THINK. LEARN. DISCOVER.
Immunology STEERING THE BODY’S IMMUNE SYSTEM Feature interview with Dr. Li Zhang
Exploring the hygiene hypothesis
PERSONALIZED TREATMENT FOR LUPUS Dr. Murray B. Urowitz follows his passion
White Blood Cells
by Sam Holmes
READ IT ONLINE
IN THIS ISSUE Letter from the Editor................................... 4 Director’s Message...................................... 5 News at a Glance........................................ 7 Year in Review............................................. 9 Feature....................................................... 12 Special BMC Feature................................. 26 IMS News.................................................. 28 Faculty Spotlight........................................ 30 Student Spotlight....................................... 32 Book Reviews............................................. 36 Special TRP Feature................................... 38 Behind the Scenes..................................... 40
FEATURE INFOGRAPHIC P12 CANADIAN CHRONIC PAIN STATISTICS Immune diseases by Kelly Speck
MAGAZINE STAFF EDITOR-IN-CHIEF EXECUTIVE EDITORS
Annette Ye Kasey Hemington Rebecca Ruddy Katherine Schwenger
JOURNALISTS & EDITORS
Anna Badner Arunima Kapoor Ayda Ghahremani Chelsea Lowther Danielle Cha Gaayathiri Jegatheeswaran Jabir Mohamed Jonathon Chio Joshua Lipszyc Mirkamal Tolend Muhtashim Mian Petri Takkala Usman Saeed Vanessa Rojas Luengas Yetka Dowlati
Sam Holmes Sarah Kim Melissa Phachanhla Sonia Seto Kelly Speck
Chung Ho Leung Elizaveta Semechko Meital Yerushalmi Pratiek Matkar Tahani Baakdhah
Past Events................................................. 42
YEAR IN REVIEW
by Sarah Kim and Sam Holmes
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.
THINK. LEARN. DISCOVER.
Cover design by Sonia Seto
Immunology STEERING THE BODY’S IMMUNE SYSTEM
The design of the cover was based on an interview with Dr. Li Zhang (p. 14) who is researching how to steer the body’s immune responses. For this illustration the act of driving and steering a car was adopted as a visual analogy to the controlling of the immune system.
Feature interview with Dr. Li Zhang
Exploring the hygiene hypothesis
PERSONALIZED TREATMENT FOR LUPUS Dr. Murray B. Urowitz follows his passion
IMS MAGAZINE WINTER 2016 IMMUNOLOGY | 3
LETTER FROM THE EDITOR
EDITOR I n the animated movie Osmosis Jones, Ozzy, a thrill seeking white blood cell with a good sense of humour fights off a deadly virus after Frank the human applies the ‘ten second rule’ to a dropped hard-boiled egg. Though fictional, Ozzy’s adventure depicts the magnificence and significance of the human immune system. Nearly every cell, organ, and tissue in the body is involved in this well-coordinated network that fights infection. But what happens when things go awry in autoimmune diseases, cancer, and inflammatory diseases? With the help of our experts, we address the immune system in this Winter issue of the IMS Magazine.
To understand autoimmune disease, we sat down with Dr. Alan Lazarus and Dr. Murray Urowitz to discuss therapeutic antibodies and novel subtypes of systemic lupus erythematosus. In addition, Dr. Li Zhang explains to us how we can boost the immune system to combat cancer in patients with acute myeloid leukemia. We also talk about the hygiene hypothesis in light of the recent rapid rise to atopic disorders, and look into the immune privileges of the central nervous system.
ANNETTE YE Editor-in-Chief, IMS Magazine Annette is a fourth year PhD candidate at the Institute of Medical Science. She is currently conducting research on biomarker discovery in neurodevelopmental disease at the Hospital for Sick Children.
As we welcome the new year, we look back upon 2015 with a special Year in Review highlights of newsmakers in the science community. We also bring you closer to the IMS community with a recap of our annual Ori Rotstein Lecture in Translational Research, and brought back our ‘Spotlight’ articles featuring IMS faculty and students. This issue, we chatted with Dr. Mario Masellis and PhD Candidates Li Guo and Serisha Moodley. They offer just a glimpse of the many compelling stories of who we are at the IMS, and I strongly encourage you to have a look. I would like to thank Dr. Mingyao Liu and the IMS department for their ongoing support, and congratulate the design team on another brilliant production of this magazine. Thank you to the incredible IMS Magazine team for their dedication and enthusiasm. To you, our readers and supporters, please feel free to add your own thoughts to any of the stories in this issue at firstname.lastname@example.org as we continue to showcase to you the best of the IMS. Happy reading!
Annette Ye, Editor-in-Chief, IMS Magazine Photo credit Tahani Baakdhah
4 | IMS MAGAZINE WINTER 2016 IMMUNOLOGY
n behalf of the IMS community, it gives me great pleasure to welcome you to another year and issue of the IMS magazine. This issue highlights immunology through discussions of cancer and autoimmune diseases. We hear from Dr. Alan Lazarus, Dr. Li Zhang, and Dr. Murray Urowitz. Our students also take on current scientific theories in immunology surrounding the central nervous system and more. We had another successful Ori Rotstein lecture in translational research in October 2015, featuring Dr. Paul O’Byrne, and highlighted in this issue. Also featured are photos from the IMS Holiday Party in December 2015. Students, faculty, and IMS alumni gathered for a ‘red carpet’ celebration organized by our student council, IMSSA. Congratulations to IMSSA for hosting an impressive event.
DR. MINGYAO LIU Director, Institute of Medical Science Professor, Department of Surgery Senior Scientist Toronto General Research Institute, University Health Network
Photo by Tahani Baakdhah
I wish to announce that the IMS Scientific Day will be taking place on Friday, May 20, 2016 at St. Andrew’s Club and Conference Centre. This year we are very excited to welcome Dr. Victor Dzau from the Institute of Medicine at the National Academy of Sciences. Dr. Dzau is a pioneer and leader in cardiovascular medicine and genetics, as well as health care innovation. Please make sure to mark this day in your calendars. Congratulations to Annette Ye and her team for their continued dedication and collective creative energies in producing this publication. The IMS Magazine has been a tremendous success and is just one of the many wonderful, student-led initiatives to make the IMS a very special institute. I fully support the ongoing publication and look forward to reading and learning about the outstanding research that is being conducted by our faculty and trainees in IMS. On behalf of everyone at the IMS, I wish you wonderful new year ahead. Sincerely, Mingyao Liu, MD, MSc Director, Institute of Medical Science IMS MAGAZINE WINTER 2016 IMMUNOLOGY | 5
NEWS AT A GLANCE
important dates January 13 Most formal graduate courses and seminars begin in the week of January 11 15 Final date to submit doctoral theses without fee payment for Winter session 20 Fall session grades available for viewing by students on Student Web Services (ROSI/ACORN) 22 Final date for receipt of degree recommendations and submission of any required theses for March or June graduation for masterâ&#x20AC;&#x2122;s students without fees being charged for the Winter session
Family Day (University closed)
March 1 25
Final date to drop full-year and Winter courses without academic penalty Good Friday (University closed)
Final date for receipt of degree recommendations and submission of any required theses for masterâ&#x20AC;&#x2122;s degrees for June Convocation Final date for submission of final doctoral thesis for students whose degrees are to be conferred at the June Convocation
Institute of Medical Science Annual Scientific Day
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Statistics from: http://www.aarda.org/autoimmune-information/autoimmune-statistics/ IMS MAGAZINE WINTER 2016 IMMUNOLOGY | 13
Dr. Li Zhang, MSc, PhD, MD Senior Scientist, Toronto General Research Institute Professor, Institute of Medical Science, Immunology, and Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto Full Member, Institute of Medical Science
FIGHT CANCER An Interview with Dr. Li Zhang on T-Cell Immunotherapy By Anna Badner 14 | IMS MAGAZINE WINTER 2016 IMMUNOLOGY
Photo credit Elizaveta Semechko
BOOSTING THE IMMUNE SYSTEM TO
Could you tell us a little about your background, training and the events that have brought you to the University of Toronto? After completing my medical training and Master’s degree in China, I moved to the Netherlands for my doctoral thesis. My PhD work was in the field of transplantation immunology, under the supervision of Prof. Jon van Rood and Dr. Frans Claas at Leiden University. In 1991, I began my post-doctoral studies at the Ontario Cancer Institute and the University of Toronto. In 1992, I was offered a faculty position at the University of Toronto. Toronto is a wonderfully diverse city and I am very happy here. What has motivated you to work in cancer and transplantation immunology? What do you find most appealing?
r. Li Zhang, a Senior Scientist at the University Health Network’s Toronto General Research Institute, is the first to characterize the peripheral population of Double Negative T regulatory cells (DNT cells).1 Her group has also developed a protocol to expand these therapeutic cells ex-vivo for clinical application. The amplified DNT cells are meant to boost the patient’s immune system and help combat cancer. Pre-clinical studies have been promising; DNT cells appear to possess potent antitumour activity, prevent recurrence of acute myeloid leukemia (AML), and do not have any adverse side effects.2 The IMS magazine sat down with Dr. Zhang to hear more about her successful scientific career and the progress of DNT cell therapy.
