IMS Magazine Spring 2015 by IMS Magazine

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IN THIS ISSUE Letter from the Editor..............................5 Important Dates......................................6 Director’s Message.................................9 Feature .................................................10 Viewpoint..............................................20 Expert Opinion.......................................24 Spotlight................................................26 Book Reviews........................................28

FEATURE GRAPHIC

P10

Infectious Diseases & Viruses

Special Articles.....................................30 Close-up................................................33

MAGAZINE STAFF

Future Directions...................................34

CO-EDITORS-IN-CHIEF

Travel Bites............................................36 Research Highlights..............................38

EXECUTIVE EDITORS OUTGOING MANAGING EDITOR JOURNALISTS & EDITORS

Past Events............................................40 Diversions..............................................42

DESIGN EDITORS

PHOTOGRAPHERS

FEATURE

P16 Interview with Dr. Kevin Kain

Annette Ye Susy Lam Kasey Hemington Katherine Schwenger Rebecca Ruddy Nancy Butcher Anna Badner Annette Ye Arunima Kapoor Ayda Ghahremani Gaayathiri Jegatheeswaran Jabir Mohamed Jonathon Chio Joshua Lipszyc Kasey Hemington Katherine Schwenger Mirkamal Tolend Muhtashim Mian Petri Takkala Rebecca Ruddy Sarah Gagliano Susy Lam Usman Saeed Vanessa Rojas Leungas Yetka Dowlati Cassandra Cetlin Natalie Cormier Naveen Devasagayam Ashley Hui Jerry Won Chung Ho Leung Laura Feldcamp Matthew Wu Patriek Matkar

Copyright © 2015 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited. The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Cover design by Naveen Devasagayam Feature Infographic by Ashley Hui & Jerry Won

IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 3

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4 | IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES

LETTER FROM THE EDITORS

Annette Ye & Susy Lam

Co-Editors-in-Chief

Letter from the Editors E

bola. The horrific implications of this virus are still ringing in the back of our minds as we go about our day-today routines in a developed country, primed from the media and their efforts to illustrate the situation in countries Liberia, Guinea, and Sierra Leone, and others. To garner more insight on this topic, we bring to you this issue of the IMS Magazine focused on ‘Infectious Diseases and Viruses.’ We’ve highlighted a special seminar from Doctors without Borders (Médecins Sans Frontières), where physicians and volunteers spoke about their first-hand experience in face of this deadly virus. We also feature an inspiring interview with Dr. Kevin Kain, a tropical disease expert who discusses the “human problem” in infectious disease. Aside from Ebola, we also focus on other aspects of viruses, including human immunodeficiency virus (HIV)–a global epidemic affecting as many as 35 million individuals. We’ve asked Dr. Sean Rourke, a specialist in this field, to discuss mild brain injury in HIV, a commonly overlooked condition. Aside from being parasitic and harmful to their hosts, viruses can also do good. Viruses can be modified and engineered to function for the benefit of organisms–perhaps even to cure disease. We are excited to feature Dr. Jeffrey Medin and Dr. McKillop in this issue, who discuss retroviruses in cancer immunotherapy. We would like to acknowledge Dr. Mingyao Liu and the IMS department for their ongoing support and encouragement, the IMS Magazine team on their outstanding contributions, and congratulate the incredibly creative Design Editors who have been integral in the production of this edition of the IMS Magazine. We hope that you will find these articles stimulating for your research and for discussion within the scientific community! Cheers,

Annette Ye & Susy Lam Co-Editors-in-Chief, IMS Magazine IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 5

IMPORTANT DATES May 11

Final date to enroll in May-June or May-August session courses

May 12

IMS Scientific Day

May 13

Winter session grades available for viewing by students on the Student Web Service (ROSI)

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May 18

Victoria Day (University closed)

June

June convocation information and dates are posted at www.convocation.utoronto.ca

July 1

Canada Day Holiday (University closed)

IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 7

Create. Innovate. Translate. Master of Health Science in Translational Research Translational Research Program trp.utoronto.ca Make a Difference: Translate Your Ideas into Action! 8 | IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES

UofTIMS

DIRECTOR’S MESSAGE

Mingyao Liu Director, Institute of Medical Science Professor of Surgery, Medicine and Physiology Associate Director, Institute of Medical Science Faculty of Medicine, University of Toronto Senior Scientist Head, Respiratory and Critical Care Research Group Toronto General Research Institute, University Health Network

DIRECTOR’S MESSAGE: Infectious Diseases and Viruses

As Director of the Institute of Medical Science (IMS), I am excited to introduce our most recent contributions of our IMS students and faculty, focusing on the topic of infectious diseases and viruses. The University of Toronto has long been a leader of translational research, from the days that it still went by the name of “King’s College” and was granted its royal charter by King George IV, to the first successful insulin injection to a diabetes patient at Toronto General Hospital. IMS is the largest graduate department at the university, and is an important translational research hub that accelerates advances in medical research, due to our unparalleled graduate education and research scholars. Within the focus of infectious diseases and viruses, I hope to share with you compiled pieces by our IMS graduate students. This spring issue highlights very motivating research advances by IMS faculty pertaining to this topic. Particularly, the first two focuses of this issue’s feature will be on HIV/AIDS and the Ebola virus—both exceptionally debilitating diseases that warrant a spotlight, and the students feature important research scholars who will share their medical research advances in detail to us. However, that is not to say that all viruses do harm. The legacy of University of Toronto continues as this issue also highlights a third feature, consisting of research using viruses in cancer therapy to benefit patients and the community. Very soon, the IMS will be holding its annual Scientific Day this upcoming May—a magnificent day showcasing the hard work and research of our graduate students in a friendly poster and manuscript competition. Just as exciting is the Data Blitz session, where scientific oral presentations will be delivered in a rapidfire format. On this exciting day, we welcome Dr. Christopher P. Austin, Director of National Center for Advancing Translational Sciences at the NIH, for the keynote address. For certain, this day will be insightful and rewarding, and I am looking forward to witness science and medicine at their best. Sincerely, Mingyao Liu, MSc, MD Director, Institute of Medical Science

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IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 11

FEATURE

MILD BRAIN INJURIES IN HIV OFTEN GO UNRECOGNIZED – MORE NEEDS TO BE DONE By Sean B. Rourke, PhD, FCAHS Scientist, Li Ka Shing Knowledge Institute of St. Michael’s Professor of Psychiatry, University of Toronto Scientific and Executive Director, Ontario HIV Treatment Network Director, CIHR Centre for REACH in HIV/AIDS Director, CIHR Collaborative Centre for Community-Based Research in HIV/AIDS Director, Universities Without Walls (CIHR STIHR) Alex Terpstra, MSc (Candidate) Rehabilitation Sciences Institute, University of Toronto 12 | IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES

Robert Reinhard Coordinator, Health Policy and KTE, Ontario HIV Treatment Network Community Liaison, The Canadian HIV Cure Enterprise, Institut de Recherches Cliniques de Montréal Francisco Ibáñez-Carrasco, PhD Director, Education & Training, Ontario HIV Treatment Network Manager, Universities Without Walls (CIHR STIHR)

FEATURE

n recent years, the topic of traumatic brain injury has received more and more media attention. We watch with amazement as our favourite Canadian athletes, like Sydney Crosby, perform on the rink, and cringe when they sustain what could be career-ending blows to the head. We’ve learned that these bell ringers—which used to be a rite of passage for real athletes— are bad for a person’s health. In fact, brain injuries can increase a person’s chance of developing cognitive changes in later life. In some cases, they can even lead to earlier onset of dementia.

cognitive changes may be subtle and have no noticeable impact on their day-to-day life. However, over time, the changes can progress and begin to interfere with their ability to carry out daily tasks and activities, like reading, managing medications, and paying attention to conversations in social situations. They can also affect the ability to do more demanding, “multi-tasking” things at work and often result in people getting frustrated, l o s i n g confidence, and going on disability. For the doctors caring for people with HIV, subtle cognitive changes are extremely difficult to diagnose and to treat or manage.

associated with HIV, and compensate for the impacts they have in their lives.

Although it’s less well known, and often not well identified, HIV can affect the brain and produce similar changes in cognitive abilities (e.g. attention, memory, and thinking) as concussions. Although 90-95% of people who experience mild concussions and brain injuries recover from these injuries in weeks to months, people who experience mild brain injuries caused by HIV often do not recover. The changes in their brains often persist, fluctuate over time, and never completely reverse.

Our Centre for Brain Health in HIV at St. Michael’s Hospital in Toronto is one of over a dozen international centres around the world working to identify better ways to assess, screen, treat, and manage HIVassociated cognitive impairments. We are developing clinical treatment guidelines and benchmarks for brain health in HIV/ AIDS that will help clinicians manage and support their patients. We are also exploring and testing out different nonpharmacological interventions, such as brain fitness, physical exercise, and mindfulness-based cognitive behaviour therapy, to see if we can identify tools that people with HIV can use to lessen, manage, or even reverse the cognitive changes

HIV can cause damage to the brain, both directly and indirectly, through inflammation and the release of harmful chemicals. The damaging effects of HIV on the brain can also be magnified by excessive drinking and drug use, as well as by other medical comorbidities, like cardiovascular and liver disease.

“Although people with HIV are now living longer, they are developing medical complications earlier than people who don’t have HIV.”

The brain injuries caused by HIV are extremely challenging for the people affected and for the clinicians caring for them. For people with HIV, the first

Although people with HIV are now living longer, they are developing medical complications earlier than people who don’t have HIV. For example, they often develop signs of cardiovascular disease 10-15 years earlier. In our centre, we are also trying to understand how these medical conditions—which often occur in conjunction with other mental health issues, such as depression— may accelerate and increase the cognitive impairments associated with HIV, especially as people age.

How does HIV affect the brain? What is HIV-associated neurocognitive disorder (HAND) and how common is it?

Cognitive impairment caused by HIV is called HIV-Associated Neurocognitive Disorder or HAND. Not everyone living with HIV will develop HAND. Among those who do, the level of impairment ranges widely, from nearly undetectable to mild to more severe. The most severe of these conditions is far less common today

IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 13

FEATURE it was in the past, thanks to combination antiretroviral therapy (cART) which, in addition to protecting and strengthening the immune system, protects the brain from HIV-related damage. The use of cART has dramatically reduced the prevalence of the most severe forms of HAND. However, despite the protective effects of cART, several research studies, including our own in Toronto, estimate that about 30-55% of middle-aged adults living with HIV still experience some form of HAND.

So, what is HAND? There are three main conditions/disorders that can occur: (1) asymptomatic neurocognitive impairment or ANI; (2) mild neurocognitive disorder or MND; and (3) HIV-associated dementia or HAD. The earliest stage of HAND, ANI (which occurs in about 1 of 3 people living with HIV), can only be detected using psychometric tests of attention, speed of processing, learning and memory, and thinking skills. These tests are sensitive enough to pick up subtle changes in cognitive abilities that are not apparent in daily life. While people with ANI will have mild and “spotty” cognitive impairments, they are often asymptomatic or symptom-free. The subtle and mild cognitive impairments do not interfere with their day-to-day life. The second milder HAND condition is MND, which affects about 15-20% of persons with HIV. People with MND experience cognitive changes that have a mild, but noticeable impact on their daily activities, including work, school, or social interactions. HAD is the most severe and, now, the rarest form of HAND (<2-3% of persons living with HIV). Most people who develop ANI or MND will not progress to HAD if their HIV is well managed with cART.

patients tell you about their attention, memory, and thinking skills is highly influenced by how someone is feeling emotionally and physically. For example, when people are feeling down or depressed, or even fatigued, they report cognitive issues that are often temporary and may not signal any “fixed” brain changes at all. Second, the cognitive impairments that people experience are often spotty—that is, not everyone will have the same complaints or present them in the same way. Third,

many problems that patients report occur commonly as we all age. For example, when we are 60, we do not process or learn information as quickly as we did when we were 20 years old.

