IMS Magazine Fall 2015

IMS MAGAZINE FALL 2015 AGING | 1

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IN THIS ISSUE Commentary............................................4 Letter from the Editor..............................5 Director’s Message.................................6 Important Dates......................................7 Feature..................................................10 Special BMC Feature............................18 Close-up................................................20 Viewpoint..............................................22 Special Event........................................24 Behind the Scenes................................26 Expert Opinion......................................28 Travel Bites...........................................31 Scientific Day........................................32 IMS Special Event................................34 SURP Award Winners..........................36 Past Events...........................................38

EXPERT OPINION

P28 USING EXPERIMENTS OF NATURE TO ASSIST IN HIV VACCINE DESIGN

Copyright © 2015 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.

FEATURE GRAPHIC

P14 P10 CANADIAN CHRONIC PAIN STATISTICS AGING & DEMENTIA

MAGAZINE STAFF Annette Ye Kasey Hemington Rebecca Ruddy Katherine Schwenger Rebecca Ruddy FEATURE SUBCOMMITTEE MANAGER Danielle Cha UNDERGRADUATE ARTICLE MANAGER SPONSORSHIP & PROMOTIONS MANAGER Antigona Ulndreaj Anna Badner JOURNALISTS & EDITORS Annette Ye Arunima Kapoor Ayda Ghahremani Gaayathiri Jegatheeswaran Jabir Mohamed Jonathon Chio Joshua Lipszyc Kasey Hemington Katherine Schwenger Mirkamal Tolend Muhtashim Mian Rebecca Ruddy Usman Saeed Vanessa Rojas Luengas Yetka Dowlati Cassandra Cetlin DESIGN EDITORS Natalie Cormier Naveen Devasagayam Sam Holmes Ashley Hui Sarah Kim Melissa Phachanhla Sonia Seto Kelly Speck Jerry Won Chung Ho Leung PHOTOGRAPHERS Matthew Wu EDITOR-IN-CHIEF EXECUTIVE EDITORS

Cover design by Sam Holmes

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.

Feature Infographic by Sarah Kim IMS MAGAZINE FALL 2015 AGING | 3

COMMENTARY

EBOLA OUTBREAK

Lessons Learned

By Yekta Dowlati

A

s we followed the dramatic news of the Ebola outbreak in West Africa a few months ago and the hysteric fascination of the media with the few cases of Ebola that trickled into Western Europe and North America (mostly among health care workers who were in contact with Ebola patients), there may have been a small group within the scientific and healthcare community and many more in the public at large that considered this outbreak as a prelude to a “Viral Armageddon.” Of course there is no question that the epidemiologic characteristics and mortality rate of this disease are quite scary. That may explain why people throughout the world stared at their TV screens while the US Center for Disease Control issued regular updates.

But if there is anything to be learned from this event, it is that the future focus of the healthcare community should not only be on a rapid and comprehensive response to the original cases identified, but also and more importantly on the prevention of such an outbreak in the first place. It is this concept of prevention that leads to the thought of many other potential disease outbreaks of infectious nature that

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are waiting to happen. And if this focus on particular outbreak is still unclear, but the prevention is correct, what should society possible explanation points towards an think about diseases much more likely to “imported” case of measles from beyond result in outbreaks? Do they deserve less of the borders or perhaps overseas. Is it possithe public’s attention? ble a tourist from outside North American introduced the disease? Possibly yes. What Take for example the measles outbreak that makes it more concerning is that once began in December 2014 in the Califormeasles enters our assumingly protected nia Disneyland resort, which originally society, it can then rapidly spread through consisted of 147 cases of individuals who pockets of communities which do not had visited Disneyland (of which 131 were believe or adhere to standard vaccination California residents). Quickly the outpractices. Whatever the epidemiological break and spread of the disease was traced course of this event, fortunately, it currentfurther north and across the US-Canadian ly appears that the health authorities have border. This was possibly the direct result launched an appropriate and sustained of two families from the Lanaudière region response in order to contain it. We are safe of Quebec that had visited California in for now! Or, are we? the preceding weeks. Subsequently, the number of Canadian cases quickly escalat- What I take from these events and from ed to 159 which surprisingly exceeded the the world of infectious diseases is that original number of American cases. Alwe all need to be ever so vigilant for any though the past few decades have observed case of an infectious agent, particularly great strides in the prevention of measles those that have the potential to spread worldwide through the use of appropriquickly in our modern world. Some may ate vaccination techniques, there is no sound frightening while some may not misconception that the disease continues be as bone chilling when we hear about to have a potentially dramatic spectrum of them. Nevertheless, they all deserve a well morbidity and even fetal-related morthought and comprehensive response. tality in pregnancies. The origin of this

LETTER L FROM THE EDITOR

LETTER FROM THE EDITOR

et’s face it; we’re not getting any younger. As our lives are getting longer, we, as a society, are aging quicker than ever before. By the year 2030, about 1 in 4 Canadians will be over the age of 65. As we look forward to more years ahead, the idea of a long life can also trigger anxiety. Fortunately, we are close to building a world where arriving at old age mentally sharp, financially secure, and physically fit is no longer just science fiction. From the science side of things, we are beginning to understand how aging affects our bodies, and more importantly, how to slow down and even reverse some of these processes.

In this issue of the IMS Magazine, we highlight some ways the IMS is advancing our understanding of the biology of aging, and even possibly building therapies and cures.

We describe how Dr. Cindi Morshead is harnessing the power of the brain to repair itself after stroke, and hear from Dr. Shabbir Alibhai discuss the impact and clinical relevance of decision making in geriatric oncology. We also feature Dr. Tarek Rajji’s work in understanding the relation between aging, mental illness, and cognitive disorders such as Alzheimer’s.

In addition, I strongly recommend you check out our special articles tackling the timely topic of physician-assisted suicide, including our Viewpoint article on euthanasia, Special Events article covering the ethics of physician-assisted suicide, and coverage of our very own IMS feature event, “Beyond the Debate: The Future of Physician-Assisted Suicide.”

Last but not least, we feature articles from the winners of our annual IMS Summer Student (SURP) Writing Competition, Denisha Puvitharan and Dustin Sokolowski, who discuss their summer projects related to stroke and attention deficit hyperactivity disorder.

I would like to thank Dr. Mingyao Liu and the IMS department for their ongoing support, and congratulate our newest design team on their fantastic production of this issue.

Thank you to the phenomenal IMS Magazine team for their dedication and enthusiasm. I strongly encourage you, our readers and supporters, to send us comments and feedback letters as we continue to showcase to you the best of the IMS. Happy reading!

Annette Ye Editor-in-Chief, IMS Magazine

ANNETTE YE Editor-in-Chief, IMS Magazine Annette is a fourth year PhD candidate at the Institute of Medical Science. She is currently conducting research on biomarker discovery in neurodevelopmental disease at the Hospital for Sick Children.

IMS MAGAZINE FALL 2015 AGING | 5

DIRECTOR’S MESSAGE

Mingyao Liu, MSc, MD Director, IMS

Mingyao Liu became the IMS Director in January 2015 after serving as Interim Director since July 2014. He is currently a Senior Scientist at the University Health Network, Toronto General Research Institute, and a Professor of Surgery, Medicine and Physiology in the Faculty of Medicine. Dr. Liu has published over 250 peer-reviewed research articles, and is the recipient of the Queen Elizabeth II Diamond Jubilee Medal for his work in developing molecular therapies for lung injury during, and after, lung transplantation.

W

elcome to the new academic year and the 15th edition of the IMS Magazine. This issue of the magazine addresses the timely topic of aging, including a uniquely Canadian perspective on the issue of physicianassisted suicide. We have a collection of contributions from Dr. Tarek Rajii, Dr. Cindi Morshead, and Dr. Shabbir Alibhai.

This past summer, there were several events addressing the ethics of physicianassisted suicide held across campus. We highlight two events featuring prominent speakers at University of Toronto: a Joint Centre for Bioethics seminar and an event titled, “Beyond the Debate” organized by the IMS Student Association.

In recent IMS news, I am very pleased to announce that the first cohort of 17 students have begun in our Master of Health Science in Translational Research Program. Translational research in health sciences is a bi-directional movement that emphasizes the prevention, diagnosis, and treatment of disease. It is also the cornerstone under which our institute was established, and one that our institute makes a priority. This new professional masters program will challenge students to understand how fundamental research may lead to changes in patient care, commercialization and health policy; and help them see these ideas to fruition in the real world.

On October 23, 2015, IMS will host the annual Ori Rotstein Lecture in Translational Research at the Li Ka

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Shing Knowledge Institute, St. Michael’s Hospital. The lecture will be given

by Dr. Paul O’Byrne, Chair of the Department of Medicine and the E.J. Moran Campbell Professor of Medicine at McMaster University. He is also the Executive Director of the Firestone Institute for Respiratory Health at St. Joseph’s Healthcare. Dr. O’Byrne is world renowned for his research on allergeninduced asthma and his talk will focus on developing new treatments for allergen-induced asthma. I warmly invite you to join us for what is sure to be an enriching morning.

Congratulations to Annette Ye and her incredible team for their continued dedication and collective creative energies in producing this impressive publication. The IMS Magazine has been a tremendous success and just one of the many wonderful, student-initiated projects to make the IMS such a very special institute. I fully support the ongoing publication of the magazine and look forward to reading and learning about the outstanding research that is being conducted by our faculty and trainees in IMS. Best wishes for a successful, happy, healthy fall period and upcoming holiday season.

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

IMPORTANT DATES AUGUST 28 Last date for payment of tuition fees to meet registration deadline

SEPTEMBER 10 IMS New student orientation 18 Registration for Fall session ends; after this date, a late registration fee will be assessed 28 Final date to add full year and Fall session courses

OCTOBER 2 Final date to submit final doctoral thesis for Fall convocation 23 Ori Rotstein Annual Lecture in Translational Research

NOVEMBER 2 Final date to drop Fall session full or half courses without academic penalty 9 to 13 Fall Convocation

DECEMBER Dec 23 to Jan 1 University closed for winter break

IMS MAGAZINE FALL 2015 AGING | 7

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IMS MAGAZINE FALL 2015 AGING | 11

FEATURE

Aging and Mental Health: A Focus on Depression and Dementia

BY Tarek Rajji, MD, FRCPC Associate Professor, Department of Psychiatry, University of Toronto IMS Associate Member

A

bout 5 million Canadians were aged 65 or older in 2011 and this number will increase rapidly over the next 15 to 20 years such as by 2036, about 1 in 4 Canadians will be a senior. While we are getting older as Canadians and our life expectancy is above 81 years on average, our functional abilities decline at an accelerated speed after the age of 65.

Brain health and disease states are critical factors in determining functional decline in late life. About 10% of people aged 65 or older and up to 50% of those aged 85 or older have Alzheimer’s or another form of dementia. About 6% will experience depression and others will experience other forms of mental illness including anxiety, bipolar disorder, and schizophrenia. Some older people will experience these disorders for the first time in late life, others would have had them since earlier age and have grown older with them.

Understanding the relation between aging, mental illness, and cognitive disorders in late life is critical for the development of interventions that will maintain brain health and prevent the onset of cognitive decline and dementia. Most mental illnesses in late life are associated with cognitive deficits.

