Winter 2018

Page 1






Inflammatory Pathways as Therapeutic Targets to Insulin Resistance


New Treatment Model Reverses Beta Cell Dysfunction


Altering diet may alter risk for Type 1 Diabetes

Student-led initiative IMS MAGAZINE WINTER 2018 DIABETES |



connecting brain disorders to the immune system

BioLegend develops innovative reagents to support research within multiple neuroscience areas with a great focus on the fields of neurodegeneration and neuroinflammation. We offer a wide selection of high quality and specificity antibodies with utility in multiple applications such as IHC, IF, WB, and Flow Cytometry. Choose from a variety of targets covering:

• Immune cells • Signaling molecules • Complement system FFPE mouse brain tissue stained with astrocyte marker anti-GFAP antibody (clone SMI 25).

Learn more at: BioLegend is ISO 13485:2003 Certified Toll-Free Tel: (US & Canada): 1.877.BIOLEGEND (246.5343) Tel: 858.768.5800


World-Class Quality | Superior Customer Support | Outstanding Value

IN THIS ISSUE Letter from the Editors............................... 4


Director’s Message.................................... 5


Anna Badner Lindsay Caldarone


Beatrice Ballarin Jonathon Chio Meital Yerushalmi Natalie Osborne


Aadil Ali Aaron Wong Abanti Tagore Akshayan Vimalanathan Alaa Youssef Ana Stosic Aravin Sukumar Arman Hassanpour Bowen Zhang Chantel Kowalchuk Colin Faulkner Corinne Doroszkiewicz Craig Madho Cricia Rinchon Elizabeth Cho Erika Opingari Frank Pang Grace Jacobs Jason Lau Jessie Lim


Amanda Miller Chelsea Canlas Jerry Gu Lisa Qiu Patricia Nguyen


Grace Jacobs Krystal Jacques Iris Xu Mikaeel Valli


Tahani Baakdhah Louise Pei


Carina Freitas

Commentary............................................... 7 Retrospective............................................. 8 Feature..................................................... 12 BMC Feature............................................ 24 Viewpoint................................................. 26 Faculty Spotlight...................................... 30 Student Spotlight..................................... 34 IMS Events............................................... 38 Past Events............................................... 40 Book Review............................................ 43

Technological Innovations for the Future of Diabetes Care

2.1 million

Males (7.6%) were more likely than females (6.4%) to report that they had diabetes.1

Canadians reported being diagnosed with diabetes.1

The aging population is the most important demographic change affecting diabetes prevalence worldwide.2

Developed by Intarcia, ITCA 650 is a small subdermal pump inserted in the abdomen that continuously releases the drug Exenatide (GLP-1) for the treatment of type 2 diabetes.

Percentage of Canadians living with Diabetes in (2013-2014) according to age 18% 9% <1%


12-16 yrs

20-34 yrs

Replacing the pump takes only a

3% 35-44 yrs

45-64 yrs

few minutes,

65+ yrs

which is done every at an outpatient visit.7

1. 2.




$547 million spent annually treating diabetic foot wounds in Canada.5

Foot ulcers will occur in 15% to 25% of diabetic patients.3

In Ontario, there is one amputation due to a diabetic foot ulcer every four hours.4

• Improves patient compliance in diabetes management because it eliminates the need for daily or weekly injections. • As of fall 2017, ITCA 650 is not yet approved by the Food and Drug Administration. However, stage III clinical trials showed promising results including improved blood glucose control and weight loss compared to an oral diabetes medication.8

7. 8. Rosenstock J, Denham D, Prabhakar R, et al. Superior efficacy of ITCA 650 vs sitagliptin in uncontrolled type 2 diabetes on metformin: the FREEDOM 2 randomized, double-blind, 1-year study. Diabetes. 2016; 65(suppl1):183-OR.

Diabetic patients can lose sensation in their legs and feet. This makes it harder to notice injuries, which left undetected can become infected and even require amputation.


3 to 6





ITCA 650


Strategies that can prevent these wounds can provide a cost reduction of



Glooko Smartphone App

Initially conceived as a way to help educate millennials with Type I Diabetes, the DiaBITEsize “explainer videos” are a series of short animated videos that show young people how to manage their diabetes.9

Glooko is a user friendly app that helps diabetic patients keep track of their diet, blood glucose levels, and activity by syncing diabetic devices together including blood glucose meters, insulin pumps, and fitness trackers.10

40% 6



Blood glucose

Low cost device that helps diabetic patients monitor their legs and feet for ulcers founded by Dr. Karen Cross and Dr. General Leung and their team at St. Michael’s Hospital in Toronto. • The first early warning tool that can tell patients that tissue injury is developing. • Takes photos using different colours of infrared light and with a computer algorithm, measures oxygen delivery and blood flow. • Images can be taken anytime and anywhere by a diabetic patient on their cell phone and then sent to a healthcare provider for review.

3. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005 Jan 12; 293(2):217-28. 4. Impact of offloading devices on the cost of diabetic foot ulcers in Ontario. Ontario Report. Canadian Diabetes Association. 5. Hopkins RB, Burke N, Harlock J, et al. Economic burden of illness associated with diabetic foot ulcers in Canada. BMC Health Services Research. 2015;15:13. 6.


Josh Rapps Keith Colaco Krystal Jacque Melissa Galati Mikaael Valli Mirkamal Tolend Mohammed Zavvarian Parita Shah Pontius Tang Ranya Barayan Rehnuma Islam Sarasa Tohyama Tamadher Alghamdi Usman Saaed Yekta Dowlati Yena Lee Yousef Manialawy Yvonne Bach


Videos cover a wide range of topics, including: • How to fill prescriptions • How to treat a low blood sugar • How to handle the responsibility of diabetes self-care

Videos created by Dr. Andrew Advani & Dr. Janet Parsons and The DiaBITEsize project funded by a St Michael’s Foundation’s Translational Innovation Fund. 9.


Collects and displays data in interactive tables and graphs for patients, and data can also be shared with physicians. Sets reminders to take medication and provides information on how to adopt a healthier lifestyle. 10.

By Amanda Miller MScBMC Candidate

Copyright © 2016 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited. The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Cover Art By Lisa Qiu MScBMC Candidate





Photo by Meital Yerushalmi



appy New Year! As we enter 2018, we wanted to create an issue of the IMS Magazine that is both reflective of the past 50 years of research within the Institute of Medical Science (IMS), and representative of the exciting current and future research being undertaken within our department. Our team decided that a focus on diabetes would be perfect for this issue. As a part of the IMS 50th Anniversary Retrospective series, we are thrilled to include an article about Dr. Ernest McCulloch, with a commentary from Dr. James Till–the co-discoverers of stem cells, and integral members of the IMS. We are proud to feature faculty members who are investigating all aspects of this complex disease. Dr. Denis Daneman recounts his experience with global as well as local diabetes initiatives. Dr. Daniel Drucker discusses his investigations of the role of glucagon-like peptides in diabetes pathophysiology. We hear from Dr. Tony Lam, who explains the relationship of the gut and the brain in diabetes, and Dr. Minna Woo, who studies signaling pathways in diabetes pathogenesis. Dr. Ravi Retnakaran explains how he attempts to delay and reverse the course of early diabetes development, and Drs. Catharine Whiteside and Gary Lewis team up to describe the development of the highly impactful, national Strategic Patient-Oriented Research Network. We are also excited to share stimulating discussions in our Viewpoint articles about why we need to publish negative results, and the relationship between metabolic and mood disorders. In addition to Faculty Spotlight articles on Dr. Kerry Bowman and Dr. Paula Rochon, we highlight the creators of the Grad Minds Magazine, Rachel Dragas and Jaclyn Kelly, as well as Humayen Ahmed, the founder of 99point9. We also cover the IMS Mentorship program event, the annual Ori Rotstein lecture, and include two insightful book reviews. As always, we would like to thank our team of talented journalists, editors, designers, and photographers, whose hard work and creativity are key to every aspect of the Magazine and are clearly reflected in this issue. We are also grateful to Dr. Mingyao Liu and the IMS for their continued support of the IMS Magazine. We hope you enjoy this issue, and would love to hear any questions, comments, thoughts or feedback that you may have. Please feel free to email us, visit our website (, or reach out to us in person. Happy Reading!

Anna Badner

Lindsay Caldarone

Anna is currently a PhD student in the IMS studying therapies for traumatic spinal cord injury under the supervision of Dr. Michael Fehlings at the Krembil Research Institute.

Lindsay is currently a MSc student in the IMS studying the role of neutrophil extracellular traps in lung transplantation under the supervision of Dr. Shaf Keshavjee at the Toronto General Hospital Research Institute.




T Photo by Mikaeel Valli

DR. MINGYAO LIU Director, Institute of Medical Science Professor, Department of Surgery Senior Scientist, Toronto General Research Institute, University Health Network

he 2018 Winter issue of the IMS Magazine focuses on Diabetes, highlighting some of the diverse and internationally renowned research at the Institute of Medical Science (IMS). The feature articles showcase the work of Dr. Minna Woo, Dr. Tony Lam, Dr. Daniel Drucker, Dr. Ravi Retnakaran and Dr. Denis Daneman. There is also a feature on Dr. Catharine Whiteside and Dr. Gary Lewis, who discuss Diabetes Action Canada, a Strategic Patient-Oriented Research (SPOR) Network, which aims to drive communication and collaboration among healthcare providers, researchers, and patients. Importantly, the IMS turns 50 this year! With the anniversary in mind, the Retrospective articles continue to spotlight distinguished faculty. In this latest issue, we tell the story of Dr. Ernest McCulloch with a commentary by his close colleague, Dr. James Till. Please stay tuned for the series of special IMS 50th anniversary events and initiatives, which will be released throughout the year. I also ask you to save the date, October 3, 2018, for the 50th Anniversary Gala Reception and Dinner. In addition to the 50th anniversary celebrations, there have also been some exciting events taking place at the IMS. These include the 2017 Ori Rostein Lecture, with keynote speaker Dr. Connie Eaves, and the new Mentorship Program’s “Pillars of Health” networking opportunity. Congratulations to both organizing committees for their success! I would also like to congratulate the Editors-in-Chief, Anna Badner and Lindsay Caldarone, as well as the entire IMS Magazine staff on another thoughtful issue. The magazine continues to engage the IMS community and I look forward to reading about the outstanding work of our faculty and trainees. Sincerely, Mingyao Liu, MD, MSc Director, Institute of Medical Science




Unconventional Cancer Treatments: Complementary Truths vs. Alternative Facts By Meital Yerushalmi


he deadly truth behind alternative cancer therapies, featured in our last issue, raises the danger in resorting to unsubstantiated alternative therapies as means of curing one’s cancer. Though many such anecdotal “cures” exist online that may lure patients away from conventional care, the article begs the question—are all non-conventional cancer treatments created equal? The interest in therapies outside conventional oncology is not limited to alternative treatments. It is estimated that 40% of cancer patients worldwide use alternative or complementary therapies, and that 40% of American cancer survivors use complementary therapies following their treatment.1, 2 The distinction between the two is important: whereas alternative methods are those used instead of conventional care, complementary therapies are used alongside conventional methods to help relieve their side effects, ease pain, and improve symptoms and quality of life.3 And while the former is unequivocally discouraged by the medical community, the jury is still out on the latter. Or is it? Evidence is emerging in support of complementary modalities in cancer patients, ranging from mind-body therapies to body-based practices and supplements. Systematic reviews and meta-analyses of numerous clinical trials of mindbody techniques (including meditation, relaxation, yoga, and mindfulness-based approaches) in cancer patients have consistently shown their efficacy in reducing anxiety and stress and improving sleep quality and overall quality of life.3, 4 In addition, acupuncture was shown to be safe and effective for several symptoms of cancer patients including chemotherapyinduced nausea and vomiting, as concluded by a Cochrane review of 11 randomized control trials (RCTs).5, 6 Similarly, two systematic reviews of cancer-related RCTs concerning massage therapy concluded that while the research methodology of most trials included was poor (due to small sample size or lack of control for nonspecific effects), the data do support massage therapy as an effective adjunct in

supporting cancer care to reduce anxiety and pain.7, 8 Yet, evidence regarding supplements alongside conventional cancer care is less clear. Vitamin D has been the subject of many studies to investigate its role in cancer, as its optimal status may be associated with fewer occurrences of cancer. And while a Cochrane review of its supplementation shows a benefit in decreasing cancer mortality, the current state of evidence is not sufficient to draw firm, universal conclusions about its benefits in cancer patients.9, 10 Additionally, albeit less extensively, meta-analyses of RCTs also support probiotics in preventing radiation-induced diarrhea and melatonin in reducing side effects of chemotherapy.11, 12 High-dose vitamin C, curcumin, and other supplements remain controversial due to the inconclusive state of evidence regarding their safety and efficacy. Ostensibly, the term complementary and alternative medicine (CAM) is problematic particularly in the realm of cancer therapies, for it relates two principally distinct—and often mutually contradictory—concepts. In lieu of this outdated term, Integrative Medicine (IM) has been increasingly used to refer to the complementary treatments used in medical settings alongside conventional practices. Similarly, Integrative Oncology refers to patientcentered, evidence-informed cancer care that utilizes complementary approaches alongside conventional cancer treatments.13 Currently, the US Consortium of Academic Health Centers for Integrative Medicine has a membership of 55 esteemed academic medical centers and schools that have IM programs, including in oncology. Notable members of the Consortium include the Mayo Clinic, Stanford, John Hopkins, Harvard, and the University of Toronto.14 The latter’s Centre for Integrative Medicine not only aims to support IM research but also mandates to train conventional health professionals and collaborate with clinical partners on developing integrative health care services.15 When patients seek complementary cancer treatments, oncology teams work to maintain the delicate balance between

providing patient-centered and evidencebased care. Resources and guidelines16, 17 are available regarding the safety and efficacy of complementary treatments, which can help care teams approach the issue in a compassionate, yet evidencebased fashion that enhances trust and rapport with patients, and improves quality of life for patients and their caregivers. Integrating these care models requires a critical, yet balanced evaluation of the evidence rather than a global repudiation of all complementary treatments; in other words, let us not throw the baby out with the bathwater. I would like to thank Dr. Daniel Lander, ND and Dr. Jill Shainhouse, ND for their help with the background research for this article. 1. Gansler T, Kaw C, Crammer C, et al. A population-based study of prevalence of complementary methods use by cancer survivors: a report from the American Cancer Society’s studies of cancer survivors. Cancer. 2008;113(5):1048-57. 2. Horneber M, Bueschel G, Dennert G, et al. How many cancer patients use complementary and alternative medicine: a systematic review and metaanalysis. Integr Cancer Ther. 2012;11(3):187-203. 3. Deng G, Cassileth B. Complementary or alternative medicine in cancer care-myths and realities. Nat Rev Clin Oncol. 2013;10(11):656-64. 4. Piet J, Wurtzen H, Zachariae R. The effect of mindfulness-based therapy on symptoms of anxiety and depression in adult cancer patients and survivors: a systematic review and meta-analysis. J Consult Clin Psychol. 2012;80(6):1007-20. 5. Garcia MK, McQuade J, Haddad R, et al. Systematic review of acupuncture in cancer care: a synthesis of the evidence. J Clin Oncol. 2013;31(7):952-60. 6. Ezzo JM, Richardson MA, Vickers A, et al. Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database Syst Rev. 2006(2):CD002285. 7. Ernst E. Massage therapy for cancer palliation and supportive care: a systematic review of randomised clinical trials. Support Care Cancer. 2009;17(4):333-7. 8. Wilkinson S, Barnes K, Storey L. Massage for symptom relief in patients with cancer: systematic review. J Adv Nurs. 2008;63(5):430-9. 9. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014(1):CD007470. 10. Theodoratou E, Tzoulaki I, Zgaga L, et al. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035. 11. Liu MM, Li ST, Shu Y, et al. Probiotics for prevention of radiation-induced diarrhea: A meta-analysis of randomized controlled trials. PLoS One. 2017;12(6):e0178870. 12. Seely D, Wu P, Fritz H, et al. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012;11(4):293-303. 13. Witt CM, Balneaves LG, Cardoso MJ, et al. A Comprehensive Definition for Integrative Oncology. J Natl Cancer Inst Monogr. 2017;2017(52). 14. Member Listing: Academic Consortium for Integrative Medicine & Health; 2018. Available from: members/members.cfm. 15. About the Centre for Integrative Medicine: Leslie Dan Faculty of Pharmacy. Available from: about. 16. Memorial Sloan Kettering Cancer Center 2017. Available from: 17. Cassileth BR, Deng GE, Gomez JE, et al. Complementary therapies and integrative oncology in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):340S-54S.