While working as a physician, I realized there are many things that we do not understand. I have always been a curious person and I was not satisfied having my questions go unanswered. Research not only helps us understand the mechanisms of diseases, but it also guides us to find better treatments. This is why the focus of my research has been largely translational. Further, my fascination with the immune system stems from its complex regulation. My dream is to be able to control our immune system like driving a car, and I would like to learn how to steer the body’s immune responses. DNT cells have been at the center of your research career. What makes these cells unique and exciting? My work and research direction has been data-driven. I have been studying T lymphocytes since my PhD, and, to this day,
we continue to discover the very important role they play in regulating immune responses. DNT cells, which we first identified in 2000, are a sub-population of T lymphocytes that express CD3 and T cell receptor but lack CD4, CD8, and markers of natural killer cell differentiation. When we apply DNT cells in cancer, the results are striking. These cells have very significant anti-cancer effects. In 2012, you received the prestigious Leukemia & Lymphoma Society grant to apply DNT cell immunotherapy for AML. How successful has this approach proven to be? What are the next steps? DNT cell immunotherapy has been very successful in pre-clinical studies and we are moving into human trials. The first patient was infused yesterday and we are eagerly awaiting the results. Since there have been no adverse side effects in our animal experiments, we are optimistic that the trial will be positive. What advice can you give current graduate students? The most important quality is passion. You really need to love doing research to be successful. Experiments are timeconsuming and often fail, which can be very discouraging to an apathetic student. If you look at science as a typical job, you will not have the drive to persevere. Curiosity and hard work are also important traits for discovery and success. As for me, I love that research let’s me be creative. References
1. Zhang ZX, Yang L, Young KJ, et al. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med. 2000 Jul;6(7):782-9. 2. Merims S, Li X, Joe B, et al. Anti-leukemia effect of ex vivo expanded DNT cells from AML patients: a potential novel autologous T-cell adoptive immunotherapy. Leukemia. 2011 Sep;25(9):1415-22.
IMS MAGAZINE WINTER 2016 IMMUNOLOGY | 15
Dr. Alan Lazarus, PhD Scientist, Keenan Research Centre of The Li Ka Shing Knowledge Institute of St. Michaelâ&#x20AC;&#x2122;s Hospital and the Canadian Blood Services, Center For Innovation Professor, Faculty of Medicine, University of Toronto Full Member, Institute of Medical Science
Photo credit Chung Ho Leung
WHAT CAN EXOGENOUS ANTIBODIES DO FOR YOU? Dr. Alan Lazarus discusses the translational potential of therapeutic antibodies in treatment of autoimmune diseases
By Jonathon Chio 16 | IMS MAGAZINE WINTER 2016 IMMUNOLOGY
r. Alan Lazarus is a Staff Scientist at Keenan Research Centre of the Li Ka Shing Knowledge Institute at St. Michael’s Hospital and a scientist with the Canadian Blood Services Center for Innovation. He is also a Laboratory Medicine and Pathology and Institute of Medical Science Professor within the Faculty of Medicine. Dr. Lazarus is renowned for translational research on therapies involving antibodies to treat autoimmune and newborn haemolytic diseases. In October 2015, he received the Tibor Greenwalt Award from the American Association of Blood Banks. I sat down with Dr. Lazarus to discuss his passion for autoimmune research and ask his advice to future, budding scientists. Please describe your education background and past time interests. I obtained my Bachelor of Science in Biology and Chemistry at Concordia University and completed my PhD in Microbiology and Immunology at McGill University with Dr. Malcolm Baines. I knew I wanted to be in academia and lead a research laboratory after undergraduate, and have never had any regrets in pursuing this career and field. In fact, I am living my dream! While being a scientist is my full time job, one of my favorite pastimes is wood working. I often take on mini-construction projects and share with my loved ones and colleagues. Another one of my hobbies includes photography; I take my camera wherever I go. One of my most memorable photos was at a small airport in Namibia. I witnessed a sandstorm that blew wonderful patterns across the ground, reminiscent of fancy whirls and shapes on the ground after a windy snowstorm.
mice and rat models, it is possible to consider making laboratory-based therapies to replace such aging plasma-derived blood products. In particular, my lab focuses on how antibodies are used to treat conditions such as hemolytic disease of the fetus and newborn (HDFN) and autoimmune diseases like idiopathic thrombocytopenic purpura (ITP). For the past 25 years, IgG has been used to treat a number of autoimmune diseases. The first autoimmune disease ever treated with intravenous IgG was ITP. In ITP, a patient’s immune system has antibodies against its own platelets, causing the platelets to be destroyed. Platelets are small cell-like fragments in blood that play a crucial role in sealing broken blood vessels and stopping bleeds. As a result, patient will suffer from uncontrolled bleeding. Currently, patients are treated with antibodies (IgG) purified from healthy donors. Another aim of our laboratory is to examine how antibodies prevent hemolytic disease of the fetus and newborn (HDFN). This is a very severe condition that can occur if a mother does not express the “rhesus D antigen (RhD)” on her red blood cells and becomes pregnant with a RhD positive child. A prophylactic treatment to prevent HDFN is to administer antibody derived from the plasma of blood donors who have antibodies against RhD (anti-D). Anti-D can be given to rhesus D-negative mothers pregnant with RhD-positive child. Congratulations on receiving the Tibor Greenwalt Award! What has your laboratory found in regards to treating autoimmune diseases that led you to win the award?
With our targeted audience coming from vast number of scientific fields, please describe your research in nonprofessional terms.
This prize is in recognition of my laboratory’s contributions towards elucidating mechanisms to explain how IgG treats autoimmune diseases.
A common issue in developing therapies for autoimmune disease is that despite their effectiveness, their actual mechanism of action is unknown. Hence, many therapies rely on blood donation from human donors. By establishing mechanism(s) through exploratory work in
As I’ve said before, IgG is very effective in treating autoimmune disorders. Exactly how this works is unknown, and scientists have devised numerous hypotheses. This special scenario allows me to apply my unique research techniques. Rather than solely identifying IgG relevant
mechanisms, we have worked to determine which of the numerous hypotheses are incorrect. My laboratory has made significant contributions on both ends, as we have shown many hypotheses to be flawed. Concurrently, we have made a landmark discovery linking IgG with dendritic cells to mediate beneficial effects in autoimmune diseases. Admittedly, it is difficult to publish “negative results,” but at the same time, someone has to take on this role. This is especially prevalent in IgG research. What are some of the challenges that you have faced in your career as a researcher? Like other scientists, one significant barrier I have faced is securing research funding, especially on projects where one has a true passion. In addition, with papers being published daily, I worry that I might miss something important. While I read many papers on different topics, it is important to stay focused on what you are doing. On the other hand, there is a richness in reading papers in other fields. It is similar to walking through the forest: if you only stick to the path, you will not see anything new. If you wander through the brush, you will be overwhelmed. Striking the right balance is key! What advice do you have to give to potential graduate students? I cannot stress the importance of being excited for one’s own project. Throughout graduate school, you will run into many challenges and one’s passion is critical in maintaining motivation during those times. Second, consider how often you want to meet with your supervisor. If you enter a lab that has 30 or so trainees, daily discussions with your supervisor are less likely. Talk to other students or postdoctoral fellows in the lab to gain insight. Last, but not least, since graduate school is a huge commitment, explore where you want to be in five to ten years. This foresight will be immensely helpful in deciding whether graduate school is the right choice. Looking ahead is important to finding a lab and project that will be a good match!
