in Dr. Lap-Chee Tsui’s group at the University of Toronto (U of T) following the completion of her PhD on cystic fibrosis at the University of London in England. This move across the pond marked the beginning of Osborne’s successful career at U of T. During her fellowship, Osborne identified and mapped the genes that are deleted in WBS, and soon after she was hired by the University to lead her own research on the 7q11.23 region. She takes a multi-faceted approach to her research, studying both a large cohort of WBS patients as well as knockout

mouse models of the syndrome to investigate genotype-phenotype correlations and the molecular pathways disrupted in WBS. According to Osborne, “Knowledge of the pathways that lead to the symptoms of WBS is largely unknown and needed in order to develop proper treatments.”

As a part of her research on WBS, Osborne and her colleagues have made an important discovery: the duplication of the region that is deleted in WBS leads to a separate, identifiable syndrome, called 7q11.23 duplication syndrome. Individuals with 7q11.23 duplication syndrome have three copies of the genes located in the 7q11.23 region and have a phenotype that is milder than WBS. The mechanisms underlying the symptoms that appear in individuals with 7q11.23 deletions and duplications remain largely elusive.

To elucidate this ambiguity, Osborne takes a new approach to an old problem through the investigation of changes in DNA methylation patterns in WBS patients. She suspects this may help explain some of the wide-ranging clinical features observed in WBS. Her research group also examines mouse cells and utilizes human-induced pluripotent stem cells to study how the genetic changes in WBS may lead to abnormal neuronal functioning and wiring.

In addition to maintaining her active research program, Osborne remains involved in the IMS and her cross-appointed departments of Medicine and Molecular Genetics. She is an instructor in the popular IMS course titled ‘Molecular Medicine in Human Disease’, a member of the IMS curriculum committee, and she recently participated in the IMS strategic planning initiative. She is currently supervising three graduate students through IMS and estimates that she is a member of no less than 20 program advisory committees. Despite her impressive career track and funding support from the Canadian Institutes of Health Research and the Simons Foundation Autism Research Initiative, when asked about her seamless pathway into such an outstanding academic career Osborne claims that there is no secret to her success. Her advice to aspiring young scientists and graduate students is sound: “Just work hard, and you’ll get out what you put in.”

By Nancy Butcher

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 24

Book Reviews Excellent

Worth missing a day at the lab

Dr. Atul Gawande Complications: A Surgeon’s Notes on an Imperfect Science Henry Holt and Company, 2002; 269 pages

A

public health researcher, Rhodes Scholar, Harvard Medical School (HMS) graduate, former government health policy adviser, and staff writer for The New Yorker, Dr. Atul Gawande adds a fresh and exciting perspective to medical practice with his narrative non-fiction book Complications: A Surgeon’s Notes on an Imperfect Science. Gawande explores fallibility, mystery and uncertainty in medicine in a collection of 14 essays that reflect on his experiences as a senior general surgery resident at Harvard Medical School. These pieces—some of which are published in The New Yorker and Slate magazines—are built on extensive scientific research and interviews. They also incorporate Gawande’s personal stories about working as a surgeon in HMS.

Very Good

Try to squeeze in between experiments

In the first section of the book, “Fallibility,” Gawande provides a behind-the-scenes glimpse of the operating theatre that lays bare the “imperfect science” that is surgery. He sheds light on the errorprone nature of medicine through recollections of real-life cases in the wards and operating theatre: the orthopedic surgeon who amputates the wrong limb; the long-respected yet burned-out doctor who suddenly loses his touch; and the young resident who forgets to remove a surgical sponge from inside the patient. Gawande confesses his own mistakes too, from his failed attempts learning how to place a central venous catheter line for the first time, to his emergency tracheotomy crisis scenario that almost killed the patient. Through these cases, Gawande raises delicate questions that continue to stir controversy within the medical community: how many of these medical mistakes—or to be politically correct, “adverse events”—can be prevented? To what extent are doctors responsible for their mistakes? And to what extent should these mistakes be tolerated?

Surgeons work in an extremely high-pressure environment where any deviation from the procedure can result in serious complications, possibly leading to death. By tradition, it is the surgeon who is held accountable for any complication or adverse patient outcome, regardless of extenuating patient risk factors or comorbidities. However, Gawande highlights the naivety in placing the blame on the individual surgeon, as human error is a natural phenomenon in any high-risk industry—the operating room of a hospital, the cockpit of an airplane, or the conveyer belt of a car manufacturing factory. In fact, any system that relies on human perfection is particularly prone to “latent errors”—errors caused by the system, such as inadequate staff training, poorly designed medical equipment, lack of standardized protocols (i.e., “safety checklists”) and lack of organization in hospital management. The unfortunate truth is that surgeons are easier to blame than the system, and this makes it difficult to learn more about the systemic problems that underlie a complication.

In the second section of the book, “Mystery,”

25 | IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING

Good

Wait for the weekend

Average

Wait until degree is complete

Gawande delves into the strange and perplexing patient cases that remind us how little we really know about the human body. A middle-aged man suddenly experiences excruciating chronic back pain with no identifiable physical abnormality. A pregnant woman suffers uncontrollable, debilitating nausea—far beyond the typical pregnancy sickness—for the entire duration of her pregnancy. A young anchorwoman is plagued with an unexplainable blushing problem that puts a halt to her career. The mysterious symptoms presented in these patients reveal the gaping holes in our current medical knowledge, despite decades of research devoted to understanding the complex machinery of the human body.

The repercussions of these medical knowledge gaps are further discussed in the final section of the book, “Uncertainty,” where Gawande describes the messy, chaotic, and uncertain world of medicine. Life-and-death decisions are often made in the spur of the moment, based on the “gut feeling” of the doctor rather than concrete evidence found in medical literature. The power of intuition is illustrated in the case of a young girl who presented a rash on her leg. First diagnosed as cellulitis, the rash was later tested positive for flesh-eating bacteria, an incredibly rare yet aggressive infection that is almost impossible to detect in time. So what spurred the decision to order the test? Gawande had a creeping suspicion—a suspicion that ended up sparing a young girl’s life.

Interested in reading more by Dr. Atul Gawande?

Check out his other best-selling books Better: A Surgeon’s Notes on Performance and Checklist Manifesto, as well as his regular columns in The New Yorker magazine.

Column by Jill Cates

BOOK REVIEWS afflicted. The book often quotes them to give an artistic and clinical perspective on what they felt. For example, Edgar Allan Poe noted, “My feelings at this moment are pitiable indeed. I am suffering under a depression of spirits such as I have never felt before.” The book also uses the words of some of the world’s greatest artists such as Byron, Van Gogh, Schumann and Woolf to describe the feelings of sadness, loss of interest, suicide, grandiosity, substance abuse, and general mania felt by these artists.

Kay Redfield Jamison Touched with Fire Random House Publishing, 2010; 348pages

“W

e of the craft are all crazy, some are affected by gaity, others by melancholy, but all are more or less touched.” This quote by Lord Byron referring to himself and other poets is the start of Touched with Fire by psychiatry professor Kay Redfield Jamison, PhD at the John Hopkins University School of Medicine. This well thought out and controversial book discusses the possible link between manic-depressive illnesses and the artistic temperament.

Jamison explains that the comparison of madness and creativity has a rich, persistent, and controversial history. “By the time of Plato and Socrates, common lore held that priests and poets communicated with the gods through inspired madness and sacred enthusiasms.”

Jamison very elegantly speaks to what is often unspoken of about mental illness; that is, the creative exploration often seen in those with these ailments. This book is ultimately about the temperament and moods of these creative minds and voyagers, and addresses the arguments and controversies that surround “madness” and artistic genius.