Changing the Scientific Landscape: The Discovery of Stem Cells

Dr. E. McCulloch By Melissa Galati


r. Alan Bernstein, President and Chief Executive Officer (CEO) of the Canadian Institute For Advanced Research (CIFAR), once wrote in a Globe and Mail article, “If Canada’s game is hockey, it’s science is stem cells.”1 When we think of Canadian contributions to medical research, we’re quick to recall the discovery of insulin for the treatment of diabetes by Drs. Frederick Banting and Charles Best. It seems a shame, however, that so few Canadians recognize that stem cells were discovered in their own backyard. In fact, Canada has a storied history of contributions to stem cell research, the implications of which hold immense promise for the treatment of a myriad of conditions and diseases including spinal cord injuries, blindness, cancer, Parkinson’s Disease, and many others. This history begins in 1961 with a discovery by two University of Toronto (U of T) scientists, Dr. Ernest Armstrong “Bun” McCulloch—co-founder of the Institute of Medical Science (IMS)—and his colleague Dr. James Edgar Till. Dr. McCulloch, who was born and raised in Toronto, attended U of T for his undergraduate studies. Despite his penchant for humanities—he was editor of his high school’s magazine and studied English literature throughout his undergraduate education—he decided to pursue medicine, believing that this 8 | IMS MAGAZINE WINTER 2018 DIABETES

would allow him to govern his own career. “I learned enough about myself to settle on a career in medicine: I did not like discipline—therefore I wanted to work for myself—to be my own boss.”2 After graduating from medical school at U of T in 1948, Dr. McCulloch spent the following year training at the Lister Institute in London, where he was exposed to clinical research—in particular, studies of the immune system. Upon his return to Toronto, Dr. McCulloch spent the next decade specializing in haematology and slowly taking on a greater role in teaching and research. In fact, by the time Dr. McCulloch received his appointment to the newly formed Ontario Cancer Institute (OCI—now the Princess Margaret Cancer Centre) in 1957, he had almost completely transitioned out of the clinic and on to the laboratory bench. At the OCI, Dr. McCulloch set out to cure leukemia. He received funding to study the effects of radiation on mammalian cells, a project that was of particular interest to the public in light of the Cold War. The task, however, would require the knowledge of a fellow OCI scientist. Dr. Till, a Canadian physicist who had studied radiation Radiation Biology during his PhD at Yale University, had enjoyed Dr. McCulloch’s presentations at some of the more informal meetings they attended and

Photo courtesy of UHN

offered his expertise as Dr. McCulloch set out to conduct these seminal experiments. Perhaps unbeknownst to them, their partnership would last for decades. Although the existence of stem cells was already suspected and postulated, Dr. McCulloch and Dr. Till were the first to find and quantify them. Their now famous experiments involved injecting both healthy mouse bone marrow cells—which we now know include hematopoietic stem cells (HSCs)—and irradiated mouse bone marrow cells into mice that had been given a lethal dose of radiation. Although they had originally sought to determine the effects of radiation on normal cells compared to cancer cells, their results showed that the survival of the irradiated animals depended on the number of live bone marrow cells injected. The more cells injected, the better the survival of the mice. They also discovered tiny nodules on the surface of the spleens of mice injected with normal bone marrow cells. The number of nodules, which Dr. McCulloch and Dr. Till very cautiously termed “colony forming units” (CFUs), was directly proportional to the number of cells injected.3 As you might guess, these spleen CFUs were full of proliferating cells and were able to generate red blood cells, white blood cells, and platelets—the three main components of blood! We now know that Dr. McCulloch and Dr. Till had observed


the two defining features of stem cells: that they could both give rise to all the different blood cells in the body, as well as “selfrenew” (create more of themselves). Their results, although exciting at the time, did not receive much attention until nearly 30 years later. Even their trainees, many of whom would later become giants in their respective fields, could not have predicted the weight of those initial findings. Dr. Connie Eaves, current Director of the Terry Fox Laboratory BC Cancer Agency recalls, “I don’t think I knew that they were making history in the way that we understand now.”4 At the time, the stem cell field did not attract the attention and excitement it does today. Another trainee, Dr. Norman Iscove—now Senior Scientist at the OCI—comments, “Till and McCulloch created a landscape for scientific investigation where none had existed prior to their arrival.”4 Many of the PhD candidates that passed through Dr. McCulloch’s laboratory also possessed Medical Doctorate (MD) degrees. Because these students were thought to have formal training in biological sciences, they were prevented from taking biology related courses in graduate school. This rule grew to frustrate Dr. McCulloch, who taught the graduate courses in biology and knew that his course material would not have been taught in medical school. At the same time, Dr. John (Jack) Coleman Laidlaw, an endocrinologist at Toronto General Hospital, became similarly dissatisfied with the research training received by MD graduate students. This training, which typically took the form of a yearlong apprenticeship, often lacked proper evaluation. As a result, it was unclear whether students were taught proper research methodology. A more structured training regime was needed, but one that was not quite as rigid as those basic science departments already existing in U of T’s School of Graduate Studies (SGS). The IMS was conceptualized in response to this need, achieving official approval in September of 1968.

Dr. James Till, PhD

Professor Emeritus, Department of Medical Biophysics, Faculty of Medicine, University of Toronto Prior to 1968, when Ernest McCulloch began to help Jack Laidlaw to prepare for the founding of the Institute of Medical Science, Ernest had some useful previous experience. He had been a member of the Department of Medical Biophysics since 1959. Photo courtesy of J. Till The graduate program in this Department was unusual. The initial graduate faculty was drawn from the senior staff of the Ontario Cancer Institute (now the Princess Margaret Cancer Centre). It included scientists with a background in Physics, as well as ones with backgrounds in various Biomedical disciplines. This experience with a graduate program designed for a multidisciplinary set of participants was of great help during planning for the establishment of the IMS. Many people knew Ernest McCulloch by his nickname, “Bun”, given to him at an early age by his grandmother. It was used initially only by family members and close friends. He tried to limit its use by his professional colleagues in medicine and science, but was not successful. I don’t know why the nickname was so popular. I can only speculate that the name “Ernest” did not seem to describe him at all well. He certainly could show aspects of “earnestness”, such as “enthusiasm” and “purposefulness”, but synonyms such as “solemnity” and “sobriety” were not at all appropriate. On the other hand, the nickname “Bun” (or “Bunny”) involved such a ridiculous allusion to some kind of cuddlesome little rabbit that it was mind-boggling. Perhaps it was the utter absurdity of the nickname that tempted people to use it. I tried to limit my use of it, but sometimes failed. This commentary provides an example of such a failure.

Dr. McCulloch, who was the first IMS Graduate Secretary—now termed Graduate Coordinator—and its second director (succeeding Dr. Laidlaw), was essential to the department’s formative years. It seems fitting that McCulloch’s career had and would continue to embody the central tenets of the IMS. His partnership with Dr. Till—the marrying of biological and physical sciences—was a multidisciplinary team conducting groundbreaking translational research before the term was even coined. It is hard to imagine that Dr. Laidlaw and Dr. McCulloch faced so much scrutiny in the early years of the IMS—now the largest department in the Faculty of Medicine with greater than 600 faculty and 500 students. Dr. McCulloch passed away at the age of 84 on January 20, 2011, 50 years after his initial discoveries were first published. He and Dr. Till are two of Canada’s most decorated scientists, receiving nearly every

major honour and award including both the Gairdner Foundation International Award in 1969 and the Albert Lasker Award in 2005. They were both named Officers of the Order of Canada and inducted into the Canadian Medical Hall of Fame. Moreover, their research became the foundation for future breakthroughs in the stem cell field, many of which were achieved by Canadian scientists. For his contributions to research, his scientific integrity, and for his fostering of the next generation of Canadian scientists, we in the IMS are proud to call Dr. McCulloch one of our founding fathers. 1. Bernstein A. If Canada’s game is hockey, its science is stem cells. The Globe and Mail [serial online]. 2012 Mar 7 [cited 2018 Jan 3]. Available from: 2. Ernest McCulloch, Cell Biologist [Internet]. c2013 [last updated 2013 Oct 28; cited 2018 Jan 3]. Available from: http://www. 3. Stem Cell Foundation. Till & McCulloch’s Stem Cell Legacy [Internet]. 2012 [cited 5 January 2018]. Available from: https://www. 4. Mak TW. Ernest Armstrong McCulloch. 21 April 1926—20 January 2011. Biogr Mems Fell R Soc [serial online]. 2017 [cited 2018 Jan 3] DOI: 10.1098/rsbm.2017.0019. Available from: http://rsbm. rsbm.2017.0019




Technological Innovations for the Future of Diabetes Care DIABETES FACTS

2.1 million

Males (7.6%) were more likely than females (6.4%) to report that they had diabetes.1

Canadians reported being diagnosed with diabetes.1

The aging population is the most important demographic change affecting diabetes prevalence worldwide.2

Percentage of Canadians living with Diabetes in (2013-2014) according to age 18% 9% <1%


12-16 yrs

20-34 yrs

3% 35-44 yrs

45-64 yrs

65+ yrs

1. 2.

NEW METHOD FOR MANAGING DIABETIC COMPLICATIONS Diabetic patients can lose sensation in their legs and feet. This makes it harder to notice injuries, which left undetected can become infected and even require amputation.






$547 million

spent annually treating diabetic foot wounds in Canada.5 Foot ulcers will occur in 15% to 25% of diabetic patients.3

In Ontario, there is one amputation due to a diabetic foot ulcer every four hours.4

Strategies that can prevent these wounds can provide a cost reduction of

40% 6

MIMOSA Low cost device that helps diabetic patients monitor their legs and feet for ulcers founded by Dr. Karen Cross and Dr. General Leung and their team at St. Michael’s Hospital in Toronto. • The first early warning tool that can tell patients that tissue injury is developing. • Takes photos using different colours of infrared light and with a computer algorithm, measures oxygen delivery and blood flow. • Images can be taken anytime and anywhere by a diabetic patient on their cell phone and then sent to a healthcare provider for review.

3. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005 Jan 12; 293(2):217-28. 4. Impact of offloading devices on the cost of diabetic foot ulcers in Ontario. Ontario Report. Canadian Diabetes Association. 5. Hopkins RB, Burke N, Harlock J, et al. Economic burden of illness associated with diabetic foot ulcers in Canada. BMC Health Services Research. 2015;15:13. 6.



ITCA 650 Developed by Intarcia, ITCA 650 is a small subdermal pump inserted in the abdomen that continuously releases the drug Exenatide (GLP-1) for the treatment of type 2 diabetes.

Replacing the pump takes only a

few minutes, which is done every at an outpatient visit.7

3 to 6


• Improves patient compliance in diabetes management because it eliminates the need for daily or weekly injections. • As of fall 2017, ITCA 650 is not yet approved by the Food and Drug Administration. However, stage III clinical trials showed promising results including improved blood glucose control and weight loss compared to an oral diabetes medication.8

7. 8. Rosenstock J, Denham D, Prabhakar R, et al. Superior efficacy of ITCA 650 vs sitagliptin in uncontrolled type 2 diabetes on metformin: the FREEDOM 2 randomized, double-blind, 1-year study. Diabetes. 2016; 65(suppl1):183-OR.



Glooko Smartphone App

Initially conceived as a way to help educate millennials with Type I Diabetes, the DiaBITEsize “explainer videos” are a series of short animated videos that show young people how to manage their diabetes.9

Glooko is a user friendly app that helps diabetic patients keep track of their diet, blood glucose levels, and activity by syncing diabetic devices together including blood glucose meters, insulin pumps, and fitness trackers.10

Diet Blood glucose Activity

Videos cover a wide range of topics, including: • How to fill prescriptions • How to treat a low blood sugar • How to handle the responsibility of diabetes self-care

Videos created by Dr. Andrew Advani & Dr. Janet Parsons and The DiaBITEsize project funded by a St Michael’s Foundation’s Translational Innovation Fund. 9.

Collects and displays data in interactive tables and graphs for patients, and data can also be shared with physicians. Sets reminders to take medication and provides information on how to adopt a healthier lifestyle. 10.



Diabetes Action Canada:

Shift Shift Shift

A paradigm

in Research

By: Erika Opingari


magine a national network of talented researchers, dedicated patients, and one vision: to transform the health outcomes of diabetes. With Diabetes Action Canada, this has become a reality. Launched in 2016, Diabetes Action Canada is a Strategic Patient-Oriented Research (SPOR) Network sponsored by the Canadian Institutes of Health Research (CIHR). It’s mission is to transform the health outcomes of patients living with diabetes and address disparities in diabetes care. By promoting communication and collaboration among healthcare providers, researchers, and patients, the Network can study and implement solutions for the most important health concerns identified by persons living with diabetes. Canada’s SPOR program is a national, multidisciplinary network with the objective of fostering evidence-informed health care and applying research knowledge to improve healthcare systems. Provinces across Canada co-invested with CIHR in order to build the capacity and infrastructure for this transformative approach to research. In 2015, there was further investment to support national networks in chronic disease, including diabetes, chronic kidney disease, chronic pain, gastrointestinal disease, and childhood disability. As the Director of the Banting and Best Diabetes Centre, and nominated principal applicant for the CIHR SPOR Network grant, Dr. Gary Lewis spearheaded the establishment of Diabetes Action Canada as one of the SPOR Networks in Chronic Disease. He credits much of his achievement to the 12 | IMS MAGAZINE WINTER 2018 DIABETES

Photo by: Krystal Jacques-Smith

DR. GARY F. LEWIS, MD, FRCPC Professor, Department of Medicine and Department of Physiology, University of Toronto Director, Banting and Best Diabetes Centre, University of Toronto Sun Life Financial Chair in Diabetes Drucker Family Chair in Diabetes Research Co-Lead of a Strategy for Patient-Oriented Research (SPOR) Network – Diabetes Action Canada DR. CATHARINE WHITESIDE, CM MD PhD FRCP(C) FCAHS Executive Director, SPOR Network in Diabetes and its Related Complications Professor Emerita and Former Dean of Medicine, University of Toronto support and guidance of Dr. Catharine Whiteside, former Dean of Medicine at the University of Toronto and current Executive Director of the Network. Dr. Lewis believes Diabetes Action Canada exemplifies an exciting and emerging

paradigm shift in research, moving away from competition between individuals and groups and instead encouraging effort towards the common goal of collective impact; improving the care of patients with diabetes.