“..people who experience mild brain injuries caused by HIV often do not recover. ”

In recent years, we have published a significant amount of work that helps to clarify the “signs and symptoms” of HAND, the relationships between “subjective” and “objective” findings, and the factors like physical and mental health (depression) that can interact with and complicate the clinical diagnosis of

Advancing the field and supporting people living with HIV manage HAND What are we doing at St. Michael’s Hospital? If there are most often only mild cognitive impairments in HIV and we know in which areas they occur, why can’t we just ask patients what their problems are, diagnose HAND, and develop a treatment plan? Diagnosing HAND is more complicated than this for three reasons. First, what 14 | IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES

Sean B. Rourke, PhD, FCAHS

FEATURE HAND, particularly the milder forms of HAND. This new knowledge has been very helpful in educating clinicians about the factors in diagnosing and managing HAND. One of the most important clinical issues has been to clarify whether a patient has HAND, signs of major depression, or both since there are different strategies and interventions to address these conditions. We have also been involved in a recent international initiative with leaders in neurology, neuropsychology, psychiatry, primary care, and infectious disease called Mind Exchange. We have developed clinical assessment, diagnostic, and treatment guidelines for HAND that are now available in open access for practitioners. Given that there are few neuropsychological services available to clinicians (we are one of only a few HAND clinics in Canada), we have spent considerable time evaluating cognitive screening instruments that clinicians may be able to use to screen clients for HAND in the clinic. According to a recent systematic review we conducted, most of the existing screening tools are relatively good for detecting the more severe forms of HAND, but they performed poorly in diagnosing milder forms of HAND. In fact, most of the studies done had significant methodological weaknesses, including small samples, poor attention to HAND diagnostic issues, and lack of a proper “gold standard” to compare each screening test against. These findings led us to apply to CIHR to conduct a study now underway to address these weaknesses and provide better guidance on the value and utility of a handful of HAND screening tests that could be used with more confidence in the clinic. We have now enrolled about 150 patients and our results are encouraging. We will soon be testing some new screening tools in development in the US, using validated smartphone iPad applications, that may offer even more flexible ability to assess patients in different environments and contexts.

Living well with HAND and managing a mild brain injury. Shifting the conversation and dialogue to support and health promotion

the lives of people with HIV. In addition to these successful individual approaches, educating and supporting family members or others involved with people who have some form of HAND can help enhance their health.

In most cases, HAND is a mild, manageable brain injury that people living with HIV can learn to respond and adapt to—much like those growing up with a learning disability or those with persistent effects from a mild traumatic brain injury. In addition to managing the virus through cART, one of the most effective interventions for patients with mild HAND is education and support in adjusting to living with a mild brain injury and disability. Having a mild, persistent brain injury can really shake a person’s sense of self and confidence. People often need a lot of support to learn how to adapt to this new condition that has often developed in subtle ways and gone unnoticed by health care practitioners.

There is also evidence that some specific activities stimulate the brain and can improve brain health, including: meaningful social interaction and social support, such as outings and activities with friends and family, reading, learning a new language or skill, enrolling in a university course or cooking class, and playing traditional brain games like Sudoku or completing crossword puzzles. A number of private companies are now developing computer and smartphone-based brain games for those interested in sharpening their cognitive skills. We are currently testing out these brain games in pilot studies in our centre and the results so far are encouraging. Most people who do these interventions report significantly fewer cognitive symptoms, which can have a dramatic improvement in their quality of life. Some also show measurable improvements on our tests. We are now preparing for a larger randomized, control trial that we hope will provide more evidence of the impact of these interventions on improving HAND in people living with HIV.

“There is also evidence that some specific activities stimulate the brain and can improve brain health, including: meaningful social interaction and social support...”

Health promotion strategies are now getting a lot of attention as ways to stop any further cognitive losses and to address any concurrent medical and mental health comorbidities. One of the most effective health promotion interventions starts with a simple statement like: “whatever is good for your heart is often good for your brain.” Activities designed to maintain a healthy heart—such as exercising, eating a healthy diet, getting enough sleep—and addressing harmful habits, such as substance use and smoking—can improve brain health and cognitive abilities. Managing stress, anxiety, and depression can also have a very positive impact on the brain. Treatment for emotional and mental health problems, as well as engaging stress-reducing activities like yoga or meditation, can go a long way in promoting a healthy brain (and heart). Stress-reduction activities are often referred to as “complementary” or “alternative” medicine and recent research has shown they can have a positive overall impact on

In all our work, we are building evidence to improve the diagnosis and management of HAND. While more research is needed, we are definitely on the right path.

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FEATURE

Infectious Disease: “The Human Problem” Interview with Dr. Kevin Kain Kevin C Kain, MD, FRCPC Senior Scientist, Toronto General Research Institute Director, SAR Laboratories, Sandra Rotman Centre for Global Health Science Director, Tropical Disease Unit, UHN-Toronto General Hospital Canada Research Chair, Molecular Parasitology

By Brittany Campbell

f you need to feel inspired to change the world, have a sit-down with Dr. Kevin Kain. The tropical disease expert’s passion for global health is unmistakable. The multi-award winning doctor and researcher has advised for Health Canada, been featured in TIME magazine, and holds a Canada Research Chair in molecular parasitology. Based in Toronto General Hospital, he serves as the director of The Tropical Disease Unit at the University Health Network and the Director of the SAR Labs at the Sandra Rotman Centre for Global Health. Much of Dr. Kain’s work has focused on malaria, but his expertise and on the ground experiences all over the world makes him a most qualified person to talk about the impact of infectious disease on our society today. As it turns out, the most prominent infection in our news is one that could have been contained, but got away, while other infections are being linked to illnesses that we never would have connected before. When Ebola started to make Western headlines, Dr. Kain wasn’t surprised. He believes that the size of the current outbreak is due to failed health systems in low resource settings and a slow and uncoordinated global response. It is known that Ebola is a Class IV virus: transmissible person-to-person, highly lethal, with no vaccine and no specific treatment. Yet it has been systematically ignored while running its course in African countries. “We work in Uganda, there’s been multiple outbreaks in Uganda and the

DRC yet nothing dramatic has happened because it is rural and largely containable,” Dr. Kain explains. A viral hemorrhagic fever decimating African communities should, presumably, raise some concern, given the interconnectivity of today’s world. However, when we could have foresightfully reacted, we didn’t, and we waited until the viral problem intertwined with the human problem. When discussing the spread of Ebola, and any other fast-acting transmissible disease, Dr. Kain says, “it’s often more of a human problem than an infectious disease problem.” Once a virus collides with a densely populated community with poor infrastructure and a floundering health-care system, it is bound to take off. Public mistrust in government authorities understandably exacerbates the problem; if a group of people is constantly betrayed by those who’s job it is to protect them, they likely will not respond in times of crisis. Where was the World Health Organization when Ebola was threatening and containable, but not yet a crisis? Another part of the human problem that Dr. Kain pointed out is our tendency to shift blame away from ourselves when it comes to a number of emerging infectious disease threats, including antimicrobial resistance. We focus squarely on the microbe or virus itself, a squiggly illustration of the molecular structure plastered on magazine covers all over newsstands. Except, contrary to your average Economist headline,

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the bugs are not out to get us. “The microbe, once inside, is usually trying to adapt to you, at least over time. There is no evolutionary pressure for a bug to kill its host, because then it can no longer propagate its gene pool.” Moreover, focusing on the bug detracts from the responsibility we have as humans to reduce our activities that cause them to emerge in the first place and to establish living conditions and health systems that reduce the chances of transmission and spread. “We tend to demonize microbes, when in reality, many of these outbreaks have human fingerprints all over them,” he says. This phenomenon is all over our news outlets, instilling fear in the general public and even going so far as to create hostility towards West Africans.1 Dr. Kain is quick to point out that it’s not just low resource countries that struggle with the ‘human problem’. Here in Canada, the three biggest negative economic impacts have been infectious: Severe Acute Respiratory Syndrome (SARS) took billions of tax-payer dollars out of the economy, the highly infectious avian flu virus led to the culling of millions of poultry, and mad cow disease was a huge hit to Alberta’s beef industry. Infectious outbreaks are a societal eye-opener to the vulnerabilities of our health care system, showing us that even Canada’s famed publicly funded system has its limits. The importance of properly allocating every public health dollar becomes increasingly clear.

FEATURE Dr. Kain is both unique and widely known for his ability to translate scientific findings into dollars and cents. His research focuses on “trying to get the biggest bang out of your public health dollar.” This experience comes from working in resource-constrained communities where they just don’t have resources to waste and want to see “impact” (i.e. preventing disabilities, premature deaths, and dollars wasted) for public investments in health care. The ‘sweet spot’ for these investments is clearly in maternal child health. He contrasts this way of thinking to the health expenditures in the West, where we tend to spend the majority of health resources at the end-of-life. For example, we spend billions of dollars annually on cardiovascular and pulmonary conditions, when the number one cause of preventable death, smoking, is, well, preventable. Is enough being done to promote smoking cessation and to prevent teenagers from starting to smoke in the first place? Similarly, the United States spent an estimated 265 billion dollars last year on Type 2 diabetes, another lifestyle-related and potentially preventable disease. Even a small proportion of these resources directed to diseases of impact in low resource settings could have a profound influence on global health, security, and productivity. “If you only have $10 per year per child for health in low income countries, you want to make sure you maximize the impact and circumvent the biggest risks to your next generation, the one that will ultimately result in the most productive and healthy fu-

ture generation,” he explains. He and other global health researchers refer to this phenomenon as “looking into the future.” The future of the planet is in the hands of the fastest growing populations, where the majority of children are being born, which is, currently, in South Asia and Africa. A major threat to the health and productivity of future generations in all countries is pre-term birth; it is the leading cause of mortality of children under five. Pregnant mothers who acquire an infectious disease are at higher risk for pre-term births. While studying how malaria in particular affects the risk for pre-term birth, Dr. Kain is stumbling upon compelling new data that challenges the way we perceive a number of diseases. In any ‘Intro to Global Health’ class, we learn that there are two main types of disease: communicable and non-communicable, where one has the ability to spread from person to person, and one, presumably, does not. However, in studying how malaria affects pregnancy outcomes, it appears that children born to moms who had malaria during pregnancy may be at increased risk for affective disorders and neurocognitive deficiencies. For the first time ever, evidence is suggesting that infections acquired during pregnancy may increase the risk of mental illness in exposed offspring; linking “communicable” and “non-communicable” illness in novel ways and providing intriguing new avenues to prevent mental illness.2

laria. Treating mental illnesses is notoriously difficult and creates an enormous financial stress on Ontario’s health care system. Dr. Kain and his lab are working on finding simple, safe, and inexpensive interventions that protect the unborn in nations where malaria and other infections run rampant. He believes that focusing resources to that critical 9-month period could have a huge payoff for global health and contribute to a lifetime of healthier, more productive people and populations. He also believes that the affordable solutions that work in low resource settings will also impact the west, since these advances may well get retrofitted into our health care systems, so we can invest more wisely in our own population’s health. Dr. Kain’s work shows health researchers that examining and circumventing risk in early life should be a priority all over the world.

References: 1. Sack K, Fink S, Belluck P, et al. How Ebola Roared Back. New York Times. 30 Dec 2014. Available from: http://www.nytimes. com/2014/12/30/health/how-ebola-roared-back.html 2. McDonald CR, Elphinstone RE, Kain KC. The impact of placental malaria on neurodevelopment of exposed infants: a role for the complement system? Trends Parasitol. 2013;29(5):213-19. 3. Parboosing R, Bao Y, Shen L, et al. Gestational influenza and bipolar disorder in adult offspring. JAMA Psychiatry. 2013;70(7):677-85.

An interesting series of experiments are being performed in Dr. Kain’s lab to test this in model systems. Pregnant mice that survive infection and carry to term have pups that perform poorly in neurocognitive tests originally designed for Alzheimer’s mouse models. Despite the full-term pregnancy and normal birth weight, the mice are hyperactive with altered neurotransmitter levels. Similarly, another study in humans followed the children of mothers exposed to influenza during pregnancy and found them to be four-fold more likely to develop bipolar disorder.3 Mental illnesses still have a significant genetic component, but “exposure in utero may be a second hit that alters your neurological capacity to handle later life stressors.” The notion that moms can ‘catch’ an infection that might increase the risk of mental illness creates an urgency to prevent the disease, whether it’s the common flu or maIMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 17

By W. Monty McKillop and Jeffrey A. Medin University Health Network Vector Core Facility Manager Dr. William M. McKillop (Center) with Lead Production Operators Nadejda Andreev (Left) and Cesar Moncada

Lentiviral Vector-Mediated Cancer Immunotherapy Retroviridae in cancer immunotherapy

he Canadian Cancer Society reports that almost 30% of all deaths in Canada are attributed to cancer, making it the most likely cause of death in the country. One therapeutic strategy with significant potential for the treatment of cancer is the use of viral vector-mediated gene therapy. The exceptional ability of viruses to infect human cells can be harnessed to deliver therapeutic genes rather than pathogenic genes. Gene therapy laboratories are currently employing cutting-edge recombinant Retroviridae vectors to convey long-term expression of therapeutic DNA in the targets cells. Such an approach may allow for the treatment of a variety of cancers. In 2000 the first successful clinical trial using γ-retroviruses to treat (SCID)-X1 disease in children was reported in the journal Science.1 In 2006 another clinical trial made use of a recombinant γ-retrovirus to alter the T-cell receptor so as to target cancer cells for the treatment of melanoma.2 Although these early studies proved encouraging, their success was somewhat marred due to the finding that γ-retrovirus treated patients display increased activation of nearby protooncogenes, which has since been attributed to γ-retroviral gene insertion.3 Retroviridae family members integrate throughout the genome, but whereas γ-retroviral vectors preferentially integrate near active host cell promoters and enhancers, regions rich with oncogenes, lentiviral vectors (LV), another member of the Retroviridae family, do not share this integration bias.4 LVs are also more efficient at transgene delivery as γ-retrovirus requires the target cell to undergo cell division for viral DNA to enter the cell nucleus, whereas LVs transport their DNA through intact nuclear membrane and thus can target non-dividing cells as well.5 Clinical-grade LVs can also be

produced at a higher, more useful, titer than can recombinant γ-retroviral vectors.3 Thus, it is not surprising that in recent years LVs have emerged as a potentially superior gene therapy delivery method.