The book starts by outlining to a lay reader what mood disorders such as depression and manic-depression entail. Jamison describes an “awful chaos” in the context of artists who were

Jamison uses several approaches to examine the relationship between mood disorders and artistic creativity. She uses biographical anecdotal evidence by quoting leading authorities of the time. She mentions how artists such as Aristotle have constantly questioned, “Why is it that all men who are outstanding in philosophy, poetry or the arts are melancholic?” She outlines that it is clear that historically a large proportion of artists suffered from mood disorders. However, though these arguments are compelling, anecdotes are not conclusive evidence. Jamison goes on to examine recent population studies, which show that mood disorders are higher in proportion in the artistic population compared to the non-artistic population. She also examines the creative achievements of affectively ill patients while considering the familial link of psychopathology and creative accomplishments. Though the evidence put forward is compelling and interesting, it must be taken with a grain of salt.

Jamison points out that biographical reports from artists may be biased as they often come from a single perspective. In addition, she argues that since the assumption that within artistic circles mood disorders, substance abuse and suicide are “normal,” it is important to parse truth from expectation.

Biological and psychological evidence are also explored in the later chapters of the book to further substantiate the author’s argument.

Jamison explores ideas such as the observed similarities in thought patterns and behaviors in the artistic and manic-depressive mind. She also argues for links in the seasonal patterns of manic-depressive disorder where the same patterns of productivity are observed in artists such as Robert Schuman and Vincent Van Gogh.

The purpose of Touched with Fire was to outline the association between two temperaments, the artistic and the manic-depressive. The book is full of interesting and controversial arguments, which are both scientific and anecdotal in na-

ture. It is clear and in plain language, though at times reads as more of a thesis than a typical work of non-fiction. The minds of artists and the minds of those affected by mental illnesses are mysterious and complex. Touched with Fire successfully outlines what can be deduced from our current state of knowledge on the association between the artistic mind and the manicdepressive mind.

Column by Brett Jones

What are you reading?

Tetyana Pekar, MSc candidate, recommends The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee “The Emperor of All Maladies is a fascinating Pulitzer Prize winning novel about the history of cancer treatment and research. At the same time, it is much more than that. Mukherjee masterfully weaves together the history, science, medical practice, and personal narratives that pertain to cancer and cancer research.

The book is highly accessible and will surely interest most readers. Mukherjee is a talented writer and The Emperor of All Maladies is definitely one of my favourite medical books. ” Benjamin Mora, PhD candidate, recommends Civilization and its Discontents by Sigmund Freud “Freud’s seminal text, Civilization and its Discontents (Das Unbehagen in der Kultur), attempts to carry psychoanalysis over to the cultural community. The main theme of the book is the irremediable antagonism between the demands of instinct and the restrictions of civilization, viz. the struggle between Eros and the death instinct, perpetually instilling unbehagen (discomfort or malaise). An intriguing and stimulating read—at least for the appreciation of Freud’s theorizing.”

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

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 26

CLOSE UP

Dr. Joel Katz Interview with

Recent recipient of Distinguished Career Award, Canadian Pain Society

By Brittany N. Rosenbloom research career, his past and present students, collaborators, and his future ambitions.

Katz focused much of his career on elucidating the mechanisms involved in the transition from acute to chronic pain and on the treatment of pain. Interestingly, this was not always his focus.

Katz received his undergraduate degree in psychology from McGill University where he first focused on research relating to human memory. This was followed by a Master’s degree in experimental psychology at Dal-

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housie University where he studied speech perception in infants, specifically, “whether 9 month-old-infants could distinguish between various speech sounds that differed in their place of articulation, such as ‘ba’ and ‘da.”

Following the completion of his Master’s degree, Katz was faced with the decision of whether or not to accompany his supervisor, who had been offered a faculty position, to Oregon. Instead, Katz jumped at the opportunity to become a research assistant at the Montreal General Hospital Pain Center

Photo by Yekta Dowlati.

W

hen one asks a world-renowned researcher if they would like to be interviewed to discuss their work and recent accomplishments, one expects to travel to the expert’s office for the interview. Dr. Joel Katz is not like this – in fact, he and I met for an afternoon tea at a café, which had a relaxing hum of background chatter and an occasional yell from excited toddlers out for a treat.

As I sat down, Katz’s enthusiasm immediately seeped through the ambient noise as we dove into an intriguing discussion about his

CLOSE UP working for Dr. Ronald Melzack, Professor of Psychology and author, with Patrick Wall, of the now classic Gate Control Theory of Pain.

This bold move took Katz into a field that he knew nothing about, yet it turned out to be the launching pad for a career in pain that culminated in the 2013 Distinguished Career Award from the Canadian Pain Society.

Katz spent two formative years at the pain center where he was exposed to people with a variety of chronic pain problems. Among the people he saw were amputees with severe, intractable phantom limb pain and people with spinal cord injuries who suffered from intense phantom body pain.

When the MGH Pain Centre was forced to close due to funding problems, Katz entered the doctoral program in clinical psychology under the supervision of Dr. Melzack, whose theory of pain has revolutionized our current understanding of what it means to feel pain. At the time, Katz walked into relatively uncharted territory because of his interest in pursuing phantom limb pain. The primary question that he was in search of an answer for was, “what is going on in the periphery and central nervous system to explain how someone who has had a limb amputated continues to feel that the cut-off part is still present and that it is still painful?” Among the various types of phantom limb pain, the one that captured Katz’s attention was a class of pain that he has since called “somatosensory pain memories.” These pain memories are described by the amputee as replicas of pains that were present at or near the time of amputation and are referred to the phantom limb after amputation with the same intensity, qualities of experience and location as the pre-amputation pain. If an enduring, sensory memory-like mechanism was responsible for these types of phantom pains, Katz wondered what the effect was of noxious intraoperative stimuli (such as the cutting of tissue, nerve and bone during surgery) on the subsequent development of acute and chronic postoperative pain. Was it possible that these noxious intraoperative events also set up a memory-like mechanism that contributed to increased pain (hyperalgesia) and increased analgesic consumption after surgery? He knew that general anesthesia did not block the transmission of nociceptive impulses from reaching the spinal cord and brain even though patients are unconscious during surgery. Would a pre-operative local anesthetic,

administered regionally or centrally, block the noxious afferent input associated with surgery from reaching the spinal cord and thereby prevent the establishment of a somatosensory pain memory?

Katz’s curiosity and interest in better understanding the mechanisms underlying these pain memories brought him to Toronto in 1990, where he did postdoctoral work in the Departments of Psychology and Anesthesia & Pain Management at the Toronto General Hospital (TGH) and where he subsequently became a member of the Institute of Medical Science in 1996. At TGH Katz joined the Anesthesia Department’s Acute Pain Research Unit, then led by Dr. Alan Sandler. Supported by Fellowship awards from the Ontario Ministry of Health and the Medical Research Council of Canada (MRC, now CIHR) he and

The primary question that he was in search of an answer for was, “what is going on in the periphery and central nervous system to explain how someone who has had a limb amputated continues to feel that the cut-off part is still present and that it is still painful?” his colleagues began to translate some of the ideas generated from his doctoral research into clinical studies in patients undergoing surgery. This included the role of pre-emptive analgesia (i.e. analgesics given directly prior to surgery) in preventing the establishment of surgery-induced central sensitization and in reducing postoperative pain intensity and analgesic consumption. “This was a really exciting, productive time,” Katz recalled. “One of my closest collaborators at the time was a Fellow in Anesthesia, Dr. Brian Kavanagh, who has gone on to great things and who is now the Chair of Anesthesia at the U of T.”

main areas, including: (1) the minimization of acute post-operative pain through pharmacological and psychological measures; (2) working towards the prevention of chronic post-surgical pain; (3) identifying the biopsychosocial risk factors for chronic post-surgical pain in adults and children; (4) understanding placebo analgesia; and (5) improving the understanding and management of pain in infants. Future areas of research will target psychotherapeutic interventions for chronic pain patients.

In 2002, Katz joined the Department of Psychology at York University as the Canada Research Chair in Health Psychology. Even with the move to York, he maintained an active research program in the Department of Anesthesia and Pain Management at TGH and he continues to supervise and mentor students at the IMS.