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Dr. Murray B. Urowitz MD, FRCP(C) Director, Centre for Prognosis Studies in Rheumatic Diseases; Senior Scientist, Toronto Western Research Institute, Professor of Medicine, University of Toronto Full Member, Institute of Medical Science
PHENOTYPING SLE: The Framework is in Place, the Journey is just Beginning By Vanessa Rojas-Luengas
t is widely said that if you follow your passion, success will follow you. Dr. Murray B Urowitz is an exemplary case. His deep curiosity and concern for Lupus afflicted patients led him to become a trailblazer in translational clinical research, establishing personalized medicine within the context of this highly variable disease. Along the way, his contributions to the field have been recognized nationally and internationally; most notably, he received the 1995 Distinguished Rheumatology Award from the Canadian Rheumatology Association, the 2004 Duncan Graham Award by the Royal College of Physicians and Surgeons of Canada, and the 2009 18 | IMS MAGAZINE WINTER 2016 IMMUNOLOGY
Evelyn V. Hess Award by the Lupus Foundation of America. Why lupus? Dr. Urowitz gleamed with pride as he shared what drew him to the field of lupus. During his years as a medical student at the University of Toronto, he fell in love with the various biological systems involved in the study of medicine. Early on, as he saw patients with Systemic Lupus Erythematosus (SLE), he quickly recognized the involvement of the various systems in this autoimmune disease, affecting most if not all organs of patients. Every patient seemed to be a unique case, and it was the complex nature of this
disease that drew Dr. Urowitz into the field of SLE. Inspired, in 1974 he went on to complete his post-graduate training in rheumatology at Johns Hopkins University and at the University of Toronto. SLE is a chronic, systematic autoimmune disease estimated to affect 1 in 2,000 Canadians.1 Although this heterogeneous condition affects men and women of all ages, the majority of patients are women in their child-bearing years.2 In fact, women are affected ten times more than men. Dr. Urowitz recalls that in the past, women presenting with multiple symptoms were assumed to have a type of connective
FEATURE tissue disease characterized by multiple organ involvement.1,2 Although diverse in manifestation, they were all grouped together as lupus due to an underlying immunologic abnormality. Many investigators, including Dr. Urowitz, have since addressed the mechanisms of this pathology. The immune system of these patients, instead of being protective, attacks “self ” tissue, resulting in multiorgan damage. The two major mechanisms involved consist of cytotoxic autoantibody and immune complex- mediated pathways. First, autoantibodies against dsDNA, chromatin proteins, ubiquitous ribonucleoprotein antigens, and other proteins form immune complexes and inflammatory responses.2,3 The resulting inflammation leads to symptoms such as skin rash and oral ulcers, culminating in organ damage. Cytotoxic antibodies against red blood cells, white blood cells, and platelets often lead to anemia, leucopenia, and thrombocytopenia in SLE patients. The second mechanism involves free antigens in the serum which bind to antibodies and create immune complexes. The deposition of these immune complexes on tissue basement membranes can then lead to local inflammation and tissue damage. Examples of this mechanism include nephritis, dermatitis, and arthritis. The tissue damage and thus the symptoms, are dependent on the location of the immune complex deposition. Therefore, SLE often presents with diverse symptoms ranging from skin rash, oral ulcers, and arthritis to seizures and psychosis.2,3 This diverse symptomatology poses a great challenge for effective treatment of SLE patients. Dr. Urowitz asks, “Why do we think that a patient with pleurisy will have the same treatment as a patient with psychosis?” In order to effectively treat a patient with cancer, the physician must know the subtype of cancer. Thus, “We are in that stage with lupus. We haven’t better phenotyped the lupus patient as of yet. Lupus is probably not one disease but five or six diseases.” Furthermore, in order to effectively research lupus, the researcher must recognize the various subtypes of lupus and decide which subtype they would like to investigate. This is where the work of Dr. Urowitz comes in. His major initiative has been
to better phenotype this disease. Early on when he joined the staff at the Wellesley Hospital as a rheumatologist, he noticed that a subset of his SLE patients who achieved symptom-free status developed cardiovascular complications years later, and succumbed to heart attacks shortly after. Dr. Urowitz was the first to describe this phenomenon as a “bimodal mortality pattern” among SLE patients, with early deaths being attributed to active disease, infections, and glomerulonephritis, and later deaths to heart disease.4,5 Dr. Urowitz explains that these cases are not common, and when “physicians have a few cases such as these among the rest, it might not trigger an association.” However, with a detailed long-term patient database, Dr. Urowitz was able to investigate the frequency of SLE patients presenting with cardiovascular complications. Presently, the relationship between SLE and cardiovascular disease is a major area of investigation. In 1970 he established the University of Toronto Lupus Clinic and the Lupus Databank Research Program and in 1995, Dr. Urowitz moved his practice and work to the Toronto Western Hospital and Toronto Western Research Institute. This comprehensive databank enabled him to build the necessary clinical and research framework in order to adequately characterize the various subtypes and presentations of lupus. This extensive longitudinal database is now one of the largest in the world, with data of around 47,000 visits from 1850 patients. Dr. Urowitz and his team see patients every three months, collecting data through various standardized questionnaires, as well as collecting biological samples including sera, plasma, and DNA. Using this patient information, Dr. Urowitz and his team can go back and correlate clinical features with the patients’ serological profiles. Furthermore, recognizing the importance of patient numbers in clinical studies, Dr. Urowitz was a founding member of the Systemic Lupus International Collaborating Clinics (SLICC), a team of scientists from 33 centres and 11 countries in Europe, Asia, South America, and North America who contribute patient samples and information in order to collaborate and answer crucial translational questions in lupus. In addition, to ensure that measures at multiple centres are consistent and
quantifiable, Dr. Urowitz worked with colleagues to develop the SLE Disease Activity Index (SLEDAI) to quantify disease activity, the Adjustment Mean SLEDAI (SLEDAI AMS) to measure disease activity over time, and the SLICC Damage Index to measure the damage caused by SLE. These are now widely used tools in the SLE research field. With an international team of researchers, as well as his TWRI team of physician, fellows, and graduate student researchers, Dr. Urowitz has used his established, standardized system of questionnaires and sample collection to define and characterize novel subtypes of SLE in order to personalize therapies and optimize patient outcome and quality of life. Aside from his research, Dr. Urowitz is widely known for his exemplary teaching. He has received eight Outstanding Teaching Awards from the University of Toronto and held the role of Associate Dean of Post-Graduate Medical Education at the University of Toronto for ten years. Asked what his advice is for the over 100 fellows he has trained and young student readers, Dr. Urowitz replies, “Have a hunger for knowledge. The biggest thrill in research is to create new knowledge. There is nothing more satisfying. Some questions may be answered in the lab while others may look to medicine in the clinic.” He then adds, “Where is your burning desire? If you want to do good research, you should do some graduate work. This will help you develop the skills and knowledge to start addressing your burning question. A graduate degree will help you know where to start.” By pursuing his passion, Dr. Urowitz has provided the basis for developing personalized treatment options for SLE patients. What are you most passionate about? References 1. Statistics Canada- Government of Canada [Internet]. Muskoskeletal Diseases: Systematic Lupus Erythematosus. 2006 [cited 2015 November 12]. Available from: http://www.statcan.gc.ca/pub/82619-m/2006003/4053548-eng.htm 2. Tsokos GC. Systemic Lupus Erythematosus. New England Journal of Medicine. 2011 Dec;365(22):2110-2121. 3. Ben-Menachem E. Systemic Lupus Erythematosus: Review for Anesthesiologists. Anesthesia and Anelgesia. 2010 Sep;111(3):665-676. 4. Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerosis cardiovascular disease among patients with SLE: A systematic review. Seminars in Arthritis and Rheumatism. 2013 Aug;43(1):77-95. 5. Urowitz MB, Bookman AA, Koehler BE, et al. The bimodal mortality pattern of systemic lupus erythematosus. American Journal of Medicine. 1976 Feb;60(2):221–225.
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FROM VARIOLATION TO VACCINATION:
THE HISTORICAL CONTEXT ON
SMALLPOX’S ERADICATION By Mirkamal Tolend
tudents of immunology are familiar with the name Edward Jenner, the English physician credited with developing the smallpox vaccine, and hailed as the father of immunology. But as with most scientific discoveries, the fruition of this progress is indebted to many unsung heroes, and it is an important case study for appreciating the complexity and beauty in scientific change.
Variolation in history It was common knowledge that survivors of smallpox gained lasting immunity to the 20 | IMS MAGAZINE WINTER 2016 IMMUNOLOGY
disease. Between the 10th and 17th centuries, the deliberate transfer of the smallpox virus was being practiced for prophylactic purposes independently in parts of Asia, the Middle East, and Africa. 1–3 Chinese texts describe the intranasal inhalation of material from smallpox postules. Indian texts describe wrapping susceptible children with pox-laden blankets. In Turkey, the practice of inoculation with smallpox (variolation) involved instilling scabs or fluid from ripened smallpox postules subcutaneous onto the vaccinee’s arm. Teasing out a causal connection between recovering from an infection and being immune to subsequent infections certainly
required original thinking and experimentation in an era where this phenomenon could have easily been attributed to fate or some intangible personal character, like strength or faithfulness. In 1714 and 1716, European physicians Emanuale Timoni and Giacomo Pilarino independently witnessed variolation in Turkey, and sent letters to the Royal Society of London.1,2 The Society responded with skepticism. During the same time in America, Reverend Cotton Mather and Dr. Zabdiel Boylston helped facilitate widespread uptake of inoculation. Mather learned about inoculation from a slave
Photo credit Gillray, James. The Cow-Pock–or–the Wonderful Effects of the New Innoculation! 1802. Color engraving. Puclications of Ye Anti-Vaccine Society, Library of Congress.
Figure 1: An 1802 satire of vaccination shows cows sprouting out of the bodies of vaccinated patients.
FEATURE who had been inoculated as a child in Africa.1 He later read the reports from Timoni, and when a smallpox epidemic hit Boston in 1721, urged the city’s physicians to practice variolation immediately. Dr. Bolyston was the only physician Mathers was able to persuade, and thereafter, the two began the variolation program in Boston. Physicians in Boston opposed the practice, even entertaining the notion that smallpox was God’s Providence and not to be interfered with.1 Amidst the early opposition (made up of physicians no less), Mathers and Bolyston continued their inoculation practice. During the Boston epidemic of 1721, they reported that 5889 people contracted smallpox; mortality rate was 14% in the nonvariolated population, but only 2% among the 300 variolated, and the disease severity was much lower among the variolated.1,2 This observational data, however crude and confounded it may have been, was greatly influential in re-instituting the practice of variolation in England, from where smallpox had already spread to the rest of Europe. Variolation soon became common practice, and in 1757, the 8-year-old Edward Jenner himself would get variolated.5
The leap to vaccination Variolation was nevertheless a risky procedure with 2% mortality rate, and sometimes introduced the spread of the disease to new locations.4 It was observed long before Jenner’s time that Milkmaids and horse-riding troops didn’t contract smallpox. In 1796, Jenner used an experimental approach to test this connection. He inoculated his gardener’s child, James Phipps, with cowpox (vaccination), observed a mild reaction, and then purposely tested his immunity by exposing him to smallpox.1,2,4 It is important to clarify that this second phase was only a conventional variolation that Jenner was qualified and experienced in, which the child’s father may have wanted regardless. After the exposure, Phipps did not develop smallpox, or even a mild reaction that is commonly seen with variolation. Jenner wrote about this experience to the Royal Society, while continuing to successfully experiment with more patients. In addition, Jenner noted that the reaction after
vaccination was much milder than the reactions to variolation. Eventually, he harvested cowpox lymph to use as a vaccine and distributed it widely, even to professor Benjamin Waterhouse at Harvard University, who was appointed by Thomas Jefferson to start a national vaccination program.2 In 1798, Jenner published his experience along with similar positive feedback from many of his colleagues.7
The controversies and subsequent developments Although vaccination began to widely replace variolation for its improved safety, the practice still generated heated opposition, driven by not only religious but also scientific grounds. The religious believed that disease was a test sent from God, and any human intervention was seen as highly sacrilegious. The bovine source of the vaccine ingredient created further negativity, which was caricatured in the 1802 publication of ye Anti-Vaccine Society (by James Gillray, Figure 1). Anti-vaccinators continue to scrutinize the unnatural ingredients in vaccines to this day, and unfortunately in most cases, their actions spread misinformation and unfounded fear that undermine the delivery of effective prevention programs. Scientific challenges to Jenner are best documented in his written correspondence with Ingen Housz, a physician, academic, and an established variolator.8 Housz critically examined Jenner’s theories and the validity of his clinical observations. Among many inquiries, Housz asked Jenner to specify how severe the cowpox reaction needs to be for indicating a successful vaccination, and how and where to obtain cowpox material for arm-toarm inoculations. After Jenner couldn’t properly or consistently define some of the diagnostic differences or his outcome assessment, and perhaps appropriately, Housz accused him for using ad hoc justifications to explain the cases where vaccination failed to be effective.8 Despite shortcomings, Jenner’s perseverance and stubborn convictions helped vaccination survive its initial introduction. Subsequent advances in the
understanding of immunology, including the Hygiene Hypothesis,3 as well as developments by numerous other physicians and scientists improved smallpox vaccine’s delivery, storage, effectiveness, and safety. By the time the World Health Organization started its global smallpox vaccination campaign in the mid-20th century, the closely related vaccinia virus had replaced cowpox as the active ingredient. Smallpox has been eradicated since 1979, but secured stocks of the smallpox virus are kept in American and Russian government research facilities for research purposes. More recently, debates have emerged on whether to destroy the remaining stocks of the virus. However, this may not yet be practical, as there is always the potential risk of the virus existing in undisclosed or forgotten facilities, which may pose a risk of re-emergence or weaponization. Although Edward Jenner was not the first person to devise or practice this significant milestone in smallpox eradication, he certainly was the first to systematize, repeat, publish, distribute, and advocate the technique, for which he rightfully deserves credit. Nevertheless, it is important to recognize the context in which significant scientific breakthroughs are made, so as to not have unrealistic expectations about scientific progress.
