IMS MAGAZINE THINK. LEARN. DISCOVER.
Respiratory Medicine Pioneering Lung Transplantation in Toronto A Retrospective Look at the Achievements of IMS Faculty
Genomic Data Science Using Novel Statistical Methodologies to Develop Therapies for Cystic Fibrosis
Six Days Without Lungs Highlighting the Achievements of the Toronto Lung Transplant Program
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World-Class Quality | Superior Customer Support | Outstanding Value 2 | IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE
IN THIS ISSUE MAGAZINE STAFF
Letter from the Editors............................... 4 Director’s Message.................................... 5 Commentary............................................... 6 Retrospective............................................. 8 Feature: Respiratory Medicine................ 10 Faculty Interviews & Research................ 12 Translational Research Program.............. 26 Student Spotlight..................................... 28 BMC Feature............................................ 30 Viewpoint................................................. 32 Close Up................................................... 38 Past Events............................................... 40 Twitter Feature......................................... 42
Petri Takkala Sarah Peters
Anna Badner Ekaterina An Meital Yerushalmi
Christine P’ng Judy Rubin Lauren Huff Midori Nediger Ursula Florjanczyk
JOURNALISTS & EDITORS
Aadil Ali Aaron Wong Adam Betel Alexandra Mogadam Aravin Sukumar Archita Srinath Arman Hassanpour Arpita Parmar Beatrice Ballarin Benjamin Markowitz Carina Freitas Cricia Rinchon Fadl Nabbouh Felicity Backhouse Gaayathiri Jegatheeswaran Hira Raheel Jessie Lim Joshua Rapps Jonathon Chio Jung (Lily) Ye Lindsay Caldarone Lisa Qiu Melissa Galati Muhtashim Mian Nancy Ji Natalie Osborne Pontius Tang Pratiek Matkar Rachel Dragas Samia Tasmim Sarasa Tohyama Shokoufeh Yaseri Tahani Baakdhah Tazeen Qureshi Usman Saeed Valera Castanov Yekta Dowlati Yena Lee
10 FEATURE INFOGRAPHIC By Christine P’ng
38 STUDENT SPOTLIGHT
1ST SUC CCE CESSFU UL LONG-TERM M SING NGLE LE LUN NG TR TRANSP PLA LANT NT Performed by Dr. Joel Cooper at Toronto General Hospital
1ST U USE OF NOVALUNG IN NN NOR NORTH AMERICA
1ST SUCCESSFUL DOUBLE LUNG TRANSPLANT Performed by Dr. Joel Cooper at Toronto General Hospital 1987 – Toronto: 1st successful paediatric lung transplant
CFTR GENE DISCOVERY
OOLF T E “F TH FAT ATHE HER OF RES ESPIRO SPIROLO LOGY”
Created the Respiratory Failure Unit at the Toronto General Hospital
Dr. Lap-Chee Tsui and his team at the Hospital for Sick Children discover CFTR, the gene responsible for causing cystic fibrosis
LOW POTASSIUM DEXTRAN SOLUTION
Novalung, an external artificial lung is used to keep patients alive until a set of donor lungs are available
SLEEP APNEA BresoDxTM, in partnership with Drs. Hisham Alshaer and Douglas Bradley, developed a battery-operated, home sleep apnea test
First use of gene therapy to repair injured human donor lungs, making them viable for transplantation
SURGICAL SU AL SUC UCCE CESS S
TORON NTO EX VIVO O LUNG LU NG PERFUSION SYSTEM M Developed by Dr. Shaf Keshavjee and his team, this technique was designed to treat, reassess, and improve the function of damaged or high-risk donor lungs before they are transplanted
Developed to make donor lungs safer and recipient response more predictable
Dr. Shaf Keshavjee and his team removed a patient’s lungs and kept her alive for 6 days using a Novalung and extracorporeal membrane oxygenation (a treatment that circulates blood around the body) until a set of donor lungs became available
COVER ART By Judy Rubin
I was inspired by this issue to create a cover motif evocative of springtime. Alveoli are the smallest functional unit of the lungs and branch off the larger bronchioles much like flower blossoms do in the spring.
Copyright © 2017 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited. The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.
Grace Jacobs Iris Xu Mikaeel Valli
SOCIAL MEDIA TEAM
Archita Srinath Lily Ye Tahani Baakdhah
IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 3
LETTER FROM THE EDITORS
SARAH PETERS PETRI TAKKALA Photo by Meital Yerushalmi
pring is in the air!—so, it is only appropriate that we devote our latest issue of the IMS Magazine to Respiratory Medicine. The Institute of Medical Science has a long and distinguished history in the field of respiratory medicine, and the innovative contributions of faculty and students are fittingly at the forefront as we celebrate our past and present pioneers in this field.
In 2018, the IMS will be celebrating its 50th anniversary (#IMS50). Leading up to this milestone, the IMS Magazine will feature some of our greatest achievements in medicine, science, and translational research. Each issue will feature a past or current member of the IMS, who will share their experiences in a “Retrospective” piece. This issue features Dr. Joel Cooper, who played a pivotal role in accomplishing the first successful lung transplant surgeries in the early 1980’s. We are excited to connect the past to the present in the wake of several groundbreaking developments in respiratory medicine. Our interviews with Drs. Shaf Keshavjee and Marcelo Cypel, two leaders of the Toronto Lung Transplant Program, take you through the thought process of the team who removed a patient’s lungs for six days in order to save her life. We also discuss Dr. Lisa Strug’s ‘big data’ approach to cystic fibrosis genomics, Dr. Chung-Wai Chow’s dual role as a clinician-scientist investigating the effect of air pollutants on health, and Dr. Haibo Zhang’s efforts to develop effective treatments for acute respiratory distress syndrome. Finally, Dr. Nades Palaniyar, Dr. Theo Moraes, and our own Dr. Mingyao Liu share personal motivations and aspirations that inspire their research. Our stimulating viewpoint articles are inspired by current events in biology, the media, and culture. We explore ethical considerations of growing transplantable organs in animal models, the consequences of genetically-modified food products, and the future of developing new assessments to appropriately monitor marijuana use in impaired drivers. We hope that you learn more about the experiences of our colleagues in the Translational Research Program and the Master of Science program focusing on Medical Radiation Science. Additionally, our journalists highlight the progress of the evolving Medical Assistance in Dying initiative, following an insightful panel hosted by the IMS Students’ Association. Finally, we would like to express our sincere gratitude to the outgoing Editors-in-Chief, Kasey Hemington and Rebecca Ruddy, for trusting us to build on their foundation of hard work and dedication to the IMS Magazine. Along with the support of our dedicated Executive Editors, creative Design Team, and talented team of journalists, photographers, and illustrators, we are honoured to continue the tradition of highlighting the IMS’s spectrum of discovery. Sincerely,
Sarah Peters & Petri Takkala Editors-in-Chief, IMS Magazine 4 | IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE
t is my pleasure to present the 21st issue of the IMS Magazine, which features the topic of Respiratory Medicine. Respiratory medicine has a long history in Toronto. In this issue, the pioneering work of Dr. Joel Cooper (now at the University of Pennsylvania) is featured in the first of a series of Retrospective articles looking back at the great achievements of IMS faculty. In the 1980’s, Dr. Cooper and his team performed the world’s first successful lung transplant surgeries at the Toronto General Hospital. These achievements impacted my research, as well as many of the people featured in this issue. This issue includes contributions from several IMS faculty, including Drs. Shaf Keshavjee and Marcelo Cypel, Lisa Strug, Nades Palaniyar, Theo Moraes, Haibo Zhang, and Chung-Wai Chow. I also had the opportunity to share my own research in respiratory medicine, and I am honoured to have my work featured alongside my distinguished colleagues. This issue of the IMS Magazine also includes a close up of the work being done in the IMS Professional degree programs: the Translational Research Program, the Biomedical Communications program, and the Medical Radiation Sciences program. The Institute of Medical Science has grown extensively over the years, and we are all excited to see what our great faculty and students will achieve in the years to come. This issue also marks the occasion of our annual Scientific Day. The keynote speaker, Dr. Marina Picciotto, is the Charles B. G. Murphy Professor of Psychiatry, and Professor of Neurobiology and Pharmacology at Yale University School of Medicine. She is world-renowned for her work on the neurobiology of addiction, depression, learning, and memory. Along with Dr. Picciotto’s keynote address, our student presentations, symposia, and poster presentations offer a thought-provoking and inspirational day of scientific research. I want to congratulate the IMS Magazine staff for continuing to put together a high quality publication that highlights the outstanding research, developments, and student initiatives taking place at the Institute of Medical Science. The IMS is a world leader in translational research because of the industrious efforts of our faculty, staff, and students.
Mingyao Liu, MD, MSc
Director, Institute of Medical Science Professor, Department of Surgery, and Physiology, Faculty of Medicine, University of Toronto Senior Scientist, Toronto General Research Institute, University Health Network
I look forward to celebrating our work and achievements at Scientific Day.