FEATURE “The beauty of the Network is that it is not restricted to drawing on expertise from one hospital, or even one university. It’s not about personal or institutional ego; it’s all about serving patients suffering from a very serious disease, and finding the best resources to do so,” explains Dr. Lewis. “With SPOR and Diabetes Action Canada, we have no boundaries or restrictions. We pool resources from across the country and collaborate to achieve our goals; breaking down these barriers that are huge impediments to medical advancement.” To secure the CIHR SPOR Network grant of $12.45 million over a period of five years, the Network had to include investigators from five provinces across Canada, match the funding through external sources, and incorporate persons with diabetes in their governance and advisory committees. While pulling the Network and resources together was challenging, Dr. Lewis describes it as being an organic process that started with two cores: one here in Toronto, and the second in Quebec City, led by Dr. JeanPierre Després from the Université Laval. Together, Dr. Lewis and Dr. Després are co-scientific leads for the Network. In just under two years, the Network has grown to include over 80 dedicated investigators across Canada, conducting research with a focus on primary care and developing the informatics framework needed to have an impact on improving health and preventing diabetes complications. Each project focuses on outcomes in alignment with the Quadruple Aim, which includes: 1) improved health at the population level, 2) improved patient experience and outcomes for individuals, 3) improved experience for health professionals, and 4) reduced or improved costs. Over time, Diabetes Action Canada has expanded its research network to include other investigators and increase the scope and scale of their projects with the advice of patients, their families, and caregivers. The Network functions with multiple stakeholders (federal, provincial, health ministries, industries, academia), and involves a multidisciplinary team of experts in health economics, health policy, implementation science, pragmatic clinical trials, and knowledge translation. The

Network leads are working simultaneously at both research and policy levels, in order to achieve results that will truly impact the lives of Canadians living with diabetes. By partnering with key delivery systems, such as the Ontario Telemedicine Network, Diabetes Action Canada can evaluate primary care outcomes of evidencebased programs on a larger scale. Precise evaluations of evidence-based programs can then be used to influence policy and primary care practices. “It’s a very exciting and different method of research; it’s right at the interface of health care delivery and research”, says Dr. Lewis, “We are developing new, innovative healthcare delivery mechanisms to impact a problem, and using resources across the country to do it.” Essentially, Diabetes Action Canada-and by extension SPOR-is contributing to the development of a learning health system. This refers to iterative models of care that evolve and can be evaluated fairly quickly, ultimately allowing researchers, patients, and healthcare providers to learn what actually works. The learning health system allows for high priority patient concerns to be linked to evidence-based solutions in the clinical setting. This is an emerging concept that provincial ministries of health are now adopting, and a part of the future for Diabetes Action Canada. “Diabetes Action Canada aspires to be front and center in enabling this learning health system to evolve,” says Dr. Whiteside, “And I think that’s the great opportunity for academic medicine.” Not only is Diabetes Action Canada leading the way in the evolution of the Canadian health system, but it is also challenging the traditional view of patient involvement in research. One of the key principles and distinguishing characteristics of SPOR and its affiliated networks is that patients are integrally involved in the planning, directing, and guiding of research projects. Canadians across the country living with diabetes are recruited as patient advisors and incorporated into the governance system. They meet regularly to advise the network on high priority areas in need of further research, such as lower extremity amputations.

The patient advisory circles are reflective of the community population, and thus include various demographics such as new immigrants, Francophones, and Indigenous peoples. Given that Indigenous research has been done with the full participation and leadership of the community, the Indigenous patient advisors are most deeply engaged in the Network and are leading the way. While some patient advisors may have been unsure of their role initially, they are starting to take ownership and realize the benefit they can have to the organization. They now see a role for themselves in disseminating and communicating research information to others living with diabetes. The development of patient roles in research and the consequent sense of patient empowerment is extraordinary and a testament to the value of Diabetes Action Canada. Looking forward, one of the biggest challenges will be the sustainability of the Network at the end of the current five year funding period. As of now, it is not known whether there will be an opportunity for a renewal or extension of CIHR funding. While the loss of funding is an issue of great concern, the Network is working diligently at various levels to create sustainability. It is developing important relationships with health ministries, academic institutions, and organizations such as Diabetes Canada and Juvenile Diabetes Research Foundation, to enable continued impact in the future. As I listened to Dr. Lewis and Dr. Whiteside, I couldn’t help but feel a sense of great pride and excitement for the future of research and healthcare in Canada. In many ways, this SPOR Network is transcending conventional barriers and paving the way for a new approach to research. It is establishing shared resources and expertise across the nation to create results that will have direct impact on the lives and care of persons with diabetes. It captures the true power of networking and the boundless possibilities that can be achieved through collaboration.



A Molecular Quest for Understanding Type 2 Diabetes and Insulin Resistance By: Tamadher Alghamdi


lthough the groundbreaking discovery of insulin by Banting and Best in 1922 at the University of Toronto has saved millions of lives, there is still no cure for diabetes. Today, almost half a billion people live with diabetes.1 In Canada alone, it is estimated that the number of people with diabetes will increase to 5 million by 2025.2 Moreover, the costs for medications and supplies to manage diabetes are estimated to range from $1,000 to $15,000 per year per person with diabetes.2 The substantial health and economic burden of diabetes in Canada and worldwide continues to demand novel effective therapies and urges for more fundamental research to better understand the causes of diabetes. At the forefront of this research is Dr. Minna Woo, who holds the Canada Research Chair in Signal Transduction in Diabetes Pathogenesis. For almost 20 years Dr. Woo and her team have aimed to provide a clearer picture of exactly how diabetes, particularly type 2 diabetes, develops. She believes understanding the complexities of this disease will be the key to finding the most effective treatments. 14 | IMS MAGAZINE WINTER 2018 DIABETES

Dr. Woo is a scientist at the Toronto General Hospital Research Institute (TGHRI) and a professor in the Departments of Medicine, Immunology and Institute of Medical Science at the University of Toronto, where she completed her medical degree and residency in general internal medicine with subspecialty training in endocrinology. She is the head of the Division of Endocrinology and Metabolism at the University Health Network and Mount Sinai Hospital. During her clinical training, she became interested in academic medicine and basic science research. She decided to pursue her PhD in immunology under the supervision of Dr. Tak Mak, a world-renowned Canadian scientist and the discoverer of the T cell receptor. After completing her PhD, she decided to employ her clinical and research background to understand the molecular mechanisms implicated in diabetes pathogenesis using the powerful tools of genetics and in vivo models. “Diabetes as we define it today is really poor and its diagnosis is still glucosecentric,� says Dr. Woo. It is commonly known as a chronic disease characterized

by elevated levels of glucose in the blood, either due to lack of insulin or resistance of the body to insulin.1 However, diabetes is far more complex than that and its pathogenesis is not fully understood. Diabetes comes in multiple forms. Typically, there are two main forms of diabetes, commonly known as type 1 and type 2. Type 1 is an autoimmune disease which results in destruction of insulinproducing beta cells in the pancreatic islets, and often affects children and adolescents.1 Type 2 is the most common type and is often associated with obesity, poor diet and physical inactivity. Hyperglycaemia in type 2 diabetes results from relative deficiency in insulin and the inability of the body to respond to insulin, which is known as insulin resistance. This initially leads to an increase in insulin to compensate for the high levels of glucose, and over time, the pancreatic beta cells fail to produce adequate insulin.1 Dr. Woo’s research was inspired by the many patients she sees with type 2 diabetes. The challenge with type 2 diabetes is that its onset is often difficult to determine at an early stage and it is clinically asymptomatic.

FEATURE There is a growing body of evidence suggesting that inflammation is implicated in the pathogenesis of type 2 diabetes and insulin resistance.3 Work from Dr. Woo’s lab has highlighted several inflammatory pathways that could serve as potential therapeutic targets for type 2 diabetes and insulin resistance. Using genetically engineered mice, her group unraveled the role of an important negative regulator that prevents activation of the insulin signalling pathway known as phosphatase with tensin homology (PTEN). Initially, they showed that deletion of PTEN in muscles, one of the insulin target tissues, increased glucose uptake and protected against type 2 diabetes.4 Interestingly, in a separate study, deletion of PTEN from pancreatic beta cells in mouse models of type 2 diabetes also exhibited protective effects against hyperglycemia and insulin resistance.5 Following these studies, Dr. Woo’s group showed novel findings, published in Nature Medicine, about the role of PTEN in inflammation and type 2 diabetes. They demonstrated that in vivo deletion of PTEN in select neurons not only enhanced insulin sensitivity and completely protected against type 2 diabetes, but it also reduced inflammation through activation of the anti-inflammatory reflex, a neural circuit that controls the immune responses and inflammation during pathogen invasion and tissue injury.6 Another major signalling pathway implicated in inflammation that has been the focus of Dr. Woo’s research group is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, or more simply, the JAK/STAT pathway. This pathway is an important downstream mediator for a wide array of cytokines and growth factors essential for various cellular functions including cell proliferation, differentiation, formation of blood cells (hematopoiesis), and immune response. Improper regulation of the JAK/STAT pathway contributes to hematopoietic malignancies and inflammatory conditions, which led to the development of drugs that target this pathway for treatment. However, in the context of type 2 diabetes, the role of the JAK/STAT pathway has yet to be elucidated. Several studies from Dr. Woo’s research group helped identify

Photo by: Grace Jacobs

DR. MINNA WOO Scientist, Toronto General Hospital Research Institute (TGHRI) Professor, Departments of Medicine and Immunology and Institute of Medical Science, UofT Head, Division of Endocrinology and Metabolism at University Health Network Canada Research Chair in Signal Transduction in Diabetes Pathogenesis Professor the role of the JAK/STAT pathway in the peripheral metabolic organs such as adipose tissue, liver, muscle, pancreas, and the immune system, using tissue-specific knockout mouse models. The findings of these studies suggest that the role of this pathway is highly context-dependant.7 For example, deficiency of JAK2 in macrophages–white blood cells with a role in the immune response–improves insulin sensitivity and reduces inflammation.8 In the liver, however, JAK2 expression plays a protective role against fatty liver and it is essential for growth hormone signalling.9 Although modulation of the JAK/STAT pathway provides potential therapeutic targets, the tissue-specific role of this pathway needs to be fully understood. “It is a small piece of a puzzle, but it is a critical one, especially for ubiquitous pathways. As technologies advance, these data will help in identifying the best therapeutic strategy,” says Dr. Woo.

was asked how far we are from finding a cure for diabetes, she said, “I think more research is needed for a clear understanding of this incredibly complex disease, and only by progress in good science will we find the answer.” 1. International Diabetes Federation. (2017). IDF Diabetes Atlas. 8th ed. 2. Canadian Diabetes Association. The Prevalence and Costs of Diabetes. Available at 3. Donath, M. Y. and S. E. Shoelson (2011). Type 2 diabetes as an inflammatory disease. Nature Reviews Immunology. 11(2): 98-107 4. Wijesekara, N., D. Konrad, M. Eweida, C. Jefferies, N. Liadis, A. Giacca, M. Crackower, A. Suzuki, T. W. Mak, C. R. Kahn, A. Klip, and M. Woo (2005). Muscle-specific Pten deletion protects against insulin resistance and diabetes. Molecular and cellular biology 25(3): 1135-1145 5. Wang, L., Y. Liu, S. Yan Lu, K. T. Nguyen, S. A. Schroer, A. Suzuki, T. W. Mak, H. Gaisano and M. Woo (2010). Deletion of Pten in pancreatic beta cells protects against deficient beta cell mass and function in mouse models of type 2 diabetes. Diabetes. 59(12): 3117-3126 6. Wang, L., D. Opland, S. Tsai, C. T. Luk, S. A. Schroer, M. B. Allison, A. J. Elia, C. Furlonger, A. Suzuki and C. J. Paige (2014). Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex. Nature Medicine. 20(5): 484-492 7. Dodington, D. W., H. R. Desai and M. Woo (2017). JAK/STAT– Emerging Players in Metabolism. Trends in Endocrinology & Metabolism 8. Desai, H. R., T. Sivasubramaniyam, X. S. Revelo, S. A. Schroer, C. T. Luk, P. R. Rikkala, A. H. Metherel, D. W. Dodington, Y. J. Park and M. J. Kim (2017). Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation. Scientific Reports 7(1): 7653 9. Sivasubramaniyam, T., S. A. Schroer, A. Li, C. T. Luk, S. Y. Shi, R. Besla, D. W. Dodington, A. H. Metherel, A. P. Kitson and J. J. Brunt (2017). Hepatic JAK2 protects against atherosclerosis through circulating IGF-1. JCI Insight 2(14)

Dr. Woo’s research seeks to dissect underlying mechanisms of type 2 diabetes and unravel insulin resistance at the molecular and cellular level. When she IMS MAGAZINE WINTER 2018 DIABETES | 15


The Connection between

the Gut,

the Brain,

and Diabetes. By: Krystal Jacques


he worldwide prevalence of diabetes has almost doubled, from 4.7% of the global adult population in 1980 to 8.5% in 2014.1 This is thought to reflect increases in obesity, an important risk factor associated with type 2 diabetes. Now, diabetes researchers are taking a closer look at the connection between our gastrointestinal tracts and our brains to understand how gut-brain communication may impact body weight and glucose levels. Dr. Tony Lam and his team at the Toronto General Hospital Research Institute study how the unique relationship between the gut and the brain regulates blood glucose and body weight homeostasis. After majoring in biochemistry at McMaster University, Dr. Lam completed his PhD in the Department of Physiology at University of Toronto studying liver glucose metabolism with Institute of Medical Science (IMS) faculty, Dr. Adria Giacca, whose lab studies energy excess and diabetes. “It was a challenging time-my first paper only came out towards the end of my PhD in my 5th year,” recalls Dr. Lam. However, the fulfillment of small gains each day, “performing experiments and discovering new things”, inspired him 16 | IMS MAGAZINE WINTER 2018 DIABETES

to persevere and go on to complete a postdoc (2003-2006) with Dr. Luciano Rossetti, at the Albert Einstein College of Medicine in New York. “Dr. Rossetti was the first to posit that the brain could sense nutrients (glucose and lipids) and hormones to subsequently regulate glucose homeostasis,” Dr. Lam explains. During his postdoc, Dr. Lam expanded on his previous PhD work by determining whether the brain plays a role in regulating changes in liver glucose metabolism in rodents with diabetes and obesity. To answer this, he performed the same experiments used during his PhD, but with the addition of blocking molecules and pathways in the brain. His work in Dr. Rossetti’s lab in a relatively new field investigating the brain’s role in diabetes and obesity caught the attention of other scientists. Dr. Lam accredits his research progress to being at the right place at the right time. “I just happened to be fortunate enough to be there to learn from him [Dr. Rossetti], which resulted in my ability to publish a few first-author papers in respectable journals.” Dr. Lam’s early and exemplary scientific contributions on the neurophysiological profile of diabetes during his postdoc

work showed that the brain-liver axis can control blood-glucose levels. In parallel, other researchers in the field had shown that nutrients in the gut activate a negative feedback pathway, via the gut-brain axis, to lower appetite. These two phenomena led Dr. Lam and his own lab in Toronto (started in year 2006) on a mission to discover whether ingested nutrients in the gut-brain communication pathway can also lower glucose levels. Specifically, the Lam lab wanted to know whether nutrients ingested after a meal could activate a negative feedback pathway that stems from the gut to the brain (via the vagus nerve afferent), and whether the brain then relays a signal to the organs of the body (e.g. liver) to regulate glucose levels. To answer this question, mice and rats are implanted with a catheter tube that stretches from their upper small intestine to an opening in their upper back, via a subcutaneous route. Nutrients, such as glucose and lipids, can then be infused directly into different parts of the upper small intestine, in an attempt to mimic the natural gastric emptying flux of nutrients into the gut that is experienced after a meal. This activates the nutrient sensing pathways in this particular part of the gut.