Safety features for LV-mediated gene therapy

The LV genome has been modified to increase its utility and maximize safety for use as a gene therapy vehicle. The viral genes causing disease in humans are removed from LV vectors and are replaced with the therapeutic transgene of interest. The LVs generated are replication-deficient due to the deletion of required viral genes.6 This reduction in viral genes also reduces immunogenicity and the possibility of recombination with a host virus leading to production of replication-competent LVs.7 The viral genome has also been altered to improve nuclear transport and successful proviral integration by including a central polypurine tract (cPPT)8 and to increase transgene expression by the addition of the woodchuck hepatitis B virus posttranscriptional regulatory element (WPRE).9 LVs can also be engineered to contain an inducible promoter so that transgene expression can be turned on or off by the addition of an exogenous additive such as an antibiotic.10 In this manner the over-expression of the transgene of interest can be modulated to mitigate any unwanted side effects that may result from treatment. LVs can also be designed to contain a cell death or ‘suicide’ cell-fate control transgene that would bring about the selective elimination of LV-transduced cells following their administration to the patient. For example, the Medin laboratory in IMS (University Health Network) has developed a novel patented cell-fate control gene based on a modified human Thymidylate Kinase (TMPK) enzyme.11 Its TMPK system acts in the pathway converting an exogenous drug azidothymidine (AZT) to its toxic form

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AZT-triphosphate, allowing for inducible programmed cell death on administration of AZT. The results of these genome modifications are LV particles yielding increased safety, infectivity, and therapeutic transgene expression.

Current application of LVs to cancer immunotherapy:

The immune system seeks out and removes the threat posed by invading infectious organisms and dying cells. It also eliminates transformed cells. Modulation of the immune system so as to stimulate or enhance an anti-tumor response is becoming an important conceptual strategy to fight cancer. LVs can be used to present a tumor-associated antigen (TAA) target to the immune system and then stimulate the immune response against that target. One of the antigen-presenting cells (APCs) capable of inducing a strong proinflammatory immune response is the dendritic cell (DC). DC-based anti-cancer treatments use a sample of the patient’s own DCs loaded with TAA and re-infused into the patient to induce the desired anticancer immune response.12 Conventional methods of loading DCs with antigen ex vivo generally result in short-term antigen presentation, preventing a long-term immune response. The transduction of DCs with viral vectors can result in continuous expression of the tumor-associated protein, allowing the DC to process and present that antigen for a longer period of time. Loading DC with TAA is effective at activating cellular and humoral immunity and providing prophylactic protection against specific prostate13 and liver14 cancer tumor challenges, as well as the treatment of melanoma15 in pre-clinical mouse models. Autologous T-cell therapies show promise for treating cancer, however one of the primary problems with such treatment schemas is an inability to generate a

FEATURE significant number of expanded T-cells that maintain their anti-cancer specificity. To generate optimally-effective T-cells for adoptive immunotherapy, artificial APCs (AAPCs) have been developed. A leukemia cell line, K562, has been converted into an AAPC by LV transduction with 2 costimulatory molecules; CD80 and 4-1BBL. Incubation with these AAPCs resulted in 10000-fold expansion of CD8+ T-cells ex vivo, a significant improvement over other methods.16 It is also possible to circumvent antigen presentation entirely and directly alter autologous T-cell receptor complexes for adoptive transfer. Bicistronic LVs can infect and co-express both the α and β T-cell receptor subunits from the same virus in the same T-cell.17 Clinical trials using this technology to target cancer are currently underway.18 Unfortunately cancer cells employ a method to naturally avoid T-cell recognition. T-cells naturally recognize antigens processed by APCs and presented on MHC molecules. Cancers can down-regulate their MHC (HLA) expression. Chimeric antigen receptors (CARs) have been developed to provide MHC-independent immunity. CARs consist of recombinant polypeptide sequences that assemble into an elongated single-chain antibody on the surface of target effector cells. The CAR extracellular domain binds to a specific TAA on the surface of tumor cells while the intracellular domain activates or enhances the immune cell’s cytolytic and expansion capabilities.19, 20 LV engineered expression of a chimeric antigen receptor targeted against CD19 proved efficient against B cell lymphoma and leukemia.21, 22 In pre-clinical studies LV expressing a CAR targeting CD44V6 is being explored for immunotherapy against acute myeloid leukemia and multiple myeloma.23 There are also many CARs currently being developed to target other TAAs in both solid and hematopoietic cellbased cancers. Another of the difficulties in combating cancer is that the body’s immune system does not normally target its own cells. Many cancer cells display TAAs that distinguish them from healthy cells but - as these are still self-antigens - the immune system may not act on that recognition. LVs can be used to stimulate these cancerous cells to also express co-stimulatory factors that will promote an anti-cancer response that otherwise might not occur. This treatment

modality has demonstrated pre-clinical success in the treatment of leukemia. As an example, an IL-12 producing autologous tumor cell vaccine treatment has shown promise as an anti-cancer agent. Injection of mouse leukemia cells transduced with LV expressing IL-12 results in rejection of both the injected IL-12 producing leukemia cells as well as endogenous non-transduced leukemia cells.24 This treatment paradigm also demonstrated effectiveness in the clearance of solid tumors in mice.24 When a squamous cell carcinoma cell line was injected subcutaneously into the flanks of mice, it readily developed into a solid tumor mass. When engineered to express IL-12 by LV-mediated transduction, elimination of not only the injected IL-12-producing sarcoma cells but also non-transduced squamous cell carcinoma cells resulted.24 Similar observations were reported with three additional solid tumor models, osteosarcoma, prostate cancer, and Lewis lung carcinoma, indicating the broad utility of this immunotherapeutic approach.25 As can be seen, LV-mediated gene therapy treatments have shown promise preclinically and in the clinic for a wide range of cancer treatments, and new viral vectorbased treatments will undoubtedly follow.

Custom LV production at University Health Network in Toronto

UHN currently has a state-of-the-art LV production facility in the Krembil Discovery Tower at the Toronto Western Hospital. This Vector Core Facility opened in Fall 2013. It is headed by W. Monty McKillop and offers comprehensive LV production packages including custom gene therapy transgene design and synthesis, LV packaging, LV purification, concentration, and delivery of high titer vectors. Specialized LVs can be made with bi/tricistronic orientations that introduce 2 and even 3 transgenes into a cell at the same time. As well, potent tissue-specific promoters or vector pseudotypes can be selected to effect expression in alternative target cells or tissues. Further, transgenes of interest can be generated in a codonoptimized format to potentially achieve the highest level of expression. Therefore, non-integrating LVs can also be created. The staff is always open to discussing new projects and is looking forward to serve the community’s need for high titer custom LV. In early 2015 the Vector Core Facility will begin production of adeno-associated

virus (AAVs), viral particles well-suited to nervous system gene therapy and cancer immunotherapy applications due to their inherently small size, minimal induction of an immune response, ability to infect both dividing and quiescent cells, and persistence in an extrachromosomal state without integration into the genome of the host cell. If you have a project you would like to discuss with the Vector Core Facility they can be reached by e-mail at info@ uhnvectorcore.com. References: 1. Cavazzana-Calvo, M., et al., Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science, 2000. 288(5466): p. 669-72. 2. Morgan, R.A., et al., Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 2006. 314(5796): p. 126-9. 3. Persons, D.A., Lentiviral vector gene therapy: effective and safe? Mol Ther, 2010. 18(5): p. 861-2. 4. Felice, B., et al., Transcription factor binding sites are genetic determinants of retroviral integration in the human genome. PLoS One, 2009. 4(2): p. e4571. 5. Bukrinsky, M.I., et al., A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature, 1993. 365(6447): p. 666-9. 6. Zufferey, R., et al., Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol, 1998. 72(12): p. 9873-80. 7. Zufferey, R., et al., Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol, 1997. 15(9): p. 871-5. 8. Sirven, A., et al., The human immunodeficiency virus type-1 central DNA flap is a crucial determinant for lentiviral vector nuclear import and gene transduction of human hematopoietic stem cells. Blood, 2000. 96(13): p. 4103-10. 9. Zufferey, R., et al., Woodchuck hepatitis virus posttranscriptional regulatory element enhances expression of transgenes delivered by retroviral vectors. J Virol, 1999. 73(4): p. 2886-92. 10. Gossen, M., et al., Transcriptional activation by tetracyclines in mammalian cells. Science, 1995. 268(5218): p. 1766-9. 11. Sato, T., et al., Engineered human tmpk/AZT as a novel enzyme/ prodrug axis for suicide gene therapy. Mol Ther, 2007. 15(5): p. 962-70. 12. Nestle, F.O., et al., Vaccination of melanoma patients with peptideor tumor lysate-pulsed dendritic cells. Nat Med, 1998. 4(3): p. 328-32. 13. Mossoba, M.E., et al., Tumor protection following vaccination with low doses of lentivirally transduced DCs expressing the self-antigen erbB2. Mol Ther, 2008. 16(3): p. 607-17. 14. Wang, B., et al., An effective cancer vaccine modality: lentiviral modification of dendritic cells expressing multiple cancer-specific antigens. Vaccine, 2006. 24(17): p. 3477-89. 15. Metharom, P., et al., Lentiviral vector-mediated tyrosinase-related protein 2 gene transfer to dendritic cells for the therapy of melanoma. Hum Gene Ther, 2001. 12(18): p. 2203-13. 16. Suhoski, M.M., et al., Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules. Mol Ther, 2007. 15(5): p. 981-8. 17. Jones, S., et al., Lentiviral vector design for optimal T cell receptor gene expression in the transduction of peripheral blood lymphocytes and tumor-infiltrating lymphocytes. Hum Gene Ther, 2009. 20(6): p. 630-40. 18. Chodon, T., et al., Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res, 2014. 20(9): p. 2457-65. 19. Finney, H.M., A.N. Akbar, and A.D. Lawson, Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol, 2004. 172(1): p. 104-13. 20. Imai, C., et al., Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia, 2004. 18(4): p. 676-84. 21. Porter, D.L., et al., Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med, 2011. 365(8): p. 725-33. 22. Grupp, S.A., et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med, 2013. 368(16): p. 1509-18. 23. Casucci, M., et al., CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood, 2013. 122(20): p. 3461-72. 24. Labbe, A., et al., IL-12 immunotherapy of murine leukaemia: comparison of systemic versus gene modified cell therapy. J Cell Mol Med, 2009. 13(8B): p. 1962-76. 25. Wei, L.Z., et al., Localized interleukin-12 delivery for immunotherapy of solid tumours. J Cell Mol Med, 2013. 17(11): p. 1465-74.