Sincerely, Mingyao Liu, MD, MSc Director, Institute of Medical Science
IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 5
MATERNAL HEALTH: time to deliver
By Beatrice Ballarin
aring for a growing world means caring for women and their children, says the Financial Times.1 Preventing maternal death is about more than access to drugs and tools. Education is necessary too. According to the World Health Organization (WHO), more than 10 million women around the world have died from pregnancy and childbirthrelated causes since 2014, including hypertension, sepsis, haemorrhage, and HIV/AIDS.2 Is it possible that many of these deaths could have been avoided? Maternal health extends from the mother to her child, and steps should be taken to further understand how the health of a mother affects her unborn or newborn child. The maternal health Millennium Development Goals (MDGs)3 were developed at the G8 Summit in 2000 by the United Nations to reduce extreme poverty and set out a series of time-bound targets to be achieved by the year 2015.4 Among those goals is a focus on improving maternal health. Unfortunately, these goals have long been considered underachieved and are among the last items on political priority lists. What is underlying the high maternal mortality rates in some countries? In 2010, the WHO, UNICEF, and other health agencies came together to publish a report on global trends in maternal mortality.5,6 Part of this report focused on the link between HIV infection and maternal mortality. For an unknown reason, this relationship has received little attention from the media. The report estimated that 5% of pregnancyrelated deaths worldwide are in some way related to HIV.7,8 Furthermore, some
Artwork by Lisa Qiu
experts have noted a higher frequency of obstetric complications in HIV-infected women. However, the biological basis of HIV-related maternal mortality remains unclear, and more research is needed in this area.9 In addition to understanding the biological causes of HIV-related maternal mortality, stigma and discrimination faced by HIV-positive women is often a major obstacle in seeking necessary perinatal care. Although we have not discovered a definitive treatment for HIV, antiretroviral therapy (ART)—a combination of medications that prevents the virus from replicating—is a treatment option taken by many HIV-positive women during pregnancy.9 Care should also concern the newborn child of an HIV-positive mother to rule out the possibility of a transmitted infection. Statistics show that in the absence of ART, infected children often die before the age of two.7 To decrease the probability of HIV infecting the fetus, a caesarean delivery is usually recommended. This decreases the possibility of placental rupture during vaginal delivery, which could expose the unborn baby to any virus present in the mother’s blood.10 While little is known about the ability of HIV to cross the placenta and infect the fetus, breastfeeding is considered one of the major routes for HIV transmission from mother to child.11 Although a group of researchers from Duke University showed that only one in ten HIV-infected mothers may pass their virus to the infant, HIV-positive mothers in many countries are encouraged to use baby formula as a safe and healthy alternative to breast milk.12 Interestingly, ongoing research also suggests that the mother produces antibodies from her
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B-cells that are capable of neutralizing the common strain of HIV in the milk.12 The necessity to decrease pregnancy and childbirth-associated deaths among women is urgent. A well-rounded solution should improve access to treatment and encourage global healthcare workers to provide more thorough education to women. Despite advances in maternal healthcare, education that provides women with thorough knowledge about maternal health and safety is necessary to encourage the obtainment of effective perinatal care. Additionally, women should have access to treatments to combat infections that contribute to maternal mortality, and to reduce the incidence of obstetric complications. Goals to reduce HIV incidence and its link to maternal mortality are already part of the MDGs, but whether reevaluation of the approach to achieving these goals is necessary remains to be seen. References 1. Jack A. Maternal and child health: caring for a growing world means halting mother and child deaths. The Financial Time 2016 Nov 17. 2. Moran NF, Moodley J. The effect of HIV infection on maternal health and mortality. Int J Gynaecol Obstet. 2012; 119(S26-29). 3. UN Millennium Project - Commissioned by the UN secretary General and Supported by the UN Developmental Group. 4. World Health Organization Millennium Development Goals (MDGs) 2012. Available from: http://www.who.int/mediacentre/factsheets/fs290/ en/index.html 5. World Health Organization: the world health report 2005—make every mother and child count. Available from: http://www.who.int/whr/2005/ whr2005_en.pdf 6. World Health Organization trends in maternal mortality: 1990 to 2008. Available from: http://whqlibdoc.who.int/publica-tions/2010/9789241500265_eng.pdf 7. Gorman S. A new approach to maternal mortality: the role of HIV in pregnancy. Int J Womens Health. 2013;5:271-274. 8. Calvert C, Ronsmans C. The contribution of HIV to pregnancy-related mortality: a systematic review and meta-analysis. AIDS. 2013(27(10):1631–1639. 9. Abdool-Karim Q, Abouzahr C, Dehne K, et al. HIV and maternal mortality: turning the tide. Lancet. 2010(375(9730):1948–1949. 10. Al-Husaini AM. Role of placenta in the vertical transmission of human immunodeficiency virus. J Perinatol. 2009;29(5):331–336. 11. Labbok MH, Clark D, Goldman AS. Breastfeeding: maintaining an irreplaceable immunological resource. Nat Rev Immunol. 2004;4(7) 565–572. 12. Pollara J, McGuire E, Fouda GG, et al. Association of HIV-1 envelope-specific breast milk IgA responses with reduced risk of postnatal mother-tochild transmission of HIV-1. J Virol. 2015;89(19):9952–9961.
The Nuts and Bolts of Peanut Allergy T By Meital Yerushalmi
he Addendum Guidelines for the Prevention of Peanut Allergy in the United States, published in January 2017, have illustrated that our understanding of peanut allergy (PA) has come a long way.1 Endorsed by the American Academy of Paediatrics (AAP) and the Canadian Society of Allergy and Clinical Immunology, the new guidelines recommend early introduction of peanut protein for infants, particularly those with an increased risk for PA*†.1 Yet, my mission to unravel just how far these guidelines have come from their predecessors in the past two decades has, surprisingly, sent me on a trip down memory lane. I grew up in a small desert town in Israel and moved to Canada as a teenager in the mid-2000’s. It was then when I first built a snowman, tried real Canadian maple syrup, acquired a taste for Tim Horton’s coffee, and got my own Team Canada hockey jersey. It was also the first time in my life that I learned about an allergy to peanuts. Peanut allergy is quite rare in Israel, insofar as I had neither met nor heard of anyone living with this life-threatening hypersensitivity prior to moving to Canada.
For years I was perplexed about the striking difference in the rates of PA between the two countries. Several visits to local Jewish schools in Toronto, featuring allergy alerts and peanut-free zones, suggested that genetics alone are not the answer to this conundrum. Could, then, cultural differences be at play? A 2008 study aimed to answer this question, and revealed that the prevalence of PA among Jewish children in the UK is ten-fold higher than that of their Israeli counterparts.2 As the two groups have a similar genetic background, investigators hypothesized that their findings may have resulted from differences in the children’s peanut consumption. Indeed, while UK parents were advised to avoid introducing peanuts to infants in the first year of life,2 echoing the AAP 2000 guideline recommendation to delay their
introduction in high-risk‡ children until three years of age,3 Israeli parents provide them peanut products liberally during that time. Peanuts are undoubtedly popular in Israel, commonly in the form of Bamba—an iconic peanut snack considered a staple of Israeli childhood. Bamba Baby, its mascot, speaks to its popularity among children (though, as my Israeli friends can attest, we still pick it up for ourselves in the Kosher aisle from time to time…). Could Bamba be at the cornerstone of tackling the growing rise in PA in North America? Recent updates to the guidelines suggest that this may be the case. Whereas the 2008 AAP guideline rescinded the peanut avoidance advice, concluding that no convincing evidence supported a significant protective effect by delayed peanut introduction beyond four to six months,4 current guidelines go further by promoting early peanut consumption in high-risk infants.1 These new guidelines are based primarily on the results of the Learning Early About Peanuts (LEAP) trial,5 in which 640 high-risk* infants, ranging from 4 to 11 months of age, were randomized to ingest or avoid peanuts until age five. An oral peanut protein challenge at that point revealed that 17.2% of children in the avoidance group exhibited a PA, as compared with only 3.2% in the consumption group.5 In other
words, early introduction of peanuts in high-risk infants was shown to prevent PA. Furthermore, a follow-up study reported a persistence of Oral Tolerance to Peanut (LEAP-On) among children in the consumption group following a 12-month avoidance period.6 Given that PA is the leading cause of death due to food-induced anaphylaxis in the US, the implications of such findings cannot be underestimated.7 As for Bamba, on my visit home in June I learned of some of its new variations— filled with Halva (sesame), hazelnut, or almond cream—evidently, we Israelis go nuts for peanuts. *Infants with severe eczema and/or egg allergy †Infants with mild to moderate eczema ‡Children with a first-degree relative who suffers from an allergy
References 1. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: Report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. Ann Allergy Asthma Immunol. 2017;118(2):166-73. 2. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008; 122(5):984-91. 3. American Academy of Pediatrics Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics. 2000;106(2 Pt 1):346-9. 4. Greer FR, Sicherer SH, Burks AW, et al.. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008; 121(1):183-91. 5. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015; 372(9):803-813. 6. Du Toit G, Sayre PH, Roberts G, et al. Effect of Avoidance on Peanut Allergy after Early Peanut Consumption. N Engl J Med. 2016;374(15):1435-43. 7. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol. 2007;119(4):1016-8.
IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 7
Pioneering Lung Transplantation in Toronto Highlighting the Achievements of Dr. Joel Cooper, MD. By Petri Takkala
ung transplantation is a relatively new approach to treating endstage lung diseases. The first lung transplant was attempted by Dr. James Hardy in 1963, but the patient died 18 days later. Subsequently, lung transplants were attempted unsuccessfully in 44 patients, making it clear that a number of challenges had to be overcome before lung transplantation could be possible—for example, immunological complications that led to organ rejection, and failed wound healing in lung transplant recipients. Indeed, failure of the bronchus connection to heal properly has often been called the “Achilles’ heel” of lung transplants. Through the 1970’s and 1980’s, a group of surgeons in Toronto—including former Institute of Medical Science (IMS) clinician-scientist, Dr. Joel Cooper— devised strategies to solve this problem. Dr. Joel Cooper came to Toronto in 1972 after obtaining his medical degree from Harvard Medical School and completing his clinical training. At the time, Dr. Griffith Pearson was a leading figure in his field: as head of thoracic surgery in Toronto, he established a thoracic surgery research lab and recruited Dr. Cooper to work on extracorporeal membrane oxygenation (ECMO)—the artificial heart-lung system. Several years later, Dr. Pearson invited Brazilian clinician Dr. Oriane Lima to join his lab under the mentorship of Dr. Cooper. To be allowed to supervise a graduate student, Dr. Cooper joined the IMS, which provided structure for the PhD training. In 1978, Drs. Cooper and Bill Nelems— another clinician working on Dr. Pearson’s team—performed an autopsy on a lung transplant patient who had died shortly after the operation after being removed from their artificial ventilator. They determined that death resulted from bronchial dehiscence—wound rupture at the bronchial connection between the donor organ and recipient. Thus, the “Achilles’ heel” was identified: they
Toronto General Hospital Division of Thoracic Surgery (1987): (left to right) Drs. Thomas Todd, Joel Cooper, Alec Patterson, and Griffith Pearson (seated). postulated that this failure in wound healing could be due to the effects of immunosuppression, or ischemia (insufficient blood supply) of the donor bronchus. In the lab, Drs. Cooper and Lima devised a set of experiments to investigate the wound-healing problem. In the first set of experiments, Dr. Cooper and his team removed and replaced the lungs of individual dogs, to avoid the issue of donor lung rejection. Next, they gave the dogs prednisone and azathioprine, two types of steroid immunosuppressants commonly used in lung transplantation. Drs. Coopers and Lima observed that compared to dogs that did not receive
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steroid immunosuppressants, the airway connection of immunosuppressed dogs did not heal properly. Therefore, they concluded that steroid immunosuppression had been preventing wound healing. As a substitute for high dose steroids, cyclosporine—an experimental drug used in some heart transplants—was found to significantly improve wound healing while still exerting beneficial immunosuppressant effects. The next problem to solve was ischemia of the donor bronchus, which appeared to cause stenosis of the airway. In initial lung transplant surgeries, the donor bronchus had its arterial blood supply cut, leaving its only remaining blood supply
from collaterals from the pulmonary circulation. This was reasoned to be insufficient, and led to ischemia that increased progressively up the bronchus. The solution to this problem was to use the omentum—a section of the peritoneum attached to the stomach—and wrap it around the bronchial anastomosis. This would bring the systemic circulation up and form collaterals around the bronchus. Similar to the previous set of experiments, this solution was tested in dogs, with much success.
lung transplantation could be successful in patient groups with varying pulmonary pathologies. The success of lung transplantation is still limited by the availability of healthy donor lungs. Researchers in lung transplantation, and from the Toronto Lung Transplant Program team, are developing innovative
After demonstrating the feasibility of successful lung transplantation in dogs, in the late summer of 1982, Dr. Cooper submitted a proposal to the Toronto General Hospital to perform experimental lung transplants in humans. Dr. Cooper asked the hospital be allowed to perform unilateral lung transplant operations in patients with end-stage, disabling pulmonary pathology. Specifically, patients would be selected who were expected to have less than six months to live. Ultimately, the decision was made to perform this procedure in patients who had idiopathic pulmonary fibrosis (IPF)—a progressive, and ultimately fatal, disease involving scarring of lung tissue. On November 7, 1983, the world’s first human single lung transplant was successfully performed at the Toronto General Hospital. The patient, 58-year old Tom Hall, would go on to become world famous as the first successful lung transplant recipient, and would live for six more years before passing away due to renal failure. In Dr. Cooper’s view, “the mark of success [in lung transplantation] is to give a patient at least two years of life with good health.” The success of the procedure was reproduced in several other patients with IPF, and the team of surgeons in Toronto would go on to perform the first successful bilateral lung transplantation in 1986 for a patient with emphysema. Then in 1988, the first successful bilateral lung transplantation was performed in a patient with cystic fibrosis. In light of these procedures, Dr. Cooper and his team demonstrated that
ways to improve the health and availability of donor lungs for recipients, and to ultimately increase the success of lung transplantation. Dr. Joel Cooper has since moved back to the United States, and is currently the head of thoracic medicine at the Hospital of the University of Pennsylvania.
50 years of Building Academic Medicine Catharine Whiteside, CM MD PhD FRCP(C) FCAHS Executive Director, SPOR Network in Diabetes and its Related Complications Professor Emerita and Former Dean of Medicine, University of Toronto
ith the 50th anniversary of the Institute of Medical Science approaching, I reflect on the great significance of my personal journey with the IMS. The original goal of the IMS remains to create an environment of scholarship where our Faculty of Medicine members in clinical departments can supervise graduate students in collaboration with colleagues across all health and biomedical disciplines. In the early 1980’s, I completed my PhD in the IMS under the supervision of Professor Mel Silverman. A decade later during Mel’s tenure as Director of IMS, I was recruited as the Graduate Coordinator, launching my academic administrative path at the University of Toronto. My fondest memories are daily interactions with the remarkable IMS students and faculty members, learning about their accomplishments, their challenges, and chairing the thesis defense—an event of great pride for all. During the 1990’s, unprecedented growth of the IMS coincided with the launch of many of our clinician investigator training programs. These graduates have populated leadership positions in our Faculty, across Canada and beyond, and created one of the most important legacies of the IMS. It has been a privilege to evolve my relationship with these IMS graduates as colleagues and friends over the decades. The IMS has uniquely shaped our careers.
IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 9
1ST SUC CCE CESSFU UL LONG-TERM M SING NGLE LE LUN NG TR TRANSP PLA LANT NT Performed by Dr. Joel Cooper at Toronto General Hospital
1ST SUCCESSFUL DOUBLE LUNG TRANSPLANT Performed by Dr. Joel Cooper at Toronto General Hospital 1987 – Toronto: 1st successful paediatric lung transplant
CFTR GENE DISCOVERY
OOLF T E “F TH FAT ATHE HER OF RES ESPIRO SPIROLO LOGY” Created the Respiratory Failure Unit at the Toronto General Hospital
Dr. Lap-Chee Tsui and his team at the Hospital for Sick Children discover CFTR, the gene responsible for causing cystic fibrosis
LOW POTASSIUM DEXTRAN SOLUTION
Developed to make donor lungs safer and recipient response more predictable
10 | IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE
1ST U USE OF NOVALUNG IN NN NOR NORTH AMERICA
Novalung, an external artificial lung is used to keep patients alive until a set of donor lungs are available
GENE THERAPY First use of gene therapy to repair injured human donor lungs, making them viable for transplantation
2011 TORON NTO EX VIVO O LUNG LU NG PERFUSION SYSTEM M Developed by Dr. Shaf Keshavjee and his team, this technique was designed to treat, reassess, and improve the function of damaged or high-risk donor lungs before they are transplanted
SLEEP APNEA BresoDxTM, in partnership with Drs. Hisham Alshaer and Douglas Bradley, developed a battery-operated, home sleep apnea test
SURGICAL SU AL SUC UCCE CESS S
Dr. Shaf Keshavjee and his team removed a patient’s lungs and kept her alive for 6 days using a Novalung and extracorporeal membrane oxygenation (a treatment that circulates blood around the body) until a set of donor lungs became available
IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 11
Designed by Christine P’ng
genomic data science: using novel statistical methodologies to develop therapies for CYSTIC FIBROSIS
By Jonathan Chio
ystic fibrosis (CF) is the most common potentially fatal genetic disease affecting Canadian children and young adults. Toronto’s Hospital for Sick Children (SickKids) is a world leader in CF research, a reputation that dates back several decades. Its first paramount contribution was in 1989, when Dr. LapChee Tsui and his team discovered that CF, an autosomal recessive genetic disease, is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.1 Dr. Tsui was awarded the Henry G. Friesen International Prize for his discovery. During his acceptance speech, he attributed its name to his team’s uncertainty as to whether the gene encodes for a chloride channel or a protein that regulates a cyclic adenomonophosphate (cAMP)-mediated chloride channel.2 In humans, the CFTR gene is located on chromosome 7 and encodes for a transmembrane protein that transports ions across the surface of epithelial cells. Individuals homozygous for the CF-causing mutation in the CFTR gene experience morbidity in several organs, including the lungs. Importantly, our knowledge of CF heredity stems from Dr. Tsui’s landmark discovery, which has shaped subsequent decades of CF research.