Tony Lam, PhD Professor & J.K.McIvor Endowed Chair in Diabetes Research. Senior Scientist & Canada Research Chair in Obesity. Toronto General Hospital Research Institute & University of Toronto. Associate Director, Banting & Best Diabetes Centre.

After 12 years of rigorous research, the Lam lab has shown that nutrients in the gut induce a neuronal signal to the brain, which in turn, can regulate glucose levels in healthy rodents. However, during pathological states, such as when rodents are fed a high fat diet, “a defect in these nutrient sensing mechanisms occurs, leading to a dysregulation of blood glucose levels,” explains Dr. Lam. “Interestingly, our lab has found that metformin and bariatric surgery—the two most common treatments for type 2 diabetes—can partly rescue this nutrient sensing pathway defect in the gut to restore glucose levels.” One of the Lam lab’s most recent findings was published in Cell Metabolism in January 2018 by one of his many exceptional students, Paige Bauer, who is currently pursuing a PhD.2 She performed genetic sequencing of an extract of the microbiome, the community of microbes living in the lumen of the small intestine. This revealed a correlation between the abundance of the Lactobacillaceae family of bacteria and metformin’s antidiabetic effect on the gut nutrient sensing pathway. Subsequent cause-and-effect studies were conducted and the findings indicate that metformin increases Lactobacillus and restores

glucose sensing mechanisms in the upper small intestine to lower glucose levels in diabetic/obese rodents. The basic scientific findings produced by the Lam lab warrants possible future clinical investigation. However, as with all meaningful research, Dr. Lam believes that “It takes time to find out whether your results in the lab can stand the test of time, and whether it’s clinically relevant. Nonetheless, we do have an idea of some molecules in this gut pathway that could work to be as effective as the existing therapies because they mimic the effect of metformin and bariatric surgery, which are both clinically effective to lower blood glucose levels.” In addition, the Lam lab’s findings on Lactobacillus are contributing to the currently exploding field of the microbiome, and to our repertoire of information on how gut bacteria has a significant role to play in several diseases.

Photo by Krystal Jacques-Smith

helped him in the rigorous research career—“It [research] is an extremely rewarding career, because it takes a lot, a lot of effort and time to validate that what you are showing is right to other people. And in exchange, to admit that you are wrong sometimes... it takes a lot of learning. And I love that about academics. It’s an art form—there’s a part of being a researcher that may not only have to do with discovering new things, but how you communicate, how you treat the field, and how you respect others.” 1. World Health Organization. Global report on diabetes. [document on the Internet]. 2016 [cited 2018 Jan 10]; Available from: http:// pdf. 2. Bauer P, Duca F, Waise T, et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 2018;27[1]:101-117.

Reflecting on his career as a researcher, Dr. Lam stresses the importance for students and scientists to be “open minded in both what you want to pursue as a career as well as in research, because nobody really knows what could happen tomorrow.” Dr. Lam continues by hinting at the philosophy he lives by, which has IMS MAGAZINE WINTER 2018 DIABETES | 17


Missing pieces of the puzzle: How glucagon-like peptides can improve our understanding of diabetes By: Mohammad-Masoud Zavvarian glicentin, oxyntomodulin, and two intervening peptides (Figure 1). Dr. Drucker’s pioneering research—through genetic knockouts and pharmaceutical interventions—demonstrates that GLP1 plays a critical role in multiple target tissues (Figure 1). In particular, GLP1 is an important regulator of appetite, by targeting hypothalamic satiety centers. It also acts on the islet β-cells and α-cells in a glucose-dependent manner to promote insulin and inhibit glucagon secretion. GLP1 has also been shown to affect cardiovascular function. These properties make GLP1 a suitable candidate for diabetes treatment.3

Dr. Daniel Drucker, MD, FRCPC, FRS

Professor at the Faculty of Medicine


espite significant advances made in managing diabetes over the past century, there are still looming questions about its pathophysiology and the molecular mechanisms involved. With a worldwide increase in diabetes prevalence and its risk factors, such as obesity, it is becoming even more crucial to examine these questions.1 Taking up this challenge is Dr. Daniel Drucker, who has spent more than three decades investigating the role and clinical relevance of glucagon-like peptides (GLPs) and other proglucagon-derived peptides (PGDPs) in diabetes. His research has demonstrated that these hormones are essential regulators of various homeostatic processes in the body. Trained as a clinician in molecular endocrinology, Dr. Drucker became interested in the bioactivity of glucagon and GLPs early in his career. He published a foundational 18 | IMS MAGAZINE WINTER 2018 DIABETES

Photo by Krystal Jacques-Smith

article in 1987 regarding the impacts GLP1 on insulin production,2 thereby opening new possibilities in diabetes research. Diabetes is characterized by insufficient insulin activity, either through lack of insulin production or insulin resistance. Insulin is responsible for reducing blood glucose level and opposes the action of another pancreatic hormone called glucagon. Protecting the body from hypoglycemia, glucagon is transcribed from the proglucagon gene, which also codes for glucagon-like peptides— GLP1 and GLP2. The presence of prohormone convertase 2 (PG2) in the pancreatic α-cells makes the necessary post-translational modifications to convert proglucagon into glucagon. Conversely, the intestinal prohormone convertase (PG1) results in the conversion of proglucagon into GLP1, GLP2,

“Our lab’s goal is trying to understand the hormones’ action; hormones made in the gut, their synthesis and action. We have stayed very focused. We are looking at glucagon, GLP1, GLP2, gastric inhibitory polypeptide, and dipeptidyl peptidase IV. We want to understand how they work, and what therapeutic potentials might be there,” said Dr. Drucker. His extensive research on these hormones was crucial for the development of new classes of medication for diabetes as well as short bowel syndrome (SBS), a gastrointestinal disorder also influenced by GLPs levels. For the treatment of diabetes, these medications are mainly aimed at increasing GLP-1 activity.4 It is important to note that although administration of GLP-1 reduces the serum glucose level, these peptides are degraded rapidly in the body by the enzyme dipeptidyl peptidase IV. As such, Dr. Drucker’s team focused on inhibitors of dipeptidyl peptidase IV, which has proved to be an effective treatment for diabetes patients because of its effects on GLP-1 stabilization, which ultimately helps to lower blood glucose level.

FEATURE Dr. Drucker’s team is also studying an alternative therapeutic method involving activation of GLP1-receptors, which has been shown to enhance insulin biosynthesis, increase β-cell proliferation, restore β-cell sensitivity to glucose, reduce apoptosis, and ultimately expand the β-cell mass. Since β-cells are responsible for production of insulin, their enhancement would be a great strategy for diabetes treatment. For instance, extendin 4 (an agonist of the GLP1-receptor), which has been heavily investigated by Dr. Drucker’s team, has gained FDA approval as a treatment for type 2 diabetes.3

the Order of Canada, established by Her Majesty Queen Elizabeth II to recognize outstanding achievement, dedication to the community, and service to the nation. These are in addition to numerous domestic and international recognitions and awards granted for his vigorous and valuable contributions to diabetes research. When asked to comment on his accomplishments, Dr. Drucker stated, “Everything we work on has either become a drug for diabetes, obesity, or gastrointestinal disease, but more research is required to further understand the mechanism behind their actions.”

For his exceptional work in diabetes research and short bowel syndrome (SBS), Dr. Drucker was elected as a Fellow of the Royal Society of Canada, an award granted to individuals that have made remarkable contributions in 2015. That year he also received the recognition of Officer of

Dr. Drucker’s research and accomplishments are inspiring to many students and scientists in his field. According to Dr. Drucker, the most significant challenge faced by early-career researchers is to remain focused and driven. “My advice to younger scientists

is to surround yourself with lots of mentors, and learn from the path they have traveled,” said Dr. Drucker. “Some will be very critical, and some might be supportive. But it is important not to allow negative drums to prevent you from trying.” Of utmost importance, he added, is the “realization that there is no harm in trying and failing, but that is a much better path than never trying.” Dr. Drucker remembers that as a clinician his path to laboratory research was faced with great obstacles. He was confronted with dissuading messages from his peers that his scientific endeavors would be faced with a low success rate. Yet, he endured the discouragements by surrounding himself with great mentors, and today he has become an internationally recognized scientist on diabetes research. When asked to comment about the role of the Institute of Medical Science in his success, Dr. Drucker replied that Toronto has benefited by having an inclusive system of hospitals and an academic institution. However, he added that having only one Faculty of Medicine has removed the necessary competitiveness in clinical research. Dr. Drucker believes that the future of diabetes research will benefit from a more comprehensive understanding of PGDPs and their receptors. The discoveries made thus far have greatly influenced our understanding of diabetes and its concomitant gastrointestinal or cardiovascular complications. However, there are still many questions to be answered. It is thus essential for both institutions and scientists to build upon the findings that have already been made, pursuing one of the pillars of scientific discovery: incremental research. 1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine. 2006;3(11):e442. 2. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagonlike peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proceedings of the National Academy of Sciences. 1987;84(10):3434–3438. 3. Drucker DJ. Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nature Clinical Practice Endocrinology & Metabolism. 2005 Nov;1(1):22–31. 4. Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metabolism. 2016 Jul;24(1):15–30.

Figure 1: Differential modifications of proglucagon gene and the role of GLP1 throughout body. Proglucagon is processed into glucagon, GLPs, glicentin, oxyntomodulin or two intervening peptides depending on the cell type. GLP1 is crucial for reduction of food intake, inhibition of glucagon secretion, and glucose-dependent insulin secretion. Picture modified from Drucker D. (2005).2 IMS MAGAZINE WINTER 2018 DIABETES | 19


DR. RAVI RETNAKARAN MD, MSc, FRCPC Clinician-Scientist, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Professor, Division of Endocrinology and Metabolism, University of Toronto Photo by: Mikaeel Valli

Reversing Diabetes: It must be Understood and Addressed Early 20 | IMS MAGAZINE WINTER 2018 DIABETES

FEATURE By: Mikaeel Valli


ype 2 diabetes (T2D) is a chronic metabolic disorder marked by insulin resistance and high blood glucose levels (hyperglycemia). If not managed carefully, chronic hyperglycemia may lead to cardiovascular disease, stroke, retinopathy, and kidney failure. With upwards of 60,000 new cases each year in Canada, current methods to manage diabetes (such as lifestyle changes and medication) only provide satisfactory results, as they fail to stop disease progression. Thus, clinicians and researchers are focused on developing novel interventions to treat diabetes. One promising strategy involves reversing diabetic symptoms early in its course. Dr. Ravi Retnakaran is an endocrinologist, clinician-scientist, and a leader in this field. For these reasons, in addition to many more, the IMS Magazine was pleased to interview Dr. Ravi Retnakaran. Reviewing his career trajectory, Dr. Retnakaran recalled the pivotal decision he made regarding the subspecialty to pursue in internal medicine. “When I did clinical research in diabetes during my residency, the significant scope and breadth of diabetes caught my attention” he explained. “It became clear that endocrinology is what I wanted to do. Motivated by the significant impact of T2D on his patients, Dr. Retnakaran established his research laboratory at the Lunenfeld-Tanenbaum Research Institute in Mount Sinai Hospital. Since 2006, his research group has been focused on understanding the early pathophysiology of T2D and using this knowledge to develop novel therapies for clinical trials. A major cause of T2D is the declining ability for pancreatic beta (β)-cells to produce insulin. While in vivo and in vitro experiments have made strides in preserving β-cell function, these results have not been replicated in humans. This led Dr. Retnakaran to emphasize, “[that in order] to intervene in a rational way, we need to understand the biology of diabetes early in its course.” In hopes of addressing this question, Dr. Retnakaran leads randomized control trials at Mount Sinai Hospital to test novel interventions on patients with T2D. Evidence suggests that early in the course of T2D, there is a window of opportunity in which β-cell dysfunction is reversible. Currently, the best therapy

to achieve this reversal effect is shortterm intensive insulin therapy (IIT) for two to five weeks immediately after T2D onset. Although this intervention has been known for over 20 years, it is not popular in clinics, as the effects are temporary. At 12 months following IIT, approximately 46% of patients remained in remission. “This effect is a good thing. However, we need to figure how we can maintain the initial benefit”, explained Dr. Retnakaran. Taking a modern spin on this intervention, Dr. Retnakaran incorporates concepts from oncology and rheumatology to design new strategies for improving β-cell function and maintaining the protective effect. Results from the first clinical trial, called “BEST”, showed that a dipeptidyl peptidase-4 inhibitor, Sitagliptin, failed to preserve β-cell function achieved by IIT therapy. However, results from a subsequent trial, called “LIBRA”, were more promising. Following IIT, the injectable anti-diabetic medication, Liraglutide, maintained β-cell function. However, when patients were taken off Liraglutide, the effect was lost. When analyzing these results, Dr. Retnakran commented, “This suggests that maintenance therapy of Liraglutide was not changing the underlying biology. Otherwise, we wouldn’t expect to see the effect completely lost.” Insights from BEST and LIBRA have led to two current clinical trials funded by CIHR, called “RESET-IT” and “PREVAIL.” In explaining the rationale of RESET-IT, Dr. Retnakaran says, “Insulin is the only therapy that has [demonstrated a] persistent and sustained effect. Therefore, we are testing intermittent insulin therapy as both, induction and maintenance therapy, in the RESET-IT trial.” This trial is currently underway with the goal of measuring β-cell function after 2 years. PREVAIL is another induction-maintenance trial that combines the use of Exenatide, a drug shown to be effective in glycemic control of diabetes, with insulin early in the course of diabetes. Current approaches for treating diabetes are focused on controlling blood glucose levels and improving insulin sensitivity. However, with this strategy, pancreatic β-cell function continues to deteriorate to a point of irreversibility and prompts the need for permanent insulin therapy in late stages of diabetes. Hence, treatment paradigms used in PREVAIL and RESET-IT are

novel, as insulin is used as an early therapy to rescue β-cell function. Based on growing evidence, Dr. Retnakaran can see a new treatment model for diabetic patients. At diagnosis, patients will be referred to an endocrinologist to start induction therapy to reverse the β-cell dysfunction. Subsequently, patients will return to their family doctor for maintenance therapy. Another aspect of Dr. Retnakaran’s work has been to longitudinally monitor young pregnant women, tracking their physiological changes. “Pregnancy is a natural physiological stress test for pancreatic β-cells”, he explained. Pregnant women may develop temporary diabetes termed gestational diabetes mellitus, which is also characterized by hyperglycemia. Gestational diabetes mellitus increases the risk of developing T2D in following years. Thus, as part of two large longitudinal cohort studies at Mount Sinai Hospital and in Liuyang (China), Dr. Retnakaran’s team has been carrying out various cardiometabolic tests on pregnant women with healthy, moderately abnormal, or gestational diabetic glucose levels. His team has observed that the abnormalities in glucose homeostasis during pregnancy are directly proportional to the underlying degree of β-cell dysfunction. “[This means that] you can use what happens with glucose in pregnancy and predict the future risk of diabetes,” he explained. Together, this study provides beneficial insight into the early pathophysiology of women at risk of T2D prior to the clinical manifestations of outcomes. Additionally, Dr. Retnakaran collaborates with teams at the Hospital for Sick Children to assess likelihood of diabetes in children born from mothers with gestational diabetes. With these cohort studies, Dr. Retnakaran found that “not only can we positively impact young pregnant women’s health early on, but we can potentially reduce the developmental issues and positively impact the next generation”. Through both aspects of his research, Dr. Retnakaran hopes to develop strategies aimed at early intervention to capitalize on the narrow window of opportunity in reversing β-cell function. He wishes to enhance the understanding of T2D and positively change the outcomes faced by patients with T2D.