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VIEWPOINT

The Utility of Homeopathy in the Era of Evidence Based Medicine By Mirkamal Tolend

omeopathy is guided by the principle that small doses of a substance that elicits a symptom in healthy patients can be effective in treating diseases that produce that same symptom.1 This “like-cures-like” principle is akin to using caffeine to treat insomnia. The main rationale is to stimulate the body’s own healing capabilities with homeopathic preparations of these otherwise pathological stimuli. One may see that the guiding principle of homeopathy resembles vaccinations, or more precisely, variolation, an obsolete practice in which patients were inoculated with small amount of smallpox virus that caused a mild but immunoprotective infection. This is the closest the two fields may come to converging, but ironically, homeopaths are often against vaccinations, and the analogy itself is also invalid. Firstly, variolation and vaccines in general can only play a preventative role, whereas homeopathic remedies claim to work in both preventative and curative treatments. The mechanism of action is also different: vaccines work by mounting a lasting and measurable immune response in the host, which is not detectable when homeopathic remedies are administered. Another difference that is much harder to reconcile–and often considered the last word in discrediting homeopathy–is that homeopaths maintain that their drugs increase in potency with further dilutions.1 Homeopathic drugs are often prepared using dilution factors ranging from orders of 103 to 10400 of their initial stock concentrations. While it is true that non-monotonic dose-response curves have been observed for some endocrine disruptor molecules,2 the effects have never been as significant or generalizable as claimed in homeopathy. Not only does this idea directly contradict basic biochemical principles, but ultradilutions run into a very real physical problem often dubbed as the “Avogadro’s Limit.” Avogadro’s constant, 6.023x1023, is defined as the total number of constituent particles, such as atoms or molecules, in one mole of that substance. The value of this physical constant is corroborated by several inde-

pendent methods, and is widely accepted. Serially diluting 1mol/L of anything down to 10-24 will give a 60% chance of finding a single starting particle in the diluted 1L solution. Since most homeopathic pills are prepared using no more than a drop of diluted solution, and many compounds are diluted down to 10-400, it is hard to deny that homeopathic remedies do not contain any molecule of the active ingredient. Homeopaths are well aware of this limitation, and argue that during the homeopathic dilution process, which involves vigorous shaking and slamming against an elastic plate at each serial dilution step (termed “succussion”), some spirit-like property of the substance becomes imprinted in the solvent molecules. Even after the last molecule of the substance is gone, the imprinted memory is thought to cause a physiological change. This is highly implausible, given that it contradicts many of the basic physical and biochemical principles that are at the foundation of effective modern-day treatments. Elaborate suggestions have been proposed over the years to support this imprinted memory effect. One group claims that ultradilutions still contain the original substance due to surface effects, 3 while others explain the imprinted memory effect by the epitaxy process (the transfer of structural orientation information from the solute to solvent), which leads to the presence of colloidal nanobubbles that contain active ingredients.4 One study has even detected the presence of nanoparticles of the starting ingredients using advanced imaging techniques.5 Even if these observations are valid, (for critiques, see6,7) their biological significance would still need to be established. It is not constructive to reject the possibility that technological limitations prevent us from detecting the homeopathic mechanisms of action. But it is also not ethical to hold onto a theory if it neither conforms to the current body of knowledge nor reliably predicts nature in experiments or observational studies. Randomized controlled trials and meta-analyses examining homeopathy’s effectiveness do not reliably illustrate an improvement over placebo,8,9

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and even positive results are often weak and infrequent.10,11 Studies confirming the effects of homeopathy are conducted with serious design flaws, including biased sample selection and outcome measurements, absent or ineffective controls and blinding, ineffective randomization, insufficient sample sizes, and publication bias. The burden of proof still rests on the homeopaths. With the current evidence base, it cannot be concluded that homeopathy is better than placebo for any indication. Despite the lack of evidence, homeopathy is still practiced in Ontario. As of November 2014, there are 258 homeopaths registered with the Ontario Homeopathic Association. Currently, homeopathic practice in Ontario is regulated at the provincial level by the Regulated Health Professions Act 1991 and the Homeopathy Act 2007. To assess the effectiveness of the homeopathic product, the product licensing agency accepts various types of evidence ranging from high quality systematic reviews of randomized controlled trials, all the way down to opinion reports, and references to traditional use. The government’s respect for freedom of choice and cultural diversity has kept assessment standards low–which, along with the scarcity of positive evidence in peer-reviewed medical literature–suggests that the majority of registered homeopathic products were approved based on low quality evidence. Nevertheless, all natural health products are prohibited from claiming to treat any condition listed under Schedule A of the Food and Drugs Act, which include acute or serious conditions such as congestive heart failure and cancer. Any homeopathic drug diluted outside the 10-24 to 10-60 range is also prohibited from carrying specific recommended indications, unless the safety profile is established. Why homeopathy persists alongside evidence-based medicine is a loaded question. The harsh reality is that not all patients’ chronic symptoms can be managed by mainstream medicine, and some will inevitably seek alternative medicine, perhaps justifiably so. Moreover, the general patient population may be gullible enough to accept the rationale of homeopathy and

VIEWPOINT believe in its claims. Selective and uncritical media coverage of positive study findings, including buzz words like “nanoparticles,” attractiveness of the natural sources for the remedies, and our acceptance of cultural diversity will also help maintain public interest. Since homeopathy is here to stay, perhaps it is more constructive for mainstream medicine to make amends with it. With an open mind, we may even justify homeopathy as an elaborate, spiritualistic form of placebo. It is easy to forget that patients do not have access to placebo treatments outside the research setting. Physicians, in an effort to maintain their patient’s trust and to avoid ethical and legal ramifications, may be reluctant to prescribe placebos themselves. Recent meta-analyses show that the placebo effect is a significant part of the mainstream medical treatments’ effectiveness, especially for psychologically experienced conditions such as pain12 and depression.13 Placebo can not only be effective, but may even be better than the alternative drugs in certain cases. For instance, patients undergoing chemotherapy may experience pain or fatigue that cannot be managed adequately with standard drugs. For these patients, seeking homeopathy may be an alternative to more potent drugs, because it would not be expected to cause adverse events or interact with chemotherapy.14 There is definitely a lack of evidence to recommend homeopathy over placebo in reducing these persistent symptoms, but if it is found to be non-inferior to placebo and more effective compared to no treatment, then perhaps homeopathy shouldn’t be discouraged. The four classic principles of medical ethics need to be considered when assessing homeopathy’s utility as a placebo. The first principle, respect for autonomy, is most problematic for homeopathy and prescribing placebos in general. The principle implies that homeopaths must not make unsupported claims about their remedies in order to allow for informed patient consent. Prescribing placebo through the traditional system involves complete deception, but the homeopathic deception is a relatively grey area. Uncertainties in the medical literature, and the lowered standards that assess the evidence base for homeopathic remedies may justify the suggestive claims by the homeopaths, and still allow for consent that is as informed as possible.

Moreover, the unsuspecting general public might give homeopathy the benefit of the doubt, depending on their satisfaction with mainstream medicine. Compliance with the second principle of medical ethics, beneficence, may have been high at homeopathy’s inception in the 18th and 19th centuries, when sham remedies were certainly better than bloodletting and purging. Nowadays, the benefits are limited to the unpredictable effects of placebo, which may still benefit some patients. Non-maleficence, the third principle, uncovers important issues. Adverse events from homeopathy are unlikely,12 especially compared to other forms of alternative medicine. However, if seeking homeopathic care either delays or interferes with the delivery of available and effective mainstream care, then homeopathy would have done harm. The Ontario Health Insurance Policy does not cover homeopathic or other alternative medicine expenses, which might serve as a financial deterrent to mitigate this problem. More population based research (such as15) is needed to assess whether homeopathy is affecting mainstream medicine and whether high-risk patients groups are being exploited. Fourth and finally, the justice principle, which advocates equal access to healthcare resources, is probably more applicable in regions such as Europe, where homeopathic care is partly funded by some governments. Formation of the new regulatory college for homeopathy in Ontario is anticipated within the next few years, which may further help protect the public interest. Alternative forms of medicine will always persist for reasons beyond scientific rationality. Perhaps no number of negative clinical trials will change this. At present, homeopathy is what appears to be the best of the alternatives, solely for its low risk and potential as a more practical placebo. Until plausible mechanisms of action are corroborated in basic science studies of homeopathy, our limited research resources should focus on studying motivations for its use, rather than trying to establish its effectiveness against placebo in clinical trials. At the public health level, the current safeguards are important, and need to be continually monitored and refined. Public awareness of regulations already in place should be promoted so that patients stay vigilant while using homeopathy. Both policy-makers and the public will benefit from research efforts aimed at studying the pattern of use of

homeopathy, and finding better strategies to refine its utility as placebo. Qualitative methodologies to examine the sources of dissatisfaction within the mainstream medicine may be helpful in identifying areas for improvement, which may also help shape the use of alternative medicines to maintain a safe and effective delivery of care. References 1. Hahneman S, Organon of Medicine. Germany: W.F. Wakeman: Germany; 1833. Available from: http://www.homeopathyhome.com/ reference/organon/organon.html 2 . Andrade AJ, Grande SW, Talsness CE, et al. A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl)-phthalate (DEHP): non-monotonic dose-response and low dose effects on rat brain aromatase activity. Toxicology. 2006;227(3):185-92. 3. Chatterjee BK. The mathematics of dilution. Homeopathy. 2014 Apr;103(2):143-6. 4. Rao ML, Roy R, Bell IR, et al. The defining role of structure (including epitaxy) in the plausibility of homeopathy. Homeopathy. 2007 Jul;96(3):175-82. Erratum in: Homeopathy. 2007;96(4):292. 5. Chikramane PS, Suresh AK, Bellare JR, et al. Extreme homeopathic dilutions retain starting materials: A nanoparticulate perspective. Homeopathy. 2010;99(4):231-42. 6. Kerr M, Magrath J, Wilson P, et al. Comment on “The defining role of structure (including epitaxy) in the plausibility of homeopathy”. Homeopathy. 2008 Jan;97(1):44-5; author reply 45-6. 7. Journal Club – “The definin g role of structure (including epitaxy) in the plausibility of homeopathy”. [Forum on the Internet]. Bad Science; 2015 [updated 2010 Dec 22; cited 2014 Dec 18]. Available from: http:// www.badscience.net/2000/01/journal-club-the-defining-role-of-structure-including-epitaxy-in-the-plausibility-of-homeopathy/ 8. Linde K, Clausius N, Ramirez G, et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet. 1997;350(9081):834-43. Erratum in:Lancet 1998 Jan 17;351(9097):220. 9. Shang A, Huwiler-Müntener K, Nartey L, et al. Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet. 2005;366(9487):726-32. 10 . Kassab S, Cummings M, Berkovitz S, et al. Homeopathic medicines for adverse effects of cancer treatments. Cochrane Database Syst Rev. 2009;(2):CD004845. 11. Mathie RT, Lloyd SM, Legg LA, et al. Randomized placebo-controlled trials of individualized homeopathic treatment: systematic review and meta-analysis. Syst Rev. 2014;3(1):142. 12. Puhl AA, Reinhart CJ, Rok ER, et al. An examination of the observed placebo effect associated with the treatment of low back pain - a systematic review. Pain Res Manag. 2011;16(1):45-52. 13. Rief W, Nestoriuc Y, Weiss S, et al. Meta-analysis of the placebo response in antidepressant trials. J Affect Disord. 2009;118(1-3):1-8. 14. Dantas F, Rampes H. Do homeopathic medicines provoke adverse effects? A systematic review. Br Homeopath J. 2000;89 Suppl 1:S35-8. 15. Williams AM, Kitchen P, Eby J. Alternative health care consultations in Ontario, Canada: A geographic and socio-demographic analysis. BMC Complement Altern Med. 2011;11:47.

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VIEWPOINT

CELEBRITIES and the stigma surrounding

MENTAL HEALTH By Rebecca Ruddy

he stigma surrounding mental illness is a

major problem and still exists despite

millions of people worldwide suffering from some form of mental illness. The mainstream media can definitely play a large role in perpetuating or reducing this stigma. One question that I would like to address is: How is the media coverage of celebrities with mental illnesses perpetuating or relieving the stigma surrounding mental health issues? An interesting article published by the Globe and Mail in 2012 began to briefly address this issue.1 In this article, the author introduced several points as to how celebrities speaking about their mental illnesses can contribute to the existing stigma. I will attempt to both add to and expand on these points. First, it is argued that celebrities “don’t represent the average person with a mental illness.”1 This is true. Celebrities typically have more money and therefore more resources at their disposal. They have the ability to seek out the best possible doctors and take time off to seek treatment. This might set up an unrealistic image of the illness and how it affects an individual’s life. Second, the article mentions that celebrities are often not as seriously ill as people in the general public and that their illness can be improved with a simple weekend getaway. However, I find that this is a potentially harmful generalization. We cannot assume to know the seriousness of the mental health issues of these celebrities and while the article goes on to list the names of celebrities who have died from their illness, it still gives the impression that mental health issues of celebrities are not as severe as those of the general population. Thus, in some cases, the media does a disservice to the public by reporting

stories about celebrities being treated for mental illness over a weekend getaway. Such reports give the impression that a short retreat is all that is needed to “fix” the mental disorder. Unfortunately, this is not the case for the majority of individuals who cope with their mental illness on a daily basis and will continue treatment for the rest of their lives. Third, this Globe and Mail article states that celebrities are able to discuss their experience with mental illness without fear of losing their job or being treated differently by friends and family. However, I feel that this may also be a generalization. While it is likely true that they are not

“It is troubling that celebrities are praised as courageous and heroes for speaking openly about their mental illness ...” at risk of losing their job after speaking publicly about their mental illness, people in their private lives or in the public may still develop a prejudice against them. Hence these famous individuals are not immune to the stigmatization surrounding mental illness simply because they are celebrities. In addition, it is unfair to say that because of their status, their friends and family would be more understanding or accepting than those of the average person. The Globe and Mail article moves on to discuss the positive aspect of celebrities