Moreover, some mental illnesses, in particular depression, are not only 12 | IMS MAGAZINE FALL 2015 AGING

associated with cognitive deficits, but also increase the risk of developing Alzheimer’s dementia (AD).

Late-life depression (LLD), defined has having depression for the first time in late life or having a major depressive disorder that started earlier in life but is recurrent into late life, is a serious public health problem. LLD is the second most promising modifiable risk factor for AD after physical inactivity.1 In two metaanalyses, a life-time history of depression doubles the risk of AD; a depressive episode within 10 years increases the risk of dementia 4-6 fold. Among patients with LLD and cognitive impairment, conversion rates to dementia are 30-45% over follow-up of up to three years and > 50% over longer periods.2 Cognitive deficits in non-demented patients with LLD are highly prevalent and they lead to dementia in a large proportion of patients. These deficits are observed in attention, executive functions, information processing speed, and both verbal and visuospatial memory.3 Deficits in executive function and memory both increase the risk of depression relapse during antidepressant maintenance and predict conversion to dementia.

The association between depression and dementia follows more than one pathway. Cerebrovascular disease could be a common pathway that

leads to both depression and dementia especially through its impact on the frontostriatal network. Depressed patients also experience increased activity in the hypothalamic-pituitaryadrenal axis resulting in high levels of glucocorticoids and related hippocampal atrophy. This atrophy increases the risk of AD through the increase in susceptibility to Alzheimer’s disease processes. Depression and dementia are also associated with inflammatory changes in the brain and the peripheral systems. Neuroinflammation can also be a common mechanism and a pathway linking depression to dementia.

Current treatments of depression do not prevent the development of dementia among patients with LLD. Over the past 20 years, several studies assessed the impact of antidepressants on cognition.

Tricyclic antidepressants are typically associated with deleterious effects on cognition, especially on memory. These negative effects are attributed to the anticholinergic properties of the tricyclic antidepressants. This is particularly true in patients with LLD. Monoamine oxidase inhibitors have neither positive nor a negative impact on cognition.

In general, selective serotonin reuptake inhibitors (SSRIs) have not been associated with a negative impact on cognition. Paroxetine has been

Photo by: Tarek Rajji

AFFILIATIONS: Chief, Geriatric Psychiatry Division, Centre for Addiction and Mental Health

FEATURE shown to cause deleterious effect on verbal memory, and this effect has also been attributed to its higher anticholinergic activity than that of other SSRIs. In contrast, some studies found that some SSRIs, particularly sertraline, noradrenergic reuptake inhibitor (reboxetine), and serotoninnorepinephrine reuptake inhibitor (duloxetine) have pro-cognitive effects in patients with depression, especially on attention, processing speed, and verbal memory. However, notwithstanding these positive results, it is not likely that these cognitive benefits are beyond the improvement in mood symptoms.

Further, more recent studies using detailed neuropsychological tests and controlling for practice effects show that while cognition improves, it does not normalize even after LLD responds to antidepressants. Finally, long-term antidepressant maintenance alone does not prevent decline in cognition, despite maintenance of recovery from LLD.

intervention.

Other than antidepressants, one relatively recent randomized controlled trial assessed the combination of donepezil with standard antidepressant maintenance in preventing cognitive decline and the incidence of dementia in patients with LLD.4 Although the addition of donepezil was effective in preventing cognitive decline and the incidence of dementia over a period of two years, it caused severe mood symptoms in many of these patients supporting the need for a different

Taken together, one approach our research team is adapting to prevent cognitive decline among patients with LLD is to target the prefrontal cortex with neuroplasticity-inducing interventions to enhance its compensatory capacity and therefore, prevent cognitive decline and dementia.

We have been using the combination of neurostimulation with cognitive remediation, two types of interventions that we think are synergistic in promoting neuroplasticity, and

Discovering an intervention that can prevent or even delay Alzheimer’s dementia will have a tremendous impact on our society and worldwide given the severe burden that this illness imposes on the individuals, their caregivers, and the public at large.

References: 1. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurology. 2011 Sep;10(9):819-28.

2. Alexopoulos GS, Meyers BS, Young RC, Mattis S, Kakuma T. The course of geriatric depression with reversible dementia - A controlled-study.

American Journal of Psychiatry. [Article]. 1993 Nov;150(11):1693-9.

3. Butters MA, Whyte EM, Nebes RD, Begley AE, Dew MA, Mulsant BH, et al. The nature and determinants of neuropsychological functioning in latelife depression. Archives of General Psychiatry. 2004 Jun;61(6):587-95.

4. Reynolds CF, Butters MA, Lopez O, Pollock BG, Dew MA, Mulsant BH, et al. Maintenance Treatment of Depression in Old Age A Randomized, Double-blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Donepezil Combined With Antidepressant Pharmacotherapy. Archives of General Psychiatry. [Article]. 2011 Jan;68(1):51-60.

5. Grady C. BRAIN AGEING The cognitive neuroscience of ageing. Nat Rev Neurosci. [Review]. 2012 Jul;13(7):491-505.

6. Fuster JM. Cortex and Memory: Emergence of a New Paradigm. Journal of Cognitive Neuroscience. [Review]. 2009 Nov;21(11):2047-72.

7. Wolkenstein L, Plewnia C. Amelioration of Cognitive Control in Depression by Transcranial Direct Current Stimulation. Biological Psychiatry. [Article]. 2013 Apr;73(7):646-51.

8. Bowie CRP, Gupta MM, Holshausen KM. Cognitive Remediation Therapy for Mood Disorders: Rationale, Early Evidence, and Future Directions. Canadian Journal of Psychiatry. 2013;58(6):319-25.

Photo courtesy of www.istockphoto.com

The frontal lobes are promising targets for such an intervention. Several lines of evidence demonstrate that the prefrontal cortex provides a neural substrate for cognitive compensatory mechanisms that are recruited in old age.5,6 The prefrontal cortex is hyperactive in healthy individuals who are carriers of ApoE4 during learning and recall.

It is also hyperactive in patients with mild cognitive impairment during a semantic task. Further, amyloid plaques and thinning of micro-columns in the prefrontal cortex of patients with mild AD are associated with decreased cognitive compensatory capacity rather than with cognitive deficits thought to be more specific to AD. Finally, the prefrontal cortex has the capacity to experience neuroplasticity in response to injury to compensate for the cognitive effects of plaques and tangles in other regions of the brain.

therefore enhancing prefrontal cortex function.7,8 A large 5-year and multi-site trial is underway to test whether the combination of these two interventions can prevent cognitive decline and AD among patients with LLD.

IMS MAGAZINE FALL 2015 AGING | 13

FEATURE

By Shabbir M.H. Alibhai, MD, MSc, FRCP(C) Associate Professor, Dept of Medicine Institute of Health Policy, Management, and Evaluation, University of Toronto IMS Member

Geriatric Oncology

G

eriatric oncology is widely used to refer to all areas of scientific inquiry related to cancer in older adults, from prevention through end of life care, spanning basic science, clinical research, and health services research.1 Two main factors have led to the emergence of geriatric oncology as an important area of research. Both relate to the compelling epidemiology. First, over 60% of all incident cancers and 71% of cancer deaths are seen in older adults (age 65+), and aging is the single greatest risk factor for malignancy across virtually all tumour sites.2,3 Second, our population is aging, especially in industrialized nations, wh ere those age 65+ are the most rapidly growing segment of the population. In the clinical world, the median age at diagnosis for patients with lung, prostate, or colorectal cancer - three of the most common tumours - is age 70. Moreover, with increasing age comes complexity and frailty, which interact to make cancer tre atment more challenging and lead to both over- and under-treatment.

So what age group does geriatric oncology actually encompass? Much of the literature uses an age cut-off of 65. Although we all recognize that age 65 is an arbitrary definition of ‘older’ adults (hearkening back to the mandatory retirement age introduced in the late 1800s), it is clear that with advancing age come many changes in the host’s ability to respond to stressors ranging from infections through surgery and chemotherapy. This is particularly true after about age 75, when the body’s reparative mechanisms and homeostatic forces become increasingly unable to cope with seemingly minor insults.4,5 I came to the field of geriatric oncology during my graduate training. I was 14 | IMS MAGAZINE FALL 2015 AGING

searching for a research area for my thesis, and after two failed attempts, my supervisor introduced me to work examining quality of life in prostate cancer. Prostate cancer is an older man’s disease. My thesis examined age bias in the treatment of early-stage prostate cancer. I was able to demonstrate, using linked administrative databases in Ontario, that older men systematically received less aggressive (potentially curative) treatment than younger men, after adjusting for disease stage and remaining life expectancy.6 I have continued to do research in this area ever since, although my focus has shifted a little over the years.

Geriatric oncology research encompasses many areas. My early work was in parallel to a number of investigators in the field, who examined treatment patterns for various cancers as a function of age. Numerous studies in various countries have demonstrated that older adults receive less screening, less intensive diagnostic and staging work-ups, less intensive treatment for both early-stage and late-stage disease, and less effective pain medication for symptomatic advanced disease.7,8 Although these studies have identified many areas of possible age discrimination, important questions remain about how to reduce age discrimination while avoiding the harms of over-diagnosis and over-treatment.

My work shifted from describing age bias in prostate cancer to understanding the toxicities of treatment. I became particularly interested in understanding the impact of both disease and treatment on patient-relevant outcomes such as quality of life (QOL) and functional status.

Numerous studies have shown that older adults with cancer and other serious illnesses often prioritize QOL or maintaining

independence as more important goals than survival prolongation illustrating the common trade-off between quantity of life and QOL.9,10. However, we also know that not all older adults have the same priorities. I continued to study prostate cancer, but began examining the toxicities of androgen deprivation therapy (ADT) in older men. ADT is one of the most widely used treatments in prostate cancer, used in almost 1 in 2 men at some point after diagnosis, particularly in advanced disease.11,12 Using large prospective cohort studies, I examined the side effects of ADT in areas of QOL, physical function, and cognitive function.13,14 In a similar way, many investigators in geriatric oncology are studying the effects of disease and various treatments on a variety of outcomes in older adults. I branched out into a second cancer site - acute myeloid leukemia (AML). In many ways, AML is a very different disease than prostate cancer. Although AML also primarily affects older adults, the onset is much more rapid and the prognosis is much worse - 50% of older adults with AML are dead 6 months after diagnosis.15 The treatment of choice in AML is intensive chemotherapy (IC), but IC is incredibly toxic, resource-intensive, and less effective in older adults than younger adults for a variety of reasons.16 Not surprisingly, many older adults with AML do not receive IC, instead receiving best supportive care or investigational agents.17,18 I started out in this area comparing the QOL and functional status of older adults receiving IC vs non-IC approaches, and found similar if not superior QOL and functional status among those treated with IC.19 This illustrates the importance of critically examining common assumptions in oncology and other areas, such as the notion that older adults cannot tolerate intensive treatments for cancer and should

FEATURE receive more conservative treatment.

While true in some settings, in many areas carefully selected older adults achieve similar benefits from treatment as younger adults, and with similar toxicities or an acceptable increased risk of some toxicities.