an interview with

Dr. Denis Daneman Type 1 Diabetes, TRIGR, and the future of diabetes research

Photo by: Iris Xu

DR. DENIS DANEMAN, MB, BCh, FRCP(C) Staff physician, Endocrinology, The Hospital for Sick Children Senior Associate Scientist, Child Health Evaluative Sciences, Research Institute Profressor, Department of Paediatrics, University of Toronto By: Ana Stosic


alking down the halls of the Hospital for Sick Children (SickKids) with Dr. Denis Daneman meant that seldom were we able to pass by a person who did not recognize and acknowledge him. “You’ll find that when you have spent as much time in one place as I have, you get to know everyone,” he remarked. As we learn more about Dr. Daneman, we come to see the passion, the dedication, and above all, the perseverance, that has fuelled his ground-breaking achievements in diabetes research. Dr. Daneman completed his medical training in South Africa, and his residency in paediatrics at SickKids in 1975. It was while pursuing his 22 | IMS MAGAZINE WINTER 2018 DIABETES

medical training that Dr. Daneman first became involved in research, with an emphasis on type 1 diabetes (T1D), a chronic condition in which the pancreas produces little to no insulin. This ultimately led to a life-long research career that has contributed to shaping the field as we know it today. “Diabetes is a phenomenally complex biochemical condition which essentially affects all bodily systems,” Dr. Daneman remarks.

the University of Toronto. In 2006, Dr. Daneman was appointed Paediatricianin-Chief, a position he held until 2016, at which time he was decorated with the Order of Canada for his outstanding achievements and contributions. Reflecting on his time at SickKids, he notes that “there was a strong culture of asking, what are we doing? And how can we do it better? Not being critical, but taking a critical view.”

In 1981, Dr. Daneman began as staff endocrinologist and was later named Head of the Division of Endocrinology at SickKids, a Senior Associate Scientist with the SickKids Research Institute, and Professor in the Department of Paediatrics in the Faculty of Medicine at

Dr. Daneman’s research spans from global initiatives, such as the multi-national Trial to Reduce IDDM (insulin dependent diabetes mellitus, another term for T1D) in the Genetically at Risk (TRIGR), to local pioneering initiatives such as addressing and defining eating disorders in the T1D

FEATURE adolescent population. His contributions to the field of diabetes research have increased the depth and breadth of the literature with regards to insulin resistance and sensitivity, its metabolic control, and the early onset of T1Drelated complications. In addition, his collaborative research with Dr. Gary Rodin has defined the field of eating disorders in T1D patients.

involved. There were no differences in the demographics or the distribution of HLA genotypes within the study and control groups. Infants were fed either the control formula, containing 80% intact cow milk protein and 20% hydrolyzed milk protein, or the intervention formula, composed of extensively hydrolyzed casein.

In January of 2018, the TRIGR Study Group, within which Dr. Daneman leads the Toronto division, published their findings on whether infants at risk for T1D should have revised dietary restrictions.1 The study was an international doubleblind randomized clinical trial that began in 2003.

Ultimately, during the ten-year follow up, 91 children in the intervention group (8.4%) and 82 children in the control group (7.6%) developed diabetes. These results indicated that weaning on a cow milk-based formula was not associated with an increased cumulative incidence of T1D. The difficulty of translating preclinical research with clinical was made apparent.

“This study was inspired when a researcher came to Toronto from New Zealand, on a sabbatical, and noted that in Western Samoa there were no children with T1D. However, when they moved to New Zealand and Australia they began to develop it,” explains Dr. Daneman. “The big difference is that [in Samoa] they drink coconut milk and eat banana bread–no cow’s milk protein and no gluten. So, we wanted to know: can you alter who develops T1D by altering their diet?”

“The question, does cow’s milk protein increase the expression of type one diabetes? took 35 years to answer. So, when individuals talk about translating research into care as quickly as possible, we need to be aware of just how long it takes to get definitive answers from research. It is not a quick process,” Dr. Daneman remarked, snapping his fingers. But no matter how difficult, Dr. Daneman continues to forge ahead to find how to improve the outlook of children with T1D.

Using BB-rats as a model for T1D, they were able to assay different feeds’ effects on T1D incidence. This model was used to demonstrate that an amino acid diet led to a 15% risk for diabetes. That risk increased to 35% with the addition of gluten to the diet, and further increased to 53% with the addition of cow milk protein. Nearly 35 years’ worth of research from the TRIGR study aimed to determine whether cow’s milk protein increases the risk of developing T1D. “This was one of the first examples of whether cow’s milk protein played a role,” says Dr. Daneman.

While Dr. Daneman’s involvement in global projects is as extensive as it is successful, his local contributions are also of significant calibre and importance. In collaboration with Dr. Gary Rodin, Senior Scientist at Princess Margaret Cancer Centre and Toronto General Research Institute, Dr. Daneman has defined the field of eating disorders in children with T1D. Dr. Daneman and Dr. Rodin have published extensively on the challenges in diagnosis, behaviour, and treatment of adolescents with T1D and eating disorders. Their studies found that eating disorders are twice as common in adolescent females with T1D in comparison with non-diabetic controls.2 Subjects with T1D displayed a 10% prevalence for developing eating disorders, relative to 4% of non-diabetic controls. A further study confirmed that the prevalence of eating disorders increases during adolescence in young women, while also being highly predictive of poor metabolic control.3 Over their lifetime, diagnosed individuals tend to show persistently poor metabolic

Dr. Daneman and the TRIGR group used the pre-clinical results to design a clinical trial to test T1D preventative measures in infants. The inclusion criteria for patients required that newborn infants had a first-degree relative with T1D and defined human leukocyte antigen (HLA) genotypes, indicative of the risk of developing T1D. Infants were randomized into study groups and stratified by study centers across the 15 countries

control, which is deemed to be indicative of subsequent health complications. While the innumerable contributions by Dr. Daneman and his colleagues have made large strides in the field of T1D, he believes in an even more promising future in diabetes research: “the future of T1D is a continued sophistication of the treatment that will ultimately lead to an artificial pancreas with a sensor for glucose that tells a computer how much insulin to distribute–more when the blood sugar is high, less when it is coming down–taking the brain out of the process. The second area will be in the use of stem cells, or something within that field, which can engineer cells to produce insulin.” Dr. Daneman remarked that the technology is there, and believes the research shows much promise. A career in research is one that can yield great success as well as Herculean setbacks. “If you don’t have setbacks, if things go too smoothly at the Master’s or the PhD level, you probably haven’t asked a big enough question. The best thing that can happen to you along the way is that you get counterintuitive answers,” says Dr. Daneman. “Sometimes counterintuitive results lead you in a whole different direction, which is very positive.” Dr. Daneman ultimately likens research to an inuksuk, where the “rocks” of sustainability and resilience hold up the “rock” of methodology, which lays the foundation for the content–the pinnacle of the inuksuk. Ultimately, much like methodology lays the foundation for experimental designs, Dr. Daneman’s work lays the foundation for the future of T1D research. His legacy transcends his publications and distinguished accolades to a career which has made, and will continue to make, enormous impacts for patients, their families, the research community, and the future of the field. 1. 1. Knip M, Åkerblom HK, Al Taji E, Becker D, Bruining J, Castano L, Danne T, de Beaufort C, Dosch HM, Dupre J, Fraser WD. Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial. Jama. 2018 Jan 2;319(1):38-48. 2. 2. Jones JM, Lawson ML, Daneman D, Olmsted MP, Rodin G. Eating disorders in adolescent females with and without type 1 diabetes: cross sectional study. Bmj. 2000 Jun 10;320(7249):1563-6. 3. 3. Rydall AC, Rodin GM, Olmsted MP, Devenyi RG, Daneman D. Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. New England Journal of Medicine. 1997 Jun 26;336(26):1849-54.



Master of Science in


Shawn Liu, 1T9 Four years of undergraduate study inspires me to pursue further study in scientific illustration, storyboarding and animation making. I developed ability in storytelling by using visualized illustrations during course presentations among human biology and microbiology courses. I am committed to the understanding and transformation of complex scientific concepts into interesting and interactive images that educate public audience. Thinking that many 24 | IMS MAGAZINE WINTER 2018 DIABETES

students like me are struggling with enormous challenges of difficult course work, I decided to write articles on a Chinese social platform (WeChat), which aims to share the basic scientific knowledge in a straightforward way by using the scientific illustration method among undergrads. Remarkably, many of the topics described by my cartoonized presentations propagated beyond student community into social media and became effective tools for popularization of science.


Mona Li, 1T9

I completed my BSc at McGill, where I fostered my love for the human mind and its interplay with health, and dabbled in various fields of research. Despite prioritizing academics, I found myself filling my free time with illustration, graphic design, and videography. Realizing that what I love most about scientific

discovery is how its communication can transform society, I applied for BMC. It is a huge honour to be working on projects that combine my passions for health and communications. My peers are diverse and talented, and I look forward to the impact we will make.

Rachael Whitehead, 1T9

From growing up in the Pacific Northwest, I developed an early love for natural history and biological subject matter and drawing it. I also developed an interest in learning and describing medical related topics from spending time as a child around hospitals and doctors. I have received a BS degree in

General Biology and a BA degree in Painting and Drawing from University of Washington, Seattle. I enjoy finding new approaches to visually describing a scientific concepts from neuroanatomy to paleontology. I hope to learn many different techniques and skills during this amazing opportunity at BMC. IMS MAGAZINE WINTER 2018 DIABETES | 25


ALL DATA DESERVES A CHANCE By: Akshayan Vimalanathan


ot every experiment you conduct will be a success; this is a universal truth of scientific research. However, negative results–results that do not confirm an expected outcome or original hypothesis–should be embraced as well. These results urge the scientific community to explore alternative methods, teach us to critically examine our pre-existing beliefs, and lead to possible improvements in experimental design.1 Although frustrating, negative results play a crucial role in the self-correcting process of science. The Stigma Surrounding Negative Results Why are negative results looked upon unfavourably? One explanation stems from the misconception that negative findings reflect poorly on the competency of scientists. Many are worried the scientific community will attribute negative results to poorly designed studies and ill-informed researchers. Another explanation stems from the fact that negative results are associated with lower citation rates,1 making them unattractive to prominent journals. In the interest of cultivating their own reputations, journals are predominantly fixated on publishing exciting, statistically significant research with perceived high impact.2 Given the current scientific culture and its preference for positive findings, publishing negative results is an extremely difficult undertaking. Studies reporting negative findings are often not considered impactful 26 | IMS MAGAZINE WINTER 2018 DIABETES

enough for many journals and remain a low priority for publication.3 Overall, the dissemination of negative results is an uphill battle for scientists. Why Publish Negative Findings? Scientists trying to establish a successful research career face immense pressure to publish high impact papers. They are expected to generate a high publication output with an excellent citation rate to be competitive for promotions, tenure, and funding opportunities.1 Considering negative results yield less scientific interest and fewer citations than positive results, many scientists opt not to devote time and resources publishing negative results.1 This phenomenon–in which the outcome of a research study influences the decision to publish–is described as publication bias. Publication bias refers to the fact that studies with statistically significant results are more likely to be submitted and published than work with non-significant results.4 With negative results not being attributed the same value as positive results, researchers have less incentive to submit negative results forward for publication. In addition, researchers feel the resources necessary to submit and publish negative findings far outweigh the perceived scientific contribution. Ultimately, these negative findings are buried and disregarded, leading to an overrepresentation of positive results that create bias in the scientific literature.5

To address this bias, it is imperative for scientists to start publishing their negative findings. Failing to report negative results can skew the literature in favour of unfounded theories proposed by positive results. The inaccurate representation of data in the literature can have potentially grave consequences. Without negative results to inform the field, flawed theories remain uncorrected and continue to receive monetary support from agencies.6 Science cannot be self-correcting when information is missing from literature.7 Thus, a complete record of positive and negative results is needed to eliminate bias and paint a holistic picture. For instance, Dr. Andrew Wakefield, along with 12 co-authors, published an alarming finding that child vaccination increases the incidence of autism.8 The infamous paper triggered a decade-long decrease in child immunization and subsequently increased morbidity of preventable diseases, including measles, mumps, and rubella.9 Between 1999 and 2000, 13 studies with compelling negative results were published dismissing the notion that vaccines cause autism.9 Sadly, these negative results failed to attract the same attention as the original study. This unfortunate incident reminds us that the scientific community remains in the dark without the meaningful input of negative findings. There is tremendous value in disseminating negative results to the broader scientific community. For instance,


reporting negative results can prevent unnecessary replication of experiments that would have otherwise exhausted considerable time, effort, and resources.10 Reporting negative results can also encourage scientists to generate new hypotheses and inspire new directions of research using refined or novel methodologies.10 Future studies can undoubtedly be guided by the valuable insights of negative results. A Welcomed Change The current scientific culture tends to dismiss the importance of negative findings, as evidenced by publication bias. However, recent initiatives in the field of science suggest a cultural shift on the horizon. Several journals have emerged solely aimed at publishing negative results.3 The Journal of Negative Results in Biomedicine, the Journal of Negative Results – Ecology and Evolutionary Biology, and the Journal of Articles in Support of the Null Hypothesis. Elsevier, a well-established publisher, has also joined the growing movement in support of negative results by launching the open access journal New Negatives in Plant Sciences.10 Additional open-access journals that have contributed significantly to the dissemination of negative results include PLoS ONE and Disease Models & Mechanisms.1 The aforementioned journals evaluate research based only on its originality and competency, with no attempt being made to pre-judge significance.2 The journals are

intended to encourage scientific debate by providing a platform for negative results to be heard and accessed by the entire scientific community. Other initiatives include the announcements of two research prizes celebrating negative scientific results. The first prize, presented by the European College of Neuropsychopharmacology, is the ECNP Preclinical Network Data Prize, valued at €10,000 (US$11,800) and being offered for negative results in preclinical neuroscience.7 The second prize, presented by the Organization for Human Brain Mapping, is the OHBM Replication Award, valued at US$2,000 and being offered for best replication study.7 These two prizes are attempting to incentivize publication of negative results and replication studies respectively, signalling a shifting scientific culture. It is encouraging to see initiatives from the scientific community address publication bias and promote reporting of negative results. An experiment should not have to show positive results to earn its place in the published literature.10 Science is clearly heading in a promising direction where both positive and negative results are being recognized for their merit. Negative findings provide valuable contributions to the literature that fundamentally move us towards unabridged science.1