Although the primary reason for my interview with Dr. Katz was to discuss his most recent career award and his singular contributions to the fields of pain, analgesia, and psychology, he repeatedly steered the conversation away from his many accomplishments and instead focused it on the research that his students and colleagues conduct. This was not surprising given what I know, and have heard, about his reputation for humility and his immense respect and appreciation for his collaborators (i.e. nurses, anesthesiologists, pharmacists and other psychologists) and students, past and present. And so I was not caught off guard by his response when I asked him what he considered to be his biggest accomplishment thus far. He laughed and said, “Does having three children count?”

After more than 20 years of research at TGH, highlighted by the prestigious Scholar and Scientist Awards from the MRC, Katz is now the Director of the Acute Pain Research Unit where, with his colleagues and students, he continues to investigate the mysteries of pain. His program of research broadened into a multipronged approach targeting five IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 28

VIEWPOINT

An Evaluation of Naturopathy and the Healing Power of Nature

Vis Medicatrix Naturae or Medicine?

S

cientists and physicians alike would be very naïve to ignore the increasingly obtrusive elephant in the room: Naturopathic or Complementary and Alternative Medicine (CAM). Much to the author’s chagrin, the use of CAM in the USA has virtually doubled, from approximately 34% in 1990 to 62% in 2002.1 The 2007 National Health Interview Survey (NHIS) estimated that 38% of adults use CAM.2 Patients are increasingly seeking out alternative medical therapies, either as a complement to traditional medical treatments, or as a replacement.

CAM is an umbrella term encompassing medical products or practices that are not part of standard care, that is, not used by conventional health professionals. The National Center for Complementary and Alternative Medicine (NCCAM) defines CAM as “a group of diverse medical and health care systems, practices, and products that are not generally considered a part of conventional medicine [i.e. “Western” or “Allopathic”]”2.

CAM therapies include dietary supplements, botanicals, meditation, acupuncture, tai chi, hypnotherapy, spinal manipulation, massage, qi gong, iris diagnosis, magnet therapy, light therapy, and Reiki, among many others.

While naturopathy has its formal origins in the 19th century “natural living” movement in Germany,3 it began in the USA in 1902 with medical doctor Benedict Lust, who himself was taught by the Nature Cure practitioner Father Kneipp in Europe.4 Naturopathic medicine today, as taught at the Canadian College of Naturopathic Medicine (CCNM) in Ontario, primarily utilizes Asian medicine, acupuncture, clinical nutrition, botanicals, and homeopathy.5 Though formally trained in these modalities, the Naturopathic Doctor (ND) is afforded the autonomy and freedom to utilize any CAM therapy, as long as it is deemed safe and “effective,” of course.

An ND is trained as a primary care provider (comparable to a family physician) in a fouryear program designed to parallel the curriculum of an allopathic medical school. In order to complete the program, students must pass the Naturopathic Physicians Licensing Examinations (NPLEX).

NDs are guided by six fundamental healing principles, a few of which include: Tolle Causam (identify and treat the causes); Tolle Totum (treat the whole person); and Vis Medicatrix Naturae (the healing power of nature).

As for the last principle, Natura Medica, it should be obvious that nature is not always

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healing. From an evolutionary perspective, a sort of Darwinian Medicatrix Naturae seems intuitive. Evolution only selects for traits that are advantageous at the time. These traits may lose their purpose in the future or even develop into a hindrance when coupled with additional traits. With all the chicanes and detours in evolutionary history, the mechanics of the human body have evolved for survival advantage, not for optimal health per se. Medicine is to be guided by science—rigorous evidence-based science—not by philosophy or by ancient wisdom. Naturopathic medicine seems to exhibit a sort of respect or adoration for “ancient wisdom,” but is it not exactly the rise of modern science and modern medicine that have freed us from the non-evidence, superstitious-based “wisdom” of the ancients? Naturopathy should not have guiding philosophical principles but evidence and evidence alone as a guiding principle.

Often, Naturopathic medicine identifies simplified theories to explain the causes of disease, such as ubiquitous “toxins”; widespread food allergies; dietary sugar, fat, and gluten; vitamin and mineral deficiencies; epidemic candidiasis; vertebral misalignments; intestinal “dysbiosis”; or imbalances of Qi, to name a few.3 The evidence for the theories and

Photo courtesy of www.stockvault.net; ID # 135411.

By Benjamin Mora

VIEWPOINT modalities utilized by NDs ranges greatly in quality and quantity, from relatively sufficient, to extremely inadequate and poor.

Many CAM therapies are by definition inadequately researched, and are thus not utilized by medical doctors (MDs). Nevertheless, some therapies are evidence-based. For instance, a significant amount of evidence exists for many of the nutritional guidelines that NDs prescribe to their patients. It is well established in the medical literature that a diet high in fruits and vegetables, whole grains, nuts and seeds, and low in saturated fat, processed foods and meats, and refined sugars is conducive to health and longevity.

Moreover, this diet has been shown to decrease the incidence of numerous chronic diseases such as cardiovascular disease, heart disease, obesity, type 2 diabetes, metabolic syndrome, and various cancers. Utilization of dietary interventions, micronutrients, vitamins, and minerals (where evidence to do so is substantial) seems very helpful for patient health and for decreasing the burden of numerous chronic diseases on the health care system. MDs can learn from NDs in their use of diet, nutrition and lifestyle interventions.

Some of the modalities used by NDs suffer from lack of evidence and efficacy. One of the cornerstone modalities of Naturopathic medicine is homeopathy. Founded by Samuel Hahnemann in the late 18th century, homeopathy is a philosophy-based medicine, centered on the principle of similia similibus curentur (like cures like), or the Law of Similars.5 A substance which would produce symptoms of illness in a healthy individual is believed to cure similar symptoms of illness in a sick individual. Homeopathic remedies are prepared with thousands of serial dilutions in alcohol or distilled water. Many of the remedies often used are diluted beyond the dilutional limit, well beyond the limit of Avogadro’s number. With literally no active substance left in the actual tincture of water administered to the patient, the only explanation left is some convoluted theory in quantum mechanics or string theory; or some sort of “water memory” effected by changes in pressure, epitaxy, and/or nanobubbles brought about through the successing process.6 Theory aside, the clinical evidence for the effectiveness of homeopathy is wanting, with much of the data presenting conflicting or

null results. In 2002, an analysis of eleven systematic reviews found that homeopathic remedies are not clinically different from placebos.7 In 2005, a Lancet review of 110 homeopathy trials concluded that when analyses were restricted to large trials of higher quality, there was no convincing evidence that homeopathy was superior to placebo.8 In 2010, an evaluation of six Cochrane reviews concluded that homeopathic medicines do not show effects beyond placebo.9 It is hard to say which is more surprising: the fact that these absurd dilutions have been used by practitioners for over 200 years, or that research efforts and government funds continue to be invested in trying to validate this pseudo-scientific quackery. Normally it would be appropriate to raise concerns over safety or inspection, and lack of regulation by the FDA or external agencies, but then again, it is only water being administered anyway.

Each of the modalities used by NDs need to be evaluated in its own right. Evidence exists to suggest that many of the botanicals used

by NDs may provide some benefit. However, knowledge of drug-herb interactions is limited and often preclinical data evaluating botanicals is erroneously generalized to human situations haphazardly.10 Another major modality utilized by NDs is Asian medicine and acupuncture. Traditional Chinese Medicine is based on ancient folk wisdom with yin yang, Qi, five elements, meridians, etc. Acupuncture should only be used where a sufficient number of properly conducted clinical trials exist. Problems arise in designing properly controlled studies, with difficulties in blinding and creating adequate placebo groups.