I moved on to comparing QOL and functional outcomes in younger versus older patients with AML, to really understand how much worse older adults did with IC. Perhaps surprising to many in the field, in the largest study of its kind, we found remarkably similar QOL and functional impairment at the time of diagnosis (prior to treatment) among older and younger adults and, more importantly, remarkably similar QOL recovery and only slightly worse recovery in physical function domains in older adults.20 Many other investigators have performed age-stratified secondary analyses within randomized controlled trials (RCTs) to answer similar questions across different diseases and treatment regimens.

I also moved from doing observational studies to intervention-based studies in an attempt to address some of the gaps in care and negative effects of treatment in older adults. A common theme in older adults is sarcopenia (reduced muscle mass), along with loss of physiological reserve as mentioned earlier. It should come as no surprise that cancer treatments are often associated with further loss of muscle mass (with subsequent worsening QOL and functional status), and one of the most effective therapies and preventative strategies is exercise. So I started

conducting clinical trials of exercise-based interventions in both AML and prostate cancer to try to reduce treatment toxicity and improve patient outcomes. Several trials have been completed, and four more are underway.21-23 Finally, many centres worldwide are moving towards geriatric assessment (GA) in all older adults with cancer prior to embarking on treatment, particularly chemotherapy. This is because aging is associated with multiple comorbidities and impairments, a number of which are subtle and not detected in traditional clinical assessments by oncologists. Geriatric clinics are used to doing comprehensive GAs and assessing multiple domains including functional status, nutritional status, cognition, comorbidity, polypharmacy, etc. Theoretically, performing GAs prior to establishing a treatment plan in older patients with cancer will identify all the issues that may impact on treatment decision-making, leading to optimized decision-making and reduction of both over- and under-treatment.24 In collaboration with Dr. Martine Puts in the Faculty of Nursing at the University of Toronto, I have become involved in multiple studies examining the value of GA in the oncology setting. First, we conducted a systematic review and meta-analysis of all the studies examining GA.25 Having identified no RCTs of GA, and recognizing that RCTs provide the highest level of evidence to support change in practice, we are currently conducting a pilot RCT of GA versus usual care in older cancer patients with either breast, gastrointestinal, or genitourinary cancer. We hope to demonstrate improvements in QOL and functional status in the group who undergoes GA accompanied by an integrated management plan to address all the issues identified during the GA.

Photo by: Chung Ho Leung

I would be remiss if I did not mention that research in geriatric oncology is truly multi-disciplinary. I work regularly with surgical oncologists, radiation oncologists, medical oncologists, haematologic oncologists, psychologists, exercise physiologists, kinesiologists, dietitians, and biostatisticians, to name but a few.

Shabbir M.H. Alibhai, MD, MSc, FRCP(C)

My final message is that there is much more work to be done in this relatively young field. Many questions remain

around targets ranging from telomeres to telemedicine, and I consider myself truly privileged to be able to work in this incredible area.

References 1. Extermann M, Aapro M, Audisio RA, et al. The SIOG 10 Priorities Initiative. International Society of Geriatric Oncology.

2011.

2. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto: Canadian Cancer Society; 2014.

3. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.

4. Sawhney R, Sehl M, Naeim A. Physiologic aspects of aging: impact on cancer management and decision making, part I. Cancer J. 2005;11(6):449-60.

5. Sehl M, Sawhney R, Naeim A. Physiologic aspects of aging: impact on cancer management and decision making, part II. Cancer J. 2005;11(6):461-73.

6. Alibhai SMH, Krahn MD, Cohen MM, et al. Is there age bias in the treatment of localized prostate carcinoma? Cancer.

2004;100(1):72-81.

7. Ganz PA. Does (or should) chronologic age influence the choice of cancer treatment? Oncology (Huntingt). 1992;6(2 Suppl):45-9.

8. Rose JH, O’Toole EE, Dawson NV, et al. Age differences in care practices and outcomes for hospitalized patients with cancer.

J Am Geriatr Soc. 2000;48(5 Suppl):S25-32.

9. S inger PA, Martin DK, Kelner M. Quality end-of-life care: patients’ perspectives. JAMA. 1999;281(2):163-8.

10. Singer PA, Tasch ES, Stocking C, et al. Sex or survival: trade-offs between quality and quantity of life. J Clin Oncol.

1991;9:328-34. Meng MV, Grossfeld GD, Sadetsky N, et al.

Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. Urology. 2002;60(3 Suppl 1):711; discussion -2.

11. Shahinian VB, Kuo YF, Freeman JL, et al. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer. 2005;103(8):1615-24.

12. Alibhai SMH, Breunis H, Timilshina N, et al. Impact of androgen-deprivation therapy on physical function and quality of life in men with non-metastatic prostate cancer. J Clin Oncol.

2010;28(34):5038-45.

13. Alibhai SMH, Breunis H, Timilshina N, et al. Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer. J Clin Oncol. 2010;38(34):5030-7.

14. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults.

Lancet. 2013;381(9865):484-95.

15. Brandwein JM, Geddes M, Kassis J, et al. Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus. American journal of blood research. 2013;3(2):141-64.

16. Alibhai SM, Leach M, Minden MD, et al. Outcomes and quality of care in acute myeloid leukemia over 40 years. Cancer.

2009;115(13):2903-11.

17. Doria-Rose VP, Harlan LC, Stevens J, et al. Treatment of de novo acute myeloid leukemia in the United States: a report from the Patterns of Care program. Leuk Lymphoma.

2014;55(11):2549-55.

18. Alibhai SMH, Leach M, Kermalli H, et al. The impact of acute myeloid leukemia and its treatment on quality of life and functional status in older adults. Crit Rev Oncol Hematol.

2007;64(1):19-30.

19. Alibhai SMH, Breunis H, Timilshina N, et al. Quality of life and physical function in adults treated with intensive chemotherapy for acute myeloid leukemia improve over time independent of age. Journal of Geriatric Oncology. 2015.

20. Alibhai SM, O’Neill S, Fisher-Schlombs K, et al. A clinical trial of supervised exercise for adult inpatients with acute myeloid leukemia (AML) undergoing induction chemotherapy. Leuk Res. 2012;36(10):1255-61.

21. Alibhai SM, O’Neill S, Fisher-Schlombs K, et al. A pilot phase II RCT of a home-based exercise intervention for survivors of AML. Support Care Cancer. 2013.

22. Santa Mina D, Alibhai SMH, Matthew AG, et al. A randomized trial of aerobic versus resistance exercise in prostate cancer survivors. J Aging Phys Act. 2013;21(4):455-78.

23. Horgan AM, Knox JJ, Alibhai SMH. The comprehensive geriatric assessment in oncology: promises, pitfalls, and practicalities. Hospital Practice. 2010;38(3):128-36.

24. Puts MT, Hardt J, Monette J, et al. Use of geriatric assessment for older adults in the oncology setting: a systematic review.

J Natl Cancer Inst. 2012;104(15):1134-64.

IMS MAGAZINE FALL 2015 AGING | 15

FEATURE

THE POSITIVE SIDE OF AGING STEM CELLS TO THE RESCUE Cindi Morshead, PhD, Professor and Chair, Division of Anatomy, Department of Surgery, University of Toronto, IMS Member Nadia Sachewsky, PhD, Post-doctoral Fellow, University of Toronto

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ife expectancy has increased by >25 years in the last century (http:// www.statcan.gc.ca) and the average Canadian now lives to an average age of 81.7 years. It is estimated that nearly half of this increase is the result of reduced infant mortality rates in the 1920-1950’s and the increases since that time are due to reduced deaths from circulatory diseases. This extended life span comes with a host of new challenges including disease and disability, which ultimately pose challenges for the health care system. For instance, there has been an increase in the prevalence of disease in the elderly including chronic diseases such as heart disease, arthritis, diabetes, and cancer. These findings highlight the need to focus our research attention on these diseases, but, equally important, the need to understand the biology of the aging population and the implications for developing therapeutic interventions to treat the elderly.

Stem cell biology is at the forefront in the field of regenerative medicine. Stem cells

are found throughout development and into adulthood and can be isolated from a variety of tissues including heart, blood, muscle, and brain, to name a few. By definition, stem cells possess the ability to self-renew and make copies of themselves, as well as give rise to cells that will differentiate into mature cell types, which are confined to the tissue of origin. A number of stem cell populations are being explored for their therapeutic potential including embryonic stem cells, induced pluripotent stem cells, and adult tissue specific stem cells. Each of these cell types has benefits and drawbacks ranging from ethical concerns surrounding the source of the cells, issues of derivation, purification, and importantly, how they integrate within the host tissue. Stem cell based regenerative medicine strategies use two main approaches: (1) Exogenous therapy involving cell isolation, expansion, and transplantation in the injured or diseased organ, and (2) endogenous strategies that aim to activate and recruit stem cells in their existing niche in order to get them to

Nadia Sachewsky, PhD, Post-doctoral Fellow, University of Toronto 16 | IMS MAGAZINE FALL 2015 AGING

contribute to “self-repair� of the injured or diseased organ. The Morshead lab focuses on endogenous repair strategies. With the goal of manipulating the resident cells within the patient using novel therapeutics or biologics, we propose that the activated resident cells will provide trophic support and/or replace lost cells. Importantly, endogenous recruitment sidesteps issues of immune rejection, cell transformation by culturing, surgical complications from transplants, and ethical concerns surrounding the source of cells. The benefits of this approach make it a promising and exciting area of research.

The Morshead lab focuses on repair of the central nervous system. The brain and spinal cord contain populations of neural stem cells that were originally identified by Reynolds and Weiss over two decades ago.1,2 In the brain, these rare cells and their progeny are found lining the fluid-filled ventricles in a region termed the subependyma. Neural stem cells are found through development and into old age, and in the murine brain they are responsible for ongoing olfactory bulb neurogenesis throughout the lifetime of the animal. These resident stem cells are the target for brain repair strategies and indeed, they have the properties that would make them good candidates to promote repair; they are found throughout the lifetime of the animal, they are proliferative, and give rise to progeny that can differentiate into all neural cell types that comprise the central nervous system tissue (neurons, astrocytes, and oligodendrocytes). The goal is to harness their potential to repair the diseased or injured brain.

What is abundantly clear is that despite their presence in the brain, injury alone is not sufficient to activate these cells and promote brain repair. Most interestingly, while brain injury alone is sufficient to increase the numbers of neural stem cells and their progeny in the young adult brain, this activation does not result in tissue repair or recovery of lost function. However, we, and others, have achieved success using biologics such as drugs, growth factors and

FEATURE small molecules, to facilitate the activation of endogenous precursors following injury.3-5 Indeed, in a number of proof of principle studies, we demonstrated that administration of biologics following stroke can lead to enhanced neural stem and progenitor activation, tissue repair, and recovery of lost function following injury. Importantly, these studies were performed in models of stroke in the young adult brain. Stroke is the third leading cause of death in Canada (second in the world) with 50 000 deaths annually and thousands left with permanent motor and cognitive impairments. Hence, while the findings were promising and suggested hope for using stem cell based strategies to promote self-repair, the question remains as to whether these strategies will be equally effective across different ages that can suffer stroke. While stroke can affect humans at any age, occurrence in the aged population is particularly high where the risk of stroke doubles every 10 years over the age of 55 (Heart and Stroke Foundation).