References 1. Gross CP, Sepkowitz KA. The myth of the medical breakthrough: smallpox, vaccination, and Jenner reconsidered. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 1998 Sep;3(1):54–60. 2. Riedel S. Edward Jenner and the history of smallpox and vaccination. Proc Bayl Univ Med Cent. 2005 Jan;18(1):21–5. 3. Biggs PM. Vaccines and vaccination—past, present and future. Br Poult Sci. 1990 Mar 1;31(1):3–22. 4. Pead PJ. Benjamin Jesty: new light in the dawn of vaccination. The Lancet. 2003 Dec 27;362(9401):2104–9. 5. Barquet N, Domingo P. Smallpox: the triumph over the most terrible of the ministers of death. Ann Intern Med. 1997 Oct 15;127(8 Pt 1):635–42. 6. Plett PC. [Peter Plett and other discoverers of cowpox vaccination before Edward Jenner]. Sudhoffs Arch. 2006;90(2):219–32. 7. Jenner, Edward. 1749–1823. The Three Original Publications On Vaccination Against Smallpox. Vol. 38, Part 4. The Harvard Classics [Internet]. [cited 2015 Dec 1]. Available from: http://www.bartleby. com/38/4/ 8. Beale N, Beale E. Evidence-Based Medicine in the Eighteenth Century: The Ingen Housz–Jenner Correspondence Revisited. Med Hist. 2005 Jan 1;49(1):79–98.
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immune privilege within the central nervous system:
Itâ&#x20AC;&#x2122;s not always what it seems T
he immune system is dedicated to the defense against exogenous molecules. When the immune system detects exogenous entities, an immune response may or may not be elicited, depending on where the foreign molecule is located.1 Some regions of the body do not react immunologically upon pathogen challenge and are defined as being immune privileged.2 With immunology being a rapidly-growing field and dividing into many subtopics, this article serves to (1) simplify the multifaceted immune response and (2) highlight one of the hottest fields of immunology: using the immune response to promote recovery after central nervous system (CNS) injury. Protection against pathogens is accomplished through a two-part response; an initial, weaker innate response that, if not strong enough, is followed by a delayed, but stronger adaptive response.1 Systemic leukocytes are recruited to sites of infection and inflammation (neuroinflammation, if occurring in CNS) will ensue. This has polarizing effects which include potent signalling biomolecules, cytokines and chemokines, and can be beneficial as it maintains tissue homeostasis through phagocytosis of dead tissue and promotion of tissue repair.3,4 To further study inflammation, it is necessary to determine where it occurs. Experiments have been performed whereby allografts were transplanted into various parts of the body and the ensuing
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By Jonathon Chio
host immune response was studied.2,5 If the grafts did not elicit an immunological response, these sites were classified as immune privileged. Based on this work, immune privileged sites formerly included the CNS, anterior chamber of the eye, placenta-fetus interface, and testicles.1 However, this list is now obsolete, as it has now been shown that the CNS participates in constant cross talk with the immune system. At the basal state, the CNS is separated from the peripheral immune system by an intact blood brain barrier (BBB) and blood spinal cord barrier (BSCB).3 However, the BBB and/or BSCB can be compromised after CNS injury; creating a breach in immune privilege. Endothelial cells undergo apoptosis in response to proinflammatory and cytotoxic biomolecules released after injury, and infiltrating leukocytes also promote the BBB breakdown through secretion of enzymes that degrade the extracellular matrix.6 The idea of â&#x20AC;&#x153;CNS immune privilegeâ&#x20AC;? was further challenged when astrocytes and resident microglia in the CNS were found to actively engage in significant communication with the immune system.7 Physiologically, astrocytes are major components of the BBB and BSCB and contribute to tissue homeostasis by buffering against excitatory neurotransmitters and ions.8 Microglia, effector immune cells of the CNS, are abundant in the brain and spinal cord parenchyma. Astrocytes and microglia are capable of secreting both
pro- and anti-inflammatory cytokines and the overall effect of these cytokines is dependent on a plethora of factors, such as timing of release, presence of competing or synergistic elements, receptor density, and tissue responsiveness.9 Unbalanced pro- and anti-inflammatory responses lead to neuroinflammation or immunosuppression respectively. Although very limited, the body possesses endogenous mechanisms for remyelination and regeneration after CNS injury.10 Researchers have been investigating strategies of using optimized treatments tailored to enhance the beneficial functions of neuroinflammation, while simultaneously minimizing those that cause injury.3 Successful experiments have indicated benefits of selectively augmenting anti-inflammatory cell populations and associated cytokines, as this is correlated with improved tissue preservation and functional recovery. However, the translational potential is unclear, as the severity of neuroinflammation is dependent on the location in the CNS and the age of the patient.11,12 Relative to the brain, the spinal cord has a more severe inflammatory phenotype.11 In addition, aged individuals exhibit leukocytes with a lower activation threshold.12 An ongoing challenge for researchers is to control communication between the CNS and the immune system in order to minimize damage while promoting recovery. Despite the progress achieved, an exponentially greater amount of knowledge
must be gained before the true power of the immune response can be harnessed towards neural repair and regeneration. While this introduces significant challenges into the field of neuroimmunology, it is also a source of excitement and potential. This article only briefly highlights the multi-faceted and mysterious aspects of neuroimmunology, but one thing is indeed true; things arenâ&#x20AC;&#x2122;t always what they seem.
References 1. Peter Parham. The Immune System, 3 ed. New York, New York: Garland Science; 2009. 2. Forrester JV, Xu H, Lambe T, et al. Immune privilege or privileged immunity? Mucosal Immunology. 2008; 1(5):372-81. 3. Carson MJ, Doose JM, Melchior B, et al. CNS immune privilege: hiding in plain sight. Immunology - Annual Review of Immunology. 2006; 213:48-65. 4. Skaper SD, Facci L, Barbierato M, et al. N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution. Molecular Neurobiology. 2015; 52(2):1034-42. 5. Niederkorn JY. The induction of anterior chamber-associated immune deviation. Chemical Immunology and Allergy. 2007; 92:27-35. 6. Goussev S, Hsu JY, Lin Y, et al. Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. Journal of Neurosurgery. 2003; 99:188-97. 7. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. Journal of Clinical Investigation. 2012; 122(4):1164-71. 8. Li YN, Qin XJ, Kuang F, et al. Alterations of Fc gamma receptor I and Toll-like receptor 4 mediate the antiinflammatory actions of microglia and astrocytes after adrenaline-induced blood-brain barrier opening in rats. Journal of Neuroscience Research. 2008; 86(16):3556-65. 9. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest2000; 117(4):1162-1172. 10. DĂśring A, Sloka S, Lau L, et al. Stimulation of monocytes, macrophages, and microglia by amphotericin B and macrophage colony-stimulating factor promotes remyelination. Journal of Neuroscience. 2015; 35(3):1136-48. 11. Zhang B, Gensel JC. Is neuroinflammation in the injured spinal cord different than in the brain? Examining intrinsic differences between the brain and spinal cord. Experimental Neurology. 2014; 258:112-20. 12. Zhang B, Bailey WM, Braun KJ, et al. Age decreases macrophage IL10 expression: Implications for functional recovery and tissue repair in spinal cord injury. Experimental Neurology. 2015; 273:83-91.
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The Hygiene Hypothesis By Muhtashim Mian
n his stand-up comedy special, “You Are All Diseased” the late George Carlin attributes his ability to avoid sickness to be the result of swimming “in raw sewage” as a child. While his routine is wildly entertaining, if exaggerated, the sentiment behind it nevertheless may carry some weight.
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Intuitively, it makes sense that our immune system would undergo the greatest development during childhood. Given that we are a product of both environment and genetics, it follows that an ideal environment exists which would foster the development of an optimal immune system. Several studies give us a clue about what this ideal environment may be. As per Strachan’s findings, important environmental factors in developing atopic disease seem to be family size and birth order. More specifically, a strong protective effect against atopic disease has been shown for children with older brothers rather than sisters.2 One explanation in support of the hygiene hypothesis is that older brothers are generally more frequently in contact with dirt than sisters, presumably because of playing habits.