Presently, a prominent gap in CF knowledge involves the variability of disease presentation in light of uniform genetic mutations. That is, individuals carrying the same CFTR mutations may exhibit a spectrum of symptom severity, including lung morbidity. Nevertheless, the CF genetics research program at SickKids has discovered that genes other than CFTR account for some of the phenotypic heterogeneity of CF. For this issue, the IMS Magazine is very proud to feature a CF researcher and IMS faculty member, Dr. Lisa Strug. Her laboratory conducts research in genomic data science—the development and application of novel statistical methods for large genomic datasets—with the goal of understanding the genetic basis of CF and other complex genetic disorders. Dr. Lisa Strug is a Senior Scientist in the Genetics and Genome Biology program at SickKids, the Associate Director of The Centre for Applied Genomics, and an Associate Professor of Biostatistics at the Dalla Lana School of Public Health, University of Toronto. During her graduate work in Biostatistics at Johns Hopkins University (MSc) and the University of Toronto (PhD) under the supervision
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of Drs. Charles Rohde and Paul Corey, she contributed to the development of a theory of statistical evidence. Following a postdoctoral fellowship with Dr. Susan Hodge and a faculty appointment in Statistical Genetics at Columbia University, Dr. Strug joined SickKids and established her research lab. The foundation for her current research in genomic data science was made possible by her extensive training in statistics and biostatistics, combined with post-doctoral training in genetics. Several decades of basic science research paved the way for the development of therapies that target the various CFTR mutations. For example, individuals with the missense mutation G551D have cellsurface localized CFTR protein channels that are characterized by reduced gating. This can be treated using Ivacaftor, an oral medication that increases the time that the CFTR channel is open.3 Moreover, in those homozygous for 508 phenylalanine deletion (Phe508del; the most common CFTR mutation), CFTR processing deficiencies result in insufficient quantities of protein reaching the cell surface. Yet, like G551D, even those Phe508delCFTR proteins that do reach the cell
Lisa Strug, PhD
Senior Scientist, SickKids Research Institute Associate Professor of Biostatistics, Dalla Lana School of Public Health, University of Toronto Associate Member, Institute of Medical Science
Photo by Tahani Baakdhah
surface exhibit reduced channel opening probability. Individuals suffering from this mutation can be treated with Orkambi, a combination drug of both Ivacaftor and Lumacaftor. Lumacaftor is a corrector that improves CFTR processing, thereby increasing its potential to reach the cell surface. However, just as individuals with the same CFTR mutations have different disease severities, individuals also respond differently to these therapies. Dr. Strug believes that this suggests additional genes could be at play, which affect variation in response to CFTR-directed therapies. Dr. Strug’s laboratory hopes to further our understanding of other genes that impact CF disease severity, known as gene modifiers. As their name suggests, these genes “modify” the expression of a second gene (such as CFTR). This can potentially explain why individuals with similar CFTR mutations vary in either disease severity or response to therapy. Regardless of whether modifier genes physically interact with CFTR, they can serve as alternative or complementary therapeutic targets to CFTR. Just as the identification of CFTR has improved our ability to diagnose CF, the discovery of modifier genes guides both the prediction of disease severity in
affected organs, and the delivery of more appropriate, individualized treatments. To identify CF modifier genes, Dr. Strug performs statistical searches of whole genome data. Such massive datasets are made possible by large international collaborations. However, standard statistical tools are not always appropriate for modifier gene studies, particularly when a contributing gene like CFTR is present. To combat this challenge, Dr. Strug’s team tailors their techniques to map modifier genes while accounting for major gene contributions. Furthermore, her team develops and applies methodologies that integrate genomic data across consortia and public functional genomics databases for statistical analysis. These analyses allow for the identification of putatively causal genomic variation that can then be prioritized for functional studies in the laboratory. Following their success in identifying genetic contributors to variation in CF disease severity, Dr. Strug’s team now focuses on improving diagnostic and predictive models for the CF community. Their findings have already demonstrated several solute carrier family genes (e.g. SLC26A9, SLC9A3, and SLC6A14) predictive of disease severity
and response to CFTR-directed therapies. Future research directions in CF include developing genetic signatures predictive of therapeutic response, understanding the mechanism of action of gene modifiers, and determining the potential for modifier-directed therapies. Also essential are methodologies that integrate the ever-expanding database of genomic information, which would facilitate more efficient and effective amalgamation of worldwide genomic data and promote a comprehensive search for CF-related mutations. According to Dr. Strug, it is an exciting time for research in genomic data science, where innovations in big data are paving the way for personalized approaches to improving health.
References 1. Lewis HA, Buchanan SG, Burley SK, et al. Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J. 2004;23(2):282-93. Epub 2003 Dec 18. 2. The Henry G. Friesen International Prize Lectures 8&9. Friends of Canadian Institutes of Health Research, 2015. 3. Pettit RS, Fellner C. CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014;39(7):500-11.
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Toronto Lung Transplant Program By Grace Jacobs
he Toronto Lung Transplant Program has reached many milestones over the last four decades with its innovative thinking and research. Groundbreaking achievements in lung preservation, transplant surgery, assistive devices, and post-transplant outcomes have made Toronto the centre of the world in the field of thoracic surgery. However, many complex challenges continue to face lung transplantations today. First and foremost, there is a shortage of lungs viable for transplant. The yearly mortality rate on the waiting list is between 18-20%. Only around one in six donated lungs are healthy enough to be used, often due to an increase in pro-inflammatory cytokines that is associated with higher rates of patient death.1 However, the recent development and implementation of the Toronto Ex Vivo Lung Perfusion (EVLP) System, which allows lungs to be preserved at body temperature, has opened a realm of possibilities. Prior to the EVLP system, lungs were preserved through cooling to slow down metabolism and deterioration. However, cold preservation prevents proper assessment of graft quality. Thus, donor lungs might be rejected solely on the basis of an inability to assess marginal organs. With the advent of EVLP, marginal organs can be monitored and assessed individually to help transplant surgeons select lungs that are suitable for transplantation. This effectively expands the donor pool of available lungs to patients in need of a transplant. In addition, the physiologic conditions of EVLP enable implementation of therapeutic strategies that would not be possible during cold storage. Thus, EVLP has served as a platform by which to improve viability by repairing inflammation and injury. Surgeon-in-Chief at University Health Network (UHN), Director of the Toronto Lung Transplant Program, and developer of EVLP, Dr. Shaf Keshavjee explains: “This is how we’ve been able to transform transplantation, [and] move into the realm of personalized medicine.”
Shaf Keshavjee, MD,
MSc, FRCSC, FACS
Surgeon-in-Chief, University Health Network (UHN) Director, Toronto Lung Transplant Program Senior Scientist, Toronto General Hospital Research Institute Professor, Faculty of Medicine, and Institute of Biomaterials and Biomedical Engineering, University of Toronto Member, Institute of Medical Science Photo by Grace Jacobs
Dr. Keshavjee hopes that one day, a molecular diagnostic nanochip will assess biomarkers of lung function, with results for one lung available in as little as 20 minutes. This is a much-needed improvement from current diagnostic tools—usually designed for chronic diseases—that take a day to get results. Currently, lungs can only be kept on ex vivo perfusion for a maximum of 12-18 hours, although research is focusing on how to improve oxygen delivery, nutrition, and perfusion to increase this timeframe. Looking forward, Dr. Keshavjee indicates that most researchers hope to extend lung survival to 24 hours; however, he hopes to eventually reach 48 hours. Another major obstacle in lung transplantation is post-transplant tissue injury caused by chronic rejection, and viral, fungal, and bacterial infections that result from systemic immunosuppression (a requirement for surgery). Injuries are particularly problematic if recovery is abnormal, which can result in the formation of fibrous tissue in place of healthy lung tissue. This can ultimately lead to lung failure. Additionally, acute or chronic rejection of the organ can be caused by differences in major histocompatibility complex proteins between donor and recipient. Current research is focusing on gene therapy as
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a potential solution to these problems. The goal is to genetically modify lungs to improve anticipation of, and adaption to, the process of transplantation. These improvements could reduce incidences of post-surgical rejection that can occur in recipients throughout their lives. Already, techniques have been developed that use adenoviral vector-delivered gene therapy to upregulate interleukin 10, which reduces inflammation in the donor lung.2 In the future, lungs might be grown using recipient stem cells; or, cells could be transferred onto a lung graft, which would avoid organ rejection completely. Dr. Keshavjee expresses confidence in the development of these techniques: “[In coming years], we will make a new trachea repopulated with your own cells and transplant it. One day, we will grow a new lung.” The thoracic surgery program in Toronto has had many successes, especially in systematically translating solutions effectively from bench to bedside. Considering the next steps, Dr. Keshavjee expresses a belief in encouraging the next generation of clinician-scientists. “[It’s about] creating people who will continue to think like this in the future, and enabling them. Just because it’s not possible now, doesn’t mean it won’t [ever] be.”