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speaking openly about their mental illness. It states that by celebrities discussing mental illness, it demonstrates that nobody is immune to mental illness. In addition, it may lead somebody suffering from mental illness to seek treatment. It is troubling, however, that celebrities are praised as courageous and heroes for speaking openly about their mental illness, while everyday people may have to deal with more discrimination and alienation for disclosing their mental disorder.2 One of the positive aspects of celebrities being willing to discuss their experience with mental illness is that they not only bring awareness to the disease but also become a role model to so many people who are suffering. People may find comfort in the fact that they are not alone and that somebody else is coping with a similar disease. Indeed, it takes a great deal of courage to admit to having a mental illness due to the ever‐present stigma despite the fact that they are celebrities. In addition, seeing celebrities that continue to cope with their mental illness and lead a normal life can bring hope to sufferers of the disease. Another positive aspect of celebrities who are open about their struggle with mental illness is that celebrities can use their mental illness and their fame as a platform to let people know they are not alone in their fight. Several celebrities have spoken candidly about their experience with mental illness and have gone on to be ambassadors for various causes. Demi Lovato, an American actress and singer, has spoken openly about her struggle with an eating disorder and bipolar disorder.3 She has founded the Lovato Treatment Scholarship to fund treatment for people

VIEWPOINT suffering from mental illness and has spoken in Washington about health‐care reform.3 Six‐time Olympic medalist Canadian Clara Hughes has spoken about her battle with depression and has used her experience to help others.4 In fact, Clara Hughes is now the spokesperson for Bell Canada’s Mental Health Initiative and Let’s Talk campaign.4 In addition, American actress Glenn Close founded a non‐profit organization called, “Bring Change 2 Mind” (bringchange2mind.org). This organization works to put an end to the stigma and discrimination associated with mental illness. In instances like these, celebrities are definitely helping in the fight against the stigmatization of mental illness by raising awareness and funds for this cause. Unfortunately, not all media attention regarding celebrities and mental illness is used for a good cause. The intense media coverage of celebrities who are suffering from untreated mental illness is a major problem. The media often uses people to sell magazines or increase viewership, but when it involves a celebrity suffering from mental illness it goes beyond an invasion of privacy and seems cruel. The

media tends to make a spectacle of an individual’s personal battle with mental illness, depicting it as funny and using it as entertainment. This has been the case with the most recent media coverage of Amanda Bynes who has been put on a psychiatric hold. This was also true a few years ago when Britney Spears struggled with mental health issues under the spotlight of the media. It is truly sad that the discussion about mental illness in the media usually occurs after it is too late. For example, following the death of Robin Williams in August 2014, several articles were written about depression and the need to have a bigger discussion on the topic, but why couldn’t these conversations have happened before this tragedy? Why can’t the discussion about mental health be an ongoing, evolving and meaningful conversation that can help people suffering from different mental illnesses and help end the stigma that surrounds them? Several celebrities who have been diagnosed with certain mental health illnesses have decided to use their experience and celebrity as a platform to

raise awareness and educate the public on mental health issues. It is these celebrities that help to eliminate the stigma and promote resources that are available to those currently suffering from mental illness without treatment. It is important to raise funds and awareness in order to end the stigma and discrimination surrounding mental illness. It is also necessary and important to start a dialogue about available resources and treatments. The media needs to stop focusing on looking at the entertainment value of celebrities suffering from mental illness and instead use it as an opportunity to start meaningful conversations about ending the stigma and empowering people with mental illnesses to seek treatment.

References 1. Stuart H. Do celebrity disclosures promote mental illness stigma? The Globe and Mail. 2012 Nov 30. Available from: http://www.theglobeandmail.com/globe‐ debate/do‐celebrity‐disclosures‐promote‐mental‐illness‐ stigma/article5822024/ 2. Robertson S. How Celebrity Hurts the Mental Helath Cause. Huffington Post. 2013 Jul 19. Available from: http://www.huffingtonpost.ca/ sarah‐ robertson/mental‐health‐celebrity_b_3621220.html 3. Kielburger M, Kielburger C. Celebrities and mental health: It’s time to transform pop culture stereotypes. 2014 Oct 28. Available from: http://o.canada.com/entertainment/celebrity/celebrities‐and‐mental‐health 4. Clara Hughes [homepage on the Internet]. c2015. Available from: http://clara‐ hughes.com/

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EXPERT OPINION

Psychotherapy: an effective treatment for mental illness By Ayda Ghahremani

ental illness is a serious public health issue with considerable impacts on individual patients with respect to symptoms, quality of life, and disability. Mental illness also affects society as a whole and the World Health Organization has recognized its importance as an under-addressed global health problem1. Over the past 50 years, numerous attempts have been made to develop more effective treatments for psychiatric disorders. These treatment developments include both medications and psychotherapies. Psychotherapy treatments for major mental disorders have been established as highly effective through rigorously conducted randomized control trials leading to their inclusion in consensus treatment guidelines.

sychotherapy is a talking-based treatment provided by a trained healthcare professional that may be a psychiatrist, psychologist, or other mental health professionals such as licensed clinical social workers. During face-to-face sessions, patients can gain an understanding of their thoughts, feelings and behaviours and find ways to manage their symptoms and stressors. Although there are numerous differing types of psychotherapy, such as cognitive behaviour therapy (CBT)2 and interpersonal psychotherapy (IPT)3, these

differing treatment models share important common factors such as the therapeutic alliance, which refers to the patient-therapist relationship. A therapist empathically connects with the patient and develops a shared understanding of the patientâ&#x20AC;&#x2122;s problem. For the therapist, to provide an effective treatment, it is necessary to make sure that the patient feels psychologically safe and that a solid therapeutic alliance has been established. The goals of psychotherapy are just the same as the goals of all medical treatments to help the patient feel and function better. We are at a very exciting time in the history of the treatment for mental health problems, since we have increased treatment options with the accumulated evidence on the efficacy of different psychotherapy techniques.

Two Psychotherapy Treatment Models One commonly used psychotherapy technique is CBT. The theory of CBT is based on thoughts, feelings and behaviours and their bidirectional relationships. The main

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concept of CBT is that the way we think affects our feelings and behaviours and, reversibly, the way we behave affects our feelings and thoughts. For example, consider we see a familiar person walking by without saying hello. We might have automatic thoughts and core beliefs about our sense of self-worth or the judgments of others, and feel downcast. In fact, our interpretation of such situations causes problems, not originating from the situations themselves. This illustrates the core concept of CBT and the role of the psychotherapist is to detect and help change patients to modify their automatic thoughts. Changes in thoughts and the way one appraises an experience can lead to significant changes in feelings and associated improvements in symptoms. CBT is offered to patients with mental health disorders including depression and anxiety disorders. CBT consists of face-toface sessions of approximately an hour between a patient and a therapist. Research studies have shown that CBT can be very

EXPERT OPINION effective in the treatment of depressive symptoms and considered as a first line treatment, an adjunctive treatment with medication, or an alternative to anti-depressant drugs in treatment-resistant cases.4 Furthermore, unlike medications, CBT can have long-lasting effects, decreasing the risk of relapse, even long after the active treatment sessions have concluded.4 CBT is also effective in psychosis. For example, in schizophrenia, CBT for psychosis leads to significant reductions in delusional distress and abnormal social behaviours, according to a randomized control trial.5 Other than CBT, IPT has also been established as an effective depression treatment validated by meta-analyses and randomized control trials. This therapy also involves face-to-face sessions between a patient and a professional therapist. The core idea behind IPT is the importance of relationships and managing interpersonal stressors associated with the onset or perpetuation of symptoms. IPT classifies stressors into broad categories of losses, changes and conflicts that can occur in the contexts of bereavement, significant social role transitions or marital disagreements. One prominent difference between IPT and CBT is that whereas CBT addresses internal cognitions, IPT addresses interperson-

al relationships and external psychosocial aspects of mental health and well-being. Research studies have shown the efficacy of IPT was superior to placebo, wait-list controls, and other active treatments in randomized control trials for depressive spectrum disorders.6

Neuroscience Links Psychotherapy to the Brain Research in psychotherapy is not limited to clinical research outcome studies testing the efficacy or effectiveness of treatment models. Understanding their mode of action has been facilitated through research on the mechanisms of these treatments and relies on new discoveries of neuroscience. Neuroscience has advanced over the last two decades by bridging complex functions of the human brain such as cognition, motivation, and relational behaviours to the physical brain systems. This has been facilitated by the development of neuroimaging techniques in measuring brain activities in real-time, such as functional MRIs or PET scans. During scans, person’s brain activity is observed, while performing specific tasks that engage their cognition, emotions, and motivations. For example, using this technique, brain scans of patients with anxiety disorders were obtained before and after CBT. In the treatment responders group, specific changes were revealed in the brain systems, specialized for regulation of negative emotion and fear extinction.7 Moreover, CBT is hypothesized to improve major depressive symptoms in depression by changing the activity of brain systems involved in emotions and cognition.8 However, we are still far from distinguishing different psychotherapy techniques and their exact mechanisms of actions in the brain. More research discoveries are needed to elucidate the neuroscience of psychotherapy that can help in the design of more strategic treatments in future.

References 1. World Health Organization. Mental health: a call for action by world health ministers. Geneva: World Health Organization, 2001.; 2001. Available at: http://www.who.int/entity/mental_health/media/ en/249.pdf. 2. Beck AT. Cognitive therapy and the emotional disorders.; 1976:356. doi:10.1016/S0005-7894(77)80293-1. 3. Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES. Interpersonal psychotherapy of depression.; 1984:342–351. doi:10.1192/ apt.bp.109.007641. 4. Driessen E, Hollon SD. Cognitive behavioral therapy for mood disorders: Efficacy, moderators and mediators. Psychiatr Clin North Am. 2010;33:537–555. doi:10.1016/j.psc.2010.04.005. 5. Garety PA, Fowler DG, Freeman D, Bebbington P, Dunn G, Kuipers E. Cognitive-behavioural therapy and family intervention for relapse prevention and symptom reduction in psychosis: Randomised controlled trial. Br J Psychiatry. 2008;192:412–423. doi:10.1192/bjp. bp.107.043570. 6. Feijo De Mello M, De Jesus Mari J, Bacaltchuk J, Verdeli H, Neugebauer R. A systematic review of research findings on the efficacy of interpersonal therapy for depressive disorders. Eur Arch Psychiatry Clin Neurosci. 2005;255:75–82. doi:10.1007/s00406-004-0542-x. 7. Porto PR, Oliveira L, Ph D, et al. Behavioral Therapy Change the Brain ? A Systematic Review of Neuroimaging in Anxiety Disorders. 2009:114–125. 8. Goldapple K, Segal Z, Garson C, et al. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004;61:34–41. doi:10.1001/archpsyc.61.1.34.

Given the importance of mental health among students and the efficacy of psychotherapy, University of Toronto offers individual psychotherapy services through Counseling and Psychological Services.

Dr. Paula Ravitz IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 25

SPOTLIGHT on Dr. Stephen Scherer

Director, The Centre for Applied Genomics, The Hospital for Sick Children Director, McLaughlin Centre for Molecular Medicine, University of Toronto Senior Scientist, The Hospital for Sick Children Professor of Medicine, University of Toronto By Yekta Dowlati

R. Stephen Scherer has recently been selected as a Nobelclass citation laureate in physiology and medicine by Thomson Reuters, and is noted by Mclean’s magazine as being among the 50 most powerful people in Canada. He is an astonishing individual who leads one of the busiest laboratories in our nation. Scherer is the Director of The Centre for Applied Genomics, at The Hospital for Sick Children and the Director of McLaughlin Centre at the University of Toronto. He is famous for his work on the genetic underpinnings of autism, which includes the role of copy number variations (CNV) — the deletions or duplication of genes in sections of DNA.

discuss the seminal concepts surrounding the human genome project. He explains, “I thought, where in Canada can I go to graduate school and perhaps contribute to this field? And I ended up at the University of Toronto.” There were very few researchers at the time that both satisfied the necessary qualifications and had an interest in this bourgeoning field, and SickKids was the ideal institution to conduct this research. Scherer worked under the supervision

mapping and sequencing of chromosome 7, which we eventually collaborated on with Craig Venter and Celera Genomics and ended up publishing a massive paper in 2003.” He also established the Genome Centre at SickKids with Professor LapChee and has been directing it for almost 20 years. He explains, “All of the major discoveries we have done happened with the help of our trainees who came here because they wanted to work in such as exciting environment. Based on our discoveries and publication track record, I think we have accomplished what I had set out to do, which was to establish in Canada a significant genomics effort.”

“I think we have accomplished what I had set out to do, which was to establish in Canada a significant genomics effort.”