What we know is that the brain changes with age. Hence, the fact that a therapeutic intervention shows promise in young adult brains does not necessarily translate into success in the aged brain. This underlies the importance of understanding the fundamental biology of neural stem cells in the aged brain - their numbers, proliferation kinetics, their responsiveness to injury and biologics-in particular as it relates to those interventions that demonstrate success in the young brain. Our lab and others have shown that with age, neural stem cells and their progeny are less active in general, and are less responsive to injury.6-7 For instance, neural stem cells and their progeny are less proliferative and generate few new neurons in the aged brain, but if you transplant these aged stem cells into a younger brain, they behave as though they were young.7 Clearly something is different about the environment in the aged brain. The differences are further demonstrated following injury. In a young brain, stroke injury alone is able to activate the endogenous stem and progenitor cells; however, this activation does not occur in the aged brain.7 This change in responsiveness to environmental cues (i.e. injury) is an important consideration when designing stem cell based interventions to treat the aged.

The Morshead lab has taken this challenge to heart and has specifically set out determine whether our brain repair strategies are effective in aged cohorts of animals. A layer of complexity is added to these studies as it is expensive to age animals, which must be housed for well over a year before they

Cindi Morshead, PhD, Professor and Chair, Division of Anatomy, Department of Surgery, University of Toronto, IMS Member can be used in the studies. Further, the health of the animals is compromised with age and this can add to the expense and time required to perform the experiments.

Despite these potential roadblocks, Nadia Sachewsky (an IMS graduate and current Postdoctoral Fellow in the Morshead group), took on the challenge. We had established that Cyclosporin A (CsA), an FDA drug used typically to prevent graft rejection following transplantation, can enhance neural stem cell survival5,8 and elicit tissue repair and functional recovery in young adult animals following stroke injury.4,5 Moreover it was effective in two distinct models of stroke and in more than one strain of mice. Would CsA be effective in old age stroke lesioned mice? Interestingly, initial experiments were not promising, as CsA did not promote survival of aged neural stem cells even in a simple culture assay. In light of the fact that injury alone did not activate aged endogenous neural stem cells, and CsA did not seem to promote their survival, we were less optimistic about seeing a positive outcome. However, what we found was that the combination of CsA and stroke injury in aged animals resulted in significant activation (increased proliferation) of neural stem and progenitor cells, effectively increasing the size of the neural stem and progenitor pool. With this in hand, we performed stroke and CsA administration chronically for one month in old age mice and, identical to what we observed in young animals, aged mice displayed functional recovery. Hence, while aged neural stem

cells are less responsive than their younger counterparts, their behavior can be modified to the same extent as young adult neural stem and progenitor cells.

These studies highlight the importance of understanding the basic biology of stem cell populations in the brain and the need to remain mindful of the fact that the population is aging. It also speaks to the promise of endogenous repair strategies as a means to promote regenerative medicine.

One cannot underestimate the importance of developing successful therapeutic interventions that are applicable to our aging population as these will ultimately have profound impact on our quality of life.

References 1. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science.

1992 Mar 27;255(5052):1707-1710.

2. Reynolds BA, Weiss S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol. 1996;175(1):1-13.

3. Kolb B, Morshead C, Gonzalez C, et al. Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab.

2007;27(5):983-997.

4. Erlandsson A, Lin CH, Yu F, et al. Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury. Exp Neurol. 2011;230(1):48-57.

5. Sachewsky N, Hunt J, Cooke MJ, et al. Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway. Dis Model Mech. 2014;7(8):953-961.

6. Enwere E, Shingo T, Gregg C, et al. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci.

2004;24(38):8354-8365.

7. Piccin D, Tufford A, Morshead CM. Neural stem and progenitor cells in the aged subependyma are activated by the young niche. Neurobiol Aging. 2014;35(7):1669-1679.

8. Hunt J, Cheng A, Hoyles A, et al. Cyclosporin A has direct effects on adult neural precursor cells. J Neurosci. 2010;30(8):2888-2896.

IMS MAGAZINE FALL 2015 AGING | 17

What is BMC? BMC is a graduate program in the design and assessment of visual media in science and medicine.

Master of Science in

Biomedical Communications Artwork by Cassandra Cetlin, 1T5 18 | IMS MAGAZINE FALL 2015 AGING

Master of Science in

Biomedical Communications

What does BMC do?

BMC bridges disciplines (art, science, medicine and communication) to develop visual material for health promotion, medical education, and scientific discovery.

Artwork by Chi-Chun Liu, 1T5 IMS MAGAZINE FALL 2015 AGING | 19

CLOSE-UP

CLOSE-UP WITH SARAH TOPA IMS THESIS AND EXAMINATION OFFICER

By Annette Ye

20 | IMS MAGAZINE FALL 2015 AGING

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or most Institute of Medical Science (IMS) students, you probably won’t meet Sarah Topa until the end of your degree—but Sarah has been there since the beginning (hint: she plans Student Orientation). Sarah is the most recent friendly face to join the IMS administration family, and is the current Thesis and Examination Officer for the IMS. I sat down with Sarah to learn about her role at the IMS, her background, and everything in between.

Let’s start with some basics!

ST: Sure. I was born in Toronto, and grew up in Mississauga, Ontario. When I was 17, I went on a plane for the first time and spent March Break in Venezuela to volunteer at an orphanage. After this, I caught the travel bug a nd went off to the west coast, where I completed my undergraduate degree at the University of British Columbia (UBC). That week of volunteering really changed my life path; I went on to study in a collaborative arts program in Religion and Literature, with a minor in Spanish at UBC. After graduating, I moved to Bogota, Columbia for six months where I brushed up on my Spanish while volunteering at an orphanage for special needs kids, and also worked with a provincial nongovernmental organization.

Sounds like you’ve had many experiences working for the charity sector. Where have you worked prior to IMS, and what attracted you to this position?

ST: I was working at the Anti-Racism & Cultural Diversity Office at the University of Toronto. Prior to that, I have a lot of experience in the non-profit sector, working abroad for a couple of think tanks and areas related to international development and human rights. Last year, I was in Nicaragua for six months working on a government-funded placement in a women’s rights agency. I really enjoy working with students, and even worked as a Residence Advisor while attending

CLOSE-UP UBC, so it was a natural transition for me to work at the IMS. I love getting to meet with students, and helping them problem solve.

Wow, you’ve been able to travel lots!

ST: For sure. I lived in the UK while completing my master’s degree in human rights at the London School of Economics and Political Science, and stayed a bit afterwards for work and travel. I’ve toured through most of Europe and Scandinavia, and also backpacked through South America for a whole summer! I also have been back to Venezuela lots to revisit the orphanage.

Other than your international volunteering, what do you enjoy doing outside of work?

ST: I think it’s a little obvious by now, but I really enjoy travelling. I also enjoy doing yoga, and own a one-year old dog, a Cavalier King Charles Spaniel.

I also help with the new IMS Translational Research Program for recruitment and advertising.

Wow that’s a long list! What do you enjoy most about what you do at IMS? ST: The people I work with, that’s the most enjoyable part. It’s a really supportive and dynamic team!

Do you have any advice for current students?

ST: Don’t be afraid to ask questions, especially when nearing the end of your program. Use myself and the graduate coordinators as a resource – if there is anything you’re not clear about, feel free to meet with me or chat over the phone!

Insider Information

Let’s talk about your role at the IMS— what does your role entail, especially beyond aspects that students may not know about?

Food:

ST: My biggest role at the IMS, akin to my position name, is to manage the exam process for students. I coordinate and process thesis submissions, master’s defense examinations, PhD final oral examinations, departmental exams, qualifying, and transfer exams. I am also here as a support role for students as they finish writing their theses and are preparing for their defense. In between, I get to participate in a lot of collaborative pieces beyond just exams; for instance, I play a major role in planning the Fall and Winter Student Orientations and the IMS Annual Scientific Day. I am also the editor for the IMS departmental newsletter, News & Views, and coordinate workshops on thesis preparation for students. Currently,

Greece.

Mediterranean for sure. I am never without hummus in the fridge!

Vacation spot: TV show:

Parks and Recreation.

Most interesting life experience:

When I was 18, I took an eight-hour canoe ride to a remote village in Papua New Guinea and volunteered at the community.

Personal inspiration?

My grandfather. He worked in the school board and was a superintendent. I have always looked up to him and he’s lived a life of service to others.

Photo by: Pratiek Matkar

IMS MAGAZINE FALL 2015 AGING | 21

VIEWPOINT

A wolf in sheep’s clothing: Physician-Assisted Suicide

By Jonathan Chio

A

recent unanimous decision made by the Supreme Court of Canada to permit physician – assisted suicide (PAS) breathes new life into the ethical landscape of facilitating suicides amongst terminally ill patients.

It begs to ask what is more important; promoting sanctity of human l ife or protecting autonomy? Through this Viewpoint article, I will advocate for the impermissibility of euthanasia and that permitting PAS will regrettably weaken our society’s respect for human life.

Before discussing my stance, for readers unfamiliar with this field of medical bioethics and philosophy, I’d like to define terminology relevant in this debate. Euthanasia can be categorized into different practices. If a competent patient requests for the health care provider (HCP) to end the patient’s life, it is voluntary active euthanasia (VAE).1 In contrast, if the HCP is requested by the patient to cause death by withholding or withdrawing treatment, this is voluntary passive euthanasia (VPE). Euthanasia can also be described as non–voluntary or involuntary. The former occurs when a surrogate decision maker requests active 22 | IMS MAGAZINE FALL 2015 AGING

or passive euthanasia on behalf of an incompetent patient, whereas the latter describes a competent patient who is either killed or has treatment withheld or withdrawn without self consent. A slippery slope argument suggests that one exception to a law will be followed by more exceptions until a point (that would initially be perceived as unthinkable and outrageous) is viewed as acceptable.

Through adopting PAS, Canada joins an exclusive list of locations (Netherlands, Belgium, Luxemburg, Switzerland, and various selective states in the USA) where PAS is fully available to all mentally– competent patients with terminal illnesses.1 Proponents for the permissibility and righteousness of PAS (and moreover, VAE and VPE) cite three main reasons: 1. Euthanasia gives patients the gift of self-determination.

2. Euthanasia provides patients with a humane and peaceful death.

3. Evidence from a series of empirical studies conducted in Netherlands suggest that responsible practice of euthanasia is practical and achievable in a country that sponsors good values and allocates

appropriate levels of social and monetary resources towards creating an easily accessible and high quality educational system.

Undeniably, Canada fits the aforementioned description (reason 3) well. To prevent misuse and abuse of the euthanasia practices, Canadian legislative bodies have established laws and safeguards which must be met for PAS to be eligible. However, these barriers are futile at protecting the moral aspects of euthanasia practices. More importantly, they distract us from a grave reality where society harbors rapidly decaying levels of respect for human life.

In the argument against permitting PAS, VAE and VPE, one of my biggest allies is Daniel Callahan.1 He condemns the act of euthanasia through a series of skillful arguments. Callahan simultaneously targets the first two reasons (where euthanasia gives patients autonomy towards self-determination and access to a humane death) by the following analogy: “If it is not permissible for another person to make you their slave despite your personal desire to live in misery, then it

VIEWPOINT is unacceptable to award the HCP with the right to kill despite obtaining patient’s explicit written consent.”