Woman Lives Six Days Without Lungs: An Interview With Dr. Marcelo Cypel Marcelo Cypel, MD, MSc, FRCSC
Thoracic Surgeon, University Health Network Surgical Director, ECLS Program Scientist, Toronto General Hospital Research Institute Associate Professor, Department of Surgery, University of Toronto Associate Member, Institute of Medical Science pressure. Without any other options, the Toronto team boldly asked: what if we removed the source of the sepsis?
Photo by Grace Jacobs
By Aadil Ali
ecently, the stellar Toronto transplant team made media headlines after performing an innovative life-saving procedure. For the first time in history, the team removed a patient’s lungs—and kept her alive for six days. Patient M.B., a mother from Burlington, was born with cystic fibrosis. Cystic fibrosis is a genetic disease that produces a variety of symptoms: such as the production of thick mucus that can block pancreatic ducts, intestines, and notably— the bronchi of the lungs. Blockage of the lungs is usually followed with episodes of respiratory infections, leading to an accumulation of bacteria within the lungs. The treatment for end-stage cystic fibrosis is lung transplantation, in conjunction with high-dose antibiotics to manage the bacterial infection. Unfortunately, bacteria that accumulate in the lungs can become resistant to antibiotics. If resistant bacteria enter systemic circulation, they may spread to different areas of the body, resulting in a large-scale inflammatory response. This phenomenon, known as septic shock, can lead to dangerously low blood pressure and metabolic abnormalities. While M.B. awaited donor lungs, sepsis began to take over her body. Her oxygen levels dipped so low that conventional ventilation was no longer an effective option. M.B. was receiving maximum doses of powerful antibiotics and medications to regulate her falling blood
Dr. Marcelo Cypel, surgical director of University Health Network (UHN)’s Extracorporeal Life Support (ECLS) Program, describes, “We felt her only potential chance of surviving was to remove the source of infection, which meant removing both of her lungs. If you do that, ideally you want to put the new lungs in right away. But we didn’t have that available to us at the moment. Another thing is that you do not want to perform a transplant when the patient is in sepsis, because this also is very risky. As a result, even if we had lungs at the time, the transplant still would have been too risky, as her chance of survival would have been very low.” At this point, Dr. Cypel sought advice from his colleagues: UHN’s Surgeon-in-Chief and the Director of the Toronto Lung Transplant Program, Dr. Shaf Keshavjee; and Head of Thoracic Surgery at UHN, Dr. Tom Waddell. After careful consideration, the team decided that this pioneering procedure was M.B.’s only option. Dr. Keshavjee, Dr. Waddell, and Dr. Cypel would perform the surgery together. Their procedure utilized two extracorporeal life support systems. Specifically, the surgeons used a venousarterial (VA) extracorporeal membrane oxygenation (ECMO) circuit paired with an artificial lung device known as the Novalung. Essentially, the Novalung served to remove carbon dioxide from M.B.’s blood, while providing a fresh supply of oxygen; the ECMO circuit helped her heart pump blood throughout her body. “The procedure took about five to six hours, and then the transplant took another five to six hours the following
week. It usually takes a bit longer to do the transplant, but half our job was already done since M.B.’s lung were already removed,” explains Dr. Cypel. Six days after the initial procedure, the transplant team learned that a set of donor lungs were available for M.B. Effectively, this procedure served as a bridge to transplantation for M.B., and can potentially be used to save the lives of other cystic fibrosis patients who are on a waiting list to receive an organ. Interestingly, this life support configuration could have potentially allowed M.B. to survive without her lungs for a longer period of time. This could be important for patients who may have weeks of waiting before matching to a set of donor lungs. Although M.B.’s prognosis is still unknown, she is currently in a state of great recovery. Dr. Cypel says he believes that this procedure will become common in coming years. “This was not the first patient [who] needed this procedure. We had many patients in the past that we just accepted had to die. This patient was different because it reached a point when this idea was mature enough between the team. We felt that now was the time to do it. Another thing was that we had the family’s support to do it… I think this will be a gamechanger, not only for us, but for other hospitals around the world. Everyone is faced with these issues, especially patients with Cystic Fibrosis.” For interested readers, a detailed description of the surgical procedure is outlined in a recent publication entitled “Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation,” published in the Journal of Thoracic and Cardiovascular Surgery.3 References 1. Nakajima D, Liu M, Ohsumi A, et al. Lung lavage and surfactant replacement during ex vivo lung perfusion for treatment of gastric acid aspiration–induced donor lung injury. J Heart Lung Transplant. 2016;11.010. 2. Machuca T, Cypel M, Bonato R, et al. Safety and efficacy of ex vivo donor lung adenoviral IL-10 gene therapy in a large animal lung transplant survival model. Hum Gene Ther. 2016; 10.1089. 3. Cypel, Marcelo, Thomas Waddell, Lianne G. Singer, Lorenzo del Sorbo, Eddy Fan, Matthew Binnie, Niall D. Ferguson, and Shaf Keshavjee. “Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation. J Thorac and Cardiovasc Surg. 2016: doi: 10.1016/j.jtcvs.2016.11.031.
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Uncover NETosis. DISCOVER NEW TREATMENTS.
By Nades Palaniyar, PhD Discovery of NETs
or centuries, scientists have known that white blood cells such as neutrophils engulf and destroy pathogens. However, until recently, no one knew that neutrophils could cast their DNA as neutrophil extracellular traps (NETs). Despite constituting 60-70% of all white blood cells, innate immune functions of neutrophils had not been studied in depth. When first discovered, NETs were met with resistance: many members of the scientific community were skeptical of NETosis, and the relevance of NETs to immunity and pathobiology. NETs were considered as an experimental artifact by some, but I was fascinated by the elegance of the biology! Today, however, NETs are so well accepted that they are covered in
student textbooks. The discovery of NETs and identifying novel NETosis mechanisms demonstrate that big ideas advance scientific knowledge, in quanta. How and why I work on DNA and innate immunity In my PhD, I worked on DNA recombination and replication, and found that many components of the molecular machinery used for these two processes are the same.1 During my postdoctoral studies, I realized that innate immune proteins bind to DNA, and that DNA-protein complexes destroy a host’s own organs and elicit an autoimmune response.2, 3 As a scientist, I have been interested in revealing the mechanisms of NETosis. It is fulfilling to combine everything that I have learned during my PhD and post-doctoral fellowship studies, to use creative imagination to decipher molecular mechanisms, and to identify drugs to treat diseases. Time flies by, and you are in the “State of Flow” every day. The truth makes you feel humble. Scientist and faculty jobs are great, and allow you to do what you like and make a big difference in the world.
Photo by Mikaeel Valli
A picture says 1,000 words. I was excited to see the strings of DNA entangled with the innate immune proteins during my postdoctoral fellowship at Oxford University in 2004.3, 4 As a postdoc, I had been contemplating the relevance of my discovery—that innate immune collectins bind to
Nades Palaniyar, MSc, PhD Senior Scientist, SickKids Research Institute Associate Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto Member, Institute of Medical Science 16 | IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE
DNA. In the same year, headlines claimed that NETs trap and kill bacteria, and my interest in NETs began.4, 5 While many researchers were focusing on the potential benefits of NETs, I started focusing on the dark side of NETs that is relevant to lung diseases, and other infectious, inflammatory, and autoimmune diseases.6 In the summer of 2004, I moved to Toronto and established my lab at the SickKids Lung Biology Research Program, and became a faculty member in Laboratory Medicine & Pathobiology (LMP) and IMS. Over the last 12 years, my lab has made several major scientific and methodological contributions to two areas—humoral and cell mediated innate immunity. Collectins and NETs at SickKids Collectins: I consider collectins as the “antibodies of the innate immune system” (Fig. 1).7 These beautiful proteins look like bouquet of flowers, or asterisks. Collectins have fibrillar collagen-like domains and lectin (carbohydrate-binding) domains. Any pathogens that reach the lower airways or alveoli encounter collectins. Unlike antibodies, collectins bind most of the pathogens because they recognize the molecular patterns present on virtually all bacteria, fungi, and viruses.7 Importantly, lung collectins do not activate complement, which is a pro-inflammatory mechanism. Too much complement activation is bad for the lungs because if you can’t breathe, nothing else matters! We identified important roles for collectins—including their specific binding to dying T-cells, altering apoptosis, and promoting apoptotic cell clearance by macrophages.8, 9 We also identified
FEATURE interconnections among collectins, complement, and NETs.10
directs neutrophil death towards NETosis or apoptosis.16
NETs: In 2004, the field of NETosis was in its infancy, so there weren’t any good in vivo models to study NETs. My lab first established a mouse model to study NETs in the lung, and showed that SP-D simultaneously bind NETs and bacteria.11 Now, for the first time, we have established several in vivo models to study NETs: lipopolysaccharide-mediated acute lung injury, bacterial pneumonia, ventilator induced lung injury, cystic fibrosis (CF), polymicrobial sepsis, and even a recurrent airway obstruction asthma-like horse model.11, 12, 13, 14 I also returned to the University of Guelph, where I did my PhD in Molecular Biology and Genetics, to set up some of these models. Labs from around the world now use these models to study NETs in vivo.