Another explanation entirely different from this hypothesis may be that that changes in the mother after each birth have a protective effect for subsequent offspring. Indeed, some studies have shown significant decreases in maternal and cord blood IgE (the antibody responsible for allergic reactions) after each birth.3 While the maternal environment may have some effect, it alone cannot sufficiently explain other observations related to external childhood environment. For example, close contact, such as bedroom sharing, which is more common in larger families, provided protection against subsequent atopic disease.2 Similarly, it has been shown that children that attended large daycare facilities had lower chance of asthma later in life.4 Although evidence for daycare attendance is inconsistent, the data suggests that at worst, there is no protective effect,5 and at best, there is significant protection against atopy (becoming hyperallergic).6 Another interesting environmental factor seems to be the type of community a child is raised: farming children, as opposed to rural children with no agricultural
Photo Courtesy of iStock
The idea that early exposure to “germs,” or lack thereof, affects the state of the immune system in adulthood is not new. As far back as 1989, David P. Strachan noticed a steady increase of atopic or allergy-related diseases over the 20th century.1 He also noticed that children with many older siblings tended to have lower incidence of such diseases. Taken together with apparent improvements in public cleanliness and sanitation laws, Strachan formally proposed what is now known as the hygiene hypothesis. He suggested that the rise of hay fever, an atopic disease caused by allergy to pollen or dust, was a result of children not being exposed to infectious agents as often. He argued that children with older siblings were more likely to be exposed to infectious agents due to frequent
unhygienic contact. Thus, the hypothesis was predicated on two essential points: 1) microbial exposure and infections during childhood have protective effect against atopic diseases and 2) the growing trend of cleanliness prevents such infections from taking place.
FEATURE exposure, have significantly lower levels of hay fever, asthma and hypersensitivity reactions.7 In fact, there seems to be a proportional relationship, with children that have intermittent exposure to farms having intermediate levels of atopy. The precise agent that provides the protective effect is poorly defined. That being said, it has been shown that contact with animals as a child, as well as exposure to stables for children under one year of age reduces the chance of allergies later in life.8 There appears to be no parallel for adults, as adults with exposure to farms did no better with respect to atopic or allergic disease.9 On the contrary, adult farmers had elevated risk. Given this data, childhood exposure to microbes does indeed appear to have a significant effect on the state of the immune system later in life. Public proponents of the hygiene hypothesis believe that the obsession with cleanliness has tended to sterilize our homes, leaving them barren of germs that are beneficial to us. While it’s true that our homes may look visually clean, it does not necessarily mean there is an overall decrease in the quantity or diversity of microbes. For example, although disinfectant cleaning products are effective at reducing microbe contamination, the effect remains for as little as 90 minutes; after this period, most sites become recontaminated.10 In other studies that monitored pathogens in periods of days to months, it was concluded that casual use of disinfectant cleaning products from days to months were unlikely to reduce the risk of pathogen exposure.11 Regarding atopic disease specifically, a 1994 study that analyzed several geographic locations found no correlation between consumption of soaps, detergents, and sterilizing cleaning products to hay fever and eczema. This data suggests that there should be no significant difference in the diversity of microbial presence between an urban home 50 years ago compared to now. An important question is whether or not infections themselves are the cause, rather than innocuous microbial exposure or colonization. The answer to this question seems to be less clear. Public improvements in infectious disease management and eradication are well known. During the late 19th and early 20th century, there were tremendous improvements made in the sanitation,
water treatment, and personal hygiene of industrialized countries, such that serious infections including cholera and typhoid began to decline. According to the hygiene hypothesis, there should have been a corresponding increase in atopic disease within 3-6 years, given the priming effect these infections should have had on children. Yet, the increase in atopy occurred much later in the 20th century. It should be noted that reported infections during this period were life-threatening as opposed to less serious infections, which go unreported in national surveillance data. Nevertheless, the delay between fall in infections and rise in atopy remains poorly explained. When looking at individual infectious agents, there is some evidence that supports the hygiene hypothesis. Childhood infections from hepatitis A virus have consistently been correlated with reduced chances of atopy in later life.12 However, it has been argued that hepatitis A infections may be a surrogate of other environmental conditions that may contribute to a decrease in atopy. Hepatitis A infections are associated with large family size and lower socio-economic status, for example.13 Together, this data paints a murky picture of the hygiene hypothesis regarding the role of childhood infections in protecting against atopic disease.
References 1. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299(6710):1259–60. 2. Svanes C, Jarvis D, Chinn S, et al. Childhood environment and adult atopy: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol. 1999;103(3 Pt 1):415–20. 3. Karmaus W, Arshad SH, Sadeghnejad A, et al. Does maternal immunoglobulin E decrease with increasing order of live offspring? Investigation into maternal immune tolerance. Clin Exp Allergy. 2004;34(6):853–9. 4. Ball TM, Castro-Rodriguez JA, Griffith KA, et al. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med. 2000;343(8):538–43. 5. Backman A, Björkstén F, Ilmonen S, et al. Do infections in infancy affect sensitization to airborne allergens and development of atopic disease? A retrospective study of seven-year-old children. Allergy.1984;39(4):309–15. 6. de Meer G, Janssen NA, Brunekreef B. Early childhood environment related to microbial exposure and the occurrence of atopic disease at school age. Allergy. 2005;60(5):619–25. 7. Braun-Fahrländer C, Gassner M, Grize L, et al. Prevalence of hay fever and allergic sensitization in farmer’s children and their peers living in the same rural community. Clin Exp Allergy. 1999;29(1):28–34. 8. Von Ehrenstein OS, Von Mutius E, Illi S, et al. Reduced risk of hay fever and asthma among children of farmers. Clin Exp Allergy. 2000;30(2):187–93. 9. Rylander R. Health effects among workers in sewage treatment plants. Occup Environ Med. 1999;56(5):354–7. 10. Scott E, Bloomfield SF, Barlow CG. Evaluation of disinfectants in the domestic environment under “in use” conditions. J Hyg (Lond). 1984;92(2):193–203. 11. Josephson KL, Rubino JR, Pepper IL. Characterization and quantification of bacterial pathogens and indicator organisms in household kitchens with and without the use of a disinfectant cleaner. J Appl Microbiol. 1997;83(6):737–50. 12. Matricardi PM, Rosmini F, Ferrigno L, et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ. 1997;314:999–1003. 13. Strachan DP. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax. 2000;55 Suppl 1(Suppl 1):S2–10.
Since the hygiene hypothesis was introduced over 25 years ago, it has been put under scientific scrutiny. Strachan’s original conclusions about infections and their importance during childhood raised critical questions for public health. There is overwhelming data to support the importance of a child’s microbial environment in the development of their immune system. However, childhood infections per se show inconclusive evidence. In light of this evidence, it would not be wise to abandon public practices of hygiene, as there can be no doubt of the positive impact such practices have had on management of infectious disease. Instead, we should try to incorporate practices that have actually shown public benefit. Therefore, a child in a modern industrialized country wishing to be protected from atopic disease should seek to have regular exposure to farms and animals, and kindly ask for older brothers.
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BMC FEATURE Transposition of the Great Arteries
Lauren Huff, 1T7
Ulnar Nerve Palsy Matan Berson, 1T7
Student work from the Master of Science in
Lepidoptera Wing Pattern Savanna Jackson, 1T7
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Wendy Gu, 1T6 Erina He, 1T6
Photo credit: Oliver Salathiel, Daniel Wesser of Salathiel & Wesser Photography
The Ori Rotstein Lecture
IN TRANSLATIONAL RESEARCH By Rebecca Ruddy
he Institute of Medical Science’s (IMS) annual Ori Rotstein Lecture in Translational Research took place on October 23, 2015 and featured Dr. Paul O’Byrne as the keynote speaker. The Ori Rotstein Lecture was founded in 2011 in honour of past IMS Director Dr. Ori Rotstein. Dr. Rotstein, Professor and Surgeon-in-Chief at St. Michael’s Hospital, was the Director of IMS between 2000 to 2011 and, under his leadership, the department grew to be the largest graduate unit in the Faculty of Medicine and the fifth largest unit at the University of Toronto. In addition to this expansion, Dr. Rotstein pioneered several important initiatives within IMS, including the introduction of additional professional programs, improvements in student policy, as well as continued development of curriculum, especially in the core departmental course. The Ori Rotstein Lecture was founded to highlight advancements and innovation in the field of surgery and translational research and features outstanding keynote speakers.