With the aforementioned analogy, Callahan further argues that the right to self–determination and to have greater control over a more peaceful process of dying are insufficient towards sanctioning HCP with the right to kill. His assault on euthanasia continues when he advocates that permitting PAS (and furthermore, VAE and VPE) will unfairly place blame on the physician in having moral and physical responsibilities in a patient’s death. Specifically, it implies that death is wholly due to medical malpractice and views the failure for a physician to administer treatment (as in VPE) as identical to killing a terminally ill patient.

To address the third argument in favor of euthanasia, Callahan views that legislature governing euthanasia will create a slippery slope that ultimately, though inadvertently, leads to IE. Despite empirical studies suggesting that euthanasia can be legalized without fear of abuse,1 results and conclusions cannot be applied universally.

In fact, recent grim evidence demonstrates that in locations where euthanasia is legalized, the contrary is becoming an unfortunate reality.

In the Netherlands, reports suggest that more than 500 people experience involuntary euthanasia annually.2 Administration of lethal substances without explicit consent accounted for 0.4% of all deaths. Furthermore, the slippery slope is rapidly developing, as euthanasia for anyone over age of 70 who is “tired of living” is now being considered.

In Belgium, the rate of non-volunary or involuntary euthanasia are three times higher than in the Netherlands.3 Furthermore, since attempts at bringing these cases to trial have failed, this suggest that the judicial system has become more tolerant and lenient over time of such transgressions.2, 4 Permitting PAS will cause us to perceive that lives of the terminally ill are less valuable than healthy individuals and that VAE and VPE are cost–effective methods for treating terminally ill patients.1,2 What’s more, cases have been reported in Netherlands where dying patients were euthanized to liberate hospital beds.2,5 Thus, ample evidence demonstrates that minor benefits gained by legalizing PAS, VAE, and VPE, cannot remotely compensate for its severe and far–reaching consequences.

immune to abuse as possible. Belgium and Netherlands are prominent examples where euthanasia practices are exploited due to faulty legislature. For history to not repeat itself, it is imperative that we learn from their mistakes. If PAS is to remain legal in Canada, I vehemently recommend that it be secondary to palliative care even though it will require additional time and emotional commitments from the physicians.2 Strict guidelines describing the non–subjective evaluations used to determine the extent and quality of suffering experienced at which PAS, VAE, and VPE are options must be introduced, enforced, and obeyed.

Despite Canada’s new legislative decisions, I strongly urge our law makers to thoroughly discuss and ensure that statutes governing PAS, VAE, and VPE are as

4. Smets T, Bilsen J, Cohen J, et al. The medical practice of euthanasia in Belgium and the Netherlands: legal notification, control and evaluation procedures. Health Policy. 2015;90(2-3):181-7.

References 1. Fisher J. Biomedical Ethics: A Canadian Focus. 2nd ed. Oxford University Press; 2009.

2. Pereira J. Legalizing euthanasia or assisted suicide: the illusion of safeguards and controls. Curr Oncol. 2011;18(2):e38-e45.

3. Van den Block L, Deschepper R, Bilsen J, et al. Euthanasia and other end-of-life decisions: a mortality follow-back study in Belgium. BMC Public Health. 2009;9:79.

5. George R, Finlay I, Jeffrey D. Legalised euthanasia will violate the rights of vulnerable patients. BMJ. 2005;331(7518):684-5.

IMS MAGAZINE FALL 2015 AGING | 23

Photo courtesy of www.istockphoto.com

SPECIAL EVENT

Care at the End of Life: An Evolving Canadian Landscape

Joint Centre for Bioethics Seminar by Jeff Blackmer, MD, MHSc, FRCPC

By Rebecca Ruddy

O

n April 1st, 2015, I had the opportunity to attend a seminar as part of the Joint Centre for Bioethics seminar series entitled “Care at the End of Life: An Evolving Canadian Landscape” by Jeff Blackmer, the Vice President of Medical Professionalism at the Canadian Medical Association (CMA).

The seminar tackled the controversial and topical subject of physician-assisted death in Canada in an enlightening and informative manner. Throughout the seminar, the speaker relayed information on the history of physician-assisted death in Canada, as well as the most recent Supreme Court decision. In addition, Dr. Blackmer highlighted the perspective of the CMA on the issue and the work that their organization has completed to better understand the viewpoints and concerns of 24 | IMS MAGAZINE FALL 2015 AGING

their members across the country.

On February 6th, 2015, the Supreme Court of Canada unanimously ruled, in the Carter vs. Canada case, to legalize physicianassisted death and that to deny a suffering individual the right to end their life would

“...end of life discussions between patients and physicians should be part of normal medical practice.” be unconstitutional.1 While the history of physician-assisted death in Canada has been marked by several milestone cases, all of

these have led to this significant and most recent Supreme Court ruling. Although these cases were only briefly touched upon at this seminar, they provided the audience with some background and a more well-rounded idea of this controversial topic with respect to its history in Canada. Overall, it is clear that this landmark decision will greatly affect Canadians, health care professionals, and the health care system in Canada.

Dr. Blackmer also discussed several key unanswered questions that were, likely intentionally, not addressed in the Supreme Court ruling and will need to be clarified before this ruling can be successfully implemented in Canadian institutions.

Firstly, there was no reference to “terminal illness” in the ruling. If it is not essential that the illness be terminal, there must be some guidelines to determine eligibility. Secondly,

SPECIAL EVENT will there be a process for “requesting aid in dying� and determining patient qualification? If so, who will be mediating these requests? Thirdly, what will the process be for determining if the patient is mentally capable of giving consent and how will consent be determined? Additionally, will doctors who do not agree with physicianassisted death be obligated to refer patients to another doctor who will comply?

Finally, will these rules and regulations be determined at the federal or provincial level?

These are just some of the questions and concerns that were raised by Dr. Blackmer at the seminar, but one can imagine the endless number of questions that accompany such a complicated and multi-faceted issue.

In order to understand the views and concerns of CMA members, the CMA held town hall meetings across the country with an unprecedented turnout, indicating that doctors are very interested in having a discussion about physician-assisted death. These town hall meetings were very informative and the CMA released a report in June 2014. They discovered that doctors are ready to lead the discussion on physician-assisted death, demonstrating that it is no longer a taboo subject. The CMA and its members recognize the need for physician-assisted death, as well as the value of palliative care.

The CMA wants to support the right of all doctors to follow their conscience on this important issue and will work to assist

in developing a legislative framework. To date, the CMA has drafted such a legislative outline which they will bring to the board for approval and receive feedback from members and stakeholders. This framework will be the basis for discussions with the federal government and will identify the important areas that the law should address.

After attending this seminar, I have gained a better understanding of the history of physician-assisted death in Canada, as well as learned the current state of the issue with the most recent Supreme Court ruling. It was interesting to hear this seminar from the perspective of a medical doctor and learn how doctors from around the country feel about physician-assisted death since this profession will be most significantly affected. During this seminar, it was thought provoking to recognize the many unanswered questions that this ruling has brought up. I will be eagerly awaiting news as to how the government will implement physician-assisted death into practice and how it will affect the lives of Canadians.

References 1. Mulholland A. Supreme Court doctor-assisted death decision: At a glance. CTV News. 2015. http://www.ctvnews.ca/canada/supremecourt-doctor-assisted-death-decision-at-a-glance-1.2223881

Photo courtesy of www.istockphoto.com

During the seminar, Dr. Blackmer detailed the CMA’s position on physician-assisted death and discussed how the CMA would be involved in the legislative process. He also discussed the efforts that the CMA has undertaken to truly understand the position and concerns of its members across Canada. As of now, current CMA policy states that the association will support members on both sides of the issue, for the medical profession, much like the public, is divided on the matter of physician-assisted death. Dr. Blackmer also explained that the CMA recognizes that there are important

practical considerations to take into account, such as capacity assessments and technical expertise. Doctors will have to be taught how to conduct physician-assisted death and understand what the process entails.

Dr. Blackmer also stated that end of life discussions between patients and physicians should be part of normal medical practice.

In addition to practical considerations, the importance of palliative care was reiterated, further emphasizing the necessity to adopt national palliative care.

IMS MAGAZINE FALL 2015 AGING | 25

BEHIND THE SCENES

Mindfulness?

Pseudoscience?

Photo courtesy of www.istockphoto.com

Think again.

B E H I N D T H E S C E N E S W I T H B R E N DA TON E R

By Katherine Schwenger Faculty featured : Brenda B. Toner, PhD, C. Psych, Professor, Department of Psychiatry,

A

s I seated outside the office waiting for my interview with Dr. Brenda Toner, I started to become anxious, as I usually do. I began to contemplate the many things I may have done to better prepare myself for this meeting and started to nervously envision how the interview itself would turn out. These thought processes weren’t unfamiliar to me and for many other students who suffer from anxiety.

Unexpectedly, the interview was a new realization. After three hours of discussing the importance of the mindbody connection as well as practicing mindfulness techniques, my anxiety was no longer present. I felt at ease and more connected with myself. It is so common for students to be focused on the past or future that we forget to live in the present. In its essence, this is mindfulness. Mindfulness is paying attention to the present moment. It is a daily practice that deepens over time.

26 | IMS MAGAZINE FALL 2015 AGING

For the past 30 years, Brenda has been involved with women’s health. Her main focus has been on mind-body connections in stigmatized disorders that are disproportionately diagnosed in women, such as eating disorders, functional gastrointestional disorders, depression, and anxiety.

Brenda’s curiosity for this connection can be traced back to her PhD thesis, which investigated test anxiety. She explained that when students were asked to speak aloud while taking a test, many students had a continuous stream of negative thoughts, fear of judgment, and selfcriticism during the test.

After discussing the concepts of the mind-body connection and mindfulness with her colleagues Dr. Zindel Segal and Dr. Wanda Taylor, Brenda became inspired to formally study and practice

mindfulness. Brenda has served as the Vice President of Education of Mindful Way Meditation and Retreat Centre, which was founded in 2009 by Dr. Taylor and is a registered charitable organization. The purpose of this organization is to provide a sanctuary for women in which to facilitate the understanding and practice of mindfulness meditation.

BENEFITS & CHALLENGES OF MINDFULNESS When asked about the benefits of mindfulness, Brenda stated, “It can be both a tool and a way of being, and it gives you the ability to acknowledge your feelings without being consumed by it.” She further explained, “Based on scientific literature mindfulness can increase mental and physical stamina and improve memory, the immune

BEHIND THE SCENES system, anxiety, depression, and decrease irritability.” One of Brenda’s biggest challenges includes “convincing people that mindfulness isn’t an extra thing to do, but has the ability to make your life more enjoyable by increasing your human and emotional connection, ultimately making you more grounded and productive.”

UNIVERSITY OF TORONTO PROGRAMS At the University of Toronto, Brenda offers two different opportunities to learn more about the mind-body connection: a drop-in class, Mindful Moments and a fourth year course, The Psychology of Mindfulness.

The Psychology of Mindfulness (PSY408H) was developed by Brenda and focuses on the theoretical, research, and clinical aspects of mindfulness.

Sitting in a circle and unplugging their devices, students gather once a week to explore and discuss their journey through mindfulness. For three hours, students are physically, mentally, and emotionally present. Students have described this course as “life changing.”

One student stated, “I used to be very stressed and had a hard time in dealing with the stress at UofT and my personal life. This course changed my life. I’m more calm, patient, mindful and happy.”