The relevance of the kinase JNK in NETosis was previously unknown. One of our recent studies shows that JNK is a molecular rheostat that senses concentrations of LPS and bacterial load and turns on NETosis.17 These studies help to understand why and how neutrophils turn on NETosis.
By combining fundamental principles and cutting edge tools available at SickKids’ Peter Gilgan Centre for Research and Learning, we were able to make several NET-related landmark discoveries. Our Proceedings of the National Academy of Sciences, Blood, and Scientific Reports papers showed the importance of mitochondria, and relative importance of specific kinases such as ERK, p38, and Akt in different types of NETosis.15, 16 We showed that Akt is a molecular switch that
Palaniyar (2010) Editorial: Antibodies of the innate immune system. Innate Immunity 16:191
Fig. 1. Collectins are “antibodies of the innate immune systems.” These proteins recognize unique carbohydrate patterns present on most of the bacteria, fungi, and virus.7
Neutrophils are short lived cells. Why would a dying neutrophil transcribe its genome? Hence, the relevance of transcription in these cells was a mystery. We were delighted to assign a new function for neutrophil transcription from our transcriptomics studies. We showed that neutrophils use genome-wide transcription initiation, the first step in gene expression, to help de-condense the entire chromatin for NETosis. Suppressing transcription initiation stops NETosis (Fig. 2).18 This 2017 Scientific Reports is expected to change the field of NETosis, particularly in terms of the understanding of molecular mechanisms and drug discovery.18
intermediates such as hepoxilins are also altered in CF airways.24, 25 Lifesaving lung transplantation could fail due to immune damage. Therefore, we are currently studying the relevance of regulating NETosis to address these clinical issues, collaboratively. The future: Regulating NETosis to treat inflammatory diseases With the new understanding of NETosis mechanisms, we screened large, focused, FDA-approved cancer drug libraries. These screens identified key classes of drugs that fully suppress NETosis, but do not compromise other neutrophil functions. Intriguingly, inhibitory functions of many of these drugs match with the NETosis mechanisms that we discovered. Therefore, these drugs could be valuable in treating
Clinical relevance of NETs Collaborating with clinicians and having the lab in a hospital setting provide me with an amazing opportunity to do clinically relevant projects. We were able to study the relevance of lung collectins and other lung proteins as serum biomarkers in several diseases. About two in ten children develop bronchiolitis obliterans syndrome (BOS) one to two years after receiving a stem cell transplant. BOS is characterized by the permanent narrowing of the airways and reduced lung function, often requiring lung transplantation. We found that a lung protein KL-6 is a great marker in predicting BOS, within one to three months.19 We also found that neutrophils are one of the key culprits in BOS.20 It is now becoming clear that cytotoxic NETs are responsible for damaging airways of the lungs of stem cell transplant patients.21 Females with CF have a higher degree of exacerbations and die mainly of the lung disease four to eight years before male patients.22, 23 We are now determining the roles of T-cells, NETs, and sex differences in immune response in these patients. Nitric oxide metabolism and levels of lipid
Fig. 2. Assigning a novel function for neutrophil transcription: Transcriptional firing drives NETosis.18 Neutophils form NETs (Blue, DNA; Red, Citrullinated histone H3; Green, Myeloperoxidase) that can be suppressed by transcription initiation inhibitory drugs. Each intact neutrophil is ~8 µm.
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some infectious, inflammatory, and autoimmune diseases. We are in the process of devising personalized medicine strategies using induced pluripotent stem cells to translate this new knowledge. I am grateful for my mentors, colleagues, students, trainees and staff, and for the funding agencies such as NSERC, CIHR, CF Canada and Mitac, and the referees, who always refer to us as a group with several original ideas. Science is a group effort. When science moves, it moves you. I am confident that my lab and the NETosis research community are on the right track for bringing new knowledge from the lab into clinical care. We are boldly going where no person has gone before; the motto of the Palaniyar lab is, “Uncover NETosis. Discover New Treatments.” NETs can be good. But, too much of a good thing can be a bad thing. My group and I are determined to fix the NETosis issue in some diseases within the next ten years.
References 1. Palaniyar N, Gerasimopoulos E, Evans DH. Shope fibroma virus DNA topoisomerase catalyses holliday junction resolution and hairpin formation in vitro. J Mol Biol. 1999 Mar 19;287(1):9-20. 2. Palaniyar N, Nadesalingam J, Clark H, et al. Nucleic acid is a novel ligand for innate, immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J Biol Chem. 2004 Jul 30;279(31):32728-36. 3. Palaniyar N, Clar H, Nadesalingam J, et al. Innate immune collectin surfactant protein D enhances the clearance of DNA by macrophages and minimizes anti-DNA antibody generation. J Immunol. 2005 Jun 1;174(11):7352-8. 4. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004 Mar 5;303(5663):1532 5. Takei H, Araki A, Watanabe H, et al. Raid killing of human neutrophils by the potent activator phorbol 12-myristate 13-acetate (PMA) accompanied by changes different from typical apoptosis or necrosis. J Leukoc Biol. 1996 Feb;59(2):229-40. 6. Cheng OZ, Palaniyar N. NET balancing: a problem in inflammatory lung diseases. Front Immunol. 2013 Jan 24;4:1. 7. Palaniyar N. Antibody equivalent molecules of the innate immune system: parallels between innate and adaptive immune proteins. Innate Immun. 2010 Jun;16(3):131-7. 8. Litvack ML, Djiadeu P, Renganathan SD, et al. Natural IgM and innate immune collectin SP-D bind to late apoptotic cells and enhance their clearance by alveolar macrophages in vivo. Mol Immunol. 2010 Nov-Dec;48(1-3):37-47. 9. Djiadeu P, Kotra LP, Sweezey N, et al. Surfactant protein D delays Fas- and TRAIL-mediated extrinsic pathway of apoptosis in T cells. Apoptosis. 2017 Feb 6. 10. Yuen J, Pluthero FG, Douda DN, et al. NETosing Neutrophils Activate Complement Both on Their Own NETs and Bacteria via Alternative and Non-alternative Pathways. Front Immunol. 2016 Apr 14;7:137. 11. Douda DN, Jackson R, Grasemann H, et al. Innate immune collectin surfactant protein D simultaneously binds both neutrophil extracellular traps and carbohydrate ligands and promotes bacterial trapping. J Immunol. 2011 Aug 15;187(4):1856-65. 12. Yildiz C, Palaniyar N, Otulakowski G, et al. Mechanical ventilation induces neutrophil extracellular trap formation. Anesthesiology. 2015 Apr;122(4):864-75. 13. Jin L, Batra S, Douda DN, et al. CXCL1 contributes to host defense
I always liked mechanisms— trying to understand how things work.
Theo Moraes, MD, PhD, FRCSC Staff Respirologist, The Hospital for Sick Children Clinician-Scientist, SickKids Research Institute Assistant Professor, Department of Paediatrics, University of Toronto Associate Member, Institute of Medical Science 18 | IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE
in polymicrobial sepsis via modulating T cell and neutrophil functions. J Immunol. 2014 Oct 1;193(7):3549-58. 14. Côté O, Clark ME, Viel L, et al. Secretoglobin 1A1 and 1A1A differentially regulate neutrophil reactive oxygen species production, phagocytosis and extracellular trap formation. PLoS One. 2014 Apr 28;9(4):e96217. 15. Douda DN, Khan MA, Grasemann H, et al. SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2817-22. 16. Douda DN, Yip L, Khan MA, et al. Akt is essential to induce NADPH-dependent NETosis and to switch the neutrophil death to apoptosis. Blood. 2014 Jan 23;123(4):597-600. 17. Khan MA, Farahvash A, Douda, et al. JNK Activation Turns on LPS- and Gram-Negative Bacteria-Induced NADPH Oxidase-Dependent Suicidal NETosis (submitted) 18. Khan MA, Palaniyar N. Transcriptional firing helps to drive NETosis. Sci Rep. 2017 Feb 8;7:41749. 19. Gassas A, Schechter T, Krueger J, et al. Serum Krebs Von Den Lungen-6 as a Biomarker for Early Detection of Bronchiolitis Obliterans Syndrome in Children Undergoing Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2015 Aug;21(8):1524-8. 20. Gassas A, Krueger J, Zaidman I, et al. Infections and neutrophils in the pathogenesis of bronchiolitis obliterans syndrome in chldren after allogeneic stem cell transplantation. Pediatr Transplant. 2016 Mar;20(2):303-6. 21. Domingo-Gonzalez R, Martínez-Colón GJ, Smith AJ, et al. Inhibition of Neutrophil Extracellular Trap Formation after Stem Cell Transplant by Prostaglandin E2. Am J Respir Crit Care Med. 2016 Jan 15;193(2):186-97. 22. Sweezey NB, Ratjen F. The cystic fibrosis gender gap: potential roles of estrogen. Pediatr Pulmonol. 2014 Apr;49(4):309-17. 23. Kushwah R, Gagnon S, Sweezey NB. Intrinsic predisposition of naïve cystic fibrois T cells to differentiate towards a Th17 phenotype. Respir Res. 2013 Dec 17;14:138. 24. Douda DN, Grasemann H, Pace-Asciak C, et al.. A lipid mediator hepoxilin A3 is a natural inducer of neutrophil extracellular traps in human neutrophils. Mediators Inflamm. 2015;2015:520871. 25. Ghorbani P, Santhakumar P, Hu Q, et al. Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth. Eur Respir J. 2015 Oct;46(4):1033-45.