Born and raised in Windsor, Scherer was a highly competitive hockey and baseball player. It wasn’t until 11th grade and reading The Double Helix by James Watson that he became interested in science. He attended the University of Waterloo, learning molecular biology. Scherer grew up in the era where researchers were starting to

of Professor Lap-Chee Tsui (who later discovered the cystic fibrosis gene) and completed his PhD in the Molecular Genetics Department. As stated by Scherer, “We ended up contributing probably more than any other group in the world on

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Scherer’s most rewarding part of his job is when someone in his group presents a new set of data, commenting, “I still pride myself that I sit down with my students and post-docs, look at data and analyze it together and exchange ideas.” He considers the highlight of his career the paper they published in 2003 on

SPOTLIGHT chromosome 7: “Although not cited a lot, it was the basis of everything we have done since. It was that paper that gave us the first hint that the phenomena of copy number variation existed.” Scherer is also the recipient of numerous prestigious awards. When he received an email from Thomson Reuters about the Nobel-class citation laureate ranking, he didn’t think it was important. “I almost deleted it. When I found out the email was not a hoax and I was actually in the ‘Hall of Laureates’, I almost dropped off my chair.” He believes that in science you always feel young—there is always someone telling you are wrong or that rejects your work. “To see your name on the list with giants of science was unbelievable, suggesting that your work is actually very important. Just to have a Canadian on the list is huge because there’s been an incredible investment in

science.” He continues, “It’s something you never think about it till you get it. It’s just a great honor.” Scherer stated that when he started his own laboratory, the gene sequencing technology was antiquated. Now researchers have the option to sequence the entire genome in a single experiment: “It’s probably as good as it’s going to get, we just have to be clever to figure out what it means. That’s essentially what we are going to do for the next 10 years.” Also, being the director of Autism Speaks Ten Thousand Genomes Program (AUT10K), Scherer is currently collaborating with Google and Autism Speaks to store data on the Google Cloud Platform and establish an open resource database to support autism research. Scherer considers science very competitive: “If you want a career in science, it should be your passion. Most of your experiments

will fail, papers and grants will get rejected, but you have to be stubborn and persistent, because you will eventually get wiser and that’s when you start to see success.” He suggests that graduate students should be well-rounded, with strong communication and written skills, which can be accomplished by reading papers both in their own area and the broader scientific field. He suggests that students should have strong statistical knowledge and should be a keen and active learner: “Watch you supervisors and committee members, learn their good and bad habits and learn your own strengths and weaknesses and continually build from these. Work hard. Over the years, I have met about 15 Nobel Prize winners and they are typically the hardest working people of the lot—smart too.”

“

If you want a career in science, it should be your passion. Most of your experiments will fail, papers and grants will get rejected, but you have to be stubborn and persistent, because you will eventually get wiser and that’s when you start to see success.”

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BOOK REVIEWS

Ebola: The Natural and Human History of a Deadly Virus by David Quammen, W.W. Norton & Company. 2014. 128 pages

Review by Rebecca Ruddy

avid Quammen’s book, Ebola: The Natural and Human History of a Deadly Virus, on the history and spread of Ebola, contained all of the necessary information to offer the reader a well‐ rounded understanding and grasp of the up‐to‐date knowledge of the virus that is currently an epidemic in West Africa. The author presents the history of the Ebola outbreaks in a gripping and informative manner by providing the perfect balance between the scientific evidence gathered thus far and the human aspect of this lethal virus. The author openly states that this book is a “partial view of the history and science of Ebola, and a somewhat personal one.” Yet, I believe the book does a commendable job in relaying the necessary and pertinent information on the Ebola outbreaks, while humanizing the virus with personal accounts of various experiences with the virus.

virus and, without this knowledge, it is difficult to know how the virus spreads to humans and therefore how to prevent the spread of the Ebola virus. Naturally, as a research trainee, I found the scientific aspects of the outbreaks, such as the collection and analysis of the specimens, very interesting. Of equal interest to me was learning about the various types of research teams that have studied the virus throughout its history. Interwoven between the scientific research and discoveries, and the detailing of the outbreak locations, is the human side to the history of the Ebola virus disease. The author tells the stories of several victims of the disease and how they contracted it, leading to questions regarding the host of the virus and viral transmission. One particular chapter tells the story of a young scientist in the United States who, while

Quammen has previously published a non‐fiction novel in 2012 entitled Spillover, a scientific reporting of how deadly human diseases result from spillover from nonhuman animals. Due to the recent Ebola outbreaks and the relevance of his previous book, Quammen gathered the sections of Spillover regarding the Ebola virus and repackaged them into Ebola: The Natural and Human History of a Deadly Virus, adding a new introduction and epilogue that touched upon the current epidemic in West Africa. Although I have not read Spillover, this sample of his work entices me to do so.

working on an Ebola antibody, accidentally pricked herself with a needle that had been in contact with Ebola infected mice. She was immediately placed in quarantine for 21 days and eventually released without having contracted the virus. Another interesting aspect of the book was when the author discussed one of his journeys to Africa with other researchers. Among the team were two men who had personally witnessed and were affected by one of the Ebola outbreaks. These personal stories truly humanized the virus and put names to the many people that have been affected by this debilitating virus.

Ebola: The Natural and Human History of a Deadly Virus takes the reader through the villages in Africa where the various Ebola outbreaks have occurred and details the data collection processes that have transpired in an attempt to better understand the virus. Much of the scientific aspect focuses on the search for the Ebola reservoir. The reservoir is the host of the deadly virus that allows the virus to live without being affected and is responsible for the transmission of the virus to humans and other species. As told in this book, scientists have yet to identify the reservoir of the Ebola

Overall, David Quammen’s Ebola: The Natural and Human History of a Deadly Virus provided a succinct yet overarching view of the history of the outbreaks, the scientific research, and the personal accounts of the Ebola virus. This book will equip the reader with the background knowledge that will enhance your understanding of the current Ebola epidemic, while also leaving a lasting impression of the countless lives impacted by this virus.

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BOOK REVIEWS

The China Study

by T Colin Campbell, PhD and Thomas M. Campbell II, M.D., BenBella Books. 2005. 280 pages

Review by Katherine Schwenger

he China Study by T. C. Campbell and T. M. Campbell explores the relationship between animal products (meat and dairy) and chronic diseases, such as cardiovascular disease, cancer, and diabetes. T. Colin Campbell, M.S., Ph.D. currently holds the Jacob Gould Schurman Professor Emeritus of Nutritional Biochemistry at Cornell University. Thomas M. Campbell, M.D. is an instructor at the University of Rochester School of Medicine and Dentistry as well as an executive director of the T. Colin Campbell Center for Nutrition Studies. The main thesis of this book is that by eating a low protein, plant‐based diet and eliminating animal products from our diet, we can prevent and cure most diseases. As a Registered Dietitian and graduate student, I was intrigued by these claims. The China Study is a research and statistics heavy book, and thus, requires sustained attention while reading. Nevertheless, it remains accessible to the general public, the target readers of the book. The China Study is divided into four parts. Part I refers to studies, which were conducted in the 1960s and 1970s in 65 villages throughout China. This study examined mortality rates due to chronic diseases. The mortality statistics were later analyzed and correlations were found between these statistics and the health and diet surveys completed by individuals residing in the same village. Part II is entitled “Diseases of Affluence.” Essentially, Campbell states that wealth leads to increased consumption of meat, dairy and refined plant products. In the following seven chapters, heart disease, obesity, diabetes, cancer, autoimmune, bone, kidney, eye and brain diseases are described, analyzed and ultimately related to animal product consumption. At the end of each of the chapters is the same take‐ home message: remove animal products from your diet and replace it with a whole‐ food, plant‐based diet. The

authors claim that such a change will dramatically reduce your rates of these diseases of affluence. This section was particularly interesting because when treating disease, nutrition is often considered after medication, however Campbell and Campbell believe the reverse should be true. In addition, they highlight the societal obsession of focusing on controlling your intake of one nutrient, such as cholesterol, glucose or fat and claim that this does not result in sustainable, long‐term health. After analyzing the aforementioned diseases, Campbell and Campbell outline “The Good Nutrition Guide” in Part III. They outline eight principles of nutrition, with the hope that by following these principles people will have reduced confusion surrounding food and health. The principles largely follow the findings outlined in Parts I and II, with animal products being a common topic and the message being to avoid them when possible. Part IV explores the reasons as to why this information has never been reported. Campbell and Campbell conclude “government, science, medicine, industry and media – promotes profit over health, technology over food and confusion over clarity.” However, in stark contrast to the other parts of the book, fewer graphs, statistics and correlations are presented. The reader is effectively left to believe the authors’ explanation at their word. There is no doubt in my mind that the “Western Diet” needs improving, and we need to increase our consumption of fruits and vegetables. Personally, I believe that nutrition is healthcare, whereas medicine is sick care, and that diseases can be improved and in some cases, prevented by nutrition. However, I am reluctant to eliminate an entire food group from my diet, even after reading The China Study. Such a course of action not only ignores the nutritional benefits that these foods provide but would likely also be impossible to follow for the majority of the population.

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LESSONS FROM THE FRONT LINES OF THE EBOLA OUTBREAK Stopping Ebola - The “MSF” Experience Seminar Coverage By Vanessa Rojas Luengas

“

Going there is hard, but leaving is even

harder,” shared Stephen Kornish, the executive director of Medicins Sans Frontiers Canada. This is a common phrase among the brave medical volunteers that have been involved in the Ebola aid response in Guinea, Liberia, and Sierra Leone since March 2014. Although great progress has been made thus far, there is still a great deal more to be done. The first step moving forward will be to educate the global community on the realities of fighting Ebola, to help eliminate the present fear that has created a barrier between the Western World and West Africa. One of several educational seminars hosted by Medicins Sans Frontiers on the Ebola response took place at the Great Hall in Hart House on October 30th.

Medicins Sans Frontieres (MSF), also known as Doctors Without Borders is an international humanitarian organization founded in 1971 with the goal of providing emergency medical aid to all victims of war and major disasters, regardless of their race, gender, religion, or political association. MSF has been able to treat over 100 million patients since their foundation. The organization has kept true to this pledge by providing an early response to the Ebola outbreak in West Africa, treating over 4 000 infected patients to this date. Three main characteristics led to both the slow recognition and the rapid spread of Ebola in West Africa. The first being the fact that this region had never seen Ebola in the past. As Stephen verified, “the closest out-

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break had been 5 000 km away.” This meant that the patients were treated as if they were infected with diseases common to that region, such as Malaria. The second contributing factor was the cultural practices of the Kissi people, the ethnic group that lives in this region. The Kissi migrate continuously between the borders, and hold specific traditions that involve the transportation of the dead to their villages of origin and the close contact with the dead during ceremonies for their passing. Thirdly, the scarcity of physicians led to late treatment and high number of infected health workers. In fact, 225 doctors were responsible for the treatment of 10 million people in Sierra Leone and Liberia. Unfortunately, one third of these regional doctors have died from the disease.

SPECIAL ARTICLE By June, the outbreak had grown out of control, the number of cases rose to 528 with 337 reported deaths. The MSF called for international assistance and scaled up their workforce from 300 to over 2 000 staff members in the span of three months. As they quadrupled their number of beds in August, they were treating two thirds of all Ebola cases. Lacking sufficient international support, MSF began training other NGOs themselves. By sharing their protocols and campsites with the Red Cross, Save the Children, and many others, several of these organizations have begun their own training programs and in the process of opening up their own treatment camps. At this stage, following the news of two infected American aid workers, “Eyes went from Africa to ourselves” and “Africa became closed off,” Stephen reports. As international fear grew, airlines and shipping companies stopped their transport to West Africa. This led to widespread chaos. Regional hospitals began shutting down, government led mass quarantine strategies took hold, and riots commenced. Patients

began migrating across borders in search of treatment, leading to the widespread of disease. Stephen reports that stemming from these containment strategies, the World Bank estimates that 1 billion dollars were lost from these three countries. Hence, Stephen now concludes, “containment is not the answer.” In September, the United Nations Security Council declared Ebola a threat to international peace and security. This provided great hope to field staff and patients as Ebola shifted from being a problem of West Africa to a global issue. Presently, there are around 14 000 cases with 5 000 casualties. MSF is currently treating 650 out of a total of 1 050 available beds. Yet, more support is still required.

tablished protocols for the management and treatment of Ebola prior to the present epidemic. Stephen Kornish highlights their three golden rules: (1) early treatment to prevent dehydration and malnutrition, (2) contact tracing to follow up individuals who had contact with patients, and (3) public education to de-stigmatize the disease and promote early treatment. There is still hope. By following those three golden rules, Nigeria and Senagal were recently declared Ebola free by WHO. In addition, over 100 patients have been cured of Ebola through MSF efforts. These patients continue working with MSF by caring for the younger patients and spreading public awareness. The struggle continues as the 3 000 U.S. promised troops have so far materialized to only over 300.

Ebola is not new to West Africa. The first recorded outbreak took place in the Democratic Republic of Congo in 1976. Since then, MSF has treated dozens of isolated Ebola flares within this region. From these experiences the organization had pre-es-

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The 2014 Ori Rotstein Lectureship in Translational Research By Gaayathiri Jegatheeswaran

n November 13th, 2014, the Institute of Medical Science (IMS) hosted the Annual Ori Rotstein Lecture in Translational Research at the Li Ka Shing Knowledge Institute. The Ori Rotstein Lectureship was established in 2011 to honour the leadership of Dr. Ori Rotstein, the Director of IMS from 20002011. The lectureship is a half-day event that features an invited keynote speaker who has made great strides in translational research.