1. Matosin N, Frank E, Engel M, et al. Negativity towards negative results: a discussion of the disconnect between scientific worth and scientific culture. Disease Models & Mechanisms [Internet]. 2014 [cited 18 January 2018];7(2):171-173. Available from: https://www. 2. Curry S. On the importance of being negative. The Guardian [Internet]. 2018 [cited 18 January 2018];. Available from: https://www. 3. O’Hara B. Negative results are published. Nature [Internet]. 2011 [cited 18 January 2018];471(7339):448-449. Available from: https:// 4. Sutton A, Song F, Gilbody S, et al. Modelling publication bias in meta-analysis: a review. Statistical Methods in Medical Research [Internet]. 2000 [cited 18 January 2018];9(5):421-445. Available from: 5. Duyx B, Urlings M, Swaen G, et al. Scientific citations favor positive results: a systematic review and meta-analysis. Journal of Clinical Epidemiology [Internet]. 2017 [cited 18 January 2018];88:92-101. Available from: S0895435616307508 6. Weintraub P. The Importance of Publishing Negative Results. Journal of Insect Science [Internet]. 2016 [cited 18 January 2018];16(1):109. Available from: pmc/articles/PMC5088693/ 7. Rewarding negative results keeps science on track. Nature [Internet]. 2017 [cited 18 January 2018];551(7681):414-414. Available from: 8. Wakefield A, Murch S, Anthony A, et al. RETRACTED: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet [Internet]. 1998 [cited 18 January 2018];351(9103):637-641. Available from: https:// 9. Gerber J, Offit P. Vaccines and Autism: A Tale of Shifting Hypotheses. Clinical Infectious Diseases [Internet]. 2009 [cited 18 January 2018];48(4):456-461. Available from: pubmed/19128068/ 10. Granqvist E. Why science needs to publish negative results. Elsevier [Internet]. 2015 [cited 18 January 2018];. Available from: https:// why-science-needs-to-publish-negative-results



Repurposing Anti-diabetic Agents to Treat Cognitive Impairment in Metabolic & Mood Disorders

By: Yena Lee


hile depression is colloquially conceptualized as a mood disturbance, such as “feeling low and down,” affective symptoms are only one part of depression. Cognitive impairment, for instance, is also a criterion item for the diagnosis of a major depressive episode within the Diagnostic and Statistical Manual of Mental Disorders (DSM). Phenomenologically, cognitive dysfunction is pervasive among adults with mood disorders and describes a diminished ability to concentrate, process information, learn, and regulate one’s behaviour and emotions. In recent years there has been a shift in psychiatry toward characterizing dimensional, transdiagnostic domains of human 28 | IMS MAGAZINE WINTER 2018 DIABETES

behaviour and physiology. The Research Domain Criteria (RDoC)—developed by the U.S. National Institute of Mental Health—posits that quantifiable biological substrates subserve various domains of psychopathology.1 These domains of psychopathology have been operationalized as the arousal and regulatory systems (e.g., sleep-wakefulness), cognitive systems (e.g., attention, working memory), negative valence systems (e.g., fear, anxiety), positive valence systems (e.g., motivation, reward-related behaviours), and social processes (e.g., attachment, social communication). Within the RDoC framework, mood disorders can be conceptualized as a multidimensional syndrome that affects multiple transdiagnostic domains.

These domains are transdiagnostic, as they include symptoms observed across multiple psychiatric and non-psychiatric medical diagnoses. Using the example of cognition, patients with diabetes mellitus often exhibit clinically significant deficits in objective and subjective measures of cognitive function. Diabetes and depression are common comorbidities, and a bidirectional association in risk elevation is well documented. Having diabetes increases the risk for depression and, conversely, depression increases the risk for diabetes. More specifically, the odds of having both diabetes and depression are approximately double that which would be expected by adding the odds of having either diabetes or depression.2

VIEWPOINT The synergistic effect observed in the incidence of diabetes and depression appears to extend to individual patient health and functional outcomes as well. The co-occurrence of diabetes and depression is associated with significantly worse physical and mental health outcomes. Individuals with diabetes and significant depressive symptoms are more likely to have other medical comorbidities (e.g., cardiovascular disease, obesity), which further compounds to the observed morbidity in patients (e.g., hospital admission length, number of visits to their family doctor). Individuals with diabetes and significant depressive symptoms also report greater difficulties related to work (e.g., unemployment, missed days of work, reduced productivity) and other aspects of life (e.g., social withdrawal, inability to complete household chores).3

exhibiting depressive symptoms. Thus, targeting cognitive disturbance may be one way to improve functional outcomes in metabolic and mood disorders. But, how are they mechanistically related? One possible explanation involves peripheral and central insulin resistance. Replicated evidence from neuroimaging studies indicate that insulin resistance and poor glycemic control may mediate the effects of default mode network dysregulation on cognitive deficits in diabetic populations.5 The default mode network is comprised of brain regions and connections that are active during resting states and inactive during goal-oriented tasks. Hippocampal insulin resistance has been hypothesized to subserve cognitive dysfunction in diabetes and Alzheimer’s disease.6 Moreover, diabetes is associated

“Diabetes and depression are common comorbidities, and a bidirectional association in risk elevation is well documented.” Emerging evidence suggests that cognitive impairment may be a key mediator of functional outcomes in metabolic and mood disorders. It seems intuitive that cognitive disturbances diminish our ability to engage and contribute meaningfully in a workplace, home, or social setting. The ability to work productively and maintain employment demands that an individual be able to function cognitively. A recent cross-national study of 3,627 working Canadians assessed cognitive and depressive symptoms and work-related impairment in adults with prediabetes or type II diabetes mellitus (as proxied by glycated hemoglobin levels).4 The investigators noted that self-reported cognitive difficulties (e.g., decreased ability in concentrating, planning, or getting organized) led to lost productivity and work absence among pre-diabetic or diabetic adults

with an increased risk for mild cognitive impairment and Alzheimer’s disease, suggesting that the mechanisms subserving cognitive dysfunction in diabetes extends to other diagnostic categories as well. Studies of diffusion tensor imaging and resting-state functional magnetic resonance imaging additionally implicate abnormalities in the default mode network, among other brain circuits, nodes and networks, in cognitive dysfunction. Replicated studies have documented microstructural white matter abnormalities and functional disconnectivity in this network in metabolic and mood disorders.

of cognitive function in 19 non-diabetic adults with mood disorder.7 Glucagon-like peptide-1 belongs to a group of insulin-sensitizing metabolic hormones called incretins, which are released after meal consumption and enhance insulin secretion. Liraglutide significantly improved objective measures of cognition after four weeks of treatment. Interestingly, baseline insulin resistance and body mass index was noted to moderate improvements in cognitive function with liraglutide treatment. Taken together, cognitive impairment is transdiagnostic and pervasive across metabolic and mood disorders, and is a critical determinant of functional outcomes. Accumulating and convergent evidence implicates central and peripheral metabolic disturbances in cognitive dysfunction. While the mechanisms mediating deficits in cognitive systems are not fully understood, interventional studies that have repurposed existing anti-diabetic agents show promise in improving cognitive function in populations with metabolic and/or mood disorders. 1. Insel TR. The NIMH Research Domain Criteria (RDoC) Project: 2. precision medicine for psychiatry. Am J Psychiatry 2014; 171: 395–397. 3. Scott KM, Von Korff M, Alonso J, et al. Mental-physical co-morbidity and its relationship with disability: results from the World Mental Health Surveys. Psychol Med 2009; 39: 33–43. 4. Vamos EP, Mucsi I, Keszei A, et al. Comorbid depression is associated with increased healthcare utilization and lost productivity in persons with diabetes: a large nationally representative Hungarian population survey. Psychosom Med 2009; 71: 501–507. 5. Lee Y, Smofsky A, Nykoliation P, et al. Cognitive Impairment Mediates Workplace Impairment in Persons with Type 2 Diabetes Mellitus: Results From the Motivaction Study. Can J Diabetes. Epub ahead of print 25 September 2017. DOI: 10.1016/j.jcjd.2017.06.013. 6. Reijmer YD, Brundel M, de Bresser J, et al. Microstructural white matter abnormalities and cognitive functioning in type 2 diabetes: a diffusion tensor imaging study. Diabetes Care 2013; 36: 137–144. 7. Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 2015; 16: 660–671. 8. Mansur RB, Ahmed J, Cha DS, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study. J Affect Disord 2017; 207: 114–120.

A recent open-label clinical trial led by Dr. Rodrigo Mansur at the University of Toronto investigated the efficacy of liraglutide—a glucagon-like peptide-1 receptor agonist—on objective measures IMS MAGAZINE WINTER 2018 DIABETES | 29


Spotlight on

Dr. Kerry Bowman

DR. KERRY BOWMAN PhD in Bioethics Fellowship in Cultural Psychiatry MSc in Social Work Assistant Professor in IMS, Faculty of Medicine Courtesy of K. Bowman

By: Yousef Manialawy

Dr. Kerry Bowman is a clinical ethicist at Mount Sinai Hospital and an assistant professor within the Faculty of Medicine at the University of Toronto. He is additionally affiliated with the School of the Environment and the Joint Centre for Bioethics, and has held a faculty position in the Institute of Medical Science (IMS) since 2010. Dr. Bowman is a leader in in addressing complex bioethical questions regarding end-of-life decision-making, cross-cultural healthcare delivery, genetic engineering, and emerging medical technologies. He is also a renowned conservationist, whose passionate interest in environmental protection has led him to venture around the world and work with leading organizations, such as the United Nations Environmental Programme. He is additionally the founder of the Canadian Ape Alliance, an organisation dedicated to protecting gorillas in the Democratic Republic of Congo. The IMS Magazine sat down with Dr. Bowman to examine the driving forces behind his illustrious career and delve into his views on pressing ethical and environmental issues.


efore we launch into your work, could you explain how you came to be a part of the IMS?

I was originally a medical social worker at Toronto Western Hospital in the early 90s, where I became incredibly interested in bioethics, specifically, in the area of end-of-life decisions after spending a lot 30 | IMS MAGAZINE WINTER 2018 DIABETES

of time overseas. In the intensive care unit, I often witnessed profound differences in cultural reactions and choices to end-oflife decisions. This spurred the interest of my doctoral thesis, which I originally proposed to the Faculty of Social Work. Despite my degrees in social work, the Faculty felt that my proposed thesis was too medically-focused. Thus, I decided to

pursue IMS, and I was grateful upon being accepted. I was initially nervous, but the structure, clarity, rigor and focus of a medical science degree helped me complete my PhD quickly and efficiently. After completing my doctoral thesis, I was recruited by IMS as a faculty member.

FACULTY SPOTLIGHT How has bioethics changed and what are some of the greatest bioethical challenges facing society today? Bioethics and medicine have both changed enormously. The influences of emerging global perspectives and globalization have made bioethics far more complex and multi-faceted today than it was in the 90s. With regards to the greatest bioethical challenge, while trending topics of euthanasia and artificial intelligence are important, the biggest challenge is to ensure equal access to healthcare for all; it’s so profoundly irregular that it truly is a massive challenge and it must be addressed.

movement. People are beginning to think much more deeply about how they live and consider what their obligations are to non-human life, the environment, and to future generations.

In addition to being a clinical bioethicist, you are also involved in several environmental initiatives, going so far as to establish a gorilla conservation organization–Canadian Ape Alliance. What led you to become so heavily involved in conservation efforts half a world away? The original focus on conservation and the great apes began many years ago when I volunteered on a research project to collect data on wild orangutans in Sumatra. My very first experience involved working with wild orangutan orphans. Making eye contact with an orangutan, I realized that this was an intimate, two-way, human-like encounter; while I was trying to figure him out, he was trying to figure me out as well. It was a pivotal point for me when I realized how similar we were. This has stuck with me over the years. Consistent with your environmental efforts, in recent years you have become a strong advocate for environmental ethics and its importance in establishing environmentally sustainable practices. Does it tie into bioethics and, if so, how? Environmental ethics is a component of bioethics that we need to take into greater account. From the perspective of justice, living unsustainably has unjust implications for current and future generations. One of the issues from an ethical point of view is the destructive belief that human life is rightly elevated to all other forms of life, while non-human life is viewed as a commodity; this is a dangerous and irresponsible view. So, environmental ethics can ultimately be labelled as a social

Courtesy of K. Bowman

A tender moment captured between Dr. Bowman and an orphaned gorilla during his work protecting the species in the Democratic Republic of Congo You have travelled extensively as part of your research into environmental ethics. Some of your most notable visits include meetings with North Korean environmental researchers and indigenous groups deep within the Amazon. What did you hope to learn from these meetings, and what came of them? I’ve met with North Korean environmentalists on three occasions. People often laugh to hear that North Korea is concerned about the environment, but they very much are. I had the opportunity to see the kinds of challenges they were facing and to share ideas and insights. From these meetings, it was evident that that North Koreans aren’t what the media portray them as, but in fact very intelligent, sophisticated people struggling with some of the same issues that we are. On the flipside, they could see that we weren’t what they had been told we were, either. I’m not a believer that the government should be the only group who should be responsible for these kinds of international contacts. It

often doesn’t work and I think on smaller levels these bottom-up approaches can be more effective. Environmentalists meeting with environmentalists rather than massive governments deciding whether there’ll be any kind of communication between the two makes more sense to me. As for the indigenous people of the Amazon, there are significant differences between indigenous peoples in South America compared to North America. There are still people in parts of Brazil and Peru that remain uncontacted and continue to live as they did 10,000 years ago. Nations sharing the rainforest have protected large swathes of land as indigenous territory. For example, one area in Brazil is the size of Austria. By protecting people in these large areas, you’re protecting the environment as well. As you would move deeper into protected indigenous territory, biodiversity levels would rise very quickly, and ecosystems were clearly intact. So, by protecting indigenous land, from a human rights point of view, you are also protecting people who have a right to live the way they choose to. But you’re also making a huge contribution to the world in terms of climate protection. With the ever-increasing threat of climate change, many people are burdened with a sense of hopelessness regarding humanity’s ability to effectively address the issue. What do you say to these people? I would say that individuals can do a lot, and that hopelessness is a very negative perspective that shouldn’t be adopted. Nature has tremendous resilience and will heal if given a chance. I’m also encouraged by the generational shift in which younger people are increasingly concerned about the environment. As solutions are emerging everywhere, I actually think there is quite a bit of hope.