Photo by Meital Yerushalmi
PAEDIATRIC RESPIRATORY DISEASES:
An Interview With Dr. Theo Moraes By Arpita Parmar
r. Theo Moraes is a Staff Respirologist at the Hospital for Sick Children, an Assistant Professor in the Department of Paediatrics at the University of Toronto, and an Associate Faculty Member of the Institute of Medical Science. Dr. Moraes leads a basic science laboratory at the Peter Gilgan Centre for Research and Learning at SickKids, and supervises three students. I had the opportunity to sit down with Dr. Moraes, who shared his passion of being a clinician-scientist at the forefront of translational research. Can you tell us about your education background and training? I completed my undergraduate degree at Queens University—I was originally in biochemistry, but I transferred to life sciences. I then went to medical school at the University of Toronto, and after that, went back to Queens for my residency in paediatrics. I subsequently completed a fellowship in paediatric respiratory medicine at SickKids, a PhD through the IMS with Dr. Greg Downey as my supervisor, and post-doctoral training in immunology with Dr. Tania Watts. What motivated you to pursue the dual role of a clinician-scientist? I always had an interest in clinical medicine. After I got into medical school, I knew that I would want to be in paediatrics, because I love working with children. It wasn’t until I did my elective at SickKids that I became interested in academic medicine. I liked the energy and excitement of being in a dynamic center where things are always changing and new knowledge is being generated. Academic clinicians generally have additional responsibilities outside of clinical medicine. As such, I had to consider my interests carefully. I always
liked mechanisms—trying to understand how things work. That is why I chose to pursue graduate training in a basic science laboratory. As a clinician-scientist I have a wonderful mix. I love seeing patients and having interactions with people. At the same time, I can also go somewhere else and think about how and why things work. What is the main focus of your laboratory? Does it involve both basic science and clinical research? The main focus is respiratory viruses; specifically, respiratory syncytial virus (RSV). RSV is the most common reason that babies [are] admitted to hospital and is a leading cause of death in infants around the world. We don’t have a great approach to managing RSV and there are no specific vaccines or therapies to impact the condition. As part of our work, we use primary human epithelial cell cultures that can be infected with RSV. This allows us to examine outcomes after RSV infection and see if our interventions are potentially useful. This model system can also be used to study other diseases, such as cystic fibrosis (CF), which our lab is also researching. Could you tell us about significant research contributions that your team has made in your area of focus? A few years ago, we were very lucky to collaborate with Dr. Richard Hegele. Together, we found that nucleolin is a cell-surface receptor for RSV; the receptor for RSV was something that was not known for many years. We are doing some work now to see if we can reduce RSV infection, by blocking or targeting that receptor. Additionally, Mike Norris, my PhD student, has completed some work examining how altering ion concentrations within the cell influences RSV infection. We hope that this will lead to more rational approaches to RSV and potentially other viruses.
Do you see the impact of your research in the clinical setting? The work that we are doing with cystic fibrosis and epithelial cells is part of a major initiative here at SickKids. The Program for Individualized CF Therapy is a collaboration between Cystic Fibrosis Canada and the SickKids Foundation. This program has the potential to be a great resource for the CF community, Canadian researchers, and potentially international researchers. The purpose of this program is to better rationalize therapies for individuals. Although many children with CF are treated with the same protocols, there may be an ability to refine therapies that better suit each individual. New studies show that CFTR modulating drugs will work for some patients but not others. Current thinking is that there may be individual factors which predict who is going to respond to different therapies. If we can better understand that, we can tailor therapies to individuals. Specifically, as part of a bigger project, our lab can take cells from patients to make epithelial cell cultures. Our collaborators in the Gonska lab can then test CFTR function. We are still in the early stages, but [we] hope this will impact clinical care in the future. What would be your best advice for someone interested in a career as a clinician-scientist? Get advice from a clinician-scientist. There are lots of us out there, so find someone you can talk to. There are many different paths you can take to end up with this career. Talking to someone who has navigated the way will help you understand these paths and what may work for you. Mentoring in this way is important.
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MANIPULATING MECHANISMS OF LUNG INJURY FROM BENCH TO BEDSIDE:
a promising future By Mikaeel Valli
cute respiratory distress syndrome (ARDS) is a life-threatening condition in which widespread inflammation in the lungs severely compromises oxygenation capacity, thereby limiting the body’s supply of oxygen. ARDS can be a complication following sepsis, trauma, or pneumonia, among other conditions, and often leads to critical illness and poor prognosis. To combat its high mortality rates, researchers have made promising strides toward improving treatment for ARDS. I had the pleasure of meeting Dr. Haibo Zhang, whose research on ARDS holds promise for management of this acute, life-threatening illness. In his sunlit office at the Li Ka Shing Knowledge Institute (LKSKI), St. Michael’s Hospital, Dr. Zhang recounts his fellowship in Belgium where he saw promise in treating sepsis patients using specific drugs as part of a clinical trial. Nevertheless, the medications were proven to be ineffective, and the trial failed to produce the anticipated results. “You would think that if you neutralize the toxic infection, you would be cured. But, it’s not quite the case,” Dr. Zhang explains. The unsuccessful trial prompted Dr. Zhang to return to research in search of the cellular origin of ARDS. Subsequently, he decided to pursue his PhD in Critical Care Medicine
at Free University of Brussels, which he completed in 1995. In keeping with his original research interest, his lab at LKSKI examines the cellular mechanisms of sepsis and how it causes acute lung injury. In particular, Dr. Zhang’s lab is interested in the mechanisms of innate immunity and infection in the lungs. By understanding ARDS at a cellular level, Dr. Zhang hopes to develop effective treatments for this life-threatening lung injury. Mechanical ventilation, which assists with or replaces spontaneous breathing, is a critical component in the care of patients with ARDS. Notwithstanding its value in ARDS management, Dr. Zhang explains that mechanical ventilation acts as a double-edged sword—on the one hand, it helps patients breathe, but on the other hand, it can injure the lungs further if not implemented carefully—inducing even more inflammation. From a pharmacological standpoint, there remains a glaring void in the critical care of ARDS patients, as no medications have been proven effective in treating the condition. For this reason, Dr. Zhang has dedicated a portion of his research to the condition most commonly responsible for ARDS in the first place: sepsis. Sepsis occurs when the immune system responds to a bacterial infection but injures the host
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in the process. That is, certain bacterial infections are associated with the release of an endotoxin known as lipopolysaccharide (LPS), which often leads to a strong inflammatory response that is damaging to the lung tissue. Surprisingly, spending time with his daughter lent Dr. Zhang an ‘aha’ moment about targeting LPS. His daughter pointed out to him that a small worm was crawling on the red skin of her apple. After washing the apple, they cut it in half, and to their surprise found more worms inside. This led Dr. Zhang to speculate that LPS molecules are like the worms in that they are not only seen on the outside of the lung cells, but possibly inside them as well. He put the idea to the test by first placing healthy cells in a petri dish, and then adding tagged LPS molecules. Much like the worms in the apple, Dr. Zhang detected LPS inside the cells, leading him to hypothesize that even upon clearance from the bloodstream, intracellular LPS can still induce an inflammatory response. Since this discovery, Dr. Zhang and his team have identified a key receptor that is responsible for bringing LPS into the cell. They also developed a molecule that can block this receptor from internalizing the LPS, thereby preventing the destructive inflammatory process from damaging the lungs. Dr. Zhang is filing a patent for this molecule, with the hopes that it can
FEATURE provide doctors with an effective way to treat ARDS in the future. “We are hoping to save patients with this molecule,” Dr. Zhang says optimistically. In addition to their work on preventing the entry of LPS into cells, Dr. Zhang’s team also works to manipulate the effect of host-secreted proteins on the inflammatory response. Specifically, Dr. Zhang studies neutrophils, a type of white blood cell that produces strong, positively charged proteins—called human neutrophil peptides (HNPs)—that kill negatively charged bacteria. In addition to their antimicrobial action, however, this cluster of proteins also activates specific lung cell receptors in the area, triggering inflammatory signaling which consequently damages the lung tissue. Importantly, the team has developed a way to block HNPs from binding to these specific receptors. As a result, HNPs can successfully kill the bacteria without triggering self-destructive inflammation. “This is a new class of antibiotics. This is exciting! Use the endogenous system to fight the infection as opposed to just using the exogenous sources,” says Dr. Zhang enthusiastically. Indeed, the potential of this finding for ARDS patients is far-reaching. In addition to manipulating the cellular microenvironment in the lungs, the use of stem cells from bone marrow has been of interest for its potential in treating ARDS. Animal models demonstrate that stem cells reduce lung inflammation and thereby the severity of ARDS. In light of these promising results, clinical trials are now under way with hopes for similar findings in humans. As Dr. Zhang explains stem cell treatments, he asks, “When do stem cells become beneficial or detrimental for ARDS patients? It depends on the microenvironment of the lungs.” He highlights the notion of personalized medicine, where one “glove” does not fit all patients. Considering this question, his lab induced mild, moderate and severe lung injury in mice, mimicking the degree of severity seen in patients with ARDS. His team then categorized the mice based on their lung injury severity profile, which was found to affect how they responded to stem cells. “We found that 80% of the profile seen in the mice model can be observed in the patient sample with ARDS. This is so exciting!” Dr. Zhang explains, suggesting that
Photo by Mikaeel Valli
Haibo Zhang, MD, PhD Scientist, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital Professor, Departments of Medicine, Anaesthesia, and Physiology, University of Toronto Member, Institute of Medical Science this finding can help clinicians categorize ARDS patients based on their severity profile to predict individual response to stem cell therapy. Furthermore, such profiling will help indicate which patients require a correction of their lung’s microenvironment before receiving stem cell treatment. “This finding is very relevant to guide clinical applications,” Dr. Zhang points out. The clinical outcomes of Dr. Zhang’s recent findings are still to be determined. “Our main goal is to translate our results into clinical practice. We are trying to take our intellectual property and develop it into pharmaceutical products,” explains Dr.