Keynote Speaker

historical overview of how materials of the natural world like silk and natural rubber were used to create tools for surgical practices. Further, he described research endeavors in his lab where they have produced artificial collagen fibers and elastin-like materials to create tissue replacements. Notably, for students, Dr. Chaikof also provided his insights on how to become problem finders and solvers. He encouraged students to identify any gaps between what we are doing at the moment and what we should do for the patients. He wanted students to think outside of the box and suggest creative solutions to the gaps that they have identified.

The keynote speaker for the 2014 lecture was Dr. Elliot L. Chaikof. Dr. Chaikof was born and raised in Toronto, Ontario. He pursued his MD at Johns Hopkins University, Residency in General Surgery at the Massachusetts General Hospital, and completed a PhD at the Massachusetts Institute of Technology in Chemical Engineering. He received further training at the Emory University in Vascular Surgery. Currently, Dr. Chaikof is the Johnson and Johnson Professor of Surgery at the Harvard Medical School, as well as the Chair of the Roberta and Stephen R. Weiner Department of Surgery, and the Surgeon-in-Chief at the Beth Israel Deaconess Medical Center. His research interest includes the development of biologically inspired materials for tissue repair. His research group utilizes both synthetic and genetic approaches to explore their research ideas. Dr. Chaikof ’s lecture, “Opportunities at the Interface of Engineering and Surgery: Lessons from Nature,” began with a

Lastly, he ended his presentation with the following reminder, “Work a bit harder this evening, remember that the work that you do in the laboratory or in the operating room is not about writing another paper or achieving a promotion. It’s certainly not about becoming a chairman... there is a family out there who really cares about your work, whose clock is ticking, who needs your best ideas, who needs you to innovate and to translate. It’s not about caring–although that’s central to what we do–it’s about curing.”

IMS Student Presentations and Panel Discussion The lectureship also included a presentation by two IMS students, Vinod Chandran and Richard Foty, who recently attended the International Certificate Program in Translational Medicine hosted by the Eureka Institute for Translational Medicine. The 7-day program was held between May 11th to 17th in Siracusa, Italy. Both attendees shared their valuable experiences, including learning and networking opportunities attained from the program, and described new initiatives by the University of Toronto to foster interdisciplinary science. The lectureship ended with a panel discussion titled, “Overcoming Barriers to Innovation: Problem Finding and Solving.” The insightful discussion was moderated by Dr. Ori Rotstein himself and included panelists Dr. Elliot Chaikof, Dr. James Rutka, Dr. Michael Sefton, and Dr. Ian McGilvray.

Keynote Speaker: Dr. Elliot L. Chaikof

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The lecture was recorded and can be found at https://www.youtube.com/ watch?v=2z2mW6tgBCs

Interview with

Dr. Paul Lem Founder and Chief Executive Officer of Spartan Bioscience By Annette Ye

he implementation of personalized data to determine our genetic predisposition to the effectiveness of certain drugs – the field of pharmacogenetics – is becoming a reality in clinical practice. To illustrate the significance of this, the drug Plavix (a widely prescribed blood thinner to prevent blood clots) has many side effects. About 30% of Caucasians, and more than 50% of Asians and East Indians, carry gene variants (mutations) that reduce response to the drug. Currently, however, it can take days for doctors to determine if a patient has the right genetic makeup to respond well to Plavix. The genetic testing has to be done in a large laboratory, and is very time consuming. But a new testing device is reducing that time to less than 60 minutes, helping to ensure that patients are treated correctly. Ottawa-based company Spartan Bioscience, launched in 2006, is the premier maker of a device that quickly tests a cheek swab for genetic markers that provide information to guide a doctor’s decisions on how to treat a patient. Its current product tests for a genetic variant of CYP2C19, a protein found in the endoplasmic reticulum of cells that helps metabolize up to 15% of all prescribed drugs, including Plavix. Up to 1 in 3 people carry CYP2C19 mutations that can impair drug metabolism. The first use of the device will help cardiologists pinpoint which heart patients in a hospital should be given Plavix and which patients should be treated with more expensive alternative drugs. I sat down with Paul Lem, Founder and Chief Executive Officer of Spartan

Bioscience to chat about his company and himself. Lem’s enthusiasm immediately took hold of the conversation as we dove into an intriguing discussion about his career, his present biotechnology company, and his future ambitions. A Toronto-native, Lem studied Human Biology at the University of Toronto as an undergraduate at University College. He subsequently moved to Ottawa to complete medical school. At that time he developed a keen interest in research and biotechnology. “I skipped school to go work at the lab and invent things,” Lem recalls with a laugh. When asked what ignited his interest in biotechnology, he recounts summers of research at Harvard Medical School as well as the Stanford Genome Technology Center. Lem was inspired by the stories of research and commercialization he heard from some of the biotechnology pioneers of our time, as well as working alongside a lab participating in the Human Genome Project. Based on research he had completed during his four years of medical school, Lem entered a business plan competition sponsored by Genesys Capital shortly after starting his residency in Medical Microbiology at the University of Toronto. His team won first prize, and soon after, Lem left Residency to chase his dream of becoming an inventor. Spartan Bioscience is the brainchild of Lem’s first company’s technology, rebooted with integrated hardware. The current device, the Spartan RX CYP2C19 System, is about the size of a shoebox. So far, Canadian hospitals including Toronto General, St. Michael’s, Sunnybrook Health

Services Center, and the University of Ottawa Heart Institute are already using the system as part of a landmark 6000-patient trial sponsored by the Mayo Clinic. More impressively, the product has been granted clearance from both the Food and Drug Administration and Health Canada for commercial marketing and sales. Lem’s product is the first near-patient DNA test for personalized medicine to be approved in Canada. Recently, the company announced a strategic investment from Canon U.S.A to the development of these products. Looking to the future, the vision for Paul Lem and Spartan Bioscience is to have people use their devices in pharmacies, doctors’ offices, and even home use. The promise to make small, fast, affordable DNA tests for personalized medicine could have a large impact on medicine, health, treatment, and diagnostics, not only in the Canadian context but also worldwide. “Our Spartan RX system is like Microsoft’s Xbox game console, and the current CYP2C19 test is its first game,” Lem stated. “We’re working on more games to put on the platform.” When I asked Lem if he had any advice for young entrepreneurs looking to chase an idea, he quickly smiled and nodded approvingly. “Invest time to get good at the business world,” he explained. “One thing that people don’t realize is how much effort and training it takes to make yourself good at business.” As the conversation was wrapping up, I asked Lem what was most rewarding about his current work, He laughed and said, “When we’re 80 and look back onto Spartan, those will be years very well spent.”

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FUTURE DIRECTIONS

Highlighting The Career Path of Conor Gallagher, Medical Director at Allergan, Inc. By Petri Takkala

Taking Critical Thinking Skills From Academia to Industry

Passion for Teaching and Scientific Communication

Conor Gallagher (PhD) uses the skills that he developed during his scientific training to guide research and development for commercial therapeutic applications as the Medical Director for a specialty pharmaceutical company.

Conor took on active roles in teaching and designing courses during his PhD studies. He quickly realized that scientific communication and teaching were his passion, and thus took steps to gain as much relevant experience as possible. Capitalizing on his expertise in anatomy, Conor made connections in the Departments of Physiotherapy, Anatomy, and the Michener Institute to teach anatomy. He further worked as a demonstrator in the medical student anatomy labs, and developed an anatomy course at the University of Toronto Scarborough campus. All this experience was pivotal in making the transition to work in the private sector, first as a medical science liaison, a position heavily dependent on scientific communication. However, the lack of exposure to alternative careers in science at the time meant that many students were unaware of different career paths after completing their graduate studies.

Comprehensive Scientific Training Originally trained as a physiotherapist at University College Dublin, Conor subsequently completed a Masterâ&#x20AC;&#x2122;s degree in anatomy at University College Cork. He moved to Canada and worked as a physiotherapist for two years before embarking on his PhD at the University of Toronto (UofT), where he obtained his PhD from the Institute of Medical Science (IMS) in 2003 under the supervision of Dr. Michael Salter. His thesis focused on spinal cord neurophysiology. Research at the time suggested that the glial cells surrounding neurons are not inert and may have an intrinsic communication function. In the central nervous system, astrocytes surround neurons and their synapses and may serve to modulate synaptic transmission. For his thesis, then, Conor worked on developing a better understanding of purinergic signaling in astrocytes in the spinal dorsal horn and also on cells that had been transfected to express ATP-activated P2Y receptors. He spent much time examining propagating calcium waves evoked by ATP in astrocyte networks in primary dorsal horn cultures in order to elucidate the mechanism of cellcell communication in astrocytes.

By taking an active role in learning about alternative careers, and networking to learn about job opportunities and the required skills he would need in industry, Conor made the transition to work as a Medical Science Liaison at Allergan, Inc. a US-based pharmaceutical company. A Medical Science Liaison is the external scientific face of a company, working with physicians to help educate them about the extensive body of clinical studies associated with a drug, and they work with clinical studies groups in identifying clinical trial sites to investigate the potential application of new therapies. A Medical Science Liaison also connects physicians/scientists interested in conduct-

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ing independent research on a companyâ&#x20AC;&#x2122;s products with the appropriate people at the company. This role is integral to corporate Medical Affairs which is responsible for ensuring a companyâ&#x20AC;&#x2122;s compliance with regulatory guidelines, working with regulatory agencies, and provides technical support for internal teams and customers. Conor began by working on Botox for therapeutic uses. Botox had been previously approved for treating cervical dystonia and a number of other indications but the company wanted to examine whether it can be used to treat spasticity and migraines, and overactive bladder. This was the perfect project to get started on, since Conor had abundant background knowledge of the mechanism of action of Botox, and was familiar with the physiology of botulinum toxins from his time at UofT. As a vesicular exocytosis inhibitor, Botox can be used to treat muscle spasms after stroke, or chronic migraines, and is currently being investigated for the treatment of osteoarthritis and depression. Although Botox has a relatively simple mechanism of action, it has plenty of potential applications. To tackle this project, a crucial first step was making connections between his physiotherapy background, and understanding the therapeutic area and the science behind it. A Medical Science Liaison is exposed to many areas of industrial science, and in particular regulatory affairs, and Research and Development. For a company, Research involves discovery and the basic science of a potential new product. This is where you get to see early pipeline ideas. For a pharmaceutical company, Development involves clinical trials, addressing regulatory guidelines, and the further steps involved in taking a drug to the market. A Medical Science Liaison works at the interface between clinical and

FUTURE DIRECTIONS basic science.

Science in Industry Allergan Inc. is a specialty pharmaceutical company working with many different drugs and devices approved in several therapeutic areas. In the case of Botox, it was important to identify points of differentiation between Botox and competitor products, examining the comparative safety and efficacy profiles of products, and developing clinical and preclinical studies that would show differentiation. Conorâ&#x20AC;&#x2122;s next role at Allergan Inc. was to develop and drive the global scientific competitive strategy for the BOTOXÂŽ product, and understanding and communicating the key points of clinical and basic science differentiation between the various botulinum toxin products on the global market. To take this role Conor moved to the corporate head office in Irvine, California, to work on the global competitive strategy for Botox. While working closely with basic scientists, clinical development, and marketing teams on the competitive strategy for Botox, he quickly climbed the ranks to become a Medical Director. Each therapeutic area has a Medical Director who is in charge of designing and running Phase 4 clinical trials, coordinating data analyses and interpretation, designing a scientific strategy, and working closely with medical teams. As a Medical Director, Conor is responsible for the overall post-approval scientific strategy for a number of drugs and products at Allergan Inc. Each product has its own challenges and unique regulatory environment that must be appropriately addressed. Although he may not be returning to bench work anytime soon, Conor still gets to experience science everyday! Looking at data tables, reviewing clinical trials, and designing new trials are some of the key tasks that a Medical Director must juggle in their daily work. Publication of science in industry is as important as it is in academia. Results of clinical studies are scrutinized and carefully reviewed before publication, and all clinical trials in the US have to be added to a government website that monitors ongoing trials.

Dr. Conor Gallagher, PH.D. Director, Facial Aesthetics and Medical Dematology Medical Affairs, Allergan Inc.

Transitioning from Academia to Industry Everything you do in industry is collaborative. A basic science education provides the training to be able to look at data from different perspectives, and to think critically about results and studies. However, when moving into industry, it is also important to have skills that extend beyond lab techniques. Being a great communicator and having appropriate social abilities to effec-

tively collaborate with internal and external colleagues are essential for working in medical affairs. Conorâ&#x20AC;&#x2122;s advice to IMS graduate students is to be aware of their requirement to become a confident presenter, and to have the ability to speak comfortably and explain scientific concepts in simple terms. Look for opportunities to collaborate and establish a healthy work-life balance which helps develop the soft skills that are crucial in industry!