Spotlight on

Dr. Paula Rochon By: Colin Faulkner

At the Institute of Medical Science (University of Toronto; U of T), Dr. Paula Rochon is associated with a multitude of physician-scientists, many of whom have careers that navigate medicine, research, and the social sphere. As a leading Canadian health services researcher in geriatric medicine, her work focuses on the unique issues surrounding elderly populations; in particular, women. Considering her leadership in women’s health and geriatric medicine, Dr. Rochon shares her perspective with the IMS Magazine on her career, clinical research, and involvement with Women’s Xchange.


r. Rochon began her career at McMaster University, where she completed an undergraduate degree in psychology. She aspired to become a doctor, and ultimately fulfilled this dream by attaining her MD at McMaster in 1983. Subsequently, she completed her residency in internal medicine at the U of T as one of the few women in her group. During her chief year, Dr. Rochon began to identify the concept of aging as a research focus she wished to explore. She pursued a Master’s of Public Health at Harvard University, with a novel interest in geriatrics. The inspiration for this academic interest was, in fact, personal: her own grandparents demonstrated incredible longevity, as they lived to be 104 years old. In July 2015, Dr. Rochon was appointed as the inaugural Retired Teachers of Ontario Chair in Geriatric Medicine at UofT. In Toronto, Dr. Rochon began collaborative research at Baycrest Health Sciences as the Director of Research. At Baycrest, 32 | IMS MAGAZINE WINTER 2018 DIABETES

Dr. Rochon investigated two areas related to optimal drug prescription in elderly adult populations: she aimed to determine the effect of pharmacologic management of chronic disease in older adults, and to elucidate the pattern of adverse drug events that informs the quality of drug therapy used by long-term care residents. In unison with her research, Dr. Rochon adopted a leadership role by becoming the interim Director of Research. She is currently the Vice-President of Research at Women’s College Hospital (WCH). At WCH, Dr. Rochon has led several projects examining the need for sex-specific research, the optimization of drug therapy, and the issues surrounding use of antipsychotics in older adults. Dr. Rochon was recently designated as the co-principal investigator of a CIHR project grant titled, “A multi-method approach to exploring prescribing cascades”. A ‘prescribing cascade’ is when the side effects of a prescribed drug result in the misdiagnosis of a new disease, in which case a

new prescription may follow, only further complicating the patient’s health profile. As Dr. Rochon’s prior research is well-encompassed within the focus of this grant, the project invites collaborating scientists who have noticed prescribing cascades in their own medical field. Women’s Xchange is another innovative and blossoming project led by Dr. Rochon. The project stems from a provincial mandate of creating a hub for knowledge translation and exchange in women’s health research. With the criteria of the project left open to Dr. Rochon and her team, they diverted away from the traditional academic sphere and towards a “community-based model that would be more lively and engaging.” With this goal in mind and given the local members of the WCH community, Women’s Xchange developed three main areas of support for women’s health research. The first area is the $15K Challenge Program, which serves as an avenue to

FACULTY SPOTLIGHT This need is addressed by providing a service that guides researchers to incorporate the important distinctions of sex and gender into their ongoing or proposed research, and by offering a resource library that includes recently published metrics on assessing sex and gender in publications. As an extension of this, Dr. Rochon is also involved in presentations for knowledge translation in sex and gender difference research, training for organizations, and Canadian health promotions. Dr. Rochon also hosts a semiannual live event, in the spring and fall. These events promote women’s health research focusing on a particular theme; the most recent event was titled, “Women & Substance Use–Tailoring Services to Meet Diverse Needs.” The events also profile recent $15K projects, highlight graduate-level student researchers, and catalyze discussion on a variety of women’s health topics from different backgrounds.

Courtesy of P. Rochon

DR. PAULA ROCHON Senior Scientist, Women’s College Research Institute Vice-President, Research, Women’s College Hospital Professor, Department of Medicine and Institute of Health Policy, Management & Evaluation, University of Toronto Senior Scientist, Institute for Clinical Evaluative Sciences Retired Teachers of Ontario Chair in Geriatric Medicine, University of Toronto

offer substantial research funding for projects related to the understanding and improvement of women’s health, in a manner that does not intimidate investigators who are early in research careers. Dr. Rochon and her team work to eliminate barriers to access and offer logistical support for research projects. Operating under these aims, Dr. Rochon and her team have supported several fantastic projects in Ontario. For example, one funded project focused on Indigenous women near the Northern Ontario School of Medicine. By listening to the women’s narratives on partner relationships, the community-based researchers created an exhibit that looked at healthy relationships, violence, and other elements of

relationships. This exhibit is now being accredited for continuing medical education. This project exemplifies how a small, attainable grant can stimulate significant growth of an idea. In an effort to build the capacity of women’s health researchers, the program also offers support for proposal development, a resource that can be used by graduate students and community scholars. Dr. Rochon remarked that from minimal funding and an emphasis on support and feedback, “you begin to see a legacy of things that are having an impact in the country.”

As a leader in the research teams at both WCH and Women’s Xchange, Dr. Rochon emphasizes the importance of work-life balance. While work is important, taking care of yourself and spending time with loved ones are also highly important priorities. Regarding guidance for graduate students, she notes the importance of embracing alternate routes with ambition and an open mind, because “when developing your career, certain things don’t run in a straight line.” Dr. Rochon further comments, “20 years ago, I would never have thought that I would be a part of something like Women’s Xchange.” With her roots in internal medicine, then health research, and eventually a strong focus on geriatric and women’s health, Dr. Rochon’s career demonstrates that following your passions is rewarding if you stay open to all opportunities.

Lastly, Dr. Rochon’s leadership has inspired the Women’s Xchange team to further work on improving the visibility and accessibility of sex and gender research. IMS MAGAZINE WINTER 2018 DIABETES | 33


Student Spotlight

the Grad Minds Team

Photo by: Mikaeel Valli

By: Chantel Kowalchuk




raduate school is stressful, and much of that stress comes from the unique challenges faced by students. That’s one of the reasons Rachel Dragas and Jaclyn Kelly joined Grad Minds—to help run the program that provides dedicated mental health services and programs for graduate students. Rachel is a second year MSc candidate at IMS, working in a lab focused on stem cell therapies for spinal cord injuries. She is the Co-Chair of Grad Minds, a G2G Peer Advisor at the Graduate Conflict Resolution Centre, and the Founder & Editor-in-Chief of Elemental Magazine, the official mental health magazine of the University of Toronto. Jaclyn, a second year PhD candidate in Medical Biophysics, studies pediatric brain cancer. She is the other Co-Chair of Grad Minds and also serves as a member of the Dean’s Advisory Committee for Mental Wellness in the Faculty of Arts and Science. Under Rachel and Jaclyn’s leadership, Grad Minds hosts numerous mental health initiatives such as advocacy events, yoga classes, dance de-stressor classes, and a student speaker series featuring students’ lived experiences. Rachel’s interest in mental health began when she started graduate school and experienced first-hand the multitude of stressors graduate students face. In hindsight, she does not find it surprising. “A culture of excellence is pervasive in graduate school. You put highly motivated and competitive students in this new environment, and then you have unsuccessful projects and you start doubting your capabilities,” says Rachel. Jaclyn noticed a similar trend amongst her peers, as well as a stigma surrounding discussions on stressors and their impact on mental health. Undoubtedly, most graduate students can relate to these issues, and consequently many experience struggles with their mental state. Grad Minds provides a variety of mental health programs to help combat the stressors of graduate life while also connecting students to the right resources, such as community partners, faculty, and other students. And while there are many student-led mental health initiatives on campus, many go unnoticed due to the large size of the University of Toronto (U of T) and the sheer volume of events. The University’s lack of an integrated

platform for mental health resources has inspired Grad Minds to establish Elemental, U of T’s new tri-campus mental health magazine. Elemental combines mental health initiatives across all three campuses in a compact, easily accessible online platform that serves to raise awareness about, and improve accessibility to, mental health events across U of T. Elemental is not just for students, as it also features U of T faculty and staff, with the vision of connecting everyone at the university: faculty, staff, and students in all three campuses, because everyone needs to take care of their mental health. Elemental hopes to spark a conversation and campus-wide collaboration regarding mental health initiatives, and ignite a collective action at the university. Under the leadership of Rachel and Jaclyn, Elemental is off to a strong start. The inaugural issue provides information on emerging mental health research, an interview with a mindfulness expert, information on mental health initiatives, tips for self-care, and even a colouring page. It truly covers mental health from all angles and for a wide audience. Rachel and Jaclyn believe that diversity of media is important to project information. As a resource, Elemental magazine complements the conferences, speakers, and workshops put on by Grad Minds by providing a variety of ways mental health initiatives can be accessed by students on campus. Going forward, Rachel and Jaclyn are excited to help mental health become a greater focus on campus and in society in general. They hope that as the awareness for mental health increases, the surrounding stigma will decrease. As Jaclyn says, “people grow up with pre-stigmatization, making it hard to change their minds. But the more the university as a whole advocates for mental health, the more that stigma will change.” And with the existence of initiatives such as Grad Minds and Elemental, and the passion of students like Rachel and Jaclyn, the de-stigmatization of mental health is a true possibility. You can find the latest issue via the Elemental Facebook page, or here (if you’re viewing this issue online): https://issuu. com/elementalmagazine/docs/elemental_ wintz er2017_web

And if you’re feeling inspired, Elemental is always looking for creators interested in contributing! Email mentalhealth@utgsu. ca if you’d like to share your experiences in mental health, a piece of art, or talk about your mental health-related research. Rachel and Jaclyn’s Top Tips for Maintaining your Mental Health: 1) Talking is essential. Talk about what’s on your mind to your colleagues, your parents, or on-campus counsellors. Another great under-used resource is the peer advisors at the Graduate Conflict Resolution Centre. They have free drop-in hours where you can talk to students trained on common issues faced by graduate students. 2) Educate yourself on symptoms of common mental health conditions. Chronic stress, anxiety, and depression are so prevalent in the student community that it’s easy to dismiss. Knowing the signs and symptoms helps you to know when you need a break and when you need to ask for help. 3) Integrate self-care into your schedule. We all schedule in our experiments, meetings, errands, but none of those things are possible if you don’t take care of yourself both physically and mentally. Exercise is one of the easiest and most common ways to care for both your physical and mental health, but that doesn’t mean that eating popcorn and watching Netflix isn’t equally as refreshing! 4) Put yourself in a healthy environment. Many of our labs and offices are not environmentally appealing (harsh lighting, no windows, re-circulated air) and often that does not result in great moods. Sometimes a quick fix to a low mood is to leave the lab and go for a walk; even better if you take that walk with someone else. 5) Read about imposter syndrome (there’s an article in Elemental Magazine!). Remind yourself that you’re not expected to know all the answers, and that everyone feels like an imposter sometimes. 6) Get involved in Grad Minds activities!




umayun Ahmed is only in the second year of his Master’s at the Institute of Medical Science (IMS), and has already been featured on various global leadership platforms. For instance, Humayen has been included in “Change Generation”(a global youth leadership network), and is featured in a book based on the online blog InTheirShoes, by Samuel Sawchuk, which shares the stories of 64 innovators across the globe. However, what truly makes Humayun stand out as a student, researcher, teacher, and entrepreneur, is his ability to skillfully incorporate a multidisciplinary approach to all his endeavors–a quality that stems from his desire to be a positive influence. At Drake University in Iowa (United States), Humayun was an avid learner during his undergraduate years. He constantly strived to challenge himself, and explored anything that piqued his interest—regardless of how daunting the topic. His infatuation with the life sciences was nurtured by the ample opportunities and resources available to 36 | IMS MAGAZINE WINTER 2018 DIABETES

him throughout his undergraduate career. He was inspired to explore medicine, and cultivate his newfound passion for teaching. He began to lead courses for fellow students to help them prepare for standardized exams because, as he explains, “I just love teaching.” As an undergraduate student, Humayun’s friends would frequently turn to him for academic advice. Eventually, this evolved into free tutoring sessions for a small group of students. Word spread quickly, and Humayun found himself teaching official prep course material to classes filled with up to 200 students. While he initially taught the standard offered courses, such as MCAT and LSAT, he noticed that there was a lack of student support “from the ground up” and a gap in the contents’ ability to clearly convey complex concepts. This prompted him to improve on the current deliverance of test-prep courses, by designing and teaching his own. In 2015, Humayun and his two colleagues, Sophia and Sohaib, co-founded a standardized test-prep company called

99point9. The goal was to continue to help students optimize their test scores. By emphasizing personalized, strategycentered instruction, the average student was able to score within the 94th percentile. Humayun argues, however, that it is most important for him to teach his students “that learning should be something that energizes and empowers you.” Student testimonials reinforce his unique teaching style and its impact on their learning experience. 99point9 is rapidly expanding, and can be a highly demanding and timeconsuming side project. However, Humayun manages to maintain a stellar academic reputation as an IMS graduate student. Humayun balances his passion for teaching with an unyielding commitment to research—he has contributed to multiple successful academic publications since his undergraduate studies. He has published peer-reviewed papers, reports, presentations, and book chapters in nine distinct disciplines. As a member of the University of Toronto (UofT) research community, he is able to fully explore



Humayun Ahmed

Voice of Youth Empowerment Today By: Ranya Barayan

Photo Courtesy of H. Ahmed

his multifaceted interest in medical research. He was particularly drawn to the IMS for the broad range of disciplines: “The University of Toronto, and IMS in particular, are great avenues to wander if you make use of them!” Although his initial plan was to become a medical doctor, Humayun finds his research to be very rewarding and plans to continue down this path. “By joining the graduate program, I have a chance to solve some of the most important problems in the field of medical science and give back to the community,” he explains. In Dr. Narod’s Lab at the Women’s College Hospital—known for its significant contributions to breast cancer genetics and epidemiology—Humayun’s work focuses on identifying the role of a new gene candidate in breast cancer, known as RECQL. The epidemiological aspect of his research involves examining the role of this gene not just within the Canadian population, but also in the Caribbean. “I wanted to impact both local and distant communities with my work,” he says, while appreciating the true value in “making a

change in another country from right at home.” In light of his desire to influence different communities, Humayun also ventured into the field of health policy. From Humayun’s perspective, policymaking has the potential to influence more than just our health care system: “Policy is the realization and implementation of theoretical insight; while it isn’t a quick fix, it’s the first step to proactive discussion.” As a result, he joined the G7/8 Research Group, a global network of academics aiming to be a major global source of research and information, in 2015 as a compliance analyst, lead analyst, and compliance director. His recent appointment as co-chair of the Executive Committee on Summit Studies at the Munk School of Global Affair’s G7 Research Group allows him to work alongside undergraduate and graduate students in the development of several internationallypublished reports, including one that was presented at the 2017 G7 Taormina Summit in Italy. In this role, Humayun also contributes to investment research (via Seeking Alpha, a stock market insight

website) by examining corruption and the rule of law with the International Research Group on Rule of Law and the Fight Against Corruption group. In fact, Humayun has studied his native country of Pakistan, and has contributed to a paper outlining the current state and future possibilities of medical policy in the nation. In fact, Humayun and several colleagues will be presenting this paper, titled “The State and Future of Medical Regulation in Pakistan: Self-Regulatory Corruption in the Aftermath of Colonization”, at the International Sociological Association (ISA) World Congress this upcoming July. Peering into the future, Humayun envisions himself continuing to integrate his love of theoretical academia and qualitative research with entrepreneurship and knowledge translation. He plans on building businesses, pursuing doctoral work, and investigating potential solutions to pressing problems in healthcare. Above all, Humayun’s “biggest personal mission” is to motivate students through his work, and help them recognize their own potential. IMS MAGAZINE WINTER 2018 DIABETES | 37