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This year was no exception. Dr. Paul O’Byrne is a Distinguished Professor at McMaster University. He is an E.J. Moran Campbell Professor of Medicine and Chair of the Department of Medicine at the Michael G. DeGroote School of Medicine. Dr. O’Byrne is an accomplished researcher with over 400 peer-reviewed papers, 98 book chapters, and over 100 review articles, as well as the recipient of numerous awards and honours. Dr. O’Byrne’s research interests include “the mechanisms and treatment of asthma, with particular reference to the role of environmental allergens and the mechanisms by which these cause airway inflammation.”1 It was this research topic that was the focus of the keynote address entitled, “Developing New Treatments for Allergic Asthma.” Dr. O’Byrne commenced the lecture by outlining the problems and obstacles encountered with new drug development in asthma; the number of asthma medications approved is decreasing
Photo credit: Oliver Salathiel, Daniel Wesser of Salathiel & Wesser Photography
IMS NEWS while the cost per new drug approved is increasing. Therefore, this process needs to focus on more efficient and robust methods to identify drugs whose results in early phases are predictive of their success in later clinical trial phases. Although there are safe and effective drugs currently available for the treatment of asthma, there is still a fraction of patients that despite these medications still suffer from severe refractory asthma. This patient population is heterogeneous and often has co-morbidities and other issues that present challenges in the drug development and clinical trial process. Therefore, Dr. O’Byrne presented a potential solution to this obstacle in asthma drug development. Dr. O’Byrne presented the idea of studying new drugs in patients with mild asthma by presenting them with an allergen to elicit a reaction (allergen challenge) and determining the effect and efficacy of new drugs at treating the asthmatic symptoms. The goal would be to use this as a predictive tool to determine drugs that will be effective in later clinical trial phases. Using this method, Dr. O’Byrne has identified true positive and negative controls that are respectively effective or ineffective in the treatment of allergeninduced asthma. However, there have been instances of false positives, with drugs that treat the allergy response, but are not effective in treating asthma, but there have been no false negatives. This approach is currently being used in the Allergen NCE Clinical Investigator Collaborative study, a Canadian Phase II trial testing potential drug candidates for different types of asthma. Dr. O’Byrne presented data from different drugs that were tested using the allergen challenge approach and identified different drugs with some failing and some succeeding at attenuating the allergic reaction. These drugs therefore validated the allergen challenge model and allowed the allergen challenge to be a well-established clinical model to study new drugs. In addition, the reliability of this model will allow for smaller sample sizes. These results demonstrate that this model shows promise and will greatly improve current methods for the testing of drug candidates for asthma.
Although there are safe and effective drugs currently available for the treatment of asthma, there is still a fraction of patients that despite these medications still suffer from severe refractory asthma.
Following the remarkable keynote speech by Dr. Paul O’Byrne, Dr. Ori Rotstein moderated a panel discussion entitled, “Clinical Trials in a Canadian Context: What are we doing right? What could we be doing better?” The panellists included Dr. Paul O’Byrne, Dr. John Marshall (Professor, Department of Surgery, University of Toronto), Dr. Michael Tymianski (Senior Scientist, Toronto Western Research Institute), and Dr. Michael Farkouh (Associate Clinical Professor, Department of Medicine, University of Toronto and Director, Heart and Stroke/Richard Lewar Centres of Excellence). The panellists led a lively discussion regarding the current landscape of clinical trials in Canada, tackling such topics as investigator-initiated trials, the necessary skill-set for clinical trials in Canada, multicenter trials and collaborations, and funding challenges. The panel discussion provided audience members the opportunity to ask questions and provide input into the ongoing conversation, introducing the subjects of orphan drugs, funding drug research for uncommon diseases, and bringing a business aspect to drug discovery and clinical trials. Overall, the panel discussion successfully touched on important topics related to current clinical trial practices in Canada and offered insight into the existing challenges and potential solutions to improve the state of these trials.
The 5th annual Ori Rotstein Lecture in Translational Research has certainly continued to achieve what it intended when it was first founded and much more. Dr. Paul O’Byrne presented innovative approaches and data in translational research and demonstrated a new solution to the problem of inefficient methods in asthma drug discovery. Through his collaborative research, he presented promising results in validating a clinical model to study new drugs and therapies for asthma. In addition to the keynote speech, this year’s lecture also held an informative discussion on the current state of clinical trials in Canada, which gave the audience an opportunity to participate and ask questions. The panel discussion was insightful and offered varying opinions and viewpoints, which led to a successful well-rounded discussion. The Ori Rotstein Lecture in Translational Research succeeded in presenting innovative research in the field of surgery and translational research and demonstrated the excellence in research currently underway in Canada. Reference
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Dr. Mario Masellis MSc (Pharm), MD, PhD, FRCPC Associate Scientist, Evaluative Clinical Sciences, Hurvitz Brain Sciences Research Program Co-Director, Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre Assistant Professor, Neurology, University of Toronto, Associate Member, Institute of Medical Science
ith expertise in four principle research disciplines: Neurology, Neuroimaging, Genetics, and Pharmacology, Dr. Mario Masellis is a remarkable individual who is at the forefront of global research on dementia. Recently, he was part of an international multi-centered study published in The Lancet Neurology,1 which identified some of the earliest structural neuroimaging and cognitive markers in individuals at risk of frontotemporal dementia. Dr. Masellis serves as the co-director of one of the most productive laboratories, L.C. Campbell Cognitive Neurology Research Unit, at the Sunnybrook Health Sciences Centre. His clinical expertise are in the diagnosis and treatment of early-onset and other dementias associated with movement disorders. Needless to say, he cherishes both of these roles–those of an avid investigator and a skillful clinician. Not long ago in 1997, Dr. Masellis completed his MSc degree in Pharmacology under the supervision of Dr. James Kennedy and Dr. Werner Kalow at the University of Toronto. He explains, “I didn’t think I would be interested in clinical research, but I had some great opportunities offered to me by my supervisors.” Dr. Masellis, following the footsteps of his own father, completed an MD degree at the University of Toronto and pursued a fellowship in cognitive neurology. “I was always intrigued by hearing some of the cases my father had dealt with in his
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By Usman Saeed practice,” he adds, “I became interested in brain disorders, initially from a research perspective and then medicine allowed me to integrate my investigative curiosities with clinical knowledge.” Masellis defended his PhD thesis in Clinical Neurosciences studying a rare progressive neurological disorder known as Corticobasal Syndrome (CBS), under the supervision of Dr. Sandra Black. Dr. Masellis considers research a valuable aspect of a clinician’s role and important for the advancement of scientific knowledge. He expressively states, “In many regards, clinicians have studied the human condition and dealt with the patients’ suffering on a personal level. The hypotheses I investigate in studies are often generated from observations made from individual or groups of patients that I see in my clinic. As a Clinician-Scientist, I am not only able to understand the disease from a textbook reading, but also able to appreciate its consequences directly on the patient and develop studies to improve upon the current treatments.” The most rewarding part of the job, according to Dr. Masellis, is helping his patients by using standard of care therapies and offering them the opportunity to participate in research studies and clinical trials. He comments, “Although neurodegenerative dementias remain incurable, standard of care therapies are available and clinical trials have the potential to help
Photo credit: Shariq Mujib
SPOTLIGHT ON A DEMENTIA AND MOVEMENT DISORDERS EXPERT
Dr. Mario Masellis these and other patients with similar problems in the future.” Further elaborating on his patient interactions, he enthusiastically comments, “I try to learn from my patients. Every patient has a slightly different presentation of the same disease and understanding this person-to-person heterogeneity is of great interest to me.” Talking about his most significant works, Dr. Masellis points out that every article he has written is an accomplishment for him in its own right, irrespective of the publishing journal. He describes two of his current projects as groundbreaking, “We are participating in a large international cohort study in patients at genetic risk of developing frontotemporal dementia, which is a terrible neurodegenerative disease that causes huge functional decline in very young working families. Using a multi-centered consortium approach, we have amassed large brain imaging and fluid biomarker data in a short period of time. Having access to this cohort and engaging in some of the neuroimaging works with my team will help improve our understanding of this devastating disease.” His second recent contribution has been a study where he examined pharmacogenetic responses to anti-parkinsonian drugs. He explains, “We have recently tapped into a very large clinical trial of a drug called ‘Rasagiline’ used to treat Parkinson’s disease and have identified biomarkers that determine the clinical response to this drug”
When asked about the future of research in dementia, Dr. Masellis believes that it involves integration of different techniques and disciplines to answer some of the toughest questions. He elaborates, “For example, combining neuroimaging with genomics to identify mechanisms that influence the brain functions.” He also foresees a greater emphasis on finding treatments in asymptomatic at-risk individuals in order to stop or delay the dementia onset. I couldn’t help but ask: what advice would you give to a graduate or medical student starting off in your field? He answers, “It is a huge commitment and it is important to be sure that one enjoys all aspects of it.” He adds, “In addition to mastering the relevant knowledge and skills, one should also be prepared to develop new and better studies to assist in the understanding of complex diseases that we see as neurologists.” Outside of the professional setting, Dr. Masellis enjoys road and trail cycling. Even as he travels to out-of-city meetings, he takes the opportunity to embark on an exploratory ride around the city on a bike. In the winter, Nordic skiing is his favourite activity. Dr. Masellis has been a recipient of several major awards that include the Maud Menten New Principal Investigator Finalist Prize from the CIHR, the early researcher award from the Ministry of Economic Development and Innovation, and in his
earlier training he was honoured with a young delegate award by the International College of Neuropsychopharmacology. Upon request, Dr. Masellis offers two articles that can be of great interest to our IMS Magazine community in understanding the research field of dementia. The first article is a review paper that discusses the differences between the late and earlyonset dementias including diagnostic strategies and potential mechanisms.2 The second paper examines two neurodegenerative dementias that have parkinsonism as an associated feature.3 Dr. Masellis explains, “Sometimes, dementia with Lewy bodies presents itself without visual hallucinations which makes it difficult to differentiate from Corticobasal Syndrome. This study presents neuroimaging and neuropsychological features that can help distinguish between the two.”
References 1. Rohrer JD, Nicholas JM, Cash DM, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol. 2015; 14(3):253-62 2. Masellis M, Sherborn K, Neto P, et al. Early-onset dementias: diagnostic and etiological considerations. Alzheimers Res Ther. 2013;5(Suppl 1):S7. 3. Misch MR, Mitchell S, Francis PL, et al. Differentiating between visual hallucination-free dementia with Lewy bodies and corticobasal syndrome on the basis of neuropsychology and perfusion single-photon emission computed tomography. Alzheimers Res Ther. 2014; 6(9):71.