WHAT THE FUTURE HOLDS

staff, and faculty. On a societal level, she hopes that mindfulness is integrated early on in our education system as a preventative approach for health and well-being. Additionally, she wants to educate future mental health professionals about the importance and benefits of mindfulness as a treatment option. Brenda believes that in this fastpaced, technology-centered, and stressed environment that we live in people have lost the ability and awareness to relax.

Furthermore, while commenting on our everyday routine, she indicates that, “… people walk around on auto pilot, lost in their own thoughts and worries, and not living in the moment. Mindfulness has the ability to make you present in your life.”

Overall, Brenda’s kindness and compassion for others is apparent in every aspect of her life. When asked how mindfulness has impacted her life, she states, “It has given me a way of feeling grateful and maintaining my energy in a sustainable way, while staying true to my authentic and passionate self.”

Brenda’s hope for the future is that University of Toronto creates and integrates more mindfulness classes, workshops, and gatherings for students,

Photo by: Matthew Wu

Mindful Moments classes are free for University of Toronto students. There are many offerings and facilitators of mindful moments on campus and Brenda has lead one of these classes every Tuesday during the past Fall and Winter semesters. These classes include mindfulness exercises that can be integrated into your daily activities that will leave you more relaxed and resilient. Brenda acknowledges, “Many

students have symptoms of anxiety and depression, but only a small percentage actually seek help. Most people suffer in silence.” She hopes that this program will provide an open, comfortable, nonjudgmental and safe environment for all students to explore mindfulness.

IMS MAGAZINE FALL 2015 AGING | 27

EXPERT OPINION

USING EXPERIMENTS OF NATURE TO ASSIST IN HIV VACCINE DESIGN

By Justen Hoffman Russell BSc, Joseph Mathew Antony PhD, and Kelly S. MacDonald MD FRCPC Director, HIV Research Program, Mount Sinai Hospital and University Health Network; Departments of Medicine and Immunology, University of Toronto, IMS Member

W

ith several million patients showing new signs of Human Immunodeficiency Virus type 1 (HIV) infection globally, continued progress in the development of a vaccine against this pathogen is a priority. Canada is not immune to HIV infection and the consequent acquired immune deficiency syndrome (AIDS)associated mortality. Indeed, new infections continue to occur in Canada.

The groups at highest risk in Canada are intravenous drug users, gay men who have unprotected sex (especially if they have concurrent sexually transmitted diseases), select ethnic groups originating from countries with high endemic rates of HIV, and certain aboriginal groups in Canada (in some First Nation reserves in Saskatchewan the HIV rate is 11 times the national average at 63 cases per 100,000.1 There is no question that the long-term concurrent use of highly active antiretroviral medications has considerably lengthened the lifespans of infected patients and enormously improved their general well-being. However the unwanted 28 | IMS MAGAZINE FALL 2015 AGING

side effects of these medications and the incomplete suppression of all viral effects can result in toxicity and pathological changes in a variety of organs including the brain. It has become clear that even on intense treatment, the immune system does not completely normalize and there is persistent innate immune activation to a variable extent even among aggressively treated patients, hastening aging. Understanding why this occurs, the consequences, and how to avoid it, has joined the list of research topics on the HIV research agenda. It seems that pharmacotherapy may not be the Holy Grail and immune-mediated approaches directed at both prevention of HIV infection and disease are important. Not unlike the fields of rheumatology and oncology, we find ourselves endeavouring to enhance certain therapeutic immune responses and suppress other less desirable immune responses. The fields of prevention and therapeutics have merged as vaccine approaches that require broadly neutralizing antibodies and persistent cellular immune responses against conserved T cell protein epitopes.

Unlike diseases such as influenza or malaria that rely on mouse models to understand the basic biology of infections, we have had to rely on a nonhuman primate models to study HIV because it belongs to a retrovirus family that exclusively infects primates.

Macaque monkeys infected with Simian Immunodeficiency Virus (SIV), the macaque counterpart of HIV, have been preferred over chimpanzees for ethical and cost reasons. Rhesus macaques were used initially because of availability in North America but now the long-tailed or cynomolgus macaque is increasingly used, and together, they remain the best available animal models to study SIV.2 It should be remembered that SIVcpz gave rise to HIV-1 and SIVsm gave rise to HIV-2, which actually are very similar at a genomic level. Both SIVs are endemic in West Africa and do not normally infect macaques from Asia.

The macaque model closely recapitulates HIV infection, with opportunistic infections occurring if the animals are observed without intervention over a year or two. The MacDonald laboratory

EXPERT OPINION works by engaging in research studies with collaborators in epidemiological research, particularly where interesting observations are made that generate ideas incorporating rational approaches in the design of a vaccine against HIV. Dr. MacDonald has had a long-standing collaboration with researchers in Nairobi, Kenya where she and colleagues observed that certain genetic and immune factors3 played key roles in HIV resistance among individuals who were frequently exposed to HIV through sex work despite heavy exposure.4 Dr. MacDonald’s HIV vaccine studies have gone on to try to exploit some of these factors in vaccine design.

These factors include the presence of long-term persistent cellular immune responses at the mucosal interface and a lack of excessive immune activation in mucosal tissue. In the opinion of Dr. MacDonald, this ability to carry out human epidemiological studies to generate hypotheses and then test the basic science mechanism responsible in the lab is a key advantage of the clinician scientist research environment in the laboratory.

Current vaccine work in our laboratory focuses on the use of herpesviruses such as Varicella Zoster Virus, Oka vaccine strain (VZV-Oka) and Cytomegalovirus (CMV) as vaccine vectors for SIV vaccination.

Both herpesviruses establish lifelong cycles of latency and reactivation. When paired with SIV transgenes, asymptomatic reactivation in normal hosts provides an opportunity for re-exposure to SIV. This effectively boosts the animal on a regular basis leading to a robust and rapid immune response should the animals ever encounter actual SIV (Table 1).

We have already demonstrated that the VZV-Oka establishes infection and reactivates in cynomolgus macaques5 similar to children getting chickenpox vaccine with progressive boosting in antibody levels. This is in contrast to a typical vaccine where antibody levels drop over time. Then using the VZV-Oka vaccine with SIV transgenes inserted in it (one version with Gag-Pol, and Env, the other version with Nef-Tat-Rev), cynomolgus macaques were vaccinated against SIV. The protection was not perfect, but showed promise above and beyond contemporary vaccine attempts with about a third of vaccine recipients acquiring infection initially but then

Property

VZV

CMV

Oncogenic

No

No

Latency

Neural ganglia

Hematopoietic cells

Viral shedding

Minimal, except from primary infection

Asymptomatic. shedding frequent from saliva, urine, semen

Reactivation

Infrequent

Frequent

Cell tropism

Ectoderm origin neuronal tissue, tissue (skin), endothelium

Mesoderm origin- lung, gut, brain, liver, kidney, spleen, lymph nodes

Site of disease

Skin, mucous membranes

Liver, lymph nodes,

Frequency of circulating memory effector cells

<< 0.01% of CD8 cells Ratio tissue cells >> Blood CD8 effectors

0.01 to 2% of CD8 cells Ratio tissue cells = Blood CD8 effectors

Table 1

Figure 1: This is Kibera, Nairobiâ&#x20AC;&#x2122;s largest but not its poorest slum. It is the site of our research. It is typical of most African and Asian cities.

IMS MAGAZINE FALL 2015 AGING | 29

EXPERT OPINION apparently eradicating the virus and maintaining this state for more than a year and a half. It appears immune responses against viruses in the herpesvirus family (VZV, Herpes Simplex virus, CMV, etc.) are different from those against other viruses in that they are more â&#x20AC;&#x153;agileâ&#x20AC;? and they can attack the infected target immediately instead of requiring a delay.

This may have to do with evolution since these viruses are latent and our bodies have evolved to control reactivation quickly.

Since the primary application of a HIV vaccine will be in Africa, where chickenpox is not encountered as frequently (for reasons unknown), our laboratory has set out to better understand the immune mechanisms associated with varicella in the human genital mucosa in this population. We have initiated a clinical trial in a cohort of healthy women in Nairobi, Kenya. In collaboration with Dr. Walter Jaoko and Dr. Omu Anzala of KAVI (Kenya), Catia Perciani, a PhD candidate in our laboratory, is working to determine some of the cellular and molecular aspects of varicella-mediated mucosal immunity so as to apply them when designing a vector based on varicella. The goal is to examine the baseline and immune activation and the impact of vaccination on these parameters as well as its immunogenicity. This is a safe approach since there is no HIV transgene in the varicella zoster vaccine.

Concurrent to the work on a varicella zoster vaccine, we have explored the use of a second herpesvirus, CMV. Previously, the only known macaque CMV vector had been derived from a rhesus macaque CMV. Working in the cynomolgus macaque, a monkey model that more closely mirrors the disease progression seen in HIVinfected humans, infectivity studies were

30 | IMS MAGAZINE FALL 2015 AGING

precluded by the species specificity of CMV. Recent findings from the laboratory indicate that the viral vector derived from rhesus macaque CMV is unable to infect cynomolgus macaques.6 While human varicella can infect cynomolgus macaques,5 development of vectors based on CMV required the isolation of cynomolgus macaque CMV. We recently isolated two unique strains of CMV from cynomolgus macaques, one of Filipino origin7 and the other imported from the island of Mauritius.8 In fact, studies from the lab comparing genome sequences of macaque CMV indicate an evolutionary relationship between host and virus as well as between viruses, such that CMV might even reflect macaque population structure.8 They have recently completed the significant undertaking of developing an HIV/SIV vaccine based on this newly isolated CMV9 and are looking forward to an upcoming vaccine trial. Comparing two different herpesviruses with different tissue tropism and rates of reactivation and other factors will be very informative in understanding what is more optimal as an HIV immunogen.

The study of vaccines for HIV has had a long history, with only small successes along the way. HIV is a difficult virus for the immune system to fight and has defied conventional knowledge on vaccination. However, we have learned from previous attempts at vaccination and continue to learn from the herpesviruses that the MacDonald laboratory employs.

Although herpesviruses are the oldest viruses, they have offered a new approach in vaccination, and through their careful study and design, the MacDonald laboratory hopes to put a stop to the sombre reality that is HIV. Only with a vaccine can we hope to do more than just slow new HIV infections.

Figure 2: This dispensary serves Kibera. HIV antiretroviral drugs have been available for about 3 years here.

References 1. Public Health Agency of Canada.

2. Antony JM, MacDonald KS. A critical analysis of the cynomolgus macaque, Macaca fascicularis, as a model to test HIV-1/SIV vaccine efficacy. Vaccine 2015, 33(27): 3073-3083.

3. MacDonald KS, Fowke KR, Kimani J, et al. Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection. J Infect Dis 2000, 181(5):1581-1589.

4. Fowke KR, Nagelkerke NJ, Kimani J, et al. Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya.

Lancet 1996, 348(9038):1347-1351.

5. Willer DO, Ambagala AP, Pilon R, et al. Experimental infection of Cynomolgus Macaques (Macaca fascicularis) with human varicellazoster virus. Journal of virology 2012, 86(7):3626-3634.

6. Marsh AK, Ambagala AP, Perciani CT, et al. Examining the Species-Specificity of Rhesus Macaque Cytomegalovirus (RhCMV) in Cynomolgus Macaques. PLoS One 2015, 10(3):e0121339.