Perhaps even more interesting than the evidence or lack of evidence for naturopathic medicines and CAM therapies are the sociological questions, such as why are people attracted to CAM; why are young, intelligent students drawn to the field of Naturopathic medicine; and why does the field of naturopathy continue to thrive in a society that increasingly stresses science, evidence and rationality? Health-care consumers are drawn to this holistic, “natural” alternative, repelled and dissatisfied by Western biomedicine, perhaps due to lack of successful treatments, failed therapies, or fear of exaggerated sideeffects of pharmaceuticals. Many patients are put off by the disease-focused, technol-

ogy-driven biomedical model. Often, use of CAM is coupled with conspiratorial thinking regarding the unreliability of, and supposed biases present in scientific research.

The blatant lack of concern of patients for the inadequacy of reliable evidence, and the implicit trust in folk wisdom, is alarming. But of course, it is probably the case that most patients seeking CAM are ignorant of the scientific evidence—they seek treatment from NDs on ideological grounds. The pseudoscientific components aside, to the credit of Naturopathic medicine, at least it emphasizes healthy lifestyle, values prevention, and uses less-invasive intervention.

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. Jong MC, van de Vijver L, Busch M, et al. Integration of complementary and alternative medicine in primary care: What do patients want? Patient EducCouns.

2012;89(3):417-22.

2. National Center for Complementary and Alternative Medicine (NCCAM). [homepage on the internet].

Health Info. What is Complementary and Alternative Medicine?[updated 2011 July; cited 2013 January].

Available from: http://nccam.nih.gov/health/whatiscam 3. Atwood KC 4th. Naturopathy: a critical appraisal.

MedGenMed. 2003;5(4):39.

4. Litchy AP. Naturopathic physicians holistic primary care and integrative medicine specialists. J Diet Suppl.

2011;8(4):369-77.

5.Novella S, Roy R, Marcus D, et al. A Debate Homeopathy—Quackery or a Key to the Future of Medicine. J Altern Complement Med. 2008;14(1):9-15.

6. Milgrom LR. Conspicuous by its absence the Memory of Water, macro-entanglement, and the possibility of homeopathy. Homeopathy. 2007;96(3):209-19.

7. Ernst E. A systematic review of systematic reviews of homeopathy. Br J ClinPharmacol. 2002;54(6):577-82.

8. Shang A, Huwiler-Muntener K, Nartey L, et al. Are the clinical effects of homoeopathy placebo effects?

Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet. 2005;366(9487):72632.

9. Ernst E. Homeopathy: what does the “best” evidence tell us? MJA. 2010;192:458-60.

10. Kennedy DA, Seely D. Clinically based evidence of drug-herb interactions: a systematic review. Expert Opin Drug Saf. 2010;9(1):79-124.

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 30

VIEWPOINT

PhDs:

Training For Jobs That Don’t Exist

Image courtesy of www.istockphoto.com: ID #600882.

By Tetyana Pekar

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VIEWPOINT

I

n 1900, the University of Toronto (U of T) awarded Canada’s first Doctorate of Philosophy (it was in physics).1 In 2001—almost 100 years later—there were 3,660 PhDs given out in Canada, which is an increase of roughly 40% since 1991.1 There were also 27,340 doctoral students— more than double the number in 1981.1

In 2001, students in science, engineering and health sciences made up 49.3% of all doctoral candidates.1 Six universities train more than half of all doctoral candidates, and again, unsurprisingly, U of T alone trained almost 16% of all doctoral candidates (~4,375, almost double the next largest university) in 2001.1 In 2010, the Institute of Medical Science (IMS) had 504 students, and 231 of them were in the PhD or Direct PhD programs.2 Canada produces more and more doctoral students, and the U of T trains more graduate students than any other university in Canada. However, the creation of PhDs has vastly outpaced the creation of jobs that newly minted PhDs typically sought and trained for.

In 2003, the chance of getting a tenure-track professorship position five years after completing a PhD in biomedical sciences was 15%, down from 25% in 1993, according to the National Science Foundation.3 I don’t think there is any reason to believe the trends are different in Canada.

Imagine if only 15% of law students became practicing lawyers, or 15% of medical students became practicing doctors.

Of course, not everyone wants a tenure-track position. But if over three quarters of biomedicine PhDs do not end up in tenure or tenure-track positions (and less than half end up in academia), why aren’t universities, especially PhD factories like U of T, doing anything to train PhD graduates to successfully compete in the non-academic job market?

One can argue that the skills biomedical PhDs have are already transferable and wellsuited for the biotechnology or pharmaceutical industries. Perhaps that is true, but since 2000 the pharmaceutical industry has cut

almost 300,0000 jobs, according to a consulting firm Challenger, Gay & Christmas.4 However, according to a report NIH, in the US, approximately 30% of biomedicine PhDs work in the pharmaceutical and biotechnology industries.5 I am unsure of the numbers in Canada.

Still, current doctoral training is aimed at producing more academics, even though only 15% of the trainees end up doing what they trained to do. Imagine if only 15% of law students became practicing lawyers, or 15% of medical students became practicing doctors.

My problem isn’t the lacklustre career chances for anyone who wants to pursue a career in academia. My problem is that faculty members and graduate departments don’t do enough to prepare students to work outside of academia. In fact, they don’t do enough to even educate students about the realities of the job market.

Yes, academics probably do not know a lot about the non-academic job market. But they can create mandatory courses, or provide internship opportunities to help students prepare and successfully compete in the nonacademic job market.

Last year, the IMS Student Association (IMSSA) hosted a successful career seminar series.

The Life Science Career Development Society (LSCDS) also hosts seminars and workshops for MSc and PhD students aimed at helping students expand the scope of possible job opportunities and build connects.7 But LSCDS and IMSSA are student-run seminars and workshops. They might aid in networking and expanding the career horizons of current trainees, but they do little to help students get the skills and hands-on experience they need.

Universities are “[producing] a product for which there is no market,” wrote Mark C. Taylor, a professor at Columbia University, in a 2009 Op-Ed in the New York Times.6 My point isn’t to debate the career prospects, but to urge faculty members and graduate departments to be upfront with their students.

To quote the chair of molecular biology at Brown University, Dr. Susan Gerbi, from an article titled “The Real Science Gap”: “’pyramid paradigm can’t continue forever,’[…]

Like any Ponzi scheme, she fears, this one will collapse when it runs out of suckers — a stage that appears to be approaching.”8

A job shouldn’t be a guarantee, but there should be reasonable prospects of getting the job one spent half a decade or more training for.

A job shouldn’t be a guarantee, but there should be reasonable prospects of getting the job one spent half a decade or more training for. And when will we finally stop calling non-academic careers “alternative”? They are the mainstream, not alternatives.

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. Williams, G. Doctoral Education in Canada: 1900 – 2005. Canadian Association for Graduate Studies.

2005 Sept. [Cited 2013 Jan 10]. Available from: http:// www.cags.ca/documents/publications/doctoral_education_canada_1900-2005.pdf.

2. Feature. IMS Magazine. 2011 Winter p. 13. [Cited 2013 Jan 14]. Available from: http://issuu.com/imsmagazine/docs/imsmag_winter2011.

3. Trivedi B.P. Are we training too many scientists? The Scientist. 2006 Sept 1. [Cited 2013 Jan 12]. Available from: http://www.the-scientist.com/?articles.view/ articleNo/24301/title/Are-We-Training-Too-ManyScientists-/.

4. Herper, M. A Decade in Drug Industry Layoffs. Forbes. 2011 April 13. [Cited 2013 Jan 14].

Available from: http://www.forbes.com/sites/ matthewherper/2011/04/13/a-decade-in-drug-industry-layoffs/.

5. Working Group. Biomedical Research Workforce Working Group Report. National Institute of Health.

2012 June 14. [Cited 2013 Jan 13]. Available from: http://acd.od.nih.gov/Biomedical_research_wgreport. pdf.

6. Taylor, M. C. End the University as We Know It. The New York Times. 2009 April 26. [Cited 2013 Jan 14].

Available from: http://www.nytimes.com/2009/04/27/ opinion/27taylor.html?pagewanted=all&_r=0.

7. Life Science Career Development Society [homepage on the Internet]. [Cited 2013 Jan 15]. Available from:http://www.lscds.org.

8. Benderly, B. L. The Real Science Gap. Pacific Standard. 2010 June 14. [Cited 2013 Jan 13]. Available from: http://www.psmag.com/science/the-real-sciencegap-16191/

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 32

EXPERT OPINION

SEX & IMMUNITY the importance of biological sex in immune responses

Gillian Einstein, PhD Director of the Collaborative Graduate Program in Women’s Health, University of Toronto Associate Professor, Psychology and Public Health

Anna Podnos, MSc Candidate Member of Dr. Reg Gorczynski’s lab

M

ale and female organisms differ in terms of social, cultural, and economic roles and expectations (gender), as well as biology (sex), and they experience disease in different ways.

The immune system, which detects and protects against disease by recognizing and responding to antigens, is affected by both gender and sex.1,2 Moreover, the immune system receives regulatory signals from an extended network of cells and tissues, which themselves are affected differently by sex and gender. As therapies targeting the immune system develop to improve outcomes in cancers, viral infections, autoimmune diseases, and transplantation, taking sex differences

However, sex differences are seldom the focus of biomedical, and especially immunological research.1,3 For example, it is rare for animal and cell-based research to use females as experimental subjects.3 Tellingly, when this was discussed in our Summer 2011 edition (see “Sexism in Biomedical Research”), one student wrote the following response: “I think one should stick to conducting research in one sex to eliminate unnecessary complexity of study design and resource spending. In the field of immunology, there are sex differences in immune responses, but they are not so drastic as to necessitate controlling for sex differences.” This comment reflects a prevalent attitude in biomedical science; however, the evidence is beginning to stack up against it.

Sex-dependent factors influence the susceptibility and progression of diseases. Compared to females, male mice and humans experience higher severity and prevalence of many bacterial, viral, fungal, and parasitic infections.4 On the other hand, females exhibit more robust immune responses to antigenic challenges, such as infection and vaccination.5 Although females mount greater immune responses, which can result in faster infection clearance, they more frequently develop immune-mediated pathologies.7 Females are also at a higher risk for developing many autoimmune and inflammatory diseases than males; 80% of patients with autoimmune diseases are women.8 In contrast, the risk of death from all malignant cancers is 1.6 times higher for men.9 Sex-based differences that affect the competence of the immune system may influence susceptibility to viral or bacterial infection and severity of illness.1 Females often have lower prevalence and intensity of infections, including malaria, HIV, hepatitis C, and influenza, due to heightened immune responses.2 The efficacy of antiviral and antibacte-

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rial drugs is also different between the two sexes, and adverse reactions to vaccinations are reported more frequently in females.5,6 This may reflect either a reporting bias, or greater inflammatory responses among women. Heightened inflammatory responses in women are effective for rapid clearance of infections, but can also result in pathology.

For example, excessive inflammatory responses are hypothesized to underlie severe outcomes of influenza;10 during the 2009 H1N1 pandemic, Canadian women had a 2.4-fold higher risk of death than men,11 and women worldwide are 2-6 times more likely to die from H5N1 avian influenza, partly due to heightened immune responses.2 An increased inflammatory profile in women is evident when looking at the sex distribution of autoimmune disorders. There is a 6-10:1 female:male bias in the prevalence of Sjögren’s syndrome, Hashimoto’s thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The increased susceptibility of females to such diseases can be shown in animal models, which reveal “profound and complex effects of sex steroid hormones and sex chromosomal complement on immune responses and development of disease.”8

Sex-based differences that affect the competence of the immune system may influence susceptibility to viral or bacterial infection and severity of illness.

The immune system also plays an important role in cancer progression, and sex is an important factor in the diagnosis, pathogenesis, and prognosis of many malignancies.2 Incidence and mortality rates for a majority of cancers in non-reproductive organs are consistently higher among males than females.9 Recently, cancer research has been focused on therapies that enhance the patient’s own abilities to fight the tumour, called cancer

Photo of Dr. Gillian Einstein by Chung Ho Leung.

into account will be ever more crucial for their success.

By Anna Podnos & Dr. Gillian Einstein

EXPERT OPINION immunotherapy.12 But, importantly, the success of these therapies depends, in part, on the sex of the patient. For example, a recent study reported that the combination of having a CD200 receptor (a potential anti-cancer therapeutic target) signaling deficiency and being a female drastically increased immune-mediated pathology in influenza A infection.13 Since CD200 blocking antibodies are entering clinical trials for cancer treatment, increased inflammation during infections in women as a result of CD200 blocking therapies must be considered as a potentially harmful side-effect.

Some of the differences between the immune system of males and females may be mediated by steroid hormones, like estrogens, progestins, and androgens.14 There are changes in immune responses between various female reproductive phases.2 For instance, the activity of regulatory and anti-inflammatory cells increases in pregnant females.15 Steroid sex hormones regulate a variety of physiological processes in the reproductive, skeletal, cardiovascular, and immune systems.

The binding of sex steroids to their receptors on immune cells directly influences cell signaling pathways, which affect the migration of immune cells to sites of inflammation and the production of soluble regulatory molecules that aid in cell communication.

Estrogens can stimulate cell proliferation and differentiation via estrogen receptors in immune cell populations, such as lymphocytes, monocytes, and brain glial cells. Estrogens are associated with inflammation, but they may have different effects in males and females.16 Progesterone is typically considered to be anti-inflammatory, and progesterone receptors (PR) are differentially expressed between sexes in many immune cells. For example, dendritic cells (DC) from female rodents express higher levels of PR than male DC, and progesterone suppresses inflammation to a greater degree in females.17 Androgens, like testosterone and dihydrotestosterone, also suppress the activity of immune cells by increasing the production of anti-inflammatory cytokines.18 Therefore, sex hormones affect the kinetics and magnitude of differential immune responses between males and females.2

differences between males and females. For example, the X chromosome contains many genes that are involved in immune responses.1 It also contains 10% of all microRNAs (miRNAs) in the human genome, while the Y chromosome does not contain any.19 miRNAs are critical regulators of the immune response, and this may indicate important sex-based differences in post-transcriptional regulation of expression of molecules involved in immunity.

As therapies targeting the immune system develop to improve outcomes in cancers, viral infections, autoimmune diseases, and transplantation, taking sex differences into account will be ever more crucial for their success.

Social and cultural factors are also important determinants of disease susceptibility, since gender influences patterns of exposure to infections and treatments. Gender roles influence where and how men and women spend their time and the healthcare they receive.20 For example, in certain societies fatality rates of measles infection are higher for females than for males, since girls remain at home and thus are at a higher risk of infection from siblings inside the home.1 Also, according to the WHO, important gender differences in access to healthcare may lead to variability in the level of care given to men and women.

For instance, a study in Kolkata, India, found that boys with diarrhea were more likely to be rehydrated and taken to qualified health professionals than girls.20 The clear differences in immune responses between males and females indicate that therapeutic interventions and research with animal models should take sex into account.

For example, sex-based differences in responses to cancer immunotherapies that are already used in clinics should be investigated to optimize patient care. This would offer new directions for treatments that may have sex-based variations in efficacies and sideeffect profiles. It’s just good science.

References 1. Fish, E. N. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol8, 737-744, doi:10.1038/nri2394 (2008).

2. Klein, S. L. Immune cells have sex and so should journal articles. Endocrinology153, 2544-2550, doi:10.1210/en.2011-2120 (2012).

3. Beery, A. K. & Zucker, I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev35, 565572, doi:10.1016/j.neubiorev.2010.07.002 (2011).

4. Klein, S. L. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev24, 627-638 (2000).

5. Klein, S. L., Jedlicka, A. & Pekosz, A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis10, 338-349, doi:10.1016/s1473-3099(10)70049-9 (2010).

6. Cook, I. F. Sexual dimorphism of humoral immunity with human vaccines. Vaccine26, 3551-3555, doi:10.1016/j.vaccine.2008.04.054 (2008).

7. Meier, A. et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid. Nat Med15, 955-959, doi:10.1038/nm.2004 (2009).

8. Voskuhl, R. Sex differences in autoimmune diseases.

Biol Sex Differ2, 1, doi:10.1186/2042-6410-2-1 (2011).

9. Cook, M. B., McGlynn, K. A., Devesa, S. S., Freedman, N. D. & Anderson, W. F. Sex disparities in cancer mortality and survival. Cancer Epidemiol Biomarkers Prev20, 1629-1637, doi:10.1158/1055-9965.epi-11-0246 (2011).

10. de Jong, M. D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and.

Nat Med12, 1203-1207, doi:10.1038/nm1477 (2006).

11. Zarychanski, R. et al. Correlates of severe disease in patients with 2009 pandemic influenza (H1N1).

Cmaj182, 257-264, doi:10.1503/cmaj.091884 (2010).

12. Pardoll, D. M. Immunology beats cancer: a blueprint for successful translation. Nat Immunol13, 11291132, doi:10.1038/ni.2392 (2012).

13. Karnam, G. et al. CD200 receptor controls sex-specific TLR7 responses to viral infection. PLoS Pathog8, e1002710, doi:10.1371/journal.ppat.1002710 (2012).

14. Bouman, A., Heineman, M. J. & Faas, M. M. Sex hormones and the immune response in humans. Hum Reprod Update11, 411-423, doi:10.1093/humupd/ dmi008 (2005).

15. Mao, G. et al. Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg.

Endocrinology151, 5477-5488, doi:10.1210/en.20100426 (2010).

16. Candore, G. et al. Gender-related immune-inflammatory factors, age-related diseases, and longevity.

Rejuvenation Res13, 292-297, doi:10.1089/rej.2009.0942 (2010).

17. Butts, C. L. et al. Inhibitory effects of progesterone differ in dendritic cells from female and male. Gend Med5, 434-447, doi:10.1016/j.genm.2008.11.001 (2008).

18. McKay, L. I. & Cidlowski, J. A. Molecular control of immune/inflammatory responses: interactions between nuclear. Endocr Rev20, 435-459 (1999).

19. Pinheiro, I., Dejager, L. & Libert, C. X-chromosome-located microRNAs in immunity: might they explain male/female. Bioessays33, 791-802, doi:10.1002/ bies.201100047 (2011).

20. Anker, M. Addressing sex and gender in epidemicprone infectious diseases. (2007).

Other variations in immune responses may be due to genetic, social, and environmental IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 34

SPECIAL TRIBUTE

KAREN DAVIS

A look back at her influenTial role as the former Associate Director of the IMS

By Jill Cates and Shayne Greenberg

D

avis began her scientific career after completing her PhD in the Department of Physiology at U of T in 1988. She pursued two post-doctoral fellowships at Johns Hopkins University and U of T, and was appointed as Assistant Professor in Surgery in 1995. Davis joined the IMS faculty as a Principal Investigator in 1996, while her role as an administrator began as a member of the Student Admissions Committee at the IMS. At the time, the institute was in its early stages of evolution and expansion. “If you trace back to 1996, the biggest change [in the department] has been growth,” Davis explains. “Since that time, the student and faculty body of the IMS has nearly tripled.” In fact, the IMS is currently the largest graduate unit in the Faculty of Medicine at the University of Toronto. In addition to the expansion of the IMS, Davis has witnessed a change in educational background of the student population. The IMS was first established in 1974 as a conduit graduate unit consisting of residents and other MDs who were trained by clinical faculty who had their academic appointments in a clinical department, but did not have graduate (i.e. SGS) appointments. Over the past decade, the institute has evolved to incorporate both clinical and basic science faculty and students. Davis clarifies, “Now, half of IMS enrolment consists of students from a basic science background, the other half being students who have graduated with an MD.” The recent development of new collaborative and professional programs—such as

Biomedical Communication, Bioethics, and Medical Radiation Science—is evidence of the increasing diversity and multi-disciplinary nature of the IMS.

As current IMS students know, the Graduate Student Oath is recited in unison by all incoming students during orientation at the start of graduate training.

In 2002, Davis was appointed Graduate Coordinator of the IMS. Her role was largely student-focused, involving responsibilities such as admitting new students, providing current students with academic advice, and disseminating new policies and procedures to students and faculty. A key responsibility of a graduate coordinator is conducting student interviews as part of the admissions process. “The IMS is one of the few graduate units, or perhaps only, that interviews each and every applicant,” Davis proudly explains.

“We have maintained this interview process to ensure the highest calibre of students, and to provide an initial personal interaction between the applicant and the IMS.”

From co-creating the Graduate Student Oath, to interviewing prospective applicants, to meeting with current students on a weekly basis, Davis realized that her role as a graduate coordinator required a heavy time commitment that proved to be a setback in supervising her rapidly growing pain research lab at Toronto Western Hospital. After seven productive years, she was ready to leave her position as Graduate Coordinator and retire from administration. However, the Director of IMS at the time, Dr. Ori Rotstein, encouraged Davis to become Associate Director as an opportunity to use her to talents from an entirely different angle—shifting the focus from the students to the faculty. In 2009, Davis made the decision to step down as Graduate Coordinator and take on the role of Associate Director.

These high standards are reflected in the Graduate Student Oath, a type of “professional honour code” that Davis, along with former IMS Graduate Coordinator Dr. Mary Seeman, initiated in 2007. Adapted from the Hippocratic Oath in medicine and other professional oaths, the Graduate Student Oath is tailored to values of biomedical research and “encourages awareness and discussion of the social and moral responsibilities of [graduate] students.”1 In particular, the oath emphasizes community, professionalism, and ethical conduct in graduate training—all of which are important values of the IMS.

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The Associate Director is responsible for faculty appointments, training, and improving the academic environment at the IMS. It was a dynamic role for Davis, rewarding yet challenging: “There was a lot of activity and change during the time I took on the role of Associate Director—the end of Ori Rotstein’s decade-long term as Director, the search for a new director, and the turnover in staff.” The transition between directors—from Dr. Ori Rotstein to Dr. Allan Kaplan—involved rig-

Photo by Chung Ho Leung.

Over the past 16 years, Dr. Karen Davis has played a pivotal role in some of the most ground-breaking changes at the Institute of Medical Science (IMS) at the University of Toronto (U of T). Since she first joined the IMS in 1996, the institute has undergone radical changes in curriculum, student body, and faculty, and is now on an exciting new trajectory for the future. Davis has been a driving force behind the evolution of the IMS through her role as Graduate Coordinator from 2002-2009, and as Associate Director from 2009-2012.

SPECIAL TRIBUTE

orous self-study and internal review, a process that “requires honesty in what’s working and what’s not working.” During this period of change, Davis was presented with the challenge of continuity, while meeting the needs of the students and faculty. Looking back, Davis sees this turnover in a positive light.

“New blood is good for the system. It’s good to have new people come in and provide fresh ideas.”

In addition to the change in administration, Davis also oversaw changes in the program structure of the IMS. During her tenure, Davis contributed to modifications of the IMS seminar course and helped Dr. Howard Mount and Dr. Rotstein create the module system. The purpose of these “mini-course” modules is to promote the exploration of translational research and to expose students to new areas of research without an excessive course load. Such modules include Entrepreneurship 101, Qualitative Research, Animal Models of Human Disease, and Becoming an Editor of Your Own Work. Davis also conceptualized and is co-organizer of the popular Clinical Insights for Non-Clinicians module,

modeled after her own positive experiences as a basic scientist working in a clinical environment. These modules are a first step towards providing graduate students with opportunities to explore different career paths and expanding their training in translational research. Moving forward, Davis feels that the IMS should provide opportunities for students to explore career options outside of academia, including government, policymaking, industry, business, pharmaceuticals, writing, media and communication, and journal editing. “We need to be honest about what jobs are out there,” Davis says. Creating these opportunities for students will better prepare them for their future career.

Though Davis stepped down from her role as Associate Director in 2012, she is by no means slowing down as a scientist. Focusing her time back in the lab, she is an active member within the research community.

Her involvement continues on the advisory boards of numerous granting agencies and groups, such as CIHR, Brain Canada, and the International Association for Study of Pain.

While no longer a formal member of the IMS administration, Davis’ work as an administrator—from the IMS Graduate Student Oath, to the development of modules, to the expansion of the IMS as a multi-disciplinary institute—will play a pivotal role in the future growth and development of the IMS.

Davis’ dedication and passion as an administrator has been the catalyst for bringing change to the IMS—a five-year strategic plan to set the institute on a new course. The goals of this project are varied but the objective is clear: to continue the growth of the IMS and gain world recognition for its achievements, while grounding itself as the centre for translational research at U of T.

References 1. Davis KD, Seeman MV, Chapman J, Rotstein OD. A graduate student oath. Science. 2008;320(5883):1587-8. Epub 2008/06/21.

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Future Directions TAKING SCIENCE INTO THE THIRD DIMENSION

By Danielle D. DeSouza

WITH MERRY S. WANG, MScBMC

Biomedical communicators interpret the sci-

entific literature and use their artistic abilities to translate the ideas across a variety of media. Wang developed her artistic abilities at a young age; as a child growing up in China, some of her first exposures to art came from watching her grandfather sketch. Working as an archeologist, her grandfather would frequent the Great Wall of China to recreate historical scenes of the Great Wall based on the battle remnants he discovered. As he worked, Wang was inspired to draw her own versions of these scenes, and although visual arts were not the focus of her later studies, it always remained a hobby.

During her undergraduate degree at McMaster University, Wang set her focus on the health sciences. While in her third year, she worked in an anatomy lab as a prosector, preparing dissections for demonstration.

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It was here that one of her colleagues mentioned U of T’s Biomedical Communications (BMC) program. Curious to learn more, Wang looked into the program, and her eyes opened to the possibility of working in a field where she could fuse art and science. Wang enrolled in the program the following year.

Biomedical Communicators create images, interactive technologies, and animations/simulations to effectively communicate complex scientific topics.

Wang elected to specialize in 3D visualization. After gaining experience in stem cell research during her undergraduate thesis

Photo by Laura Feldcamp.

B

iomedical Communicators create images, interactive technologies, and animations/simulations to effectively communicate complex scientific topics. Graduating from the Master of Science in Biomedical Communications (MScBMC) program at the University of Toronto (U of T) only last year, Merry Wang has already attained a position in the research department of a multinational corporation that focuses on 3D design software. In this role, she works on various programs that target diverse realms of the life sciences. She combines her artistic abilities, background in health sciences, and technical skills to find her niche in the rapidly growing fields of 3D visualization and bio/nanotechnology and programmable matter.

FUTURE DIRECTIONS project, Wang knew she also wanted to complete her master’s research project in this field. Under the supervision of Dr. Andras Nagy, a senior scientist at the Samual Lunenfeld Research Institute at Mount Sinai Hospital, Wang undertook the challenging task of creating a 3D animation that highlighted a novel stem cell treatment for age-related macular degeneration. Wang not only used her technical and artistic abilities to create this project, but she also had to have a deep understanding of the complex scientific content she was working on. Wang noted, “Many people think that Biomedical Communicators simply convey the results of scientists to the public. One of the things I feel strongly about is that people in our field have not only the ability of understanding medical/scientific information, we are also well equipped to make significant contributions in the research process.” Impressively, throughout her master’s degree, Wang also worked on the IMS Magazine. She explained that working on the magazine was a great opportunity to gain experience and sharpen other skills by exploring design and layout.

this technique in the health field aims to use “nanorobots” to deliver drugs to specified target cells (e.g., cancer cells).3 Nanorobots change their configuration to release their contents once they detect receptors present on the target cell only; in this way, nanorobots have a specificity that other drugs lack.

Wang accepted a position at the multinational software company, Autodesk, shortly after the completion of her master’s project.

Although Autodesk is well known for their 3D computer-aided design (CAD) software in a variety of industries (including architecture, manufacturing, engineering, media and entertainment), life sciences have also become an emerging area. The group has been involved in projects with collaborators from around the world, including Organovo, a company dedicated to creating functional human tissues using 3D bioprinting technology. Their research focuses on creating human tissues in 3D that are architecturally correct and made entirely of living human cells.1 Their goal is for the tissue to function like native tissue and for it to be used in medical research, drug development, and surgical therapies. As Wang commented, “They have the hardware, and Autodesk has the software expertise; it makes for an excellent collaboration.”

Wang’s experience at Autodesk has not only confirmed her passion for biomedical communication, but also for research. It is her future goal to be able to use 3D visualizations

Another fascinating collaboration was with Dr. George Church and colleagues from the Wyss Institute at Harvard University. Their project involved using DNA as a programming language to create nanostructures through DNA origami.2 One application of

“Many people think that Biomedical Communicators simply convey the results of scientists to the public. One of the things I feel strongly about is that people in our field have not only the ability of understanding medical/scientific information, we are also well equipped to make significant contributions in the research process.”

and simulations as a tool to drive further research. Wang has already been accepted to pursue further graduate training at U of T next year. Until then, we must patiently wait until she reveals which part of science she will bring to 3D next.

References 1. Jakab, K., Damon, B., Neagu, A., Kachurin, A., and Forgacs, G. (2006). Threedimensional tissue constructs built by bioprinting.

Biorheology, 43(3-4): 509-13.

2. Ke, Y., Ong, L.L., Shih, W.M., and Yin, P. (2012).

Three-dimensional structures selfassembled from DNA bricks. Science, 338(6111): 117783.

3. Douglas, S.M., Bachelet, I., Church, G.M. (2012). A logic-gated nanorobot for targeted transport of molecular payloads. Science, 335(6070): 831-4.

The human rhinovirus produced by Merry Wang using Autodesk Maya software for the Autodesk Life Sciences initiative.

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IN THE NEWS

MIND THE MEDIA

Misattribution of Mental Health

By Laura Seohyun Park

Searching for an answer When tragedies like the 2012 Newtown shooting occur, mass media overwhelms the public with information. To explain why anyone would commit such a heartless act, the media searches for any details on the suspect that might help make sense of the situation and minimize uneasiness of the public. During this process, a complex situation may be simplified and the incident blamed on the characteristics of the shooter. Social psychologists refer to this concept as “Attribution Theory,” whereby an individual explains behaviour or an event by attributing it either to the person’s internal dispositions, or to external circumstances.1 These attributions depend on whether we are the actor or the observer.1 As an observer of the Newtown tragedy, both the media and the public tend to make dispositional attributions, a tendency to explain Adam Lanza’s actions based on his personality, attitudes, and character, rather than situational factors.

Mass media have extensively discussed possible reasons for Lanza’s atrocious act, often pointing to his personality traits that may be associated with a psychiatric disorder. Lanza has been described to be “socially awkward” and “uncomfortable in social situations,” where “several said…he had a developmental disorder…Asperger’s Syndrome.”2 Identifying a specific disorder for Lanza is not only irrelevant, as the factors leading to his

What we can learn from the tragedy actions are much more complex, but also dangerous. The high publicity of the incident leads to misattribution and misleading information resulting in the public holding false beliefs about the event3 and blaming the disorder for his actions. Such speculations may in turn lead to misinformed assumptions and generalizations–isolating individuals suffering from mental illnesses as a viable solution to prevent further tragedies, and higher rates of violence committed by individuals with mental illness. However, in reality, individuals with a mental illness are no more likely to be violent than any other group in the general population.4

Not one disorder is the same: The heterogeneity in psychiatry While terms like “Asperger’s syndrome” and “schizophrenia” are tossed around to describe Lanza, they will remain mere speculation. We will never know his “exact diagnosis,” as psychiatric diagnoses require formal assessments from a psychiatrist or psychologist, and more importantly, for Lanza to be alive. Even if experts were to identify with a disorder to describe him, the matter would not be simplified due to the heterogeneous and complex nature of psychiatric disorders.

Some examples of clinical heterogeneity of psychiatric disorders include: (a) Subtypes: While two people may be both diagnosed with anti-social personality disorder (ASPD), one may engage in aggressive behaviour such as fighting, while another in only non-aggressive behaviour such as swearing.5 (b) Severity: Two individuals diagnosed with the same disorder show differences in severity of symptoms and impairment. Moreover, they differ in prognosis, course and duration of illness. (c) Overlapping Symptoms: Symptoms may

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This heterogeneity across psychiatric disorders and within one disorder makes it difficult to generalize behaviour across individuals. Therefore, even if Lanza were to have been formally diagnosed with a disorder, we cannot generalize behavioural patterns to all individuals suffering from that disorder. So, why waste time searching for Lanza’s psychiatric diagnosis? Ultimately, this tragedy may be a culmination of an underlying psychiatric disorder combined with genetic, environmental, cultural, and developmental factors.

We cannot identify the perfect formula underlying this massacre. Rather, what we can take away from this is that we, as individuals, must recognize the pitfalls of media coverage on popularized crimes, and as a group, spark discussion and progress in mental health awareness as well as healthcare systems, policies, and research.

Disclaimer: The opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Comments are welcome at theimsmagazine@ gmail.com.

References 1. Myers D, Spencer, S. Social Psychology. 3rd ed.

USA:McGraw-Hill;2006.

2. Halbfinger DM. A gunman, recalled as intelligent and shy, who left few footprints in life. The New York Times.

2012 Dec 15; Sect.A:18.

3. Harris RJ. A cognitive psychology of mass communication. 5th ed. New York:Routledge;2009.

4. Canadian Mental Health Association. Violence and Mental Health; 2013 [cited 2013 Feb 4]. Available from: http://www.cmha.ca/mental_health/violence-and-mental-illness/#.URBIvVqw86E. 5. Burt SA. How do we optimally conceptualize the heterogeneity within antisocial behaviour? An argument for aggressive versus non-aggressive behavioural dimensions. Clinical Psychology Review. 2012;32(4):263-279.

6. Burmeister M, McInnis MG, Zollner S. Psychiatric genetics: progress amid controversy. Nat Rev Gen. 2008;9:527-540.

Photo courtesty of iStockphoto #739447.

I

n the wake of the tragedy that occurred last December at Sandy Hook Elementary School in Newtown, Connecticut, mental illness has once again entered the spotlight. In this article, I discuss that while it is easy to use mental illness as an explanation for mass murder, we should be careful in our search for not-so-simple answers.

overlap between different psychiatric disorders. For instance, psychosis can be a symptom of schizophrenia, bipolar disorder, or psychotic depression.6 (d) Comorbidities: Individuals may be diagnosed with two different disorders. An individual diagnosed with conduct disorder may also be diagnosed with attention-deficit hyperactivity disorder, while another with substance abuse.5

Ask the

Dear Experts, I am an associate professor here at the IMS with limited funding. Unfortunately my PhD student has taken a few months longer to finish his degree. Is there any way I can obtain extra funding for the final six months of his degree?

-Worried Associate Dear W.A., When you say you are an Associate Professor, we assume you mean an Associate Professor in your Department. You would need to be a Full Member (rather than an Associate Member) of IMS in order to be supervising a PhD student. It is precisely to avoid a situation of funds running out that IMS insists on abundant external funds before Membership in IMS is granted. That being said, this situation can happen to everyone, especially in today’s funding climate. Possibilities: the student should apply far and wide for personal funding; a co-supervisory arrangement can sometimes be made with two supervisors sharing both the supervision and the funding; the supervisor’s Department often has bridging funds. The student should contact the Graduate Coordinators. If all else fails, contact the Associate Director, Dr. Mingyao Liu and discuss the possibility of emergency funding.

Experts about healthy eating, exercise, sleep hygiene, and staying away from alcohol and drugs of abuse, it’s impossible to offer specific advice until the possible causes are explored. Come in to the office and talk to the Graduate Coordinators. Their time is your time.

Dear Experts, I am in my third year of undergraduate studies at the University of Toronto (major Human Biology). I am currently considering pursuing a graduate degree. Besides academia, what advantages/career opportunities are available with a Master’s degree from the IMS? -Career Planning

Dear Experts, I am a second year Master’s student hoping to defend in June. I’m aware of the deadlines to defend, but not sure how to start writing my thesis. Where can I get help with formatting and writing my thesis?

- Thesis Curious

Dear C.P., Students applying to IMS generally are interested in Medicine or Medical Research or a combination of the two. After an MSc degree, IMS students have gone on to be doctors, dentists, pharmacists, nurses and lawyers. Or they have gone into business. Or industry. Or they have gone on to a PhD. You may want to speak with students on the IMS student organization (IMSSA) executive to find out about dates of career counselling workshops.

There are usually several over the course of any one year.

Dear Experts,

Dear Experts,

I am going into my second year of my Master’s program and am feeling highly unmotivated and unproductive at the lab. What can I do to get back on track?

My supervisor is a clinician-scientist and rarely at the lab. He also takes a while to answer emails. I’m having difficulties setting up meetings with him on a regular basis. What can I do?

-Winter Blues

of town. The first step is to talk to your supervisor and see what he suggests. He may suggest that, in his absence, you consult with another member of your PAC. One idea is to set aside a regular time for the two of you to meet when he is in town.

Discuss the issue with a Graduate Coordinator. Some gentle prodding from IMS may remedy the situation.

-Eager to Meet Dear W.B.,

Dear E.M.,

Lack of motivation can be caused by any number of personal, family, financial, healthrelated, interpersonal, or research-related issues. Other than general recommendations

Unfortunately for students, this is a frequent IMS problem because our faculty have so many responsibilities and are so much in demand for presentations and conferences out

Dear T.C., The IMS meeting room is lined with bookcases full of theses. Come at any time and look through them. You can’t take them out of the office but you can spend as much time looking at them as you wish. Different topics lend themselves to different formats so it is probably best to discuss your specific needs with your supervisor, with your PAC, with other students, and with IMS Graduate Coordinators. The hardest part is getting started.

EXPERT TIP Get to know the IMS administration staff throughout your graduate degree. We are here to help!

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

IMS MAGAZINE SPRING 2013 DRUG RESCUE AND REPURPOSING | 40

PAST EVENTS

PAST EVENTS

Celebrating the holiday season in style at the IMS Holiday Party. (above) Singing like a springtime Robin at Karaoke. (right)

Out for a social night at an IMSSA pub night. (left)

IMSAA yoga event to raise money for prostate cancer research. (left)

Helping the homeless with a sandwich patrol. (right)

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Photos courtesy of IMSSA; Holiday party photo courtesy of Chung Ho Leung.

Women supporting Movember! (right)

DIVERSIONS

TRAVEL BITES While conferences provide researchers with the opportunity to make their work known, establish connections and think about their progress from various different angles, they also provide the chance to explore exciting new places around the world.

“CitySkyline01” by tonyhewison, “Mountain” by dijz, “Airplane” by chovynz, “Palm Tree” by bsantos all courtesy of http://openclipart.org/.

Whether it be a thrilling nightlife or breathtaking views, every conference is a ticket to a new city and therefore a new adventure.

Have you recently attended a conference in an exhilarating new place? If you have any conference experience you would like to share, please email the IMS magazine at theimsmagazine@gmail.com.

“Piled Higher and Deeper” by Jorge Cham http://www.phdcomics.com

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