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Spotlight on Photo credit: Meital Yerushalmi
Serisha Moodley Serisha Moodley, 5th year PhD Student, Institute of Medical Science Latner Thoracic Surgery Research Lab, Toronto General Hospital Research Institute Supervisor: Dr. Mingyao Liu By Arunima Kapoor
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Serisha chose the IMS at the University of Toronto to pursue her PhD when she realized the significance of her work in the context of medical science. She was initially drawn to the IMS for its emphasis on translational research when the “bench-to-bedside” approach was introduced. Serisha currently works in the Latner Thoracic Surgery Research Lab under the supervision of Dr. Mingyao Liu. Alongside studying protein-protein interaction and protein function, she is also exploring how these functions relate to diseases such as acute lung injury during lung transplantation and cancer. When asked what she hopes to learn, she states, “For me, it is important to understand how these proteins interact to maintain cell
Photo credit Meital Yerushalmi
he decision to pursue a PhD degree is a commitment unlike any other. This degree requires the passion to dedicate many years to one specific goal. Serisha Moodley, a 5th year PhD student at the Institute of Medical Science (IMS), decided to make this commitment after she discovered her passion for the study of protein function. While completing a Master’s degree in biochemistry at the University of Toronto, Serisha fell in love with protein structure and function. Recognizing the lack of in vitro and in vivo models in chemistry, Serisha joined the IMS to explore how protein function and interactions within a cell relate to certain diseases.
From left to right: Dr. Yingchun Wang (research associate), Serisha Moodley, and Ms. Hyunhee Kim (graduating Ph.D. student in the department of physiology)
homeostasis or to resolve injury and get back to their normal state.” She hopes that her field of study embraces further collaboration between basic and clinical science. While completing a doctoral degree is demanding for all graduate students, Serisha’s path to completing her degree has been much more challenging than it is for most students. Approximately two years ago, Serisha was diagnosed with cancer. She believes that one of her biggest accomplishments to date is being able to return to her studies with a positive mental state. She is now back in the lab finishing up her PhD degree. Indeed, one thing that we could all learn from Serisha is how to remain positive and strong despite
the overwhelming obstacles that life sometimes brings about. When asked what advice she would give to someone starting out in the field of research, Serisha says, that one of the most important things is “to be confident in yourself and to believe in what you are doing.” In the little time that Serisha spends outside the lab, she enjoys photography. However, the past year has been extremely busy for Serisha. She published multiple papers and won two Ontario Student Opportunity Trust Fund awards. Given her unwavering devotion to her research, it is hardly a surprise that Serisha is achieving excellence. After her PhD, she plans to continue
working in academia as a post-doctoral fellow or research associate, studying the molecular mechanisms governing respiratory diseases. She also hopes to bridge the gap between science, communication, and the general public by using her skills to educate the community about health-related issues and the advantages of personalized medicine. Serisha’s journey as a graduate student teaches us all that persistence, dedication, and a positive attitude are essential to succeed as a graduate student and thrive in the field of science.
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By Yekta Dowlati
Li Guo, MD, 5th year PhD Student, Institute of Medical Science Li Ka Shing Knowledge Institute, St. Michael’s Hospital Supervisor: Dr. John Semple
s an only child of a traditional Chinese family, Li Guo was fascinated by the wonders and perils of nature and biology. Living with her grandparents, she witnessed peril, as her grandfather suffered from diabetes. Li was admitted to the sevenyear program in Clinical Medicine in Shandong University. It was during her clinical rotations in the Department of Hematology that she got inspired by Dr. Ming Hou, the director of the department, whom she describes, “was not only a physician, but also a great researcher, especially in the field of immune thrombocytopenia (ITP).” This motivation and enthusiasm led Li to be among the first applicants to the 2010 Summer Undergraduate Research Program (SURP) at the Institute of Medical Science (IMS). She got accepted into the laboratory of Dr. John Semple and started evaluating platelet transfusion therapy in murine model of ITP which had come out in 2009 and was quite novel. They had a preliminary trial of platelet transfusion therapy in the ITP mouse model, showing its immunomodulatory effect. Her abstract then got accepted for presentation at the American Society of Hematology’s (ASH) annual meeting. Li indicates, “I was super excited. I had a wonderfulA productive summer here, the project went so well, I learnt a lot and my abstract also got accepted.” Among her 34 | IMS MAGAZINE WINTER 2016 IMMUNOLOGY
200 medical student peers in China, she was the first one to attend an international conference. Li received the Chinese Scholarship to pursue her PhD and contacted Dr. Semple to continue her work in ITP mouse model. She was accepted to IMS and started her PhD in 2011, “I struggled a bit leaving my family. My grandfather passed away in 2010. My grandmother was expecting me to graduate and practice in our hometown. I still applied for residency and got a position. But I decided to come here.” She is also the recipient of the prestigious Ontario Trillium Scholarship for four years. Li is currently a fifth year PhD student. She has two main projects, both of which are already complete. One evaluated whether allogeneic platelet transfusions may have a differential effect on the two immunopathologic forms of ITP. The results indicated that antibody-mediated ITP is resistant to allogeneic platelet transfusions, while the T-cell–mediated form of the disease is susceptible, suggesting that transfusion therapy may be beneficial in antibody-negative ITP. The results have been published in Blood. The other project evaluated the usage of Rituxan, a chimeric monoclonal antibody against the protein CD20 which destroys B cells,
in a murine model of ITP. The results will be published soon. Li is currently writing her thesis. Upon completing her PhD, she is interested in pursuing a post-doctoral position and returning to residency afterwards. With a medical license in China, she wishes to move back and help her community like Dr. Ming Hou. “I have always dreamed of a career path involving research and evaluating current treatments and investigating the pathogenesis of diseases to help with future guidelines,” Li explains. Besides working on an ITP mouse model, Li has initiated the Espritlibre book club. They have monthly gatherings, discussing a wide variety of books. Li mentions the change in her vision as the most rewarding part of her education so far, “Since my SURP experience here and through my PhD, I am seeing how research happens and how the frontiers of research lead the field, us being among them. Then the vision changes, you don’t follow anymore, you lead. Also, I have personally flourished during my PhD. I have struggled a lot with my project, learnt to deal with failure, learnt to live independently, and proudly I am much stronger now.”
Photo credit Pratiek Matkar
Spotlight on Li
Photo credit: Pratiek Matkar
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Overwhelmed Work, Love and Play When No One has the Time
Author: Brigid Schulte
s most graduate students know, when you run into a fellow graduate student the conversation inadvertently turns to how busy you are. There are tales of long hours spent in the lab, revision upon revision of that important manuscript, or the classic, “my PI is making me do x, y, and z by the end of the week.” I once overheard another student proclaim that he had slept in his lab overnight to keep a close eye on his experiments. My first thought was, “Really? Is this what I have to look forward to?” Don’t get me wrong, I know deadlines are necessary and that the lure of new data can bring any curious scientist into the lab on the weekend. I just couldn’t help but wonder if this constant “busyness” was really the most effective way to be productive? Shortly thereafter I came across Overwhelmed: Work, Love, and Play When No One Has the Time by Brigid Schulte. Don’t let the title scare you away, this is anything but a selfhelp manifesto. Instead, this book chronicles Brigid’s yearlong endeavor to deconstruct the relationship between work, leisure, and productivity. She spends a significant amount of time reviewing the literature on leisure and interviewing key experts
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Reviewed by Chelsea Lowther in the field, including Dr. John Robinson a Professor of Sociology at the University of Maryland. Brigid leaves no stone unturned and comes at this problem from every angle, interviewing neuroscientists, sociologists, psychologists, and everyday adults grappling with their ever growing to-do list. The book provides a neuro-biological psycho-social review of all the factors that have led our society to become obsessed with overworking. For example, do you know where the 40 hour work week came from? Do you know what percentage of North Americans don’t take their full vacation in the run of a year? Do you know what factors cause burnout? These are some of the questions that Brigid tackles in the book. The story isn’t entirely bleak, though. She does provide several examples of individuals living “the good life.” Take the Danes for example; mothers from Denmark have the most leisure time of any country in the world and the highest employment rates–how do they do it? If for no other reason, I suggest you read this book so you can begin to think about whether more hours in always equals more productivity out.
The Tale of Dueling Neurosurgeons And Other True Stories of Trauma, Madness, Affliction, and Recovery that Reveal the Surprising History of the Human Brain Author: Sam Kean
n The Tale of the Dueling Neurosurgeons, Sam Kean traces the origins of modern neuroscience through stories of brain injury and recovery. Celebrated figures from the annals of medical history come alive as Kean describes their courageous desperation to advance our understanding of the brain. Despite the emphasis on neuroscience history, reflecting the author’s intended focus, the book presents a fundamental look at how the brain works. The result is a pleasant read for all those studying, or simply interested, in neuroscience. The 12 chapters of The Tale of the Dueling Neurosurgeons are arranged in five sections. The book’s first section, “Gross Anatomy,” provides a general layout of the brain and skull. One of the virtues of this section is the lucid and comprehensive coverage of King Henri II’s fatal head injury despite the best efforts of his physicians, Ambroise Paré and Andreas Vesalius.