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Travel bites – RSNA 2014

100th Scientific Assembly and Annual Meeting, Chicago, IL By Mirkamal Tolend

he 2014 Radiological Society of North America (RSNA) annual meeting was held at the McCormick Place in Chicago from November 30th to December 5th. It is one of the largest meetings in medicine. In the previous year, 54 008 people attended the meeting from all over the globe, making it the third most attended conference in the world, closely tailing the Federation of International Medical Equipment Suppliers at 57 000, and Greater New York Dental meeting at 54 629. With this year being the 100th anniversary of its annual meeting, the RSNA probably reached first place. I had the opportunity of attend the conference this year since I was presenting study data and helping to facilitate a consensus meeting with the international collaborators for my research project. Our research group’s interest is on improving the diagnostic imaging guidelines in juvenile idiopathic

arthritis patients, and the group includes many radiologists from the US and Europe. The popularity of the RSNA meeting hence provided the perfect opportunity for us to meet in person to discuss our research progress. A great variety of educational activities were offered at the RSNA 2014, including hundreds of courses, diagnostic workshops, and scientific poster discussions. There was definitely something for everyone’s interest. The RSNA website had a very useful interface where attendees could browse through the different events and organize a personalized schedule of events to attend to. There was also a mobile app for Android phones and iPhones, but for the old-school folks, a 500 page catalogue and other pamphlets were available as well. Full participation at the six day conference could earn medical professionals up to

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93.00 continuing medical education credits. This year, there were 1 754 10-minute scientific paper presentations running in parallel throughout the week. These were either newly completed research, workin-progress, or reports on a new aspect or understanding in clinical radiology. I attended a few sessions relevant to my research, and found it quite helpful for framing the clinical relevance of my own work and the methodological challenges I can expect in the near future. One could also spend days browsing the hard-copy and electronic exhibits at the Learning Center, which consisted of countless posters and computer stations housed in a very spacious exhibit hall. In total, the patrons could access 2151 education exhibits and 949 electronic research posters presented this year, representing at least 16 subspecialties. The education exhibits consisted of hard-

TRAVEL BITES copy posters, computer demonstration booths, or PowerPoint slideshows accessible from the workstations. The authors of the posters were available at specified times for in-person discussions. Plenary sessions were held at the Arie Crown Theatre, which had seating for 4249 people. Keynote addresses, annual orations, and special lectures were held in this format. What was most memorable to me was the image interpretation session. Five specialist radiologists who are experts in their field discussed 10 difficult cases and made a diagnosis based on the images and with minimal clinical information. The correct diagnosis (confirmed by pathology) was later revealed by the moderator, and explained further. It was

very informative to hear how the experts approach difficult cases and eliminate the differential diagnoses. There was also the possibility that the experts may diagnose the cases incorrectly, which kept everyone in suspense. Fortunately, all 10 cases were diagnosed correctly by the panelists. For the centennial occasion, a special display area was set up to showcase the earliest models of imaging equipment. These nicely contrasted the latest imaging products and services being presented at the technical exhibits. It was thrilling to see how far radiology had come over the past century. Wilhelm Roentgen, the man who started it all with his discovery of X-Rays, was also commemorated this year with a life-size wax statue. Canada

and the Republic of Korea were especially honored at this centennial year, having been dedicated the “Country Presents” special courses to celebrate each country’s contributions to cardiovascular imaging. I would like to sincerely thank my graduate supervisor Dr. Andrea Doria for providing me with this opportunity to attend the RSNA meeting. It was a highly motivating and unforgettable experience. The upcoming 2015 meeting will mark the 101st annual meeting and the 100th anniversary of the RSNA’s founding, so it will still have that special centennial feeling. If you would like to present your research, abstracts need to be submitted by 12:00 pm Chicago time on April 8th 2015. For more information, please visit RSNA.org.

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EpLink: The Epilepsy Integrated Discovery Project

By Jabir Mohamed

Epilepsy as a Long-Standing Public Health Concern Epilepsy is a significant health problem. Among chronic brain disorders, it is the most common. According to the World Health Organization, the disability due to epilepsy—characterized by recurrent and unprovoked seizures—accounts for 1% of the global burden of disease, comparable to that of breast cancer in women or lung cancer in men.1 In Ontario, it affects approximately 95 000 people, with 6 500 new cases added each year.2 A number of these individuals, especially those who suffer from uncontrolled seizures, become physically disabled. Such limitations have a profound impact on their ability to lead an independent, fulfilling life. Resistance to drug therapy (pharmacoresistance) is one of the major problems in epilepsy treatment today. Although current medications effectively control seizures in 70% of the population, the remaining 30% continue to suffer from seizures despite treatment with one or more antiepileptic drugs.3 The underlying factors that lead to the development of epilepsy (epileptogenesis) are also unclear. Certain brain injuries such as traumatic brain injury and stroke are known to predate epilepsy; however, insights into the mechanisms leading to this chronic epileptic state are scarce.

Epilepsy also has a significant impact on the social and psychological wellbeing of an individual. An Ontario Health Survey found that people with epilepsy had the lowest quality of life amongst people with selfreported chronic conditions; those included conditions like arthritis, congestive heart failure, and Parkinson’s disease.4 In addition, there is a growing awareness of the psychiatric comorbidities in epilepsy patients. A populationbased study revealed that almost onethird of people with epilepsy had a diagnosis of anxiety or clinical depression—twice the prevalence in the general population.5 But despite the frequency and significance of these comorbid conditions, these patients remain underdiagnosed and undertreated.

Epilepsy Integrated Discovery Project: Bringing Excitement across the Province A palpable sense of enthusiasm has recently surfaced in Ontario. In 2011, the Ontario Brain Institute (OBI) created the Epilepsy Integrated Discovery Project (EpLink) to refocus attention on the deficits in epilepsy care. The large number of collaborators for the EpLink project— more than 25 researchers and clinicians working at nine different university and hospital sites across Ontario— demonstrates the commitment of the

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scientific community to come together and identify strategies that will improve the lives of people with epilepsy. Also contributing to this sense of enthusiasm is the alliance of these researchers with non-profit organizations and pharmaceutical companies. The non profit advisors help keep research relevant to the real world and ensure that research aims coincide with patient needs, whereas the industry partners are crucial to get novel drugs developed and accelerate their transition from bench to bedside. Headed by Dr. McIntyre Burnham, Director of the University of Toronto Epilepsy Research Program, and Dr. Jorge Burneo of Western University, the EpLink program heralds a new era of scientific collaboration. The key words in this initiative are integrated discovery. Epilepsy is a complex neurological disease that requires a multi front approach: one that spans multiple laboratories and clinical disciplines; involves collecting different types of data, ranging from imaging and behavioural to genetic and molecular; and applies findings in one epilepsy syndrome to another. The amalgam of patientfocused and basic science research is key in implementing a platform that allows researchers, nonprofit advisors, and industry partners to work together and achieve a common end.

RESEARCH HIGHLIGHTS Thus, projects are interrelated not by a single protocol but by a single goal—the desire to achieve seizure control for patients whose seizures are currently uncontrolled. To accomplish this, the OBI and EpLink committee have identified seven core research categories: 1) pre clinical/clinical drug therapy; 2) diet therapy; 3) seizure prediction and stimulation; 4) cognition, mood and quality of life; 5) epidemiology and diagnosis; 6) seizure surgery; and 7) genetics and epigenetics. More information about OBI and EpLink, and about their projects, can be found at their websites www.braininstitute.ca and www.eplink.ca.

EpLink Workshop - February 28 2015: A Year in Review It was great to celebrate progress in epilepsy research over the weekend of February 28th, 2015 . The origins of EpLink, progress in the past year, and what is likely to occur in the coming years were discussed. Despite the problems that were faced during the first two years in terms of money flow and startup, EpLink has remained a successful program. As the program moves into year three, the outcomes of the workshop offered a clear plan for moving forward. The talks in the Drug Therapy session offered many takeaways. Dr. John Andrews’ of Ketogen Inc. shared the strategies his team used to develop their novel acetone analogues: as prodrugs and/ or carriers to ensure that antiepileptic drugs (AEDs) get to the brain without getting degraded or distributed too quickly. This came after discovering that acetone potentiates the effects of AEDs. Likewise, Dr. Malik Slassi of Fluoronov Inc. discussed his group’s orally active anticonvulsants. One of their compounds has demonstrated broadspectrum activity—which means it can be used in more than one epilepsy disorder—and good tolerability. Further invitro work elucidated the mechanism in which their compound acts: inhibition of a novel voltagegated sodium channel subtype. Dr. Berge Minassian uncovered how his lab is working toward a cure for

Lafora disease, which is arguably the most severe form of epilepsy that exists. His group demonstrated that reducing production of glycogen synthase (GS) by 50%—by removing a protein targeted to glycogen (PTG), an activator of GS—in a mouse model of Lafora disease cured the condition. Future work will employ cuttingedge genetic techniques (CRISPR, antisense oligonucleotides) to target GS and PTG in animal models more selectively. Successful completion of this study may pave the way for future development of gene therapy treatment in humans. This set the stage for Dr. Rogawski’s keynote talk, which continued to describe similar kinds of translational products that came as a result of basic science research. The view that neurosteroids can be used as anticonvulsants gained some scientific heft in a landmark study published in 1942.6 Many investigators, including Dr. Rogawski, have since addressed the mechanism of action. At the workshop, Dr. Rogawski described results from his research laboratory using animal models of status epilepticus, a potentially fatal seizure that lasts more than five minutes. His group demonstrated that allopregnanolone, a metabolite of progesterone, was effective in treating this condition in animal models. Now they are in the process of developing allopregnanolone for patients who suffer from intractable forms of status epilepticus. There was a strong focus on holistic care in the Combatting Comorbidities session. Dr. Kathryn Hum’s EpUp study involving distancedelivery of a group cognitive behavioural therapy program is unrivaled in many aspects. As mentioned earlier, depression is a common problem in people with epilepsy and it often goes unrecognized and untreated. The EpUp study is designed in a way that breaks down the barriers patients may experience such as lack of access to a psychiatrist or neuropsychologist due to costs or transportation. The attractive quality of this approach is that it encourages patients to continue therapy over many weeks and months, improving the chance of lasting gains. Preliminary accounts from individuals who participated in the program are promising, and the next

cohort is set to begin shortly. Ms. Mary Secco, Director of Strategic Initiatives at the Epilepsy Support Centre in London, ended the session by addressing the socioeconomic impact of epilepsy and introduced the “Clinic to Community” program. This program strives to provide coordinated care for patients with epilepsy, with a focus on education and management for families, general practitioners, nurses, and educational providers (teachers, principals, etc.) in the community.

Conclusion The OBI funding that is supporting EpLink is the most significant contribution to epilepsy research anywhere in Ontario. Although the next few years will decide whether the patient community will reciprocate the enthusiasm of the epilepsy research community, the real transformation will come in the longterm. Ontario has an excellent reputation in neuroscience research and the hope is that EpLink’s influence will provide the impetus for the development of similar programs across Canada.

References 1. Murray CJL, Lopez AD. Global Comparative Assessment in the Health Sector: Disease Burden, Expenditures and Intervention Packages. World Health Organization. Geneva, Switzerland; 1994. 2. TellezZenteno JF, PondalSordo M, Matijevic S, et al. National and regional prevalence of selfreported epilepsy in Canada. Epilepsia. 2004;45(12):162329. 3. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):31419. 4. Wiebe S, Bellhouse DR, Fallahay C, et al. Burden of epilepsy: the Ontario Health Survey. Can J Neurol Sci. 1999;26(4):26370. 5. TellezZenteno JF, Patten SB, Jette N, et al. Psychiatric comorbidity in epilepsy: a population based analysis. Epilepsia. 2007;48(12):233644. 6. Selye H. The antagonism between anesthetic steroid hormones and pentamethylenetetrazole (Metrazol). J Lab Clin Med. 1942;27:10513.

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Past Events

IMS Intramural Co-Ed Volleyball Team

IMS Intramural Men’s Soccer Team 40 | IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES

IMS GOES SKATING GOES

SKATING

IMS goes skating with Bonhomme Carnaval at Varsity Rink

Valentine’s Day Social - St. Michael’s Hospital Site Event IMS MAGAZINE SPRING 2015 INFECTIOUS DISEASES & VIRUSES | 41

DIVERSIONS

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“One, remember to look up at the stars and not down at your feet. Two, never give up work. Work gives you meaning and purpose and life is empty without it. Three, if you are lucky enough to find love, remember it is there and don’t throw it away.” -Stephen Hawking

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