7. Marsh AK, Willer DO, Ambagala AP, et al. Genomic sequencing and characterization of cynomolgus macaque cytomegalovirus. Journal of virology 2011, 85(24):12995-13009.

8. Hoffman Russell JN, Marsh AK, Willer DO, et al. Macaques and their passengers: Exploring the divergence and adaptation of the ubiquitous viral pathogen CMV in fascicularis macaques. In: Microbiology & Infectious Diseases Research Days 2015. University of Toronto, Toronto, ON; 2015.

9. Hoffman Russell JN, Marsh AK, Willer DO, et al. Development of cynomolgus macaque cytomegalovirus as a novel SIV vaccine vector.

In: Keystone Symposia HIV Vaccines: Adaptive Immunity and Beyond Banff, Alberta; 2014.

TRAVEL BITES

REFLECTING ON THE 2015 EASTERN ASSOCIATION FOR ELECTROENCEPHALOGRAPHERS (EAEEG) CONFERENCE IN MANHATTAN, NY

By Jabir Mohamed

T

here are usually three reasons for going to an academic conference: to get informed, to get feedback, and/or to get noticed. A few weeks ago, I had the privilege of presenting at my first conference. I wasn’t presenting an original research paper, but rather a scholarly idea—an idea that took eight months of deliberation before it came to fruition and now serves as my Master’s thesis. Since I wasn’t presenting any data, getting noticed wasn’t on my priority list. I was more interested in being surrounded by experts in the field and getting constructive feedback around my topic: impaired consciousness in complex partial epilepsy.

Much to my dismay, being a seasoned presenter in my lab’s Journal Club did not alleviate my pre-performance anxiety.

Stories of audience members verbally attacking graduate students involuntarily seeped into my subconscious. I was anxious about what an audience member would say and worried that I wouldn’t be able to intelligently respond to their questions or comments. Yet I returned home with many positive memories, new leads, and a basket full of knowledge. A big thank you to my supervisor, Dr. McIntyre Burnham, and to Dr. Kathryn Hum, for being awesome and organizing the conference.

The EAEEG is the first and longest running conference of its kind. It was established in 1939 by pioneers in electroencephalography (EEG) to promote dialogue between

clinicians and basic researchers in the neurosciences. Recently, EEG has emerged from being a historical curiosity to modern brain activity monitoring techniques, such as functional magnetic resonance imaging and magnetoencephalography.

This is mainly because of the promise high frequency oscillations (HFOs) have shown as a novel epilepsy biomarker.

Unsurprisingly, this year’s meeting featured a symposium on EEG’s new frontier.

The first part of the symposium showcased talks from highly respected clinicianresearchers of Columbia University, Dr. Ronald Emerson and Dr. Catherine Schevon. Both unraveled the role of electrophysiology—particularly high frequencies in EEG—in locating the seizure onset zone (i.e. where the seizure starts).

Talks by University of Toronto’s Dr. Hiroshi Otsubo and Dr. Peter Carlen further supported the hypothesis that HFOs offer a window into understanding seizure network mechanisms. In the discussion that followed, two common points were raised by all conferees: 1) HFOs are better than interictal spikes in detecting seizure focus, and 2) its potential use in the clinic needs to be assessed in future research.

As per tradition, the second day featured a session of free communications. I received some great advice from my supervisor—as always—that put me at ease. He provided this eloquent analogy:

“A conference talk is linear, it’s not like reading a book. In a book, the reader can flip back to the previous page [if they realize they missed something important]. At a conference, if the audience misunderstands a few slides because they are too complex or the explanation is rushed, you’ve most likely lost their attention for the remainder of the talk. This is especially true for a 15-minute talk. Keep it simple and you’ll be fine.”

So as my supervisor’s words of wisdom reverberated in my mind, I took to the podium. I paced myself through the 15 minutes, and steadied my way through the questions. Aside from the fact that I broke the cardinal rule of staying on time—one minute and 37 seconds over to be exact—I was very happy with how it all turned out. I looked beyond the crowd to see my supervisor holding two thumbs up and the feedback I got from others during the reception was equally encouraging and gave me hope for future success. Mission accomplished.

Overall, I was very pleased with the time I spent talking to and meeting people, who I believe are ultimately committed to helping individuals with neurological diseases through research and/or practice. I am very thankful to have been able to present my research topic and even more thankful for the feedback I received. A toast to the success of the 69th annual EAEEG meeting in Manhattan; I look forward to next year’s meeting in Montreal!

IMS MAGAZINE FALL 2015 AGING | 31

SCIENTIFIC DAY

Scientific Day 2015

By Arunima Kapoor

E

very year, the Institute of Medical Science (IMS) gets together in its entirety to celebrate the accomplishments of aspiring students and faculty. Researchers from diverse disciplines come together to disseminate and absorb cutting-edge research that takes place in the labs within the department every day. It truly is a day to commemorate excellence, and this year was no exception.

32 | IMS MAGAZINE FALL 2015 AGING

The day started with poster presentations by IMS students. Numerous students displayed and presented their research. This year, the Alan Wu Poster Prizes for the most outstanding posters were awarded to Zachary Laksman and Tharini Sivasubramaniyam.

For the keynote lecture, Dr. Christopher Austin gave an inspiring welcome and keynote address which highlighted

the importance of translational innovation and spoke to the very essence of IMS. With a focus on translational research, Dr. Austinâ&#x20AC;&#x2122;s speech paved the way for full day of research inspired by translation.

We also saw the winners of this yearâ&#x20AC;&#x2122;s Laidlaw Manuscript Prizes, Simon Kelley and Karineh Kazazian, present their prize-winning research, which reflected

SCIENTIFIC DAY

work completed in the previous 12 months of graduate students. Following this, and new to Scientific Day, three data blitz sessions took place. Session A of the data blitz highlighted Cancer/ Regenerative Medicine while Session B and C highlighted Neuroscience/Brain Health and Infection/Immunology, respectively. Each session began with a breakout keynote by leading scientist in the field, followed by short, five minute presentations by students.

This year, the Siminovitch-Salter Award to honor a graduating IMS doctoral student

who has made outstanding scholarly contributions was awarded to Nathan Kolla. The Whiteside Award in recognition of a graduating IMS masterâ&#x20AC;&#x2122;s student was given to Ronnie Har. Susith Kulasekara, under the nomination of the graduate coordinators, received the Roncari Book Prize for his contributions to the academic experience of IMS students. Finally, the Sara Al-Bader Memorial Award to honor an international-stream doctorate student was awarded to S. Fatima Lakha. With the recognition of these outstanding upcoming researchers, IMS Scientific Day 2015 came to an end.

As the highpoint of the academic year, Scientific Day 2015 was a huge success.

The data blitz provided an opportunity for focused presentations and was a great addition to Scientific Day. As the department continues to grow and cultivate aspiring scientists, we hope that Scientific Day will always continue to be a platform to celebrate the achievements and accomplishments of the IMS community.

IMS MAGAZINE FALL 2015 AGING | 33

IMS SPECIAL EVENT

BEYOND THE DEBATE: THE FUTURE OF PHYSICIAN ASSISTED SUICIDE

By Katherine Schwenger and Jonathon Chio

O

n February 6th, 2015, the

Supreme Court of Canada struck down the law prohibiting physicians from helping a patient end his/her life. In response to this, the Institute of Medical Science hosted an event on June 19th, 2015, entitled, Beyond the Debate: The Future of Physician-Assisted Suicide. The objective of this discussion was to explore the impact of this ruling on Canadian health care system and society as a whole. Prior to the discussion, event attendees were asked to vote whether or not they believed the Canadian health care system (and society) were ready for physician-assisted suicide; 51% voted “yes” in support of this belief, while 49% believe that Canada was not yet ready. The moderator, Richard Minster, MD, JD, then opened the event by briefly discussing the medical, judicial, and social/ ethical components behind the Supreme Court’s ruling. Dr. Minster then proceeded to introduce the four panellists: Jeff Blackmer, MD, Jean Echlin, RN, MScN, Kerry Bowman, PhD and James Downar, MDCM, MHSc. Audience members listened intently as the four panellists contemplated the future of physician-assisted suicide.

The Supreme Court of Canada was very enigmatic in their description of parameters governing physician-assisted suicide (PAS). Instead, the Court delegated this responsibility for doctors and legislatures. Dr. Downar indicated that while physicians support PAS, they view themselves as inadequate in determining patient qualification criteria for PAS and hence, detest to play such role. Jean Echlin strongly advocated for hospice and palliative care as attractive alternatives to PAS. While acknowledging that PAS allows the patient to maintain autonomy over his/her pain, it depletes them of hope. A common concern—and one that Ms. Echlin 34 | IMS MAGAZINE FALL 2015 AGING

cited—was the slippery slope argument.

Jean used this philosophical platform to highlight evidence of eventual legislative abuse in Belgium and Netherlands where PAS has already been legalized. Ms. Echlin expressed great concern that accepting PAS will coerce healthcare providers to devalue lives of terminal patients, ending them for socioeconomic purposes. Despite building a strong case for hospice and palliative care, her comments were met with considerable resistance from the other panellists. Statistics have demonstrated that while numerous patients often request both hospice care and PAS, many never receive PAS due to palliative interventions. As for the slippery slope concern, Dr. Downar and Dr. Blackmer cautiously suggested that data from other countries might not accurately reflect the conditions and values of Canadian healthcare and citizens respectively.

Divided in their opinion to accept PAS, they unanimously agreed that Canada was not ready to introduce assisted death

options. The panelists focused on the issue of patient vulnerability; for which a strict definition and evaluation currently don’t exist.

Socioeconomic factors complicate matters further, as those with greater income and higher education are less likely to request for PAS compared to someone with lower education, income, and living alone. When a governing board is asked to thoroughly and transparently review PAS cases on per patient basis, is safeguard of the patient worth the emotional burdens experienced by the board members? Once the rules have been determined, top-down alterations must follow to ensure that current and future generations of physicians are prepared.

At the end of the discussion, event attendees were asked to vote on the same question: do you believe that the Canadian health care system and society are ready for physicianassisted suicide. The results were shocking: only 28% voted “yes” to being ready, while 72% believed that we are not. What do you think? Are we ready?

SURP AWARD WINNERS

Dustin Sokolowski

IMS MAGAZINE FALL 2015 AGING | 35

Photos by: Chung Ho Leung

Denisha Puvitharan

SURP AWARD WINNERS

The Final Frontier: Stem Cells and Neural Repair Following Stroke

By Denisha Puvitharan Affiliations: Queen’s University, 4th year student in Life Sciences (Specialization in Drug Development and Human Toxicology) Supervisor: Dr. Cindi M. Morshead, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto

I

n a world where space probes are sending back breathtakingly accurate photos of the surface of Pluto, there seems to be no end in sight for the leaps and bounds of technology. Once thought to be the final frontier of human exploration, scientists have now sent probes as far as 18.8 billion kilometers into deep space, yet the 86 billion neurons in the human brain still proves to be a mystery.1,2 For much of the 20th century, the brain was believed to be the most developed part of the human body, specialized to the point that it was capable of controlling actions as large as gross movement of limbs to tasks as fine as iris dilation.