Basic neurobiology is discussed in the next section, “Cells, Senses, Circuits.” The contributions of Cajal (and Golgi) on the neuron doctrine, Loewi on chemical transmitters, and Hubel and Wiesel on vision neuroscience are covered in detail. Notable examples include the 3009th neuron that made Hubel and Wiesel rejoice in their laboratory basement, or the unusual incident when Nobel Prize winner, Loewi, was permitted to enter the United States only after he had persuaded an immigration official to read about him in Who’s Who. With these foundations in place, Kean takes us through the brain’s major structures and systems in the book’s third section, “Body and Brain.” In my opinion, the two most provocative stories are recounted in this section and are reason enough to read the book. The first story is of Carleton Gajdusek, a brilliant yet deeply flawed clinician-scientist who settled in Papa New Guinea to study kuru, a degenerative neurological disease that
Reviewed by Jabir Mohamed was devastating the Fore tribe. The second story concerns the pituitary work of neurosurgeon Harvey Cushing, who visited giants and dwarfs across the east coasts to illuminate how the brain’s glands work (or fail to). The fourth section, “Beliefs and Delusions” provides incisive analyses of several psychiatric and neurological conditions. The first chapter describes epilepsy neurosurgeon Wilder Penfield’s fight to save the life of his sister, Ruth, who suffered from uncontrollable seizures. The experience had a profound effect on Penfield, who later founded the Montreal Neurological Institute, a center of excellence—then and now—for brain treatment and research. The remaining chapters explore two particularly peculiar delusions—the belief that your relatives have been replaced by impostors (Capgras delusions) and the belief that you have died (Cotard delusions). Kean devotes the final section to the most enigmatic concept of neuroscience, “Consciousness”. While the liveliest topic, this section lacks the thoroughness found in other sections. The behavioural changes of Phineas Gage, the aphasia of M. Leborgne (“Tan”), the amnesia of HM, though extensively covered, are not tied together to establish a coherent examination of consciousness. Readers must draw their own conclusions based on these wonderful sets of stories. Case studies have had a significant impact on the field of neurology. In this respect, Kean has done an excellent job of bringing together the most influential cases for this book. In general, the book is well laid out and clearly organized. Figures are carefully chosen to illustrate specific points and references are extensive and up-to-date. I highly recommend The Tale of the Dueling Neurosurgeons as a historical introduction to the field of neuroscience for students enrolled in neuroscience, but also for interested readers from other disciplines. IMS MAGAZINE WINTER 2016 IMMUNOLOGY | 37
SPECIAL TRP FEATURE Photo credit TRP team
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The program acts as a sandbox for students to explore these skills to become better scientists, investigators, and translational researchers.
SPECIAL TRP FEATURE
Transformational Translational Research FIRST COHORT OF THE TRANSLATIONAL RESEARCH PROGRAM INSTITUTE OF MEDICAL SCIENCE, FACULTY OF MEDICINE, UNIVERSITY OF TORONTO By the TRP Team
hen the first of our ancestors, after discovering the usefulness of a sharpened rock realized that a rock bound to a stick had greater utility, the discovery was transformed. In health science the mobilization of knowledge from discovery to innovation, from “bench to bedside” or “cell to society” is often referred to as translation, and it is not a new concept—make knowledge useful; apply knowledge to gain benefit. What is different today is the scope and the approach to how knowledge is translated.
Translation is rarely an individual activity. The bench scientist is rarely the prolific Edison-Inventor who is capable of having the knowledge, vision and in depth understanding of the science, regulations, legal considerations, organizational behaviour, health policy command, business acumen, manufacturing familiarity, and networks to take their scientific insight and translate it into an innovation that has tangible benefits for human health—not that this doesn’t happen, but this is rare and rarely an individual effort. The scope of translation has changed. The increased complexity of translating has created what many have referred to as valleys of death. Aspects of the translating process, where discoveries and potential innovations (even those who show great promise) die are many and complex, and increasingly require significant expertise, networks and resources required to prove, scale, and diffuse innovation. That has also changed, or is at least in the process of changing is the approach to translation. Not only is it increasingly “team sport”, but who and how it is played has increasingly many flavours—there is no cookie cutter magic formula that will
ensure that health science discoveries have direct impact. One approach to translation is training the scientist-translator; providing the researcher who is working in the lab to advance science to be mindful of the implications and directions of their work. The discovery scientist or clinician investigator is often in the best position to understand the implications and the possible directions of their work. Providing them with skills to network, communicate, and understand the process of moving beyond publications, beyond intellectual patenting and into the minefields of negotiating contracts and licenses, is undoubtedly a key step towards ensuring that discoveries are not stuck in the translational valleys of death without reason. A second approach to translation is training someone to translate. In this case the translator may not be someone who was actually involved in the initial discovery, but is someone who is able to see the potential of a discovery to meet a specific medical need. Trying to identify an ingenuity gap or medical need for which science may be employed to provide a solution is not necessarily the way most scientists are trained. Starting with a patient need to generate new knowledge, applied knowledge that attempts to solve a problem is itself a major undertaking. Moving scientific investigation towards translational science requires a different type of toolbox. The translational tool box or the core aspects of Translational Research that the new Masters in Health Science in Translational Research includes collaboration, networking, iterative prototyping, evaluation, project management skills, communication skills, and critical analysis
of needs, markets, policies, and ability to assess the potential of a translational project are key learning outcomes for the program. The program acts as a sandbox for students to explore these skills to become better scientists, investigators, and translational researchers. These two approaches to translation are not necessarily mutually exclusive. The scientific investigator who makes the new discovery may be faced with a decision of what to do with the discovery to make it useful: to develop a diagnostic, prognostic, or therapeutic. Like a clinician scientist who sees patients with a need, the scientific investigator must also decide on a medical need to address. Those scientists must like wise go through processes of ideation, iteration, and evaluation to develop something that may be of important health benefit or commercial success. And although each discovery, each need, each venture, or each commitment to advance knowledge may require particular and unique interventions, there are common ways of thinking and understanding of what it takes to transform translations. Building a better hand axe is no longer the core of translating knowledge into innovation, understanding knowledge and understanding needs are increasingly fundamental to transforming discoveries into products, processes, pathways, policies, and protocols with benefits to people and society. Join US. Be part of the second TRP cohort starting September 2016. See trp.utoronto. ca for more information and for directions of how to apply.
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BEHIND THE SCENES
Immunology and Pain By Kasey Hemington
Josiane C.S. Mapplebeck BSc, Third year PhD Student, Department of Physiology, University of Toronto Supervisor: Dr. Michael Salter Chief of Research, Hospital for Sick Children Professor, Institute of Medical Science and Faculty of Dentistry
hen you meet her, you can just tell; Josiane Mapplebeck is incredibly passionate about her research on the role of microglia in chronic pain. I sat down with Mapplebeck to discuss her recently published work in Nature Neuroscience, demonstrating sex differences in the way in which the immune system mediates pain hypersensitivity.1 Though Mapplebeck is only in the third year of her PhD in Physiology at the University of Toronto, she became involved in pain research over six years ago while interning in Dr. Jeffrey Mogil’s lab at McGill University. After working on a number of pain-related projects, she turned to sex differences research while being mentored by fellow Mogil lab member Dr. Robert Sorge, telling me, “It was the first project in research where I was 100% engrossed—I wanted to figure out what was happening in females.” In 2013, Mapplebeck moved to Toronto, allowing her to continue what she had started by undertaking a PhD in Physiology. Mapplebeck’s recent publication revolves around microglia, which are known to mediate pain hypersensitivity in rodent models of neuropathic pain (chronic pain resulting from nervous system damage). These immune cells are responsible for the dynamic interplay between the central nervous system and the immune system, releasing substances such as brain-derived neurotrophic factor that acts on neurons in pain pathways. The catch, Mapplebeck has realized, is that this relationship really only applies to male rodents—often the only sex included in a given experiment. Mapplebeck has been working in Dr. Michael Salter’s laboratory at the University of Toronto, designing experiments investigating neuropathic
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pain that include both sexes, and showing that males and females exhibit similar hypersensitivity following nerve injury. Through a series of elegant experimental manipulations, Mapplebeck was shocked to discover that killing microglia, or blocking the microglia-neuronal signaling pathway reversed pain hypersensitivity in male mice as expected, but not at all in female mice. The implications for the field of chronic pain research are substantial: “Several clinical trials have attempted to develop treatments for chronic pain in humans by inhibiting microglial function. However, microglia may not be relevant in females. This sex difference completely changes how we see drug development and shows that we might need sex-specific drug targets,” Mapplebeck explains. “This was the first time I felt I was doing a project that had real life implications. There is a lot of chronic pain in females, but the majority of rodent research is done in males—I realized my project could improve women’s health.” Mapplebeck is grateful to her supervisor Dr. Salter, Chief of Research at the Hospital for Sick Children, for promoting independent investigation and providing her with extraordinary opportunities to advance her research. When asked about future plans, she tells me she’s committed to making a career out of sex differences and pain, and eventually becoming a principal investigator. Given her recent success and passion for the pursuit of knowledge, she is well on her way to achieving her goals. References 1. Sorge RE, Mapplebeck JCS, Rosen S, et al. Different Immune Cells Mediate Mechanical Pain Hypersensitivity in Male and Female Mice. Nature Neuroscience 2015;18(8): 1081–83.
BEHND THE SCENES
Photo Courtesy of Meital Yerushalmi
This was the first time I felt I was doing a project that had real life implications. There is a lot of chronic pain in females, but the majority of rodent research is done in males—I realized my project could improve women’s health.
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PAST EVENTS IMS BALL HOCKEY
PAST EVENTS WITH IMSSA 42 | IMS MAGAZINE WINTER 2016 IMMUNOLOGY
IMS BALL HOCKEY
IMSSA THANKSGIVING DINNER
IMSSA IN TORONTO
Photo Courtesy of IMSSA
IMS HOLIDAY PARTY
IMS HOLIDAY PARTY
IMS HOLIDAY PARTY
IMS HOLIDAY PARTY
IMS HOLIDAY PARTY
IMS HOLIDAY PARTY IMS MAGAZINE WINTER 2016 IMMUNOLOGY | 43
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