Zhang. He acknowledges that translational research is not easy and requires a lot of patience, as often the process does not go in the desired direction. For this reason, he advises students pursuing research to not get lost in the technical details and, in the face of obstacles, remember the big picture. For students at the Institute of Medical Science, the big picture involves their project’s contribution to the field of medicine, through advances in diagnosis, patient outcomes, or—in the case of ARDS—lives saved.
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DISCOVERY OF POTENTIAL THERAPEUTIC DRUGS FOR
Lung Disease By Yekta Dowlati
r. Mingyao Liu is a senior scientist at the Toronto General Hospital Research Institute, a full Professor of Surgery in the Departments of Physiology and Medicine, and the Director of the Institute of Medical Science (IMS) at the University of Toronto (U of T). His research interest is focused on ischemia-reperfusion induced lung injury in lung transplantation, and the cellular and molecular mechanisms of acute lung injury. I sat down with Dr. Liu to hear more about his passionate and successful scientific career in lung research, which will have substantial impact on treatment outcomes for patients with pulmonary diseases. Could you tell us a little bit about your background, training, and the events that brought you to the University of Toronto? I obtained my Medical Degree in 1983 and my Master of Science in 1986 in China. I completed two projects during my Master studies. For the first project, I designed precise evaluation equipment to measure the activity of lung surfactant, which was manufactured in collaboration with engineers and commercialized in China. For my second project, I tried to purify the surfactant from animal lungs and then prepared the surfactant as a drug for
therapy. Later, after I left China, my colleagues commercialized that preparation and made it into a clinical drug. In 1987, I moved to Buffalo, New York, as a visiting scholar. Half a year later, I got an appointment as a research assistant professor, continuing my work in surfactant related research. After three years, I immigrated to Canada. Dr. Martin Post, at the Hospital for Sick Children (SickKids), offered me a fellowship, which helped me learn about cellular molecular biology and intracellular signal transduction. In 1994, I got a faculty position at SickKids and later moved to Toronto General Hospital. Together with Dr. Shaf Keshavjee, we created a team that started [with] the two of us. Now, we have approximately 100 people working on acute lung injury in transplantation studies. What inspired you to begin conducting research in respiratory disease? When I was a medical student, I was selected to do research in my second year. I started working with a professor who was doing acute respiratory distress syndrome (ARDS) research, and got very interested in lung research. Since then, it never changed and I have been conducting research on the lung my entire life.
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Please describe your most recent discoveries and research work. Basically, my current research can be summarized in three different categories. First is the development of a translational pipeline. There are many potential therapies; however, if you look at clinical practice, doctors are still using the same treatments as three decades ago. There is no new drug that has been effectively translated into clinical practice. One particular challenge is that most of these studies are done in small animals, such as mice, rats, or, the largest, rabbits. But the human body is much bigger, and the hemodynamics, pharmacokinetics, and cell metabolism are so different compared to small animals. Therefore, we need to verify that what we discovered in small animals in larger model organisms as a preclinical trial. If that works, then a lot of what we learned from animals could be translated to humans. Accordingly, we have developed this as a pipeline for drug discovery and delivery. We have two pig lung transplantation models. In one model, we sacrifice the animal four hours after lung transplantation in order to evaluate the therapeutic effects on ischemia-reperfusion injury. In the other model, we let the animal survive for 3-7 days to see if the therapeutic effects last. In addition, with Dr. Keshavjee and our team, we have developed a technique
FEATURE called the “ex-vivo lung perfusion system,” which intends to treat injured donor lungs before transplantation. We are using this to test the therapeutic effects on damaged human donor lungs. With this pipeline, we are exploring multiple therapeutic reagents for acute lung injury. Second, most of the transplantation studies done so far are collected from animal studies or clinical observations, and the cellular molecular mechanisms are largely unknown. Moreover, when you do an animal study, for each drug you need to have control and therapy groups, at different dosing and timing; hence it’s not easy and you cannot test too many things. So as a cell molecular biologist, my lab developed a novel cell culture model to explore mechanisms at the cellular level. Of course, the cell culture model is too simple and we need to validate our finding with animal models. Third, the clinical application of many developed drugs is limited by the absence of an efficient vehicle that allows their solubility in water. My lab used nanotechnology to make non-soluble drugs water-soluble; in other words, to formulate hydrophobic drugs, so they can be directly injected into the blood stream. What are you hoping to see in the future as a result of your work? We know translation of our research into clinical practice has a long way to go, and many people may get discouraged by high costs and the length of the pipeline studies. Our first approach is to collaborate with industry partners and pharmaceutical companies. For example, take a clinical drug that is used to treat emphysema. There is cumulative evidence that this drug has anti-inflammation and anti cell-death effects. We took this drug and ran it through our pipeline and now we are almost near the end of the tests, and will launch a clinical trial by next year. Based on our studies in cells, small [animals], and large animals, we think that the likelihood of this drug working is very high. As a result of our collaborations, we are also being chased by other companies to test their drugs in this pipeline. In my opinion, investigating old drugs for new applications is an excellent approach that can speed up translation and build up
confidence for the availability of new drugs to the clinicians. In addition, we leverage the technology and skill sets developed through collaboration with pharmaceutical companies to make this pipeline available for our own discovered drugs. I hope this pipeline will speed up our own drug discovery process, so I can see the day that our drugs can be used clinically. Finally, I hope that the cellular molecular models to select and develop new drugs will be further developed by my junior faculty members and students in the future. What are some of the challenges you are facing in your research? The major challenge for me is the continuous evolution of knowledge and technology. I still remember, a long time ago, when I was a fellow at SickKids, someone came to the U of T to give a lecture about polymerase chain reactions (PCR). The [entire] U of T community was rushing to a big auditorium. But now, everyone knows about PCR. So, many new technologies and skills are continuously evolving; thus, we as professors are also learning all the time. Currently, as I have many administrative responsibilities, my
students take a lead on their projects and they come back to teach me. So I say, “I am my students’ student.” This continued learning is challenging and at the same time very interesting as it keeps you young. What is your best advice for graduate students? Recently, the Faculty of Medicine introduced a training program for faculty members on how to help our students build an individual career development plan. In the past, our advice to our students was to work hard; but no matter how hard you are working, only 15-20% of people will eventually become professors. It does not mean that the other 80% of people did not work hard. Each graduate student, especially [those pursuing a PhD], has a personal interest and based on that, they have to gain the skills to reach their goal. For example, if one is interested in teaching, he or she needs to gain communication skills, and if one is interested in industry, he or she has to start getting connections early in graduate training. So if I need to give one piece of advice, it is this: “Prepare your career as early as possible, so [that] by preparing yourself, you will be more motivated and more successful.”
Photo by Iris