However, this mastery came at a price. It was believed at this time that the brain was so specialized that it had lost the basic function of self-repair that was present in the rest of the body. This meant that unlike skin, which heals after a cut, the brain had no method of rescuing itself or creating new neurons, presenting a dark future for those with especially damaging neural conditions. Fortunately, this is not the case. Following the creation of theories of neuroplasticity and the discovery of adult stem cells here at the University of Toronto in the early 60s by McCulloch and Till, doors were blown wide open to the possibility of curing debilitating neural conditions such as Parkinson’s, Alzheimer’s, complications due to stroke and many other devastating illnesses.3 Stroke currently represents the third largest cause of death in Canada, killing approximately 14 000 people a year in our nation alone.4 With one stroke occurring every ten minutes in a now aging population and over 315 000 Canadians living with the long-term effects of stroke, it has become increasingly relevant to not only stop the spread of damage during strokes, but also to rescue cognitive function.5,6 Currently, one of the only available drug treatments for stroke are tissue plasminogen activators which work to actively degrade blood clots present in ischemic 36 | IMS MAGAZINE FALL 2015 AGING

strokes, but not in hemorrhagic strokes.7 Other limitations of this treatment is that it must be applied within four and a half hours from stroke onset for any results to be seen and that it only addresses the neuroprotective aspect of stroke treatment, not neural repair.7 This is where stem cells enter the picture.

Following the isolation of a pool of neural stem cells present in the subventricular zone of the lateral ventricles by Reynolds and Weiss in 1992, the possibility of repairing these once thought to be permanent damages has become far more plausible.8 Though stem cells were once thought to be useful as a cure-all treatment, scientists are still trying to outline their limitations and work towards medically relevant applications. Neural stem cells and their progeny, collectively known as neural precursor cells (NPCs) present two possible avenues of this much needed neural healing, through transplantation and through endogenous activation. Due to the ethical concerns and immunological complications surrounding the transplantation of stem cells, the focus of my summer research project was to try and enhance endogenous production of NPCs in the mammalian brain. When the brain is capable of such feats, why not try to capitalize on such abilities? As indicated by previous research, NPCs travel to sites of injury in order to aid in neural repair, but this alone is not enough to heal the damage caused by stroke.9 Nevertheless, there is still hope for this method of healing. Previous research indicates that these NPC pools can be targeted and enhanced through the use of small molecules such as Cyclosporin A (CsA) and Metformin.10,11 Our lab has also shown that when enhanced with CsA, these NPCs are capable of rescuing behavioural function that was previously lost due to stroke in mice.12 But what does that mean for patients suffering from stroke related complications and other brain conditions? It means that there may be hope for these brains to heal

themselves through simple amplification of pre-existing mechanisms of brain repair.

This presents the possibility for a treatment that could restore neural and behavioural function to the hundreds of thousands of patients living with post-stroke complications. Though it may be years before this treatment is prescribed, it still represents a novel method of patient healing capable of rescuing cognition. Perhaps the final frontier of human science is not light years away as previously believed, but rather in our own heads, resting in the power to help our brains heal themselves.

References:

1. Azevedo AC, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain. Journal of Comparative Neurology. 2009 [Cited 2015 Aug 13]; 513.5:532-541.

2. Landau E. NASA confirms Voyager 1 probe has left the solar system CNN.com [Internet]. CNN. Cable News Network; 2013 [cited 2015 Aug 13]. Retrieved from: http://www.cnn.com/2013/09/12/tech/innovation/ voyager-solar-system/ 3. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963 [Cited 2015 Aug 13]; 197:452-454.

4. The 10 leading causes of death, 2011 [Internet]. Statistics Canada.

Government of Canada; 2014 [cited 2015]. Retrieved from: http://www. statcan.gc.ca/pub/82-625-x/2014001/article/11896-eng.htm 5. Hakim A, Silver F, Hodgson C. Organized stroke care: A new era in stroke prevention and treatment. CMAJ: Canadian Medical Association Journal.1998 [Cited 2015 Aug 13]; 159.6: S1.

6. Tracking Heart Disease and Stroke in Canada - Stroke Highlights 2011 [Internet]. Public Health Agency of Canada. Government of Canada; 2011 [cited 2015 Aug 11]. Retrieved from: http://www.phac-aspc. gc.ca/cd-mc/cvd-mcv/sh-fs-2011/index-eng.php 7. Stroke medications [Internet]. Heart and Stroke Foundation. 2011 [cited 2015 Aug 12]. Retrieved from: http://www.heartandstroke.com/ site/c.ikiqlcmwjte/b.3484223/k.71d9/stroke___medications.htm 8. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science.

1992 [Cited 2015 Aug 16]; 255.5052:1707-1710.

9. Sachewsky N, Morshead CM. Adult Stem Cells and Their Role in Endogenous Tissue Repair. Emerging Technology Platforms for Stem Cells. 2009 [Cited 2015 Aug 13]; 1: 87-109.

10. Hunt J, et al. Cyclosporin A has direct effects on adult neural precursor cells. The Journal of Neuroscience. 2010 [Cited 2015 Aug 13]; 30.8: 2888-2896.

11. Dadwal P, et al. Activating Endogenous Neural Precursor Cells Using Metformin Leads to Neural Repair and Functional Recovery in a Model of Childhood Brain Injury. Stem Cell Reports. 2015 [Cited 2015 Aug 20]; 5.2: 166-173.

12. Sachewsky N, et al. Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway. Disease models & mechanisms. 2004 [Cited 2015 Aug 13]; 7.8: 953-961.

SURP AWARD WINNERS

A Novel Approach to Finding Genetic Association in Attention-Deficit/ Hyperactivity Disorder By: Dustin Sokolowski Affiliations: Western University, 3rd year student in Genetics and Applied Statistics Supervisor: Dr. Paul Arnold, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning

A

ttention-deficit/hyperactivity disorder (ADHD) is a childhood-onset, psychiatric disorder that affects approximately 3.4% of people world-wide.1 Patients with ADHD are impulsive, hyperactive, and inattentive and often have trouble with various types of cognitive processes such as executive functions. For example, ADHD patients often have deficits in response inhibition, which refers to the ability to do the appropriate thing at the appropriate time (e.g., speak at appropriate times).

Individuals with ADHD are also at risk for problems in school, work, driving, and in relationships.2 To mitigate the negative outcomes associated with ADHD, we need to develop better treatments, diagnostic screens, and early detection methods.

Understanding the biological mechanisms underlying ADHD will improve our ability to develop more efficacious medications that target the specific proteins and pathways involved in ADHD and improve our ability to diagnose ADHD accurately and perhaps before symptom onset.

Genetics play an important role in ADHD. We know ADHD is heritable based on twin studies (60-90%),3 meaning that ADHD has a moderate to strong genetic component. Although we know that ADHD is genetic, the specific genes that confer risk of developing ADHD are still unknown. One method to finding novel genetic variants in genes associated with ADHD is genome-wide association studies (GWAS) which examine millions of genetic variants across the genome.

Although several GWAS comparing patients with ADHD to healthy controls have been published, no genetic variants significantly associated with ADHD have been identified. One hurdle in finding genetic variants that are involved in ADHD is the amount of complexity in both the clinical presentation of ADHD and the genetics that likely underlie the disorder. ADHD is likely, in part, the result of hundreds of genes interacting in multiple pathways. Clinically, ADHD is also

quite variable. For example, some children may have troubles with impulsivity, while others are less impulsive but hyperactive.

Accordingly, researchers are exploring new ways of approaching genetic studies that can cut through some of the complexity and provide more power to detect novel variants in the GWAS framework.

Quantitative traits and endophenotypes are two novel approaches that may help identify genetic variants associated with ADHD using GWAS. Quantitative trait GWAS design, which uses continuous measures of a trait of interest, is more powerful than the typical GWAS case/ control design.4 An example of a quantitative trait for ADHD is the number of inattentive, hyperactive, and impulsive symptoms. Endophenotypes (i.e., intermediate phenotypes) are traits that are associated with the disorder of interest but are believed to be more directly linked to the underlying genetics than the disorder, thus reducing some genetic, behavioural, and diagnostic complexity.5 An endophenotype for ADHD is stopping a behaviour that is either planned or in progress, which is a specific type of response inhibition that is common in patients with ADHD. A real life application of stopping is applying the breaks in a car when the traffic lights turn red.

Our group at the Hospital for Sick Children, under the supervision of Dr. Paul Arnold, Dr. Russell Schachar, and Dr. Jennifer Crosbie, is using both quantitative traits and endophenotypes in GWAS to understand the genetics of ADHD. In a pilot study, we examined if number of parent-rated ADHD symptoms and performance on the Stop-Signal task was associated with millions of genetic variants across the genome using GWAS. Despite a smaller sample size, we identified signals that approached genome-wide significance, showing potential for associations with stopping and ADHD symptoms. One genetic variant associated with stopping was in the SLC24A4 gene, which is

expressed in the brain, among other bodily regions, and is responsible for transporting calcium in the cell. Calcium has recently been linked to ADHD and other major mental disorders.6 Next we will meta-analyze our data with a larger sample. Once we identify genetic variants associated with stopping and ADHD symptoms, we will test if these variants are associated with ADHD in another clinical sample.

Our study is just the first step in identifying the many genes likely to be involved in ADHD. ADHD is not going to be the result of a single gene, but likely hundreds of genes, similar to other complex psychiatric disorders like schizophrenia.7 GWAS studies will be necessary to help discover these genes. Pinpointing the genes involved in ADHD will be the first step in creating novel medications that specifically target the underlying mechanisms of ADHD. Furthermore, having proper genetic screens for ADHD will improve diagnosis and it could help tailor treatments for ADHD and improve the lives of children with ADHD and their families.

References:

1. Polanczyk, GV, Salum, GA, Sugaya, LS, Caye A, Rohde, LA. Annual Research Review: A meta‐analysis of the worldwide prevalence of mental disorders in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2015; 56(3), 345–365.

2. Barkley, RA. Major life activity and health outcomes associated with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002; 63, 10–15.

3. Todd RD. Genetics of attention deficit/hyperactivity disorder: are we ready for molecular genetic studies? Am J Med Genet Neuropsychiatry Genet. 2000; 96:241–243 4. Van der Sluis S, Posthuma D, Nivard MG, Verhage M, Dolan CV. Power in GWAS: lifting the curse of the clinical cut-off. Mol Psychiatry.

2013; 18, 2–3.

5. Crosbie J, Pérusse D, Barr CL, Schachar, RJ. Validating psychiatric endophenotypes: inhibitory control and attention deficit hyperactivity disorder. Neurosci Biobehav R. 2008; 32(1), 40–55.

6. Cross-Disorder Group of the Psychiatric Genomics Consortium.

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. The Lancet. 2013; 381(9875), 137–1379.

7. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511(7510), 421–427.

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Past Events with IMSSA

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PAST EVENTS

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6

Past Events with IMSSA 8

1. Friday Night at the ROM 2. Paintball 3. Career seminar series 4. Student mentorship 5. Gilda’s Club Greater Toronto 6. CAMH Darkness 2 Light 7. Scott Mission (2 photos) 8. St. Michael’s St. Patrick’s Day

9

9. Ice cream social at Kekou

IMS MAGAZINE FALL 2015 AGING | 39

40 | IMS MAGAZINE FALL 2015 AGING