Photo by: Nakita Krucker

By: Craig Madho, Jonathon Chio

PILLARS OF HEALTH COMMITTEE Back row (left to right): Dr. Richard Foty, Paige Gilbank, Chelsea Foo-Fat, Pat Furlong, Julia Antolovich, Catherine Virelli, Craig Madho, Kaleigh Johnson-Cover, Dr. Joseph Ferenbok, Fiona Bergin, Jonathan Lee, Moni Kim Front row (left to right): Helen Liu, Kathleen Camaya, Dr. Edyta Marcon, Kathleen Mounce, Katie Tucker


hat are you going to do after you graduate?” This is a question that all students must answer, but one that most shy away from. Whether or not you know what your career will be, the path to getting there is difficult—especially in the modern health sciences. It is traditionally thought that scientists work in silos: each specialist acquires in-depth knowledge about their niche subject, upon which they subsequently build a career. However, this path is becoming less common. It is becoming increasingly apparent that a plethora of skills across several different domains are necessary to attain careers. Therefore, for students searching for careers in their desired fields after graduation, a detailed understanding of the diverse skills and full range of career paths available to them is imperative. An impetus exists for students to have a platform wherein they can interact with interdisciplinary health professionals to learn more about the career opportunities available to them. One such event designed to bring together individuals involved in many different aspects of healthcare innovation is Pillars of Health: a bi-annual interdisciplinary networking event, hosted by students in the Translational Research Program (TRP) and the Health Innovation Hub. This event brings together not only hospital administrators and physicians, but also researchers, policymakers, industry 38 | IMS MAGAZINE WINTER 2018 DIABETES

professionals, and students–and, in future events, patients as well. Together, these parties comprise the “pillars” of health. The purpose of this event is to engage stakeholders in healthcare innovation to have an open and honest conversation about the healthcare system in its current state and where it needs to be in order to address the emerging needs of the population. According to Dr. Joseph Ferenbok, the Director of the TRP and one of the lead organizers of Pillars of Health, “[...] innovation appears to be not the output of masters of any one trade, but the synthesis of many domains, experts, and teams.” Indeed, this is the guiding principle of the Pillars of Health event and a key insight for meaningful innovation in the health sciences. With two successful Pillars of Health events held to date, the impact of this platform for connecting innovators is evident. Amol Rao, a University of Toronto student who will be graduating with a Masters in Industrial Engineering, commented, “This was a fantastic event! I met interesting people and many of the connections could become important for my venture.” Regardless of the educational background, Pillars of Health creates an open environment for sharing ideas, where attendees can network and discuss emerging issues. In fact, Mari Bardavilias, who is the Managing Principal at the

Palladium Strategy, stated that this indeed was her favourite part of the event: “There was candid disclosure of insights from both speakers, which was refreshing. Their depth of knowledge, and application in [the] real world, was very good.” But how does this help students answer the question, what are you going to do after you graduate? Helen Liu, a first-year MSc student in the TRP answered, “[...] having the opportunity to interact with individuals who have experience in diverse careers and backgrounds at the Pillars of Health has definitely helped me consider how I could jumpstart my career and who I should contact if I want to learn more.” Held at the beautiful Johnson & Johnson Laboratories (JLabs) in the MaRs Tower overlooking Queens Park, the Pillars of Health events have attracted a diverse crowd of approximately 200 working professionals from major research hospitals in Toronto, private companies, and entrepreneurs. These events were held through support from the Health Innovation Hub, JLabs, University of Toronto Entrepreneurship, and University Health Network. So join us on February 26th, 2018 for the next Pillars of Health! For more information on upcoming Pillars of Health events, or to contact the organizers for more information, please visit:


Pillars of Health: Connecting Innovators




Ori Rotstein Lecture



his past October, the Institute of Medical Science (IMS) at the University of Toronto (UofT) held its sixth annual Ori Rotstein Lecture in Translational Research. The lecture series honors Dr. Rotstein, who is the surgeon-in-chief at St. Michael’s Hospital, and Professor as well as Associate Chair of the Department of Surgery at UofT. Additionally, in 2017, Dr. Rotstein was named the inaugural Keenan Chair in Research Leadership at St. Michael’s Hospital and UofT. He was also the director of the IMS from 2001-2011. Through improving the teaching curriculum and faculty development, his efforts helped IMS become a leading medical research graduate department in Canada. The annual Ori Rotstein Lecture highlights exciting and revolutionary topics in the areas of surgery and translational medicine, by means of distinguished keynote speakers and panel discussions. The 2017 lecture keynote speaker was Dr. Connie Eaves, an internationally renowned researcher and professor in the departments of Medical Genetics, Pathology & 40 | IMS MAGAZINE WINTER 2018 DIABETES

Laboratory Medicine at the University of British Columbia. Her laboratory focuses on the characterization and regulation of stem cells in patients with Chronic Myeloid Leukemia (CML) and breast cancer. Dr. Eaves has published more than 130 peer-reviewed articles in many high impact journals, including Nature and The New England Journal of Medicine. Dr. Eaves’ talk focused on cancer as well as the diverse challenges involved in cancer therapeutics. As “cancer” differs in the context of clinical diagnosis versus biological research, she compared the terminology to the ambiguity of words such like “beauty” or “satisfaction”, for they are all context dependent. Despite the diversity, in most cases, cancer stems from single cells with abnormal growth properties that manifest at the tissue level, in the form of a clone. Yet, the majority of the cells within the clone do not perpetuate the persistent growth of the tumor. As such, Dr. Eaves mentioned that “analyses of bulk tumor samples can be misleading because of their unique and continuously evolving biologic and genetically determined heterogeneity.”

Therefore, focus should fall upon the cells that maintain tumor growth. When a cancerous cell propagates into a tumor, the resulting cells are no longer the same as the original. This idea of clonal evolution and diversification makes it imperative to find methods to track behaviors of cancerous cells early on. Hence, according to Dr. Eaves, the best strategy is to investigate both normal and malignant tissue at the molecular level to understand the earliest events that cause growth perturbations. Dr. Eaves also spoke about history of stem cells. Drs. James Till and Ernest McCulloch are two UofT scientists and pioneers in stem cell research. In a famous series of experiments, Drs. Till and McCulloch injected mice bone marrow cells into irradiated mice. This resulted in observable nodules on the spleen of the mice; referred to as “spleen colonies”. These colonies developed from a single bone marrow cell, that were named “stem cells”. Importantly, Dr. John Dick, another UofT scientist, further incorporated this concept in his theory of “cancer stem cells.” Briefly, the theory suggests that cancer stem cells


differentiate into various heterogeneous cell lines that characterize a distinct morphological tumor profile. He also created the first mouse model of leukemia by transplanting human hematopoietic cells into immune-deficient mice. These early works ignited Dr. Eaves’ interest in the events that occur at the genesis and evolution of cancer stem cells in leukemia and breast cancer. In CML, disease progression occurs in two phases: the chronic and accelerated phase, respectively. For studying the early events, Dr. Eaves’ lab successfully developed a mice model of chronic phase CML. With this model, during a span of more than three decades, Dr. Eaves enhanced our understanding of many genes involved in the regulation and progression of CML (such as HOXa9, HOXa10, and IKAROS). In further discussions on her lab’s work with CML, Dr. Eaves highlighted a recent project by her student, Dr. Long Nguyen. Tasked with creating a barcode library by tagging DNA to track clonal pattern, he followed clone production of umbilical cord blood cells in immune-deficient mice. Using index

sorting and proteomic tools, they made meaningful connections between protein markers to functional readouts. In particular, despite heterogeneity of cancer cells, they found a novel biomarker (cluster of differentiation protein 33) to be commonly higher in the most massive sustainable clones. Last but not least, when highlighting the work from her lab, Dr. Eaves emphasized the interdisciplinary nature of biomedical research and credited an “army of collaborators” that made her research findings possible. Following the keynote lecture, there was a panel discussion moderated by Dr. Rotstein. Titled “Revolutionizing translational research: Can we do better?”, the panel included Dr. Minna Woo (Scientist and Head, Division of Endocrinology and Metabolism at University Health Network), Dr. Mohammad R Akbari (Director, Molecular Genetic Laboratory at Women’s College Hospital), Dr. Katherine Siminovitch (Senior Scientist at Mount Sinai), and Dr. Cindy Morsehead (Chair, Division of Anatomy, Donnelly Centre for Cellular and Biomolecular Research). Each

panelist contributed unique insight on various subjects ranging from an increased emphasis on the importance of human research to resolving logistical challenges in order to better utilize patient populations for research. However, all panelists made similar comments regarding the necessity to cross the boundaries between in vitro and in vivo studies in preclinical research. This is important for smooth translation from preclinical to clinical research. In addition, all panelists agreed that financial barriers largely impede the progress of translational research, as bureaucracy limits risk-taking and risk is often required for real advancement. Overall, this year’s event was a huge success. In addition to showcasing scientific excellence, the speakers’ highlighted the major challenges that hinder translational research, a key facet of the IMS. Needless to say, we are all looking forward to the 2018 Ori Rotstein Lecture.




by Emeran Mayer, MD

By: Beatrice Ballarin


n her lecture, “Bugs as drugs: modifying the human gut microbiome with microbial ecosystem therapeutics,” Dr. Emma Allen-Vercoe discusses the therapeutic potential of manipulating the gut microbiome.1 As a neuroscience researcher, this talk sparked my interest in the microbiome as I was intrigued by the possibility of using “bugs as drugs” to treat neurological disease. Captivated by the possibility that gut bacteria could impact one’s mind, I began the search for my next book: The Mind-Gut Connection.

the intricate biochemical dialogue between the brain, the gut, and the microbiome, suggesting it may be implicated in social behavior, decision-making, emotional well-being, and mental health. For instance, the book presents recent research that shows a decreased level of brain-derived neurotropic factor (BDNF) in germ-free animals (animals raised in a sterile environment) and, intriguingly, following antibiotic treatment in humans.3 Given that BDNF is a key protein involved in neuronal plasticity, growth, and survival, this finding suggests that the

“Your gut microbes can listen in on your brain’s ongoing conversation and vice versa.” Evidently, Hippocrates’ assertion that “All disease begins in the gut” is making its way into modern medicine. The collection of microorganisms and their genomes inhabiting the human gut, known as the gut microbiome, has been implicated in diseases including inflammatory bowel disease syndrome, obesity, cancer, and even autism spectrum disorder (ASD).2 These microorganisms not only contribute to normal gut functioning but also communicate with the brain, which acts accordingly. The Mind-Gut Connection proposes a new role for the gut microbiome as an active player in gastrointestinal events and cognitive disorders. The book discusses 42 | IMS MAGAZINE WINTER 2018 DIABETES

microbiome may contribute to neural function by way of promoting normal level of BDNF. Interestingly, distinct microbiome patterns have been demonstrated in patients with major depressive disorder, which is characterized by a low level of BDNF in the blood. Thus, evidence seems to point towards a new medical paradigm in which the gut microbiome can shape human behavior through the manipulation of BDNF levels and serotonin metabolism. When compared to control subjects, the gut microbiome of patients with major depression was characterized by an increased relative abundance of Enterobacteriaceae and Alistipes, and decreases in Faecalibacterium and

Ruminococcus. Strikingly, the book presents evidence that BDNF levels can be normalized when specific microbes are introduced into the gut of germ-free rats with depression, thereby supporting a link between the microbiome and decreased BDNF levels in this disorder. By presenting recent research, patient cases, and personal reflection, the book makes a compelling argument in support of the role of the gut microbiome in brain function and mental health, and may serve to propose a new medical paradigm in the pathobiology of neurological and psychiatric disease. It offers a provocative look at the implication of the gut microbiome in both brain and behavior, with the hope of teaching us the hidden power in our gut. Next time we face an important decision, instead of flipping a coin, let us pay more attention to the signals that our bodies send us; in other words, let’s follow our guts. (3 stars out of 5) 1. Dr. Emma Allen-Vercoe presents at the 2017 Gairdner Laureate Symposium [Internet]. Available from: 2. Human Microbiome Project Consortium. A framework for human microbiome research. Nature. 2012 Jun 13;486(7402):215–21. 3. Mayer EA, Knight R, Mazmanian SK, Cryan JF, Tillisch K. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci Off J Soc Neurosci. 2014 Nov 12;34(46):15490–6.




or many Canadians, the publicly-funded health care system is a defining icon of our society. In a survey conducted in 2012, 94% of Canadians said that our health care system is an important source of both personal and collective pride, for it guarantees all Canadians access to good quality care. Owing to its core principles of universality, accessibility, and comprehensiveness, Canadians prefer the existing health care model over others. However, health care in Canada is far from perfect. If you have ever been to an emergency room in this country you probably encountered the infamous wait times, which are among the longest in the developed world. Additionally, Canadians often wait longer than a week to see a general practitioner and several months to see a specialist. We are also among the highest spenders in the world on prescription medicines. For example, a year’s supply of Lipitor (atorvastatin), a cholesterol-lowering drug, costs only $15 in New Zealand—outrageous in comparison to its cost in Canada of $800! Better Now: Six Big Ideas to Improve Health Care for All Canadians outlines, as the name suggests, methods to improve the flaws of the current system. This book is authored by Dr. Danielle Martin, a family physician from Women’s College Hospital

known for her appearance on a US Senate Subcommittee debate on health care chaired by Senator Bernie Sanders in 2014. In her testimony, she argued that the solution to the wait times in Canada does not lie in moving away from the single-payer system, which delivers high-quality, equitable care to Canadian patients. In addition to outlining her own proposals and perspectives, Dr. Martin brings forth the perspective of field individuals— patients and health care providers—and those of system thinkers in supporting her ideas for improving the current health care system. She integrates stories of her family, experiences with patients, and research on public policy and health economics to make a passionate and compelling case that health care can be improved immeasurably. Her book is written in a highly engaging, conversational style and raises personal and relatable questions about our single-payer health care system. The book culminates in her presentation and discussion of six bold ideas to improve the Canadian public health care system: 1. increase effective relationship-based primary care, 2. include prescription medication as part of standard health coverage, 3. reduce unnecessary exams and interventions, 4. reorganize our existing resources to reduce wait times and improve quality of care, 5. implement a basic income guarantee to promote health, 6. and advance

regional and provincial successes across the country. Of all her compelling arguments, the one that interests me the most is her call for a national drug program - Pharmacare. Dr. Martin points out that one in every five Canadians does not take their prescribed drugs due to their associated costs. Most diseases can be managed, if not cured, with the right medications; but what good does medical care do if a patient is unable to comply to their recommended course of treatment? Our health care system is founded on the principle that care is accessed based on need, not on the ability to pay. This principle needs to be extended beyond the care provided by health care teams to include access to a publicly-funded essential medications. Changing our current health care system is not simple, and real changes require courage from politicians and public engagements from Canadians like you and me. To those who are working in the medical field and wish to learn more about our health care system and ways to improve its efficiency and effectiveness, Better Now: Six Big Ideas to Improve Health Care for All Canadians by Dr. Danielle Martin is a MUST read.