Summer 2017

IMS MAGAZINE THINK. LEARN. DISCOVER.

SUMMER 2017

Clinical Trials RETINAL STEM CELL TRIALS: Are we there yet?

EXPLORE TRANSPLANT ONTARIO: Providing education to improve access to kidney transplantation and living donation

DYING FOR CHANGE

How to heal Canada’s healthcare system

Student-led initiative

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 1

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IN THIS ISSUE Letter from the Editors............................... 4 Director’s Message.................................... 5 Commentary............................................... 6 Retrospective............................................. 8 Feature: Infographic................................. 10 Feature..................................................... 12 Travel Bites............................................... 24 BMC Spotlight.......................................... 26 Viewpoint................................................. 28 Alumni Spotlight...................................... 34 Faculty Spotlight...................................... 36

MAGAZINE STAFF EDITORS-IN-CHIEF

Petri Takkala Sarah Peters

EXECUTIVE EDITORS

Anna Badner Ekaterina An Meital Yerushalmi

DESIGN EDITORS

Christine P’ng Judy Rubin Lauren Huff Midori Nediger Ursula Florjanczyk

JOURNALISTS & EDITORS

Aadil Ali Aaron Wong Adam Betel Alexandra Mogadam Aravin Sukumar Archita Srinath Arman Hassanpour Arpita Parmar Beatrice Ballarin Benjamin Markowitz Carina Freitas Cricia Rinchon Fadl Nabbouh Felicity Backhouse Gaayathiri Jegatheeswaran Hira Raheel Jessie Lim Joel Tan Joshua Rapps Jonathon Chio Jung (Lily) Ye Lindsay Caldarone Lisa Qiu Melissa Galati Mirkamal Tolend Muhtashim Mian Nancy Ji Natalie Osborne Pontius Tang Pratiek Matkar Rachel Dragas Samia Tasmim Sarasa Tohyama Shokoufeh Yaseri Tahani Baakdhah Usman Saeed Yekta Dowlati Yena Lee Grace Jacobs Iris Xu Mikaeel Valli

IMSSA & Past Events.............................. 38 Twitter Feature......................................... 42

Cover Art

28 BMC Spotlight

By Ruth Chang and Ursula Florjanczyk

By Lauren Huff

10 FEATURE INFOGRAPHIC

By Midori Nediger

Copyright © 2017 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.

PHOTOGRAPHERS

SOCIAL MEDIA TEAM

Archita Srinath Lily Ye Tahani Baakdhah

SPONSORSHIP TEAM

Carina Freitas

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 3

Photo by Meital Yerushalmi

LETTER FROM THE EDITORS

LETTER from the

W

SARAH PETERS (right), PETRI TAKKALA (left) Editors-in-Chief, IMS Magazine

EDITORS

hen was the last time you took medication? For many of us, the answer likely lies somewhere within the past 48 hours. It can be easy to forget that our personal medications or medical devices—mere habits in our daily or weekly routines—were formulated, tested, and developed over many years by multidisciplinary teams of medical scientists and physicians. Clinical trials are the foundation of translational research, and the Institute of Medical Science (IMS) is fortunate to be a launching pad for clinical trials across many medical specialties.

The highly regulated process of clinical trials necessitates extensive exploration into moral and ethical implications of the research on both test subjects and target populations. Fittingly, we begin this issue with a Retrospective interview with Dr. Fred Lowy, the ‘father of bioethics’ at the University of Toronto.

In addition, we are excited to share interviews with several distinguished IMS faculty members. This issue examines a breadth of clinical trials, including hands-on surgical and clinical work being led by Drs. Michael Tymianski, Robert Chen, and Evdokia Anagnostou.

Providing further insight into clinical trials at the macro-level, Drs. Istvan Mucsi, Peter Jüni, and John Marshall discuss aspects of education and global collaboration that can serve to strengthen clinical care and clinician-scientist knowledge.

For a fresh perspective on current scientific events, we encourage you to read our viewpoint articles. Our journalists share their takes on breakthroughs in CRISPR-Cas9 gene editing, the climate of scientific funding in Canada, and novel ways to assess pain in patients with disorders of consciousness. Other highlights in this issue include a summary of this summer’s U of T Talks event, which was organized by our colleagues in the IMS Students’ Association, and a striking sampling of work by students in the Biomedical Communications stream.

Finally, it is time for us to announce that we have entered the final “phase” of our tenure as editors of the IMS Magazine. It has been an honour to lead a multi-talented team, and we are confident that both our new and returning team members will bring the magazine to bigger and better places. Thank you for your readership!

Sincerely,

Sarah Peters & Petri Takkala Editors-in-Chief, IMS Magazine 4 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

DIRECTOR’S MESSAGE

DIRECTOR’S MESSAGE

The Summer 2017 issue of the IMS Magazine features Clinical Trials, and showcases the achievements and translational research of scientists in the Institute of Medical Science.

Clinical trials are an important part of the bench-to-beside implementation of biomedical research. Their success critically depends on appropriate adherence to research and clinical bioethics. The University of Toronto Joint Centre for Bioethics has played a key role in shaping Canadian ethical policies and practices, and began as the Centre for Bioethics within the IMS in the 1980’s. In this issue, Dr. Frederick Lowy, the Dean of the Faculty of Medicine at the time, reflects on founding the Centre for Bioethics in a Retrospective interview. Also featured in this issue are prominent leaders and scientists who are conducting clinical trials with the aim to improve patient care. Drs. Michael Tymianski, Robert Chen, Evdokia Anagnostou, Istvan Mucsi, Peter JÜni, and John Marshall each share their personal experiences in translational research.

The IMS Magazine continues to inspire, educate, and share ideas institutionally, and among a broader international readership, with readers and followers from countries around the world. Dr. Marina Picciotto, Professor of Psychiatry at Yale University, Editor-in-Chief of the Journal of Neuroscience, and keynote speaker at the 2017 IMS Scientific Day, expressed her admiration for this student-led initiative while speaking with students. Together with students from the IMS Students’ Association, and the organizers of the U of T Talks symposium, the IMS continues to be a leader within the University of Toronto. I share Dr. Picciotto’s admiration for the achievements of our students, and I look forward to following their future ventures.

Photo by Grace Jacobs

This issue includes student contributions focused on key issues, including the status of research funding in Canada, the latest in human gene editing, and the ethical and philosophical questions surrounding pain in the absence of consciousness.

Mingyao Liu, MD, MSc

Director, Institute of Medical Science Professor, Department of Surgery, and Physiology, Faculty of Medicine, University of Toronto Senior Scientist, Toronto General Research Institute, University Health Network

Sincerely, Mingyao Liu, MD, MSc Director, Institute of Medical Science

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 5

COMMENTARY

BEHIND A SM

is Canada Ready for

cannabis Legalization?

By Meital Yerushalmi & Chantel Kowalchuk

A

recent article in the Spring issue of the IMS Magazine highlighted concerns surrounding cannabis legalization with respect to its impact on driving while high, as well as on the challenges associated with the enforcement of impaired driving. As cannabis use and legalization continue to be politicized and featured in the media, our focus turns to the objectives, health impact, and the potential research outcomes from legalization. Here we employ a scientific approach to dispel common misconceptions.

Recent news of the federal government’s pledge to legalize cannabis (marijuana)

by July 2018 has rekindled the globally growing and contentious debate regarding the legalization of cannabis for recreational use.1 Following marijuana legalization in nine American states, Canada will soon legalize the recreational use of marijuana, fulfilling Prime Minister Justin Trudeau’s 2015 campaign promise. While the legislation of Bill 45, the Cannabis Act,2 is currently underway, the debate surrounding this controversial issue is far from over.

purchase quality-controlled cannabis from producers licensed by Health Canada.

They are also permitted to produce a limited amount of cannabis for their own medical purposes, or designate someone to produce it for them.3 In contrast, possessing and selling cannabis for non-medical purposes is illegal under the Controlled Drug and Substances Act.4 However, the new legislation will remove marijuana consumption and incidental possession from the Criminal Code, arguing, broadly, that the current ban on cannabis does not effectively limit use and distribution.5 As a result, recreational use for those over the age of 18 will become legal. The objectives of the Cannabis Act are to deter criminal activity by imposing serious criminal penalties for those operating outside the law, to prevent young persons from accessing cannabis, to establish strict product safety for public protection, and to reduce the burden on the criminal justice system in relation to cannabis.2 Notwithstanding the importance of these objectives and considering the young age proposed for its legal use, a discussion of the impact of cannabis on health is warranted.

Currently, the use of marijuana is permitted in Canada for medical purposes only. Users of medical marijuana can

Most Canadians support the legalization of cannabis for recreational use, albeit with apprehension over the young age

6 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

proposed by the legislation. Considering the popularity of cannabis among youth combined with the fact that the brain continues to develop into a person’s mid20s, the use of cannabis by young adults raises concerns over its neurological impacts on the developing brain. Studies suggest that in young adults, frequent, long-term use may lead to deficits in cognitive function, including memory, concentration, intelligence, and decisionmaking lasting into adulthood.6,7 Changes in brain structure, particularly in regions responsible for reward response, have also been shown in young users when compared to nonusers.8 Cannabis use by people in their late teens is also linked to an increased risk for early-onset psychosis, particularly in those with preexisting vulnerability and users of high doses.9 Yet, the literature on cannabis risks in youth is not at a consensus, with some studies finding no long-term adverse effects. This discrepancy is likely due to study design, as, given their ethical complexity, studies on youth consumption of cannabis tend to be observational in nature and are therefore unable to control for confounding variables. Nevertheless, research on the impact of cannabis on youth is essential in the face of legalization.

In Colorado, youth past-month marijuana use increased by 20 percent in the two‐year

COMMENTARY

MOKESCREEN average (2013/2014) since the legalization of recreational marijuana, compared to the two‐year average prior to legalization (2011/2012).10 Given the current popularity of cannabis among Canadian youth, it is imperative that we understand its health impacts in this age group in the face of the upcoming legislation.

In addition to its neural effects on youth and adults, cannabis also impacts the respiratory system as it is commonly consumed via inhalation through the lungs. Regular cannabis smokers report more symptoms of chronic bronchitis (wheezing, sputum production, and chronic coughing) than non-smokers, and long-term use can lead to airway inflammation, and lung hyperinflation.11 Additionally, cannabis users experience more respiratory infections, as the immunological competence of their respiratory system is impaired. While public health efforts that are against cigarette smoking show success in decreasing smoking rates in recent decades, cannabis smoke contains many of the same carcinogens as tobacco smoke, with some in higher concentrations.

However, echoing the trend in other research fields pertaining to cannabis and health, the long-term effect of cannabis on the respiratory system are not fully understood. Despite the evidence on the impact of cannabis smoking on the respiratory system, no association was found between chronic cannabis smoking and an increased risk of emphysema, and studies show inconclusive results with respect to its association with respiratory cancers.12 Similarly, evidence linking cannabis use and cardiovascular health demonstrate that cannabis increases heart rate in a dose-dependent manner, raising concern about adults with cardiovascular disease.13 In fact, laboratory studies indicate that smoking cannabis provokes angina in patients with heart disease, and suggests that cannabis can increase the risk for

myocardial infarctions.12 Lastly, cannabis use has been linked to the development of psychiatric disorders. For example, cannabis has been associated with an increased risk for schizophrenia that increases with frequency of use in a dose-response manner in youth, and persisted after controlling for the effects of possible confounders. Nevertheless, other studies have been inconclusive and show no clear evidence of this association.

Similarly, risk of psychotic disorders was higher in regular users than in non-users, though the association was attenuated after adjustment for potential confounders, rendering the common causal hypothesis difficult to exclude. Finally, non-consistent and weak associations have been reported between cannabis use and depression, as a dose-response relationship between frequency of use in youth and depressive disorder was shown. However, the association did persist after adjusting for confounders, leading the investigators to argue that confounders were not controlled for to exclude the possibility that depressed youth are more likely to use cannabis.12 Evidently, studies on the health impacts of cannabis often lack statistical rigor and are therefore inconclusive, perhaps stemming from the complex nature of cannabis use and the high likelihood of confounders.

Additionally, stigmatization and poor funding toward cannabis research compound the difficulty of studying the drug’s effects on one’s health. With the new legislation, cannabis will become more accessible for research purposes and may become less stigmatized by the public and funding agencies, which may lead to more research into the neurobiology of cannabis and the health impacts of its recreational use among the different age groups. Legalization may also drive further research into its use as a therapeutic agent, allowing studies to expand from focusing primarily on substance abuse and physiological risks and into further,

thorough investigation of its possible benefits. Overall, from a research standpoint, legalization of cannabis will allow development of the necessary knowledge required to inform the public health and policy decisions going forward.

It seems as if this multifaceted, controversial issue will continue to make headlines and stir speculation surrounding the outcomes of legalization to personal health and public safety. Truth be told, it is difficult to predict whether legalization of cannabis in Canada will fare similarly to the US. Regardless, talk of legalization has brought focus upon the effects of cannabis, usage in youth, regulation, and research barriers, encouraging a discussion which, at the very least, promotes necessary public knowledge and education.

References 1. Liberals introduce legislation to legalize marijuana by July 2018 | CTV News. [cited 2017 Jun 6]; Available from: http://www.ctvnews. ca/politics/liberals-introduce-legislation-to-legalize-marijuana-by-july-2018-1.3366954 2. Wilson-Raybould J. Bill C-45 | openparliament.ca [Internet]. 2017. Available from: https://openparliament.ca/bills/42-1/C-45/ 3. Information on the new Access to Cannabis for Medical Purposes Regulations [Internet]. 2016. Available from: http://www.hc-sc.gc.ca/dhp-mps/ marihuana/about-apropos-eng.php 4. Current Cannabis Laws - Legalization and Regulation of Cannabis [Internet]. [cited 2017 Jun 6]. Available from: http://www.justice.gc.ca/eng/ cj-jp/marijuana/law-loi.html 5. A New Plan for a Strong Middle Class [Internet]. [cited 2017 Jun 6].

Available from: https://www.liberal.ca/wp-content/uploads/2015/10/Newplan-for-a-strong-middle-class.pdf 6. Health effects of cannabis - Canada.ca [Internet]. 2017 [cited 2017 Jun 6].

Available from: https://www.canada.ca/en/health-canada/services/substance-abuse/controlled-illegal-drugs/health-risks-of-marijuana-use.html 7. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RSE, et al.

Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A [Internet]. 2012 Oct 2 [cited 2017 Jun 6];109(40):E2657-64. Available from: http://www.ncbi.nlm.nih. gov/pubmed/22927402 8. Gilman JM, Kuster JK, Lee S, Lee MJ, Kim BW, Makris N, et al. Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. J Neurosci [Internet].

2014 Apr 16 [cited 2017 Jun 6];34(16):5529–38. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/24741043 9. Bagot KS, Milin R, Kaminer Y. Adolescent Initiation of Cannabis Use and Early-Onset Psychosis. Subst Abus [Internet]. 2015 Oct 2 [cited 2017 Jun 6];36(4):524–33. Available from: http://www.tandfonline.com/doi/full/10.

1080/08897077.2014.995332 10. Hidta RM. The Legalization of Marijuana in Colorado: The Impact. 2016 [cited 2017 Jun 6]; Available from: http://www.rmhidta.org/html/2016 FINAL Legalization of Marijuana in Colorado The Impact.pdf 11. Lee MH, Hancox RJ. Effects of smoking cannabis on lung function. Expert Rev Respir Med [Internet]. 2011 Aug 9 [cited 2017 Jun 6];5(4):537–47.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/21859273 12. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet [Internet]. 2009 Oct [cited 2017 Jun 6];374(9698):1383–91.

Available from: http://linkinghub.elsevier.com/retrieve/pii/ S0140673609610370 13. Franz CA, Frishman WH. Marijuana Use and Cardiovascular Disease.

Cardiol Rev [Internet]. 2016 [cited 2017 Jun 6];24(4):158–62. Available from: http://insights.ovid.com/crossref?an=00045415-201607000-00002

IMSMAGAZINE MAGAZINESUMMER SUMMER2017 2017 CLINICAL TRIALS || 7 IMS

RETROSPECTIVE

Toronto, Home of Canada’s First Centre for Bioethics

By Ekaterina An

T

oronto has long been the site of groundbreaking biomedical research, but it is also the birthplace of the Centre for Bioethics (now known as the Joint Centre for Bioethics, JCB), one of Canada’s first academic bioethics research centers. Since its inception in 1989, the JCB has grown to include partnerships with 15 interdisciplinary healthcare and science organizations, with a community of over 200 ethicists, and legal and medical experts. In 2002, it was also selected as the first World Health Organization Collaborating Centre for Bioethics, expanding its reach internationally. However, despite the JCB’s current status as a heavyweight in the field of bioethics, the centre—founded by psychiatrist Dr. Frederick Lowy—had a very humble beginning right here at the Institute of Medical Science (IMS).

Dr. Lowy arrived in Toronto in 1974 to take on the positions of Psychiatrist-inChief and Director of the Clarke Institute of Psychiatry, and chair of the University of Toronto’s Department of Psychiatry.

Six years later, Dr. Lowy was appointed the Dean of the Faculty of Medicine, succeeding Dr. Richard Holmes. During his tenure as Dean, Dr. Lowy not only strove to train excellent physicians and promote meaningful research, but also wanted to instill “a broader sense of what medicine was about, in addition to the technical features—the art of medicine, the human aspects.” At the time, no formal bioethics course was offered at the University of Toronto. So when Dr. Lowy learned that a group of medical students, among whom was Peter Singer (who went on to be appointed Officer of the Order of Canada for his contribution to research in health and bioethics), was organizing voluntary ethics lectures, he was astonished. He recalls thinking, “If it is important enough for students to do this on their own time, as a faculty we ought to be doing this in a more formal fashion.”

This marked the beginning of what would become the JCB. Having completed his term as Dean, and 8 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

with the idea of creating a formal bioethics program, Dr. Lowy looked to the United States, where the field of bioethics was more developed. Specifically, he traveled to Georgetown University’s Kennedy Institute of Ethics as a visiting fellow to learn from Dr. Edmund Pellegrino, the founding director of the Centre for Clinical Bioethics at Georgetown, now known as the Edmund D. Pellegrino Centre for Clinical Bioethics. After a year at the Kennedy Institute, Dr. Lowy returned to Toronto, ready to establish Canada’s first formal bioethics program.

During that time, Dr. Lowy was also a faculty member at the IMS, which placed him in a perfect position to begin developing the Centre for Bioethics. Dr. Lowy assembled a group of colleagues at the University of Toronto to be the driving force behind this project, including Bernard Dickens (Faculty of Law), Barry Brown (Department of Philosophy), James Till (Department of Medical Biophysics), and the late John Senn (Faculty of Medicine), along with two graduate students (Peter Singer and Eric Meslin), and administrative support from Carol Nash. “Initially, we had no budget and no physical location,” recalls Dr. Lowy. “Dr. Silverman [director of the IMS at the time] was cooperative and gave us space in the Medical Science Building.” And so, the Centre for Bioethics came into existence in 1989, with Dr. Lowy at the helm as Director. “We started with lectures and then went on to develop formal programs.

When we outgrew the accommodations, we got space in the adjoining Tanz Neuroscience building [now known as the C. David Naylor building]. As the program grew further, we went on to occupy a former church at the corner of Elizabeth St. and College.” Today, the JCB resides at 155 College Street, in the Dalla Lana School of Public Health. “[The Centre] operated on a shoestring budget at first,” recalls Dr. Lowy, “with everyone being kind enough to donate their time.” A joint effort between numerous departments at the university,

Frederick H. Lowy, OC, MD, FRCPC Psychiatrist-in-Chief, Clarke Institute of Psychiatry Professor, Department of Psychiatry, University of Toronto Director, Centre for Bioethics, University of Toronto Dean of Medicine (1980-1987), Faculty of Medicine, University of Toronto Former Member, Institute of Medical Science the establishment of the Centre occurred at a fortuitous time, when interest in and demand for a formal bioethics program was growing. “I’m amazed at how little resistance there was, especially because we had no formal mandate from governing council,” said Dr. Lowy. “I was also fortunate enough that I had personal relationships with a number of people at the university that allowed me to establish the program.” One of the first significant sources of funding for the Centre came in the form of a Government of Ontario grant for over $2 million. “As soon as we started writing papers and getting students, the university took notice and we were able to

get things formalized through IMS and the Faculty of Medicine,” Dr. Lowy recounts.

“As the program expanded, it entered the mainstream. And under the direction of Dr. Peter Singer [who succeeded Dr. Lowy as Director of the Centre], we formed our first partnerships with the local hospitals.”

Today, the JCB has formal partnerships with nine academic departments at the University of Toronto, as well as 13 partner organizations in the health center. The Centre has also trained over 150 students, published more than 500 articles, and obtained $28 million in research grants.

Although Dr. Lowy stepped down as director of the Centre for Bioethics in 1995, he continued to be active in the field of bioethics, serving as the first Chair of Canada’s Tri-Council Working Group on Ethics of Research on Human Subjects.

His work with the Tri-Council was a coast-to-coast effort to consider the ethical aspects of healthcare and the problem of research involving human subjects.

“Without research with human subjects, the progress that we take for granted would not occur. At the same time, one has to be respectful and careful concerning the rights of patients or any human being who is subject to potential risk,” states Dr. Lowy.

“We took what we considered to be the best of any existing codes, for example the Nuremberg Code, and we tried to hammer out a set of regulations for Canada. The core of these recommendations is still a part of the current guidelines around research with human subjects.”

The field of bioethics in Canada continues to evolve with new healthcare legislation, such as Bill C-14 on medical assistance in dying, introducing unique ethical considerations. Today, under the direction of Dr. Jennifer Gibson, the JCB continues to expand and is undoubtedly a leader in its field.

Dr. Lowy left Toronto for Montreal in 1995 to serve as President and Vice-Chancellor of Concordia University. Since then, he has returned to Toronto and is a Senior Fellow at Massey College.

Photo by Grace Jacobs

RETROSPECTIVE

Melvin Silverman, MD, FRCPC Senior Staff Physician, University Health Network Professor Emeritus of Medicine, Faculty of Medicine, University of Toronto Director (1991-2000), Institute of Medical Science

T

he IMS mandate as envisioned by its founding director Jack Laidlaw, was to establish a graduate training culture of the highest standard for clinical departments in the Faculty of Medicine. As the 50th anniversary of the IMS approaches, we celebrate the achievements and successes of two generations of IMS student graduates and faculty who have played a substantial, if not critical role in the emergence of the U of T as a national and international powerhouse of academic medicine. I was privileged to be the Director of the IMS from 1991-2000. With Dr. Cathy Whiteside and Dr. Reinhart Reithmeier as IMS graduate co-ordinators, and the support of the Deans of the Faculty of Medicine and SGS, along with the Chairs of clinical departments, we underwent a period of innovative programmatic expansion, accompanied by rapid growth in student and faculty numbers. We worked hard to formulate an exciting and nurturing environment for graduate education in medical sciences that attracted both talented MD and non-MD students.

Three streams of graduate research evolved—basic science, integrated biology, and epidemiology—with a focus on disease mechanisms. Not surprisingly, IMS became the home department for most of the participants in the Royal College Clinical Investigator Program, and many in the MD/PhD Program.

The result was to create a strong “farm team” of clinician scientists, many of whom have subsequently gone on to assume leadership roles in various clinical departments in the health sciences complex at the U of T, nationally, and internationally. Another example of IMS thinking “out of the box” in the decade of the 90’s was to recognize emerging areas of advanced scholarship in nursing, rehabilitation sciences, biomedical communications, and most relevant to this issue of the IMS Magazine—Bioethics, led by Fred Lowy, who established the Centre for Bioethics at the U of T. In each instance their graduate programs were first initiated, then incubated, and developed under the umbrella of the IMS. The Centre for Bioethics quickly emerged as a leader in thought provoking national and international debate and policy development, guiding patient care in the application of new therapeutic advances in transplantation, and genomics. This is a legacy of scholarship of which the IMS can truly be proud.

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 9

INFOGRAPHIC

ClinicaL TRIALS Clinical trials are research studies that test the safety and effectiveness of an intervention on human subjects.

Most clinical trials are classified into phases: PHASE I, PHASE II, PHASE III, and PHASE IV.

900

Average per-patient cost per phase for drug trials (in CAD): Phase I: $48,000 Phase II: $50,000 Phase III: $52,500 Phase IV: $20,500 Average: $45,500

PHASE I

PHASE II AIM Test efficacy and side effects TIME Several months -- 2 years SUBJECTS 100 -- 1000 participants with the condition targeted by the treatment

AIM Test safety and dosage TIME Several months -- 1 year SUBJECTS 20 -- 100 healthy volunteers

Sources:

http://www.centerwatch.com/clinical-trials/overview.aspx https://www.ic.gc.ca/eic/site/lsg-pdsv.nsf/eng/h_hn01774.html http://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/clinical_trials-essais_cliniques-eng.php http://phrma-docs.phrma.org/sites/default/files/pdf/biopharmaceutical-industry-sponsored-clinical-trials-impact-on-state-economies.pdf https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/what-you-need-to-know/phases-of-clinical-trials.html

10 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

represents 10 subjects.

INFOGRAPHIC

4%

Canada captures 4% of clinical trials conducted globally and has the fourth largest number of clinical trial sites in the world.

Health Canada authorizes around 900 phase II and III trials annually. If clinical trials show that the intervention or treatment is effective and safe, then Health Canada reviews the information gained during both pre-clinical (i.e., animal) studies and clinical trials to assess whether the benefits of the treatment outweigh the risks. The treatment is then approved for clinical use in Canada.

PHASE IV AIM

Study long-term effects and costeffectiveness of intervention

TIME Several years/ongoing SUBJECTS 1000s of participants who are

taking part in the intervention/ receiving treatment; phase IV trials occur after the intervention or treatment is approved and on the market

PHASE III AIM Test efficacy and adverse reactions TIME Several years SUBJECTS 300 -- 3000 participants with the condition targeted by the treatment; participants are randomized into the experimental or control group (which receives a placebo or similar treatment)

Phase III randomized, controlled trials are considered to be the gold standard for testing new interventions or treatments.

By Midori Nediger

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 11

FEATURE

The Promise of a Canadian Stroke Drug to Help the

Brain

By Beatrice Ballarin

S

troke is the second leading cause of death worldwide. It is the area of focus of Dr. Michael Tymianski, the principal investigator of the Neuroprotection Laboratory at the Krembil Research Institute and the discoverer of NA-1, a promising drug for treating stroke. Over the past 15 years, Dr. Tymianski and his team have worked diligently to bring NA-1 to the point where it is now being evaluated in humans in Phase 3 clinical trials. Venturing into a realm where every other pharmaceutical company has failed, Dr. Tymianski’s team hopes that NA-1 will be proven to combat damage induced by stroke to the brain— an achievement that would place NA-1 among the most meaningful contributions to modern medicine.

The young Mike Tymianski started university when he was only 16. His interest in medicine led him to become the first medical doctor (MD) in his family.

During his third year of medical school, he became fascinated by neurosurgery.

He recalls that at the time when there were many advances in heart and cancer research, the brain was a “tabula rasa.”

“All the discoveries were yet to be made,” Dr. Tymianski says. “There were so many diseases of the brain we could do so little about.” He wanted to do something good with his time that could help people, and neurosurgery met his ambitions.

During his residency in neurosurgery, Dr. Tymianski took a break to pursue a PhD 12 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

under the supervision of Dr. Charles Tator, another neurosurgeon and world-leader in spinal cord research. Dr. Tymianski didn’t know it at the time, but this would be the first step to discovering NA-1.

Dr. Tymianski’s PhD work focused on calcium homeostasis and cell death as secondary damage after spinal cord injury.

This work lead to a high-impact article published in the Journal of Neuroscience in 1994.1 Dr. Tymianski’s work showed that not all calcium is equally toxic to neurons, but if calcium entered neurons specifically through the NMDA receptor, the neurons would die quickly. At the same time, another laboratory characterized the interaction between the NMDAR ion channel with a protein called PSD95.2 It turned out that this molecular arrangement was indeed responsible for inducing calcium toxicity through NMDA: when PSD-95 was suppressed in culture, cell death was attenuated. The activity of NMDAR was unaffected and nitric oxide (NO) production (known to be very toxic to the cell) was reduced, conferring the rescue of neurons and therefore neuroprotection. This discovery was the first Science paper published by the Tymianski lab only three years after opening and marked the beginning of the NA-1 concept.3 However, there was still one more issue to be resolved: how to bypass the blood brain barrier (BBB) and deliver NA-1 to the brain. Luckily, in 2001, another group showed that it was possible to shuttle a molecule of

interest across the BBB by fusing it to the HIV Tat transduction domain.4 In 2002, the Tymianski group published their second Science paper, creating the peptide Tat-NR2B9c, the initial sequence of the interfering peptide fused with Tat (or NA-1).5 NA-1 was not only able to reduce NO production in cultured neurons, but when given in vivo to rats, ischemic brain damage was reduced. This result was achieved without interfering with normal NMDAR activity (which is involved in all basic brain functions), a major drawback of previous failed clinical trials in stroke neuroprotection.

One reason why previous clinical trials failed when the NMDA receptor was blocked completely was the dosage.

Dr. Tymianski explained, “The dosage required to protect [the brain] from stroke by blocking the NMDA receptor directly was not tolerable in humans, and at a lower dose it did not have any [neuroprotective] effect. We, instead, had a drug that could inhibit NMDA-mediated excitotoxicity without inhibiting NMDAR.” Confident that the pre-clinical work was conducted using rigorous scientific methods, Dr. Tymianski was ready to pursue a clinical trial. To his disappointment, none of the big pharmaceutical companies were interested in what they believed was a risky endeavor.

“In the old days they would have called me, but back then they had just lost

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Michael Tymianski, CM, MD, PhD, FRCSC, FAHA

Photo by Mikaeel Valli

Professor in the Department of Medicine, Surgery, and Physiology, University of Toronto Head of the Division of Neurosurgery at Toronto Western Hospital, Senior Scientist at the Krembil Research Institute, Canada Research Chair Tier 1 in Translational Stroke Research CEO at NoNO Inc., Order of Canada in December 2016

billions of dollars in stroke clinical trials and they didn’t want to do it again.” So, there was only one option left: “I had to do it by myself; I had a social responsibility to move this forward.” This was the beginning of a journey that saw Dr. Tymianski and a number of his colleagues founding a company, called NoNO Inc. (after NA-1’s mechanism of action which blunts Nitric Oxide production in neurons). NoNO Inc. is sponsoring the NA-1 clinical trials.

Today, while all major pharmaceutical companies have retreated from the field, the Tymianski team is still left standing.

After successful Phase 1 studies to demonstrate that NA-1 is safe, Dr. Tymianski and his team conducted a Phase 2 trial, the first to demonstrate efficacy in patients experiencing stroke. At the same time, more preclinical studies continued in the lab; however, it was necessary at this point to test NA-1 in higher-order brains.

To this end, the Tymianski lab conducted experiments in high-order, old world primates (Macaque monkeys). The group was able to show a reduction of infarct size in monkeys when NA-1 was delivered 3.5 hours after the start of the ischemia.6 Seeing these data, NoNO Inc. was able to move forward into the third phase of clinical trials.

Despite the clear efficacy of NA-1, permanent brain damage can occur within minutes after stroke onset and having the right drug is not enough if it can’t be administered quickly. Thus, after

approval from both the Food and Drug Administration and Health Canada, Dr. Tymianski and his team designed the trial with this in mind. The drug needed to be delivered as early as possible.

“If you wait for several hours, it’s too late, even for a magic drug.” Thus, in one of the clinical trials, paramedics administer the drug to patients in the ambulance. “Paramedics are good at following protocols, even better than doctors, they are wonderful people, and they do a great job,” says Dr. Tymianski.

NA-1 would have to be administered en route to the hospital, thereby being administered as early as possible after the onset of stroke symptoms—a strength, but also a limitation. “There is no CT scan on an ambulance, and even with the use of clinical training and judgment, it’s never possible to confirm that the patient is suffering an acute ischemic stroke, the target of NA-1 therapy.” This is one of the major limitations of the ambulance-based clinical trial: it is not easy to determine if a patient is a good candidate.

For this reason, Dr. Tymianski’s team are also conducting a second Phase 3 trial. This study is enrolling patients who have already arrived to the hospital, and have had their stroke confirmed by a CT scan. In this study, NA-1 is being tested as an adjuvant to endovascular stroke therapy—a treatment that results in restoration of blood flow to the brain by removing the blood clot that is blocking a

major brain artery. Dr. Tymianski’s team has shown in primates that giving NA-1 in this scenario produces a significant neurological improvement in the study animals.6 This clinical trial, called “ESCAPE-NA-1” is being conducted globally (in Canada, the USA, Europe, South Korea, and Australia) and will provide an answer in approximately 3 years.

As I listened to Dr. Tymianski recount his story, it struck me that as his entire career has been building up, each piece of the puzzle has been falling—slowly— into place. At this point, there is only one thing left for him to do: bring NA-1 to the clinic as a first-line defense for stroke.

Science has driven his approach to drug development and, in his words, “Science wins in the end.”

References 1. Tymianski M, Charlton MP, Carlen PL, Tator CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci Off J Soc Neurosci. 1993 May;13(5):2085–104.

2. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science. 1995 Sep 22;269(5231):1737–40.

3. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science. 1999 Jun 11;284(5421):1845–8.

4. Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, et al. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat Med. 1998 Dec;4(12):1449–52.

5. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al.

Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science. 2002 Oct 25;298(5594):846–50.

6. Cook DJ, Teves L, Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature. 2012 Mar 8;483(7388):213–7.

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FEATURE

Clinical Trials of Movement Disorders: An Interview With

Dr. Robert Chen

By Samia Tasmin

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Robert Chen, MA, MBBChir, MSc, FRCPC Catherine Manson Chair in Movement Disorders Professor of Medicine (Neurology), University of Toronto Director, The Eliot Phillipson Clinician Scientist Training Program Senior Scientist, Krembil Research Institute Editor-in-Chief, Canadian Journal of Neurological Sciences

14 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

r. Robert Chen is the Catherine Manson Chair in Movement Disorders, a Professor of Medicine (Neurology) at the University of Toronto, the Director of the Eliot Phillipson Clinician-Scientist Training Program, and a Senior Scientist at the Krembil Research Institute. After completing high school in Hong Kong, Dr. Chen obtained his MB BChir at the University of Cambridge in England, where he first developed an interest in neurology during medical school training. In particular, he found it fascinating that different neurological diseases had different manifestations, and that by using the knowledge of anatomy and physiology, it was possible to deduce the location and nature of patients’ problems. This led him to complete a Master’s degree at the University of Toronto, under the tutelage of Dr. Peter Ashby, which was followed by residency in internal medicine at Queen’s University and further residency training in neurology at Western University. At this time, Dr. Chen studied the mechanisms of breathing and developed an interest in movement disorders, including Parkinson’s disease (PD). Techniques like magnetic brain stimulation, electroencephalography (EEG), and functional imaging further piqued his interest during a fellowship at

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the National Institutes of Health (NIH) in the United States. This became the focus of his research when he returned to Toronto.

Currently, Dr. Chen has research interests in four main areas: 1. Transcranial magnetic stimulation (TMS): Dr. Chen and his team study cortical inhibition and facilitation, and the connection between brain areas. His team has conducted clinical trials using TMS, and has established methods to study connections between cortical circuits, including double and triple pulse paradigms. These paradigms have been used to understand the pathophysiology of PD and dystonia, disorders in which cerebellar and cortical connections are abnormal.

2. Deep brain stimulation (DBS): DBS is a treatment used in dystonia and PD, as well as in depression. Dr. Chen and his team have used DBS electrodes to record from deep brain areas, such as the basal ganglia, which send signals for initiating and stopping movement. Dr. Chen’s team was able to record from the subthalamic nuclei, and then stimulate at specific frequencies. As there is a person-to-person variability in the peak frequencies, by stimulating at patientspecific frequencies, they study how changes in stimulation affect patients with PD. 3. EEG and Magnetoencephalography (MEG) studies: Dr. Chen and his team utilize DBS evoked potentials for source localization through EEG and MEG. For example, stimulation of the basal ganglia enables the identification of localized cortex activation as well corresponding timing.

They are also using EEG in dystonia and PD as a potential biomarker and predictor of treatment like DBS, focusing on an analysis technique called phase amplitude coupling (PAC).

4. Functional Magnetic Resonance Imaging (fMRI):

Dr. Chen’s team examines the effects of sensory stimuli on activation of the sensory cortex, particularly in dystonia patients with “writer’s cramp” who develop voluntary contractions when they write.

Dr. Chen and his group found that this condition is associated with abnormal digit representation in the sensory cortex, and, in some cases, there is an inversion of somatotopy. In contrast, people without the condition have a very orderly digit representation. Another finding from PD patients was that certain areas of sensory cortex have increased or decreased activation compared to controls, which may account for some of the observed differences between groups. They have also looked at the effect of repetitive TMS on functional connectivity. In this project, they used theta burst stimulation of the cerebellum to see how it changes restingstate connectivity from the cerebellum to different cortical networks.

Dr. Chen and his team have conducted previous clinical trials and continue to be actively engaged in new ones. One such trial assessed the effects of repetitive magnetic brain stimulation in PD to treat motor symptoms and depression. This was a multicenter collaborative effort between the Toronto Western Hospital (TWH), the Brigham and Women’s Hospital (Boston), University of Florida, Cleveland Clinic, the New York University, and University of North Dakota. The stimulation was aimed at both the motor cortex and dorsolateral prefrontal cortex (DLPFC).

It was a randomized control trial (RCT) with a “realistic” sham procedure, as sham stimulation was delivered with similar sound and sensation to those receiving real stimulation. The main findings demonstrated that the motor signs and symptoms of PD improve compared to sham, but interestingly, there were no effects on depressive symptoms.

Currently, Dr. Chen and his lab are focusing on a new DBS device that can record long-term signals. This is significant, as deep brain signals can usually only be recorded for a few days after the initial implantation. This new device, however, has the potential to record for a much longer time.

They aim to determine if signals from the basal ganglia are stable over time, and if there is a correlation with patient symptoms. They also aim to administer “individualized” DBS, at different patientspecific frequencies. DBS parameters are currently fixed, and this is troublesome for PD patients, whose clinical status fluctuates. Thus, it is important to identify what the brain signals represent and how they change with time, in order to develop adaptive DBS in the future.

Interestingly, the mechanisms of action of DBS are not fully understood. Dr. Chen mentioned that although the initial hypothesis is that DBS inhibits target areas, this is not entirely true. For example, DBS of the thalamus facilitates activity in the thalamus and the cortex, which is an area of thalamus projection. So, this results in a mix of inhibition and activation, with an inhibition of the nucleus but fibers going in and out of the target area. DBS affects plasticity in the cortex, and suitable timing of pairs of DBS-magnetic brain stimulation can induce plasticity, leading to plasticity modulation.

In terms of future directions, Dr. Chen feels that a paradigm for “closed loop or adaptive stimulation” using DBS can be developed. If we can identify the best oscillation pattern for each patient (for example, by recording of basal ganglia signals), it could be possible to create a device that can detect brain signals, and then automatically deliver DBS to change the oscillations to a favorable pattern.

For students interested in a career as a clinician-scientist, Dr. Chen suggests that students should first be exposed to research opportunities and consider the pros and cons of different research areas.

Finding a field that they are interested in is more important than looking for a current “hot” area of research. Finally, they should look for the best mentors in the area, and seek out the best place for obtaining training in their chosen area of interest.

The role of the clinician-scientist is an exciting one. It allows for a two-way flow of information, with patients providing ideas for research that can be undertaken, and research ideas also feeding into the development of new therapies.

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FEATURE

Challenges and Promises in Translational Therapeutics for Childhood Autism

By Mikaeel Valli

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utism spectrum disorder (ASD), commonly referred to as autism, is a complex neurodevelopmental condition characterized by repetitive behaviours and challenges with social communication. ‘Autism’ is not defined by a single set of behaviours, but rather by a range of conditions that reflect many differences in symptoms, skills, and degrees of disability. The signs associated with ASD emerge in childhood, and may appear as early as 18 months of age. I had the pleasure of meeting Dr. Evdokia Anagnostou, a paediatric neurologist and clinician-scientist at Holland Bloorview Kids Rehabilitation Hospital, who is one of the few who work tirelessly to find effective treatments to improve the quality of life for individuals with ASD. On a sunny evening in Toronto, Dr. Anagnostou recounted a challenge from her neurology residency training in the early 2000’s. She was taught to use signs and symptoms to localize the brain lesion in paediatric patients; “However, this was almost an impossible task in autism,” she explained. “It was difficult to localize in these children because of the pervasiveness of the lesion.” Clinical challenges in localizing brain lesions in ASD, the elusive neural mechanisms of this condition, and the deficiency of recent improvements in its care have motivated Dr. Anagnostou to study ASD as a clinician-scientist.

She established her lab in 2008 at the Bloorview Research Institute, where she studies neuropsychopharmacology and neuroimaging of children with ASD to 16 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

elucidate the underlying lesions characteristic of this condition. Furthermore, her lab investigates novel treatments as part of clinical trials. Putting her research interests together, Dr. Anagnostou aims to unravel the biological mechanisms of ASD, which would facilitate discoveries of effective treatments to improve outcomes for children with ASD. A glaring void exists in the field of ASD symptom treatment—not a single approved drug is available except for anti-psychotics, which are often used for aggression and agitation management, not for core ASD symptoms. In addition, anti-psychotic medications have severe side effects that include metabolic disturbances and obesity. “We need medications that are effective for core symptom domains such as social challenges seen in ASD,” Dr. Anagnostou emphasized. “We need to cross this threshold.” She further explained that she does not seek a ‘cure drug,’ as such is unlikely to be found and likely not desired by many in the autism community, but rather a drug that can manipulate the condition’s neural mechanisms to enhance learning, especially during behaviour therapy. One reason for the lack of treatments that manage core ASD symptoms is inconsistencies in the biology of autism and other neurodevelopmental disorders. While these disorders are diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, the classification system does not accurately reflect the contribution of genetics to the underlying

dysfunction. In autism, genetic sequencing shows hundreds of mutations that may be implicated in the presentation of this condition. Furthering the complexity of understanding the genetics of ASD is the fact that these mutations are not exclusive to autism but are also seen in other neurodevelopmental disorders, including intellectual disability, attention deficit hyperactivity disorder, and obsessive-compulsive disorder. This lack of specificity in autism diagnosis, as well as the heterogeneity within ASD, is among the factors that hamper the success of clinical trials on the condition, as they may alter the response to treatment in these studies. The need for better diagnosis prompted Dr. Anagnostou and her colleagues to tackle this puzzle in a top-down approach by examining various neurodevelopmental disorders and ASD as one group. She is currently exploring biologically homogenous groups that may exist within the neurodevelopmental spectrum based on neuroscience, genetics, cognition, and behaviour, as opposed to traditionally consulting the DSM-5 as a sole diagnostic resource. This paradigm shift is part of an effort called the Province of Ontario Neurodevelopmental Disorders (POND) Network.

While the POND Network initiative is still in its development, Dr. Anagnostou is investigating the implications of certain mutations in ASD and whether these may reveal new molecular targets for medications. Along with her colleagues, she is carrying out clinical trials of drugs simultaneously in humans and mice. “We are

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Dr. Evdokia Anagnostou, MD, FRCPC Senior Clinician-Scientist, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital Associate Professor, Department of Paediatrics, University of Toronto

Another clinical trial that is underway focuses on oxytocin, a hormone intimately involved with social behaviour. Dr. Anagnostou explained that oxytocin may enhance the neural circuity involved in social cognition and reward processing.

She recently began administering oxytocin to adolescents with ASD and encouragingly stated, “We are seeing nice effects on aspects of social perception such as face recognition.” Dr. Anagnostou hopes

Photo by Mikaeel Valli

trying to understand whether the information we get from the mice—where we have genetic clarity—and downstream effects on the brain are translatable to humans, and whether this will help us stratify children based on biological makers that may predict treatment response,” she explains.

In addition to testing drugs aimed at molecular targets, Dr. Anagnostou also studies drugs in clinical trials that are attuned to neuropathological targets.

For example, Pioglitazone, a drug that is used to treat diabetes, has promising secondary properties that act to reduce microglial activation. Microglial cells are the main immune defense system in the brain and spinal cord which have been shown, through post-mortem studies, to be activated in ASD patients, and thereby play a role in neuroinflammation. Hence, Dr. Anagnostou is testing this drug as part of an ongoing clinical trial to evaluate its safety and efficacy in children with ASD. “This drug is showing promising preliminary findings in potentially improving challenging behaviours of ASD children,” she commented optimistically.

that these drugs will provide a meaningful improvement to the quality of life of individuals with ASD. Discovering new medications, Dr. Anagnostou explained, is not the end of the translational work. The next challenge is to translate evidence into practice and ensure access to treatment. This is a whole different arena, involving collaboration between researchers and experts in economics, knowledge translation, and public health.

Dr. Anagnostou stresses that the knowledge gaps in the ASD field need to be addressed in the next five to ten years.

One knowledge gap in particular pertains

to our understanding of aging in those with ASD. “It is unclear what happens when they age and whether they are at an increased risk for dementia or other neurological disorders,” she says.

Despite the challenges, frustrations, and long hours of being a clinician-scientist, Dr. Anagnostou continues forward with fortitude, attributing her driving force to her passion for individuals with ASD and related conditions. She advises students who seek to become clinician-scientists to pursue an area where they “feel they are contributing meaningfully, and doing what they enjoy,” reasoning that work-life balance is less of a problem when you do something you love.

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EXPLORE TRANSPLANT ONTARIO: Providing Education to Improve Access to Kidney Transplantation and Living Donation

By Dr. Istvan Mucsi

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he public is generally well informed of conditions like diabetes and hypertension—their risk factors, treatments, and repercussions. However, despite extensive public awareness, many remain unaware of an important possible consequence of these conditions: kidney failure. At its most severe presentation, End Stage Kidney Disease (ESKD), the kidneys function below 10% of their normal activity and require Renal Replacement Therapy (RRT). About 10% of Ontarians live with some degree of kidney disease and more than 17,000 suffer from ESKD, underscoring the importance of the public’s understanding of the risk factors and implications of these conditions.

Considering the essential role of the kidneys in filtering blood, ESKD patients must receive RRT to stay alive. RRT takes one of two forms: dialysis, in which blood is cleansed by a machine or through the internal membrane of the abdomen, and kidney transplant from a living or deceased donor, a form of RRT associated with better health outcomes and quality of life. Yet, despite the undeniable advantages over its alternative, only about 15% of the 11,000 dialysis patients in Ontario are on the transplant waiting list, owing to various barriers to this form of RRT. For example, many of the patients on dialysis who may be approaching ESKD may not have considered the possibility of transplant, and their families are frequently unaware that they could be living donors 18 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

for their family members. They may have questions and concerns about the surgery and recovery, and face challenges in facilitating the process even when provided with information regarding their treatment options. Furthermore, cultural differences, language barriers, anxiety and depression, and lack of time to educate providers present additional barriers to transplantation.

To improve patients’ understanding and utilization of optimal treatment options for ESKD, Dr. Istvan Mucsi, a nephrologist at the Multi-Organ Transplant Program at University Health Network (UHN), Dr. Marta Novak, a psychiatrist at UHN, and Dr. Amy Waterman, an Associate Professor at the University of California-Los Angeles, have teamed up with 25 health professionals and patient representatives to create a transplant education program called Explore Transplant Ontario (ETO).

ETO is based on the Explore Transplant program, created by Dr. Waterman, which is currently used in over 3,000 dialysis units across the United States. To adapt the program to the Ontario health care environment, the team reviewed the original program and created videos to explain the process of donor and recipient selection, transplant surgery, and post-transplant care in Ontario, and included real-life transplant stories from patients and their living donors, who shared their transplant and donation experiences. Furthermore, the ETO package is designed to address common concerns about deceased and living donor transplantation, help patients

consider their motivations to pursue transplant, and present a series of actions that interested patients can take to pursue transplant. All in all, in their collaborative work, this team of nephrologists, nurses, and patient educators has adapted the program to Ontario. Together, they provide patients from Ontario hospitals, dialysis units, and transplant centres with information about this important treatment option.

Dr. Mucsi and his group strive to make ETO available to every kidney failure patient, family member, and health care professional to ensure access to resources that are needed to make an informed decision about pursuing kidney transplantation. The ETO program was officially introduced to a professional audience in March 2016, and on May 20 of that year, approximately 75 physicians, nurses, transplant coordinators, and educators, both from Ontario and out-of-province, attended the ETO Training Day at the UHN. During this full-day workshop, Drs. Mucsi, Novak, and Waterman introduced the ETO program and provided participants with resources and advice to help patients explore transplant at their units.

Subsequently, Drs. Mucsi and Novak, the co-leads of the Kidney Health Education and Research Group, began the ETO pilot study in June, using a prospective, non-randomized, parallel group design to test the feasibility and efficacy of the ETO package in instilling transplant knowledge and readiness among dialysis

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Dr. Istvan Mucsi, MD, PhD Associate Professor of Medicine, Transplant Nephrologist at the Multi-Organ Transplant Program and Division of Nephrology at the University of Health Network

Despite the participating dialysis units’ geographical proximity and somewhat similar baseline characteristics, there was a significant difference in the average baseline transplant knowledge between the participating patients at HRH and control patients at TGH. Preliminary analysis

Photo by Iris Xu

patients. Between June and November, 228 patients were enrolled from two outpatient hemodialysis units: 103 at the control site, Toronto General Hospital (TGH), and 125 at the intervention site, Humber River Hospital (HRH). At baseline, patients completed standard questionnaires to assess their transplant knowledge, confidence, and self-efficacy, as well as a sociodemographic survey using a tablet-based electronic data capture system.

At HRH, patients received the ETO package immediately upon completion of baseline data collection and were presented the ETO videos while undergoing their dialysis. Following the intervention, research assistants conducted short follow-up visits with patients at both sites at 2, 4, 6, and 10 weeks after enrolment.

At these visits, patients were asked if they were considering living or deceased donor transplant, if they had spoken to anyone about transplant recently, if they utilized the ETO package (intervention site only), and if they had any questions. Between January and April 2017, patients at both sites were asked to complete the posttest questionnaires, which, once again, measured their transplant knowledge, readiness, and self-efficacy.

of results revealed that the mean transplant knowledge score of HRH patients increased significantly, especially among those who utilized the ETO package. In addition, improvements in self-efficacy were also noted. Lastly, the study was well received by patients and staff in both dialysis units, as both rated their experience with the ETO research team as positive, noting the videos and team were helpful in engaging with others about transplant.

The Kidney Health Education and Research group has presented preliminary findings at the 2016 Canadian Society of Transplantation and the 2017 American Transplant Congress conferences. The study is now in its final phase, post-test II, which will evaluate participants’ longterm knowledge retention. Ultimately, ETO can potentially be integrated into clinical care to help improve patients’ understanding of the various aspects of

the transplant process. ETO will be a key component of the Transplant Education Pillar of the province-wide Access Kidney Transplantation (AKT) trial, led by Dr. Amit Garg, in which Drs. Novak and Mucsi co-lead the education task force.

This comprehensive, multicomponent strategy, organized by the Ontario Renal Network and Trillium Gift of Life Network, aims to improve access to kidney transplantation and living kidney donation in Ontario and will be launched in September 2017. Over the next five years this quality improvement initiative, which will include all 26 regional chronic kidney disease programs in Ontario, will utilize an “audit and feedback” approach to enhance transplant education, patient volunteering (transplant ambassadors), and administrative support to increase transplant waitlisting and living kidney donation in the province.

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 19

FEATURE

Dr. Peter Jüni’s

Clinical Trials Module

By Cricia Rinchon

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r. Peter Jüni is internationally renowned for his methodological work and clinical research on the management of cardiovascular and musculoskeletal disorders. He also teaches the Institute of Medical Science (IMS) short course module on clinical trials. Over seven weeks, students in the module— myself included—were exposed to a broad overview of trial design, methodology, statistics, operations, and ethics.

Upon entering the first class, we were greeted by a presentation slide displaying the year of a clinical case in bold typeface: 1985. The next slide depicted an electrocardiogram of a patient experiencing ventricular tachycardia, a type of irregular heart rate. Dr. Jüni invited us to imagine ourselves as first-year residents in the Intensive Care Unit (ICU) of a small-scale hospital at two in the morning with no attending physician present. He urged that the fate of this patient was in our hands!

At this point in the roleplay, an experienced ICU nurse proposed using a newly FDA-approved drug (Drug X) for prophylactic therapy. The nurse anecdotally claimed to have seen many patients benefit from its use. With curious skepticism, we completed a literature search on Drug X and found reasonable animal studies explaining the drug’s mechanisms. Dr. Jüni then posed a question that instilled the theme for the rest of the lecture: “Do you inject Drug X?” Hesitant and skeptical, the class voted “no”.

Over the course of an hour, we were presented with various stages of pre-clinical evidence: a case-control study, a preliminary pilot study, and then a randomized control trial (RCT). At each stage, the same 20 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

question was posed, followed by a discussion on the strengths and weaknesses of each study. As the increasing hierarchy of information was progressively revealed, more of the class swayed towards “yes”.

infarctions associated with different painkillers. From 2000 onwards, the first trials in several thousand patients were published and provided us with a better understanding of the safety of painkillers.

This case study was a challenging activity that exercised critical thinking in a dynamic scenario. Those in the doctoral stream often undergo a similar decision-making process offline, as they critique scientific evidence at various stages: anecdotal observations, case-control studies, informally and formally reported pilot projects, and RCTs. Importantly, the module highlighted the ultimate goal of our work at the IMS: to have an impact on patients’ lives. Below, Dr. Jüni kindly lends his insight into the past, present, and future of RCTs, and provides personal advice for students navigating academia.

Now looking towards the future, what are you worried about? What are you excited about?

What have we learned since 1985 and how has the development of RCTs improved?

Since the mid-80’s, change could not be more dramatic. The average size of major trials was a few hundred patients or less with a very limited capacity and limited statistical precision to detect relevant signals, either for benefit or harm. Since then, our understanding of what constitutes a valid trial has exploded. Since the mid-90’s, initiatives like CONSORT (Consolidated Standards of Reporting Trials) have helped us find a way to move forward as a community to do large scale trials and appropriately report them. In osteoarthritis research, for example, before 2000, drug trials just looked at pain as an outcome in a maximum of 200-250 patients, and nobody could estimate the risks of gastrointestinal bleeding or myocardial

Many of us are worried about pivotal trials costing up to several hundred million CAD—which would make it not possible to address certain medical conditions because the potential economic gain of a new intervention for a rare condition is just too small to justify the cost. We need novel, pragmatic models, also for drug approval, to be able again to perform randomized trials at a reasonable cost. Canada, and especially Ontario, has a huge advantage with the possibility of accessing a considerable part of the routine healthcare through institutions such as the Institute of Clinical Evaluative Sciences here in Toronto. This allows us to combine traditional aspects of a clinical trial with pragmatic approaches and could reduce trial costs by a factor of five to ten.

When did you decide to make the switch from practicing medicine to clinical research?

In 1993, when I studied medicine in Bern, I went to the student bookshop and found the book Clinical Epidemiology by David L. Sackett and colleagues. It was at a time when the Swiss-German setting was very hierarchical, and professors were rather authoritarian without really being questioned. When I tried to dig deeper, many of the answers I got were superficial and merely based on opinion. Then this book, authored by Canadians, said, “Use your

Photo by Dr. Peter Jüni

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Dr. Peter Jüni, MD, FESC Canadian Research Chair, Clinical Epidemiology of Chronic Diseases Director, Applied Health Research Centre, St. Michael’s Hospital Professor, Department of Medicine, Institute of Health Policy, Management, and Evaluation, University of Toronto

own brain! The one single basis for clinical medicine is randomized trials, forget expert opinions if there is no evidence to support them.” This was revolutionary at the time for me as a medical student from a continental European university, and I was immediately hooked. I just knew I was to become a clinical epidemiologist—to me, every other professional idea became secondary.

Globalization has made international collaboration more seamless, but what are the most noticeable differences between Bern and Toronto after moving here a little more than a year ago?

I think that the most striking difference is how we all live together, coming from more than 160 different nations. Toronto is a melting pot, culturally and ethnically.

People live together here in a constructive, peaceful, and open way. Everybody is from somewhere else, so no one is really a foreigner and everyone is at home here.

The speed and extent of integration here is much more pronounced than what I’m accustomed to from Europe. My office happens to be in the middle of the Eaton Centre, and even as I walk through it on my way home, I see this diversity with any step I take, and the beauty that happens when cultures meet. I find this extraordinary. Immigration also means that we have an amazing influx of brainpower, and that people haven’t forgotten that it is actually a privilege to live here and not a right.

People don’t take everything for granted, and try to work with what they have.

What advice would you give the students of the IMS?

Beware of intellectual dishonesty in academic settings. Roger Federer could never go to a tennis court and just pretend to be a good tennis player, he actually is one. Unlike in sports, you can get quite far in academia by just pretending. I believe institutions are most functional when people are just honest: first of all with themselves, but also with others.

They dare to admit that they don’t know, and acknowledge their own mistakes. As a mentor, I try to encourage this attitude with my younger colleagues. It helps tremendously to pause and ask: “Hey, wait a minute, I just haven’t understood it quite yet, could you please re-explain?” If you allow yourself to admit what you don’t know at any given moment, it enriches your reality tremendously.

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 21

FEATURE

The Evolution of Clinical Trials in CRITICAL Care An interview with Dr. John Marshall

Dr. John Marshall MD, FRCSC, FACS, FCAHS, Trauma Surgeon and Intensivist at St. Michael’s Hospital, Department of Surgery, University of Toronto Member, Institute of Medical Science

By Hira Raheel

C

linical trials in critical care differ from trials in other fields. They focus on validating the safety and efficacy of common treatments and procedures, and recruit subjects who

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are typically unconscious and incapable of making decisions for themselves. As a leader in critical care research both nationally and internationally, Dr. John Marshall has nearly 30 years of experience

with clinical trials. It was my pleasure to speak with Dr. Marshall about his career as a scientist in the field of clinical trials in critical care.

Could you give us a brief background

FEATURE about yourself? How did you get to where you are today?

I completed medical school at the University of Toronto. I was torn between a career in public health and surgery. I completed a general surgery residency in 1984 from Dalhousie University, and became interested in trauma, sepsis, and acute care during that time. Following that, I spent time at McGill University doing a research fellowship, a mixture of basic research and clinical research.

What drew you to clinical trials in this area of medicine? Why do you think clinical trials are important?

During my time at McGill, it became apparent to me that we often don’t know whether we are helping or harming our patients, and that many interventions provided with the best rationale may actually be deleterious. The only way one can determine whether something helps is through clinical trials—using the principles of probability, and understanding what happens in populations of patients.

How did you become involved with clinical trials in your area of medicine?

I was fortunate that in the late 1980’s, a group of Canadian intensivists became interested in the idea of doing collaborative clinical trials, and formed the Canadian Critical Care Trials Group (CCCTG).We grew from about 10 or 12 people who came to our first meeting in 1989, to more than 300 Canadian members. We’ve published 250 papers, 18 of which are in the New England Journal of Medicine. We’ve developed a new model of clinical research, based on investigators identifying the questions that arose through their clinical experience. It was a model heavily based in trust and collegiality.

How do you think clinical trials in Critical Care differ from those in other research areas? Do you think you have developed a better model for trials?

I think we have a model that is successful and that merits close attention, but I may be doing a disservice to colleagues who are doing equally well in other fields. I do think that the model of collaborative research, where you fly in to an airport, meet in the airport hotel, and look to see whether you can catch an earlier flight

is lethal to good science. Good science requires time, collegiality, and collaboration. The CCCTG meets in Lake Louise and in rural Ontario and Quebec. We expect people to spend time together socially and get to know and trust each other enough to be able to work well together.

The other key strength of our model is that before we actually do a trial, we do a series of studies: systematic reviews, observational studies, standardized questionnaires, and focus groups. We fully understand the question we are asking and the knowledge base behind it. This makes for much more compelling grant applications and also benefits young trainees who might conduct and publish a systematic review even if they do not run the clinical trial themselves.

How have clinical trials in your field grown and developed since you first became involved?

After we published our first paper, other countries looked at us and liked the model.

The Australians set up the Australian and New Zealand Intensive Care Society Clinical Trials Group in 1994. Then an American group with extensive funding from the National Institutes of Health was formed to study Acute Respiratory Distress Syndrome (ARDS). Other countries followed this trial’s group model. We discovered that we have some common approaches and needs. We saw that when international groups worked together, they could address important questions, and publish studies in high impact journals.

So, we set up the International Forum of Acute Care Trials (InFACT) as a channel for these groups to collaborate and interact with each other.

What do you hope to gain out of international collaborations in clinical trials?

We are trying to promote collaboration amongst groups, because we’re finding that doing a 5,000 patient study is challenging in a single country, and it is both more efficient and more generalizable to have multiple countries collaborate. We are keen on trying to expand this model outside of Europe, North America, and Australia.

There are now critical care clinical trials groups in China, Southeast Asia (which includes Sri Lanka, Bangladesh, Pakistan, India and Nepal), sub-Saharan Africa,

North Africa, Brazil, and Latin America.

Through InFACT we are trying to mentor and promote clinical research in groups from less developed nations.

From single-centre studies, to multi-centre trials, and now international research collaborations, clinical trials in critical care have come a long way, so what’s next?

We are developing a model called a platform trial, currently run in Australia, New Zealand, and Europe to study severe community acquired pneumonia. We are seeking funding for this trial in Canada.

A platform trial focuses on a disease, like community acquired pneumonia, and looks at multiple interventions. These interventions can be different antibiotic combinations, varied immunomodulatory strategies, and alternate approaches to mechanical ventilation. Using Bayesian adaptive approaches, one establishes the parameters for deciding whether something does or does not work. Once an intervention is shown to be better, it becomes part of the control arm of the trial moving forward. If it is not found to be of any use, then it is dropped, to be replaced by another intervention to evaluate. In essence, the trial can continue in perpetuity, and becomes a hybrid model of research and quality improvement. Tens of thousands of scenarios are developed in advance to create the algorithm that drives the trial. But, once you have done this, the algorithm guides subsequent patient recruitment. Platform trials blur the boundaries between clinical research and clinical care.

Do you have any general advice for young investigators and graduate students who want to potentially transition from doing basic science research and move towards more clinically-focused research?

For the clinician, research is no longer a luxury. It is the mechanism through which we understand what we’re doing and whether it is helping patients. It is critical to become literate in science and to engage in that science. There’s a sense of humility in science, which transforms ignorance from “I don’t know” to “We don’t know” and activates a powerful tool to generate knowledge.

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 23

TRAVEL BITES

Sunshine,

sand, and science

By Grace Jacobs

Later, we travelled into the nearby park to see the renowned trees that inspired a U2 album title—and they did not disappoint.

At first, there were none of them; suddenly, there were thousands of twisted, quirky figures spanning all directions and up to six metres tall. We drove from hike to hike, mesmerized by the rapidly changing desert landscape. From pebbles to balancing boulders and rock piles to mountains, we all appreciated how different this scene was from what we are used to seeing each day in Toronto.

The sun was also a fierce and welcome change after the recent unpredictable weather in Toronto. Yet, by the evening, we were bundled in blankets, experiencing first-hand the desert temperature extremes. After one more breathtaking sunset and a few more coyote sightings, it was time to head to San Diego for the conference.

The Society of Biological Psychiatry 24 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

Meeting was the first time I presented my research internationally, and I was both tremendously excited and nervous.

I was presenting in the evening of the last day, which gave me time to prepare and absorb the experience first, for which I was grateful. The plenary speakers on all three mornings were fantastic, diverse, and incredibly compelling. Even by the end of the conference, I could not get used to meeting and hearing from the most prominent researchers in the field, those who have influenced and directed my own research. The opportunity to put faces to the names and work that I admire made the field seem more accessible. I made personal connections that I can use to reach out to learn more and improve my own research. It also provided a realistic perspective about universal challenges in research, and narrowed the gap between my work and my idealistic perception of other’s progress.

I loved that so many talks had me itching to get back to my lab and try out a new

Photo by Grace Jones

I

could not help but feel proverbial Californian optimism as I looked out at the desert medley of misfit cacti, shrubbery, trees, and flowers. Prior to the Society of Biological Psychiatry conference in San Diego, I spent a few days in a secluded and enchanting Airbnb with a stunning view near Joshua Tree National Park. Waking up early that first morning, my lab mates and I watched curious coyotes trot by not even ten metres from us, as we ate breakfast. There was also an abundance of hares, lizards, and birds at home on our doorstep of rolling hills, boulders, and sand.

method or approach, or elaborate on a concept in the context of my project. I was also deeply proud to be a part of my own lab and the large University of Toronto and CAMH presence at the meeting. I feel that I fostered important and potentially beneficial relationships, both within my immediate community and those further away.

It was difficult to take advantage of the many San Diego attractions during the conference. Throughout the day I attended talks, refusing to be enticed by the sun and ocean views. However, after evening poster sessions, I had the chance to explore the nearby Gaslamp district and downtown. I also spent a couple of days after the conference at the Ocean Beach Hostel, determined to explore the city, digest my last few days, and jump on the opportunity to learn how to surf. Between seals and sea lions at La Jolla, delicious tacos, Sunset Cliffs, and karaoke, I could not have asked for a better way to end an unforgettable trip.

TRAVEL BITES

The Canadian Sleep Society’s National Conference and the Breathtaking Beauty of Banff

By Arpita Parmar

O

learn more about the research and clinical activities in paediatric sleep medicine. I had the opportunity to attend interesting lectures by leaders in the field, including my supervisor, Dr. Indra Narang, a paediatric respirologist and the Director of Sleep Medicine at The Hospital for Sick Children. Lecture topics included sleep in

Photo by Armita Parmar

Photo by Armita Parmar

n average, humans spend about a third of their lives asleep.

Although much remains to be uncovered about human sleep, it is clearly critical to physical and mental functioning. Sleep plays a prominent role in the health and well-being of the population at large, and is a priority in clinical care as well as in research. Sleep medicine is interdisciplinary, as it is an area of focused competence within respiratory medicine, neurology, internal medicine, psychiatry, paediatrics, and family medicine. Sleep medicine focuses on healthy sleep, sleep disorders, and sleep-related conditions.

The Canadian Sleep Society holds a biennial national conference, where researchers

The Town of Banff and clinicians involved in sleep medicine share innovative research, educate professionals on high quality clinical care, and advocate for healthy sleep and sleep disorders in medicine.

As a graduate student in Respiratory Medicine at the Hospital for Sick Children, this conference was a great opportunity to

Calgary children with neurodevelopmental disabilities, paediatric narcolepsy, and childhood obstructive sleep apnea syndrome. Each presenter discussed evidence based, stateof-the-art knowledge on childhood sleep disorders, with an emphasis on areas in need of further research. New knowledge from these stimulating discussions highlighted present issues in the field, some of which are seen in our Sleep Clinic at SickKids, and brought to mind intriguing new research questions.

The Canadian Sleep Society Conference has been held in several large cities across the country, including Halifax, Montreal, Quebec City, and Toronto. The 2017

meeting was held in Calgary, Alberta’s largest city, which enabled many clinicians and scientists to exercise the perks of sightseeing during conference travel. As a Toronto native, I am accustomed to sights of soaring skyscrapers and swarming streets; for this reason, I decided to venture westwards to Banff National Park to see the Great Canadian Rockies. The drive itself was scenic, filled with breathtaking views of beautiful mountains. Banff National Park was buzzing with tourists and offered free entry in honour of Canada’s 150th anniversary this year. The Banff Village, located in the heart of Banff National Park, is a small town surrounded by striking mountain views. To get even closer to the awe-inspiring views, I recommend trying a horse ride along the tranquil Bow River. Horses can navigate the muddy and uneven terrain with ease, allowing views of wildlife amongst the thick marshes and grassy meadows from a safe distance. If you are keen on fancy hotels, the Fairmont Banff Springs is also a must-see. With luxurious dining, a spa, and even a golf course, this hotel is anyone’s paradise.

Conferences can be a great break from the lab and clinical setting. Researchers can benefit from immersing themselves in an environment full of academic energy and intellectual stimulation, while also getting the chance to unwind and explore through relaxing endeavors and exciting adventures. I’m already looking forward to my next conference!

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BMC FEATURE

BIOMEDICAL COMMUNICATIONS MASTER OF SCIENCE IN

Ruth Chang, IT7 This image, created by Ruth Chang, is part of an animation that addresses the interaction between obesity and mental health. Nearly two thirds of Canadians are overweight, and one in five are affected by mental health issues, but we are only now starting to learn about the many bi-directional interactions that connect them. This animation aims to build empathy in physicians for their patients through visual storytelling. Ruth hopes to continue creating accurate, effective, and beautiful visuals on a variety of biomedical and health topics. Examples of her work and the full animation can be viewed at ruthchangvisuals.com.

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BMC FEATURE

Ursula Florjanczyk, IT7 This is a still image from an animation on enzyme kinetics, created by Ursula Florjanczyk for her Master’s Research Project as part of the M.Sc. BMC program. The animation demonstrates how Michaelis-Menten dynamics determine how a person metabolizes ethanol. The goal of the animation was to take a dry, complicated topic like enzyme kinetics, and make it engaging, accessible, and memorable. Ursula hopes to continue creating cinematic animations about a variety of scientific topics. Examples of her work and the full animation on enzyme kinetics can be viewed at ursulavisuals.com

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VIEWPOINT

Artwork by: Lisa Qiu

A Bespoke

THE FUTURE OF HU

By Aravin Sukumar

I

n March 2017, researchers at Temple University, Philadelphia, demonstrated the ability of the CRISPR-Cas9 gene editing technology to eliminate latent human immunodeficiency virus-1 (HIV) provirus in mice.1 HIV infection targets immune cells, in particular CD4+ T-cells, which leads to a progressive failure of the immune system and ultimately to acquired immunodeficiency syndrome (AIDS).2 When T-cells are infected, HIV RNA is converted into DNA and integrated into the host genome, referred to as provirus, which is essential for replication. In some cells, the HIV provirus remains inactive and escapes anti-retroviral therapy. The provirus can become activated unexpectedly, thereby preventing the complete elimination of the virus. Although this study was conducted in mice to demonstrate the elimination of the HIV provirus through gene editing, there is hope that its immense therapeutic potential will eventually be translated to humans.

Human gene editing toolbox Three types of gene editing tools are currently employed that can delete or insert anywhere between single nucleotides to large kilobase sequences: 1) zinc-finger nucleases (ZFN); 2) transcription activator-like effector nucleases (TALEN); and 3) clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9.3 In principle, these tools all consist of an engineered DNA-targeted nuclease that acts as “molecular scissors” to create double-stranded breaks (DSB) in the genome, 28 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

which then triggers one of two distinct DNA repair mechanisms: homologous recombination (HR) or non-homologous end joining (NHEJ). When a homologous DNA template is present, HR-mediated repair can insert new sequences or introduce single-nucleotide polymorphisms (SNPs). In contrast, when a DNA template is absent, NHEJ produces random small insertions, deletions, or inversions surrounding the DSB, which can contribute to gene inactivation. The inspiration for employing gene editing in HIV treatment stemmed from a patient who was homozygous for a 32-base pair deletion in the gene CCR5, the major co-receptor for HIV entry, and whose T-cells were therefore resistant to infection.4 To mimic this patient’s protective deletion, Tebas et al.

(2014) designed ZFNs to disrupt the function of CCR5 in T-cells derived from HIV patients and evaluated their resilience to infection. Interestingly, infusion of CCR5modified T-cells in patients resulted in a lower decline in T-cells, thereby demonstrating the promising potential of gene editing as a treatment for HIV. In fact, both ZFNs and TALENs have already been tested as potential treatment target in HIV, while the application of the CRISPR-Cas9 has only just begun.

CRISPR-Cas9: a bacterial defense system The most recent gene editing tool is the CRISPR-Cas9 system, developed through discoveries originating from work in bacteria.5 This system was initially identified in bacteria as a form of adaptive immunity against foreign DNA from plasmids or viruses (bacteriophages), but has been harnessed in mammalian cells to perform

permanent genome modifications. CRISPR genomic loci are distributed extensively throughout the bacterial genome.

They are comprised of a set of CRISPRassociated (Cas) genes, which encode RNA metabolism enzymes and the molecular scissors—Cas9 protein—followed by a series of palindromic repeat sequences (“direct repeats”) interspaced by variable sequences (“spacers”) corresponding to foreign genetic elements. These CRISPR loci are transcribed as a precursor CRISPR RNA (pre-crRNA) and processed by the encoded metabolic enzymes into mature, short CRISPR RNAs (crRNA) that can interact with and direct the Cas9 enzyme to cleave foreign nucleic acids containing sequences found in the “spacers.”

Harnessing CRISPR-Cas9 in human cells Several researchers are credited with advancing the CRISPR-Cas9 system in mammalian cells. In 2012, Drs. Jennifer Doudna and Emmanuelle Charpentier engineered a single guide RNA (sgRNA) capable of recruiting the Cas9 protein to cleave DNA at a specific site.6 They were also able to program the site-specificity of Cas9 by modifying the seed sequence of the sgRNA—a sequence complementary to the target sequence and essential for binding to the genome. Building upon these important discoveries, Dr. Feng Zheng from the Broad Institute has confirmed the application of the CRISPR-Cas9 system in mammalian cells by transfecting the CRISPR machinery into human and mouse cell lines and evaluating the efficacy and sites of DNA cleavage.7 The importance of these landmark findings was recognized by the scientific community

VIEWPOINT

Genome:

MAN GENE EDITING through numerous awards, including Canada’s most prestigious international 2016 Gairdner Award, presented to Drs. Doudna, Charpentier, and Zheng, as well as to other pioneers in the field, including Drs. Rodolphe Barrangou and Phillipe Horvath.8

When compared to previous gene editing strategies such as ZFN and TALENs, the CRISPR-Cas9 system has more far-reaching applications and displays unparalleled versatility. For example, the system facilitates simpler and more effective development of transgenic animal and cell-based models to simulate disease processes, thereby benefiting researchers in medical sciences.9 Furthermore, the agricultural industry has also adopted CRISPR-Cas9 techniques to improve traits of livestock and enhance crops’ resistance to pests. Lastly, the system has a tremendous therapeutic potential in monogenic disorders such as Huntington’s disease and cystic fibrosis, whose incurable prognosis may, in the future, be altered by gene editing therapies.

raises ethical questions pertaining to its use in the genetic modification of human embryos or germ cells (sperm or oocyte), a process that is criminally banned in Canada and other parts of the world.11 In 2015, an international dialogue to discuss the scientific, ethical and governance issues of human genome editing took place in Washington, DC.12 This meeting, termed the International Summit on Human Genome Editing, was co-hosted by the National Academy of Sciences and Medicine (US), the Chinese Academy of Sciences (China), and the Royal Society (UK). A report highlighting the outcomes of this meeting was released in February, outlining recommendations for the future use of gene editing in humans.10 It concluded that basic research on gene editing is necessary to fully understand the scope of the current technology and to maintain adequate oversight on clinical trials in human somatic cells. More importantly, it was recommended that gene editing in human germ cells not be performed for enhancement of traits, and should only be allowed for compelling reasons until we gain a better understanding of whether the benefits outweigh the long-term risks.

Notwithstanding the enormous potential of CRISPR-Cas9 to medicine, many safety, ethical, and socio-economic issues are raised with respect to its applications in humans, echoing concerns regarding DNA recombination in the mid-1970’s. One of the major safety concerns with CRISPRCas9 is the possibility for non-specific DNA modifications that could potentially inactivate essential genes or activate oncogenic genes.10 CRISPR-Cas9 also

Considering its immense potential impact on mankind—from preventing and treating disease to enhancing traits like cognitive or athletic ability—gene editing has been described as a “process more rational and quicker than Darwinian evolution.”12 Evidence offered by Yin et al. (2017) and many others supports the notion that CRISPR-Cas9 genome editing in humans is plausible and offers great hope for millions affected by previously

Future of CRISPR-Cas9: promises and pitfalls

untreatable diseases.1 Yet, since the potential risks are not readily apparent, it would be wise to proceed with caution in this new era of genomic medicine. Moving forward, we must collaborate globally on gene editing research and, while abiding by the legal and regulatory policies, allow researchers the freedom to explore the potential of CRISPR-Cas9 and its potential to prevent and cure disease.

References 1. Yin C, Zhang T, Qu X, et al. In vivo excision of HIV-1 provirus by saCas9 and multiplex single-guide RNAs in animal models. Mol Ther. 2017;25(5):1168-1186.

2. Kaminski R, Chen Y, Fischer T, et al. Elimination of HIV-1 genomes from human T-lymphoid cells by CRISPR/Cas9 gene editing. Sci Rep. 2016;6:28213.

3. Drake MJ and Bates P. Application of gene editing technologies to HIV-1. Curr Opin HIV AIDS. 2015;10(2):123-127.

4. Tebas P, Stein D, Tang WW, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901-910 5. Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014;157(6):12621278.

6. Jinek M, Chylinksi K, Fonfara I, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.

Science. 2012;337(6096):816-821.

7. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013;339(6121):819-823.

8. Semeniuk, I. Nature’s Scissors. The Globe and Mail [newspaper online]. 2016 Mar 24 [cited 2016 May 28]. Available from: https://www.theglobeandmail.com/technology/science/ gairdner-awards-honour-gene-editing-crispr-researchers/article29330742/ 9. Barrangou R, Doudna JA. Applications of CRISPR technologies in research and beyond. Nat Biotechnol. 2016;34(9):933-941.

10. Human Genome Editing Science, Ethics, and Governance – Report Highlights: National Academy of Sciences and Medicine. 2017.

Available from: http://nationalacademies.org/cs/groups/genesite/ documents/webpage/gene_177260.pdf.

11. Knoppers BM, Isasi R, Caulfield T, et al. Human gene editing: revisiting Canadian policy. NPJ regenerative medicine. 2017;2:3.

12. International Summit on Human Gene Editing – Meeting Summary: National Academy of Sciences and Medicine. 2015. Available from: https://www.nap.edu/catalog/21913/international-summit-on-human-gene-editing-a-global-discussion.

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VIEWPOINT

Funding Science in Canada: STATUS AND EMERGING ALTERNATIVES

By Cricia Rinchon and Anna Badner

S

cience is expensive. Considering the significant cost of laboratory equipment, experiment materials, qualified personnel, and publishing fees, research comes at a high price. Further, the traditional academic funding model is a highly competitive and time-consuming process. Investigators are required to submit tedious applications and research proposals to granting agencies with increasingly restricted funds. For this reason, the IMS Magazine sought to review the current state of national science funding in Canada, its limitations, and the growing number of alternative funding sources.

On April 10th, 2017, the Federal Science Panel released their Review of Fundamental Science in Canada. Led by Dr. David Naylor, former president of the University of Toronto, the review was nicknamed the “Naylor Report” and highlighted shortcomings in the present national research funding model. Annually, the Canadian government spends more than $10 billion on science and technology.1 More than half of this is directed towards intramural research, which includes federal labs and scientists across multiple departments and agencies, including the National Research Council of Canada. In contrast, the Naylor Report focused on extramural research, which includes the work conducted at universities, hospitals, and institutes.

Each year, $5.2 billion of extramural funds are split up across grants and scholarships (through NSERC, CIHR, SSHC), tri-council programs (Canada Research Chairs, Canada First Research Excellence Fund, Networks of Centres of Excellence), and contribution agreements (e.g. Brain Canada, the Stem Cell Network, and Mitacs).2 The Federal Science Panel was primarily concerned with Canada’s research competitiveness, 30 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

which has progressively eroded in the past decade. Gross domestic product (GDP) is a measure of the market value of all final goods and services produced in a quarterly or yearly period and is commonly used to determine the economic performance of a whole country or region. The percentage of GDP spent on research and development from all sources is known as the Gross Expenditure on Research and Development (GERD). Canada’s GERD has been slowly declining over the last 15 years in comparison with Group of Seven (G7) nations.2 At the university level, faculty have felt this decline through the gradual reduction in CIHR grant success rates.3 For this reason, part of the Federal Science Panel’s proposed solution is a cumulative increase of base-funding for the tri-agencies (CIHR, NSERC, and SSRC) from $3.5 billion to $4.8 billion per year over a four year ramp-up period. Considering inflation, this may not sound like much; unfortunately, that is true. Contrary to popular belief, the Government of Canada is not the primary source of

$

Artwork by: Lisa Qiu

funding for academic research. Annual spending on research and development performed by institutions of higher education is referred to as HERD (Higher Education Expenditure on Research and Development). Internationally, Canada’s HERD intensity is the highest relative to the other G7 nations; however, it is important to note that HERD reflects where research is conducted, not where the funding came from. Notably, the Canadian government contributes less than 25% of that total.2 So, where does the rest of this money come from? Since 2015, almost 50% of HERD was funded by universities and colleges subsidizing the national research effort.2 Moreover, the remaining approximate quarter came from other funding sources including: contract research and/or matching from business (7.2%), grants from the non-profit sector (9.7%), provincial government research grants (8.9%), and foreign grants and awards (0.8%). More importantly, in the last decade, this extramural support has shifted dramatically, increasing emphasis on applied and commercializable

VIEWPOINT research.2 Although this movement encourages collaborations and support from industry, as discussed below, it may simultaneously deter funding from fundamental basic research—the work without any obvious translational goals.

With a focus on research commercialization, MaRS Innovation (MI) was established by the Government of Canada as a Centre of Excellence for Commercialization and Research.4 MI helps to commercialize medical research and other technologies with the support of local private enterprises. By operating as a business incubator, MI provides new and startup companies with services ranging from management and training, to funding and office space. It works with academia, industry, venture capitalists, angel investors, and the government. Since its inception, MI struggled to transform research inventions into successful startups and innovative technologies; however, that changed in 2008, when the University of Toronto (U of T), its affiliated research institutions, and other academic research institutions joined forces to group their collective intellectual property into a single commercialization platform.4 Since then, MI has created 60 companies within various sectors including medical diagnostics, devices, and therapeutics.4 An important commercialization collaboration of MI is the Centre for Commercialization of Regenerative Medicine (CCRM), which is also funded by the Government of Canada.

CCRM is a not-for-profit consortium specifically tailored to assist with the production and translation of gene, as well as cellular based, therapies. In 2015, the federal government announced a $114 million grant over seven years to propel U of T as one of the world’s leading centres for the design and manufacturing of cells, tissues, and organs to treat degenerative disease.5 Considering the distinct challenges of regenerative medicine technologies, CCRM similarly provides business and regulatory expertise in addition to technical services. The industry relationships, as well as collaborative agreements, drive financial support for further foundational research and business development.

Alongside the effort to commercialize science, online crowdfunding campaigns have also come to light as a novel and unconventional method of securing finances for research. This approach, which has shown

substantial promise in generating investment for start-ups, allows researchers to request small sums of money from numerous individuals through internet based platforms.6 By directly engaging financiers, crowdfunding is thought to democratize the allocation of research resources, reducing the institutional and investigator bias present within traditional granting agencies.7 Further, as these campaigns allow scientists to involve people outside of academia, they also present a source of public outreach, increasing science interest, awareness, and understanding.8 To date, the popular research funding platform Experiment (https://experiment. com) has 702 funded projects, 38,582 backers, and about $7,390,190 pledged.

Importantly, Experiment states that their funded projects have led to at least 20 publications in scientific journals and numerous conference proceedings, albeit the quality and impact factors are not mentioned. Nevertheless, as with industry-relevant research, translational science is also more likely to appeal to the public and secure funds, thereby discouraging support for the important curiosity-driven fundamental studies.

It is clear that the Canadian research ecosystem is changing. A growing amount of financial resources are being provided through commercialization initiatives, industrial relationships, and even through online public engagement. While encouraging, this reshaped financial landscape also comes with unique limitations.

Research accountability, allocation equity, and quality control are just a few of the emerging ethical considerations. Moreover, these increasing incentives for science

translation and commercialization are reducing the appreciation of basic mechanistic exploration. For this reason, moving forward, it will be especially important to remember that basic fundamental discoveries have led us to the application of science. Basic studies can complement or even drive future translation and commercialization. Ultimately, if Canada is to continue its progress as an active contributor to science, diverse work will need funding, thus requiring a coordinated effort on the part of the public, government, industry, and academia.

References 1. Semeniuk I. Massive review of federal science funding reveals risks to younger researchers. The Globe and Mail [Internet]. 2017 [cited 15 June 2017];. Available from: https://www.theglobeandmail.com/ news/national/review-calls-for-new-entity-to-oversee-federal-science-funding/article34650444/ 2. Naylor DC, Birgeneau RJ, Crago M, Lazardis M, Malacrida C, McDonald AB, et al. Investing in Canada’s Future: Strengthening the Foundations of Canadian Research. Available from: http://www. sciencereview.ca/eic/site/059.nsf/vwapj/ScienceReview_April2017. pdf [Accessed 6th June, 2015].

3. Government of Canada. Historical Success Rates in CIHR Open Grant Competitions. Available from: http://open.canada.ca/data/ en/dataset/af589454-caf5-4b6f-86ed-c871567c61de [Accessed 6th June, 2015].

4. http://www.nce-rce.gc.ca/NetworksCentres-CentresReseaux/ByBrogram-ParProgramme_eng.asp [Accessed 6th June, 2015].

5. Government of Canada. MaRS Innovation - MI. Available from: http://marsinnovation.com/2015/07/federal-government-awards-the-university-of-toronto-114-million-regenerative-medicine-grant/ [Accessed 6th June, 2015].

6. Vachelard J, Gambarra-Soares T, Augustini G, Riul P, Maracaja-Coutinho V. A Guide to Scientific Crowdfunding. PLoS Biol.

2016 Feb 17;14(2):e1002373 7. Benderly BL. Going Online for Research Funding. Science. 2013 Jun. Available from: http://www.sciencemag.org/careers/2013/06/ going-online-research-funding [Accessed 4th June, 2015].

8. Byrnes JE, Ranganathan J, Walker BL, Faulkes Z. To Crowdfund Research, Scientists Must Build an Audience for Their Work. PLoS One. 2014 Dec 10;9(12):e110329.

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VIEWPOINT

Image adapted from Vecteezy.com

I feel, therefore I am?

Understanding Pain in Disorders of Consciousness

By Natalie Osborne

W

hen a person’s consciousness is severely impaired after brain damage, they are said to have a Disorder of Consciousness (DOC). DOCs challenge our ideas about what constitutes the conscious human experience, and one of its most compelling mysteries: pain.

Pain is a multidimensional psychological and physical experience, combining sensory, cognitive, and emotional processes.

Whether or not patients with DOCs can experience pain is currently unknown.

However, the answer will profoundly impact their treatment and care, as no single accepted strategy for pain detection and remediation currently exists for these patients.1 To understand the experiences of a person with a DOC, we must first appreciate that human consciousness exists on a spectrum. Severe brain damage, such as oxygen deprivation from a stroke or traumatic injury from a motor vehicle accident, can 32 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

often result in a complete loss of arousal and awareness, known as a coma. While some patients wake up and recover from this state, others get “stuck” in intermediate levels of consciousness, where they can remain for months and even years.

For example, Unresponsive Wakefulness Syndrome (UWS, also known as Vegetative State) is defined as a return of arousal (e.g., sleep and wake cycles) without awareness.

UWS patients can breathe on their own, sit up, and even look around the room.

However, they do not appear to have awareness of their environment, and the behaviours they show (moving, swallowing, vocalizing, and even smiling, laughing, and crying) are considered reflexive and unconscious. Patients in a Minimally Conscious State (MCS) show fluctuating, intermittent signs of awareness. MCS patients make purposeful movements, recognize familiar objects, and can even respond to simple commands, such as

“move your right hand” or “touch your nose.”

There are many potential sources of pain for DOC patients, including severe brain injury and spasticity, as well as bedsores, muscle atrophy, and limb contraction brought about by prolonged immobility.

But without conscious awareness of the world around you, does a painful stimulus register as pain? Without awareness of the self, can the unpleasantness and suffering associated with pain be felt? Because DOC patients cannot communicate, there is no way to know for certain what they are experiencing.

Medicine urgently needs a more thorough understanding of the experience of pain in DOC patients to inform clinical management and treatment options.

Currently these options are few, as the very existence of pain in DOCs is disputed in the literature. Some physicians

VIEWPOINT recommend a “default approach,” where DOC patients are automatically treated for pain.1 However, there are concerns that the blanket use of sedative or analgesic drugs could mask or decrease arousal in patients, which would be counterproductive to recovery. Conversely, severe pain left untreated could also impair or inhibit recovery of consciousness.

Physicians currently rely on bedside behavioural assessments to diagnose DOCs. One such test has a subsection designed specifically to evaluate patients’ responses to “nociceptive” stimuli—stimuli that would cause pain in a healthy individual—called the Nociception Coma Scale (NCS). Patients considered to have neither environmental nor self-awareness can still show “nociception”—unconscious, subcortical pain processing that results in reflexive withdrawal movements or autonomic responses such as grimacing and crying.2 Behaviours thought to reflect more awareness of pain, such as verbalizing distress or touching the area where the painful stimulus was applied, result in higher NCS scores. Higher NCS scores correlate with increased levels of consciousness, as well as more activity in the anterior cingulate cortex, a brain area involved in pain processing.3 Still, behavioural tests are not always reliable. A seminal study by Owen et al. in 2009 used neuroimaging to uncover signs of awareness in a UWS patient who had been behaviourally diagnosed as unaware.4 The patient responded to commands not by moving, but by thinking—alternately imagining playing tennis or walking around their home when asked.

Their brain activity while performing these mental imagery tasks was indistinguishable from healthy participants.

This finding sparked many similar studies which revealed that about 30% of UWS patients are diagnosed as completely unaware based on behavioural tests, yet they retain signs of consciousness revealed through mental tasks.5 The misdiagnosis rate for behavioural tests raises an important question: could we similarly be missing signs of pain in these patients?

Neuroimaging studies have found that UWS patients show limited activation in the sprawling network of brain structures involved with somatosensory, cognitive, and emotional pain processing.6 This

activation extends to include higher-order pain processing networks when the intensity of the painful stimulus increases.7 Moving up the scale of consciousness to MCS, brain activation in response to painful stimuli is more reliable, and begins to resemble the patterns seen when healthy people are given painful stimuli.8 A recent study found activation in the limbic system, which is thought to be involved in the emotional aspect of pain, in both UWS and MCS patients.9 The authors suggested this could mean that some patients may be capable of experiencing the unpleasantness of painful stimuli.

Using brain activity to infer whether or not a person is experiencing pain is, however, a precarious endeavour. Pain is a highly individual and variable experience, influenced by a multitude of factors including context, emotion, previous experience, and attention. Researchers have long pursued a definitive “neural signature” of pain, which has proven difficult to establish even in healthy brains. While advances in neuroimaging techniques and analyses may improve our understanding of how pain is represented in the brain, it cannot yet be regarded as an exclusive authority on whether or not a person is in pain.

Intriguingly, neuroimaging may offer another route towards improving patient care. A small proportion of DOC patients who mentally respond to commands can use these responses to communicate.

Researchers establish with the patients which mental states represent yes and no, and then interpret their brain activity after asking them verifiable questions about their history, family, and present situation.

In another landmark experiment in 2012, Dr. Adrian Owen and colleagues asked one such UWS patient “Are you in pain?” to which the patient answered, “No.”10 If a physician suspects a DOC patient may be in pain, there are several treatment options that may be effective. A 2014 case report by Lanzillo et al. described a DOC patient suffering from spasticity who, when treated with a combination of baclofen and the analgesic ziconotide, improved dramatically on behavioural tests of consciousness. When ziconotide was removed, the patient’s condition deteriorated but was restored when ziconotide was reintroduced. The patient went on to recover consciousness.11 Baclofen itself,

commonly used to treat severe spasticity and any potential corresponding pain in DOC patients, has also been associated with improved consciousness in several other case studies.12 However, further research is needed to specifically explore if these drugs are indeed acting as analgesics, because an increase in consciousness does not necessarily equate to pain relief.

Advances in emergency medical care have made it possible for more patients to survive after catastrophic brain injuries.

Therefore, medical care providers have a responsibility to ensure these patients have the highest quality of life possible.

Researchers and clinicians should take advantage of innovations in neuroimaging technology to gain insight into these patients’ internal experiences, and make the effort to reach out to them any way they can… for they may be more in need than we think.

References 1. Schnackers C, Zasler ND, (2007). Pain assessment and management in disorders of consciousness. Curr Opin Neurol. 20(6): 620-6.

2. Pistoia F, Sacco S, Sara M, Carolei A. et al. (2013). The Perception of Pain and its Management in Disorders of Consciousness. Curr Pain Headache Rep; 17: 374 3. Chatelle C, Thibaut A, Bruno MA, Boly M, Bernard C, Hustinx R, Schnakers C and Laureys S. (2013). Nociception Coma Scale-Revised Scores Correlate with Metabolism in the Anterior Cingulate Cortex. Neurorehabil Neural Repair. 28:149-152.

4. Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. (2006). Detecting awareness in the vegetative state. Science ;313:1402.

5. Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pickard JD, Tshibanda L, Owen AM, and Laureys S. (2010). Willful Modulation of Brain Activity in Disorders of Consciousness. N Engl J Med ;362:579-89.

6. Laureys S, Faymonville E, Peigneux P, Damas P, Lambermont B, Del Fiore G, Degueldre C, Aerts J, Luxen A, Franck G, Lamy M, Moonen G, and Maquet P. (2002). Cortical processing of noxious somatosensory stimuli in the persistent vegetative state. NeuroImage 17: 732-741.

7. de Tommaso M, Navarro J, Ricci K, Lorenzo M, Lanzillotti C, Colonna F, Resta M, Lancioni G, Livrea P. (2013). Pain in prolonged disorders of consciousness: Laser evoked potentials findings in patients with vegetative and minimally conscious states. Brain Inj 27(7-8): 962-972.

8. Boly M, Faymonville ME, Schnackers C, Peigneux P, Lambermont B, Phillips C, et al. (2008). Perception of pain in the minimally conscious state with PET activation: an observational study. Lancet Neurol. 7: 1013-20.

9. Calabrò RS, Naro A, Manuli A, Leo A, De Luca R, Lo Buono V, Russo M, Bramanti A, Bramanti P. (2017). Pain perception in patients with chronic disorders of consciousness: 10. What can limbic system tell us? Clin Neurophys. 128: 454-462.

11. Fernández-Espejo D & Owen AM. (2013). Detecting awareness after severe brain injury. Nat Rev Neurosci. 14:1-9.

12. Lanzillo B., Loreto V., Calabrese C., Estraneo A., Moretta P. and Trojano L. (2014). Does pain relief influence recovery of consciousness? A case report of a patient treated with ziconotide. Eur J Phys Rehabil Med. (Pistoia et al, 2015).

13. Pistoia F, Sacco S, Sara M, Franceschini M, and Carolei A. (2015).

Intrathecal baclofen: effects on spasticity, pain, and consciousness in disorders of consciousness and locked-in syndrome. Curr Pain Headache Rep; 19: 466.

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 33

ALUMNI SPOTLIGHT

Retinal Stem Cell Clinical Trials:

Are We There Yet?

By Tahani Baakdhah

D

r. Mary Sunderland is a distinguished Institute of Medical Science (IMS) alumna who completed her Masters of Science (MSc) thesis under the supervision of Dr. Derek van der Kooy. Following her graduate studies, Dr. Sunderland pursued a post-doctoral fellowship where she gained the experience necessary for her current dynamic and multi-faceted position as the Director of Research and Education at the Foundation Fighting Blindness (FBB). I recently had the opportunity to travel back in time with her and re-live the major highlights of her research career. As Dr. Sunderland revisits her career trajectory, she also provides an outlook on the future of research for treating blindness.

During the last year of her undergraduate studies, Dr. Sunderland became fascinated and intrigued by developmental biology.

She completed a double major in zoology and philosophy, and thought of developmental biology as the perfect intersection of these two disciplines of study. Following her undergraduate studies, Mary joined Dr. van der Kooy’s lab in the year of 2001, in which he published his landmark discovery of retinal stem cells. In the van der Kooy lab, Mary evaluated the role of Pax6, a gene that regulates early eye development, in retinal stem cells.1 Residing in the ciliary epithelium of the eye, retinal stem cells are multipotent cells that can differentiate into every retinal cell type.2 After completing her MSc, she spent a few months at Dalhousie University to study model systems in stem cell biology, and subsequently pursued her PhD at Arizona State University, which had just launched 34 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

a new graduate program in Biology and Society.

Dr. Sunderland praises the PhD program, as it allowed her to study both the scientific and cultural complexities of stem cells.

Through her dissertation, which focused on the history of regenerative medicine, she had the opportunity to work with many leading figures in the field. After completing her doctorate research, Dr. Sunderland pursued a post-doctoral fellowship at the Berkeley Center for Science, Technology, Medicine and Society, University of California (Berkeley), where she explored the ethical and practical implications of conducting research with a specific translational aim. Through her projects, Dr. Sunderland published and co-authored multiple papers to evaluate how the emerging ethos of translational research acts as a powerful determinant in funding for biomedical sciences. Her work focused on three topics: how social, political, and cultural contexts can limit promising research; the importance of strategically funding research and developing innovative regulatory policies, and the necessity to mobilize patient advocates. Following her work at Berkeley, Dr. Sunderland decided to retire from the laboratory component of her research in favor of embracing her passion for science communication and translational research, a field she was very interested in as a graduate student. She studied translational research for a decade, and bringing forth her background in retinal stem cells, Dr. Sunderland was thrilled to become FBB’s Director of Research and Education.

At FBB, she oversees the translational

research portfolio and complementary educational program, both of which aim to drive the development of new treatments for eye disease causing blindness. When asked to describe her typical day, she said, “There is none—I might be designing a new research funding opportunity, speaking with patients at a community vision health event, or advocating for better access to genetic testing.”

Although there are currently no Canadian clinical trials for stem cell use in treating eye diseases that cause blindness, Dr. Sunderland believes it has been an exciting year for stem cell clinical trials nonetheless. Her optimism is based on the number of promising, albeit contradictory, experimental stem cell trials carried out internationally. Notably, Dr. Masayo Takahasi’s publication in the described the first successful stem cell transplantation that used induced pluripotent stem cells from another donor as an experimental treatment for retinitis pigmentosa.3 However, in the same issue, another publication reported that three women became blind after participating in a clinical trial that used stem cells derived from patient’s own adipose tissue to treat blindness.4 When asked about these unfortunate results, Dr. Ajay Kuriyan, who is the first author of the paper, noted that the technique is being used widely in commercial stem cell clinics. Furthermore, despite the negative data, Dr. Kuriyan indicated that pre-clinical data exists regarding the ability of these stem cells to differentiate into the retinal pigment epithelial or photoreceptor cells and restore vision.

ALUMNI SPOTLIGHT Amidst these conflicting results, Dr. Sunderland has focused her efforts on increasing public awareness about blindness, and the relevant current clinical trials and stem cell tourism industry, through her public lectures, and her engagement in public discourse via blogging (FFB blog), and Twitter (@FFB_Research; and @SciParty; a science chat forum hosted every Friday at 1pm). For example, while many researchers were successfully able to treat degenerative eye diseases in animal models using photoreceptors and retinal pigmented epithelium derived from Embryonic Stem Cells (ESCs) and Induced Pluripotent Stem Cells (iPS) cells, laboratories in the United Kingdom, Japan, and United States have not attained successful results through human clinical trials.

Juxtaposing these two findings highlights both the excitement and great challenges that lie ahead in the research for treating blindness. Evidently, a key barrier to patients is in judging the credibility of clinical trials, which prompted Dr. Sunderland to recommend FFB as a trusted source of information about emerging treatments and clinical trials. While there is tremendous potential for stem cell research to treat blindness caused by eye disease, it is tempered by the risk that a dangerous trial could hinder the credibility of the field for decades.

Finally, she advises young researchers and graduate students to keep reading. “One of my favorite things about being in graduate school was reading. I’ve always loved reading, so it was a true privilege to take a deep dive into so many important texts, and then, it was even better to discuss these new ideas with peers, teachers, and mentors. This is what’s great about being a student: it’s your job to always be learning.

I think I will always be a student at heart.”

1. Xu S, Sunderland ME, van der Kooy D, et al. The proliferation and expansion of retinal stem 2. cells require functional Pax6. Developmental Biology. 2007; 304: 713–721.

3. Tropepe V, Coles BL, Chiasson, BJ, et al. Retinal stem cells in the adult mammalian eye. Science; 2000; 287, 2032–2036.

4. Mandai M, Fujii M, Takahashi M, et al. Autologous Induced StemCell–Derived Retinal Cells for Macular Degeneration. N Engl J Med; 2017; 376:1038-1046 5. Kuriyan AE, Albini TA, Goldberg JL, et al. Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD. N Engl J Med; 2017; 376 (11): 1047 6. Nommiste B, Fynes K, Coffey P, et al. Stem cell-derived retinal pigment epithelium transplantation for treatment of retinal disease.

Prog Brain Res; 2017; 231:225-244.

Photo by Tahani Baakdhah

References

Dr. Mary Sunderland PhD, Director of Research & Education at Foundation Fighting Blindness Canada IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 35

FACULTY SPOTLIGHT

S P OT L I G H T O N

DR. MICHAEL SZEGO Director, Centre for Clinical Ethics (a joint venture between Providence Healthcare, St. Joseph’s Health Centre, and St. Michael’s Hospital) Assistant Professor, Dalla Lana School of Public Health and the Department of Family and Community Medicine, Institute of Medical Science

Photo by Iris Xu

By Yena Lee

D

r. Szego was a bench scientist by training with plans to run his own lab until he learned of clinical bioethics as an alternative career path. While completing his PhD training in molecular genetics at the University of Toronto, Dr. Szego started volunteering with a clinical 36 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

ethicist and eventually went on to complete a Master of Health Science in Bioethics and a Fellowship in Clinical Ethics at the Joint Centre for Bioethics at the University of Toronto. Now he’s the Director of the Centre for Clinical Ethics. As part of this faculty spotlight article, I interviewed Dr.

Szego about what it means to be a clinical ethicist and his decision to pursue this field of work. The following are edited excerpts of our conversation.

FACULTY SPOTLIGHT What is clinical ethics and what do clinical ethicists do?

Clinical ethics is a practical discipline that provides a structured approach to assist healthcare providers, patients and their families to help identify, analyze and resolving ethical issues in medicine.

Clinical ethicists help support healthcare organizations by conducting clinical consults, providing education to staff, through policy development and research. Clinical consults are usually requested by the clinical team when there is a conflict or moral uncertainty that has arisen over the course of delivering healthcare. Depending on the case, I will have a discussion with the clinical team or facilitate a conversation between the patient, family members, and healthcare providers. I think it is important to recognize that healthcare providers deal with ethical issues every day; however, sometimes there are difficult cases in which there is a disagreement about the right course of action. For example, I had a recent case involving a ventilated patient in the ICU. The clinical team determined that their interventions were merely prolonging the dying process and they proposed withdrawing life support. The family (since the patient was not capable of making treatment decisions) disagreed with the clinical team and wanted continued aggressive treatment. While I don’t have the space to unpack this case much further, I will end by saying the first step in cases like this is to try and determine what the patient would have wanted given the clinical scenario and use that information to guide the discussion.

What’s a typical day like for you?

There really is not a typical day, which is one of the reasons I like the role so much.

I wear a pager and clinical consults always take precedent over any other plans for the day. When the pager is quiet, I work on healthcare policy development, sit on various hospital committees, and provide ethics education to healthcare providers. I also teach at U of T and have several ongoing bioethics research projects. One of my projects involves exploring patient and family perspectives on the return of whole genome sequencing results in children.

Can you tell me a little more about your research on ethical issues and genomics

testing in children? How does the nature of your research in bioethics differ from that in the sciences, such as data collection or academic writing style?

For a child receiving conventional genetic testing, one ought to avoid tests pertaining to adult-onset disorders and wait until the child is old enough to make that choice for themselves. However, with clinical whole genome sequencing, the question is whether we should apply the same rules as for conventional genetic testing or should there be a different standard. If we performed clinical whole genome sequencing on a child, should we take the opportunity to screen for variants associated with preventable adult-onset disorders? And if we did identify a pathogenic BRCA1 mutation, for example, should we disclose the result to the parents? Such a result would have implications for the future health of the child and likely have immediate health implications for the child’s biological parents. My research focuses on using qualitative data, such as interviews, to describe the experiences of patients, families, and healthcare providers who have experience with whole genome sequencing. My goal is to use data to help inform the ethical debate.

How does your academic background differ from that of your colleagues in clinical bioethics? Do they generally have PhDs? Bioethics is very interdisciplinary, so my colleagues all have different academic backgrounds, which makes collaboration a lot of fun. Most of my colleagues have either a Master’s or a Doctorate degree in philosophy, theology, or bioethics and many come from other disciplines such as medicine, social work, nursing, or allied health (e.g. speech pathology). While a Doctorate is not strictly required, it certainly helps as does the completion of a clinical ethics fellowship program.

What made you change careers paths?

When I started my PhD in molecular genetics my end goal was to run my own lab. I really enjoyed science and the work, but I got this nagging feeling, especially towards the middle to the end of my PhD, that a scientific career wasn’t entirely the right fit. I started going to seminars

on alternate careers in the life sciences.

At those seminars, I heard a bioethicist speak about his job and I remember being intrigued. One very appealing aspect of bioethics was the variety of activities that were associated with the job. He spoke about teaching, clinical consults, policy development, and research. It sounded like what I was missing—that kind of variety in any given day—so I put it in my back pocket as something interesting but at that point I needed to get back to my lab and focus on my thesis. But later, I coincidentally heard him speak a second time and this time I decided to talk to him after the seminar. I volunteered with him and shortly after decided to switch careers.

I finished my PhD, then enrolled and completed a Master’s degree in bioethics and then completed a fellowship in clinical ethics.

What’s the most contentious case in the field right now?

There’s been a lot of discussion around medical aid in dying and conscientious objection. I am also seeing a lot of cases involving complicated transitions of care.

Many patients in the hospital are what’s called, “alternate-level of care”. They don’t require acute care anymore, but there isn’t anywhere for them to go, so essentially they’re stuck in the hospital. For example, some families won’t agree to a discharge from hospital because they feel like their loved one is not ready or they want their loved one to go to a long-term care facility (nursing home).

Any advice for graduating students preparing for the next step in their careers?

This sounds trite, but follow your heart.

You’re going to spend a lot of your life working so find something you like and are good at. If you are thinking about transitioning to another career path, talk to someone in that field and find out what path they took to get there. Volunteering is also a great way to get experience. If you want a hybrid career, it’s not a bad idea to get another degree. I know that sounds crazy at the end of a Master’s or a PhD, but having the credentials is important and you’ll also build a network which will help you in the future.

IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 37

PAST EVENTS

Indigenous

Health Perspectives

By Alexandra Mogadam On a Wednesday afternoon in late April, Institute of Medical Science (IMS) students sat down with three Indigenous leaders in the University of Toronto (U of T) community—representing both faculty and graduate students—to learn about the unique health-related struggles experienced

by Indigenous peoples in Canada.

her students, Brenda would push back the desks, and place the chairs in a circle.

Following each session, everything would be put back. After some time, one of her students asked why they always had to put the seats and tables back into rows, and why the other classes couldn’t instead place the furniture into a circle.

As attendees trickled in and started taking their seats, one of the speakers suggested everyone sit in a circle at the front of the room. Dr. Brenda Wastasecoot, a professor of Indigenous Studies at U of T and one of the speakers, later explained how engaging and learning in circles is very important in First Nation communities. She shared a story from when she was the Director of the First Nations and Aboriginal Counselling (FNAC) Program at Brandon University, Manitoba. At the time, she had been sharing her teaching space with other programs, which had set up the desks and chairs in rows. Every time she met with

A valid question, she observed. How was it that after all this time, they, as First Nations, still had to concede and curb their cultural practices to non-Native norms?

Brenda was open to and welcomed the idea of sharing spaces, yet did not understand why the concessions needed to come from her and her community, and never the other.

38 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

The conversation during the panel-discussion centered on this notion of unequally “shared space” between First Nation communities and non-Native Canadians, a space in which non-Natives continue

to determine the norms, and how First Nations’ cultural practices may be performed to fit within these norms, as well as the allocation of health and educational resources for Indigenous peoples.

One takeaway of the discussion was the importance of acknowledging Indigenous peoples’ hidden history within the greater narrative of Canada, and the need for greater support in the practice of cultural rites in what is, after all, their homeland.

Their collective history and the constraints they experience in their cultural practice weighs on all of them, impacting all aspects of their life, including their health. Brenda remarked, “When I see one [a person of Indigenous descent] on the streets, I see our history. This is what happened to all of us. Only some of us have made it”.

Dr. Kona Williams, Canada’s first Indigenous forensic pathologist and a panelist present at the event, shared her

PAST EVENTS

unique perspective on health and First Nations. As a pathologist, she investigates her patients’ cause of death, which explicitly exposes her to the urgent crisis of missing and murdered Indigenous women in Canada. The national inquisition into this problem is a human rights cause that is particularly dear to her; currently, she is involved in the “re-patriation” initiative to identify stored Indigenous bodies and return them to their communities, in hopes of helping with the mourning and healing process.

healing, as a tether point. In the Truth and Reconciliation Commission of Canada Final Report, released in 2015, 94 calls to action were given to support reconciliation, including health-specific calls. The panelists were supportive of this report, which tackled larger structural issues, but they expressed the need for open dialogue and conversation between individual people to increase awareness of the unique challenges they face as a community, due to their (recent) history, and disadvantaged access to education, health care, and safety.

Atik Bird, the third and final panelist, greatly emphasized the need for healing and rehabilitation. Atik is pursuing her MSc in Rehabilitation Sciences, and aims to use Indigenous research methodology to investigate the notion of rehabilitation within the context of Indigenous communities of modern day Canada. She is using the story of her father, for whom storytelling has been a very important means for

What was initially intended to be a panel discussion on health perspectives and the Indigenous communities of Canada blossomed into an all-encompassing conversation about (hidden) histories, loss and pain, as well as health, strength and, ultimately, the rehabilitation of Native Canadians. The speakers concluded that things were definitely changing for the better, albeit very slowly. “Our stories are

finally coming out; there is more space to be proud of who you are,” said Brenda.

There is a long road ahead, and these strong women are proudly paving the way forward towards a better and more just Canada for all of its communities.

Resources Learn more about the Truth and Reconciliation Commission of Canada: http://www.trc.ca/websites/trcinstitution/index.php?p=3 Stop by First Nations House on the St. George campus; welcome to everyone! http://www.studentlife.utoronto.ca/fnh Take a course offered by the Centre for Indigenous Studies at U of T: http://indigenousstudies.utoronto.ca Attend IMAGINative Festival to experience Indigenous film and media installations: http://www.imaginenative.org IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 39

Photo by Alexandra Mogadam

From left to right: panelists Dr. Brenda Wastasecoot, Atik Bird, Dr. Kona Williams, and IMSSA Director of Academic Affairs Nancy Liu.

PAST EVENTS

dying for change

How to Heal Canada’s Healthcare System

By Fadl Nabbouh and Swapna Mylabathula

“P

eople’s experiences with Canadian healthcare can bring you to tears of joy,” Dr. Martin comments, before adding “and shame.” After the dust had settled at the 2017 UofT Talks event, audience members were left bewildered by the state of our healthcare system, but also hopeful for the future. Our healthcare is a point of national pride, something that comes up almost as often as hockey when discussing Canadian identity. But is it really as great as we would like to believe?

Every year, the Institute of Medical Science’s (IMS) Student, Alumni, and Faculty Engagement Committee (SAFE) hosts a symposium on a relevant healthcare topic with the help of the IMS Students’ Association. Last year, PhD 40 | IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS

student Katherine Schwenger, who has long been involved in the academic wellbeing of IMS students, proposed the idea of combining different perspectives that bring together all divisions of the university to talk about a theme that affects us all.

And thus, UofT Talks was born.

UofT Talks aims to promote inter-disciplinary learning and networking through a symposium catered to students, faculty, and staff of all four School of Graduate Studies divisions—Humanities, Social Science, Life Science, and Physical Science.

This year, IMS faculty (Dr. Brenda Toner), students (Katherine Schwenger, Fadl Nabbouh, Craig Madho, and Richard Foty), and alumni (Sarah Coakeley) formed an incredible committee to

organize the UofT Talks event.

Hosted on June 8th by Richard Foty at a sold out Mazzoleni Hall in the TELUS Centre for Performance and Learning, UofT Talks was joined by esteemed members of the healthcare community: Mr. Neil D. Fraser, BASc, MBA, and Dr. Danielle Martin, MD, CCFP, MPP. Neil Fraser is the current President of Medtronic Canada, Regional VicePresident of Medtronic PLC, Chair of the Board at MEDEC (Medical Devices Canada), and a Board member & Chair of the Research Advisory Committee at the Baycrest Hospital & Rotman Research Institute. Neil and his team at Medtronic are industry leaders in medical technology services, and help improve the lives of

PAST EVENTS millions of patients through innovation and collaboration. He is a frequent speaker on the topics of value-based procurement, outcomes-based healthcare, and the role of the medical device sector in improving clinical outcomes, economic value, and access to quality healthcare.

Dr. Danielle Martin is a family physician and Vice-President of Medical Affairs and Health Systems Solutions at Women’s College Hospital. Dr. Martin gained international attention in 2014 for championing Canada’s healthcare system at a meeting of the United States Senate committee. In her new book, Better Now: 6 Big Ideas to Improve Health Care for All Canadians, Dr. Martin advocates for changes that need to be implemented in our healthcare system in order to provide all Canadians with equitable access to healthcare.

Neil Fraser spoke first, briefly summarizing the history of Canada’s healthcare system. He expressed our contributions to healthcare, including the discovery of insulin by Drs. Banting and Best, and the introduction of Medicare in Canada in 1968, a source of great national pride.

“As Canadians, we’re proud of our healthcare system, but our worldwide ranking has been slipping,” said Neil Fraser to a surprised crowd. “Canada’s healthcare spending is higher than the OECD average and coverage is not universal.” Neil spoke of the flaws in our system, noting that only about 70% of our healthcare is publically funded and access is not truly equitable.

Minorities and rural communities experience difficulty in accessing healthcare.

Relatedly, our ranking in healthcare quality has dropped outside of the top 30 in the world.

times do not exist because of a lack of resources, but because of their organization. Furthermore, Canadians pay among the highest of developed countries for pharmaceuticals, something not covered under Medicare. This was emphasized by Dr. Martin, who stated that as Canadians, we are willing to pay for expensive life-saving surgeries but not the lower priced drugs that can prevent life-threatening conditions. One of Dr. Martin’s big ideas in her book, Better Now, is to implement Pharmacare in Canada, something she believes is affordable and would improve healthcare for all Canadians.

Despite the dark cloud of our system’s flaws, the speakers also offered hope to the audience. “I don’t believe that we have an innovation problem. Our problem is making services universally accessible,” said Dr. Martin. She continued, “We have answers to the issues in our healthcare; the problem is implementation.” She concluded by stating that it will take a conversation among all of us to make healthcare worthy of our national pride.

“We do not need to choose between equity and excellence,” she noted powerfully. “We should demand both.”

Following both talks, the speakers generously engaged in a question and answer period with the audience. The discussion ranged from personal experiences to general ideas about how to improve our system. Common themes emerged during the discussion: first, how do we as patients receive better healthcare?

Additionally, audience members were interested in learning about who should be held accountable for the flaws in our system. A healthcare system should be patient-centered. The most important outcome within a healthcare system is patient-reported, something we sometimes forget. “Physicians are a self-regulating profession—we must ensure that we uphold our professional standards,” noted Dr. Martin. It is up to us to report unprofessional medical doctors (MDs) and conflicts of interest between MDs and pharmaceutical companies. She added, “It’s not just about MDs—we need collaborative medical teams to increase equitable access.”

UofT Talks concluded with one final question that resonated with every audience member: “Where do we go from here?”

Mr. Fraser concluded that it is time for patients, doctors, and the government to have a conversation, because the process for implementing solutions and innovations needs to begin now. Dr. Martin added that we all have an obligation to engage as citizens. This is an important discussion to have, as we celebrate Canada’s 150th anniversary, and will ultimately lead to the changes that will truly make our healthcare system a source of national pride and wellbeing for Canadians for many more years to come.

Most notably, our healthcare is challenged by waiting times and expensive pharmaceuticals. Our wait times are among the highest in the developed world and among other universal healthcare systems. Recently, the Ontario provincial government released a budget that hopes to counter this, although it does little but account for inflation. The Ontario Medical Association has argued that more spending in the same areas will not help; a better solution would require allocating funds to areas that can take pressure off of the urban hospital system. Outpatient services and rural health centres need to be funded to reduce wait times in hospitals. Our wait IMS MAGAZINE SUMMER 2017 CLINICAL TRIALS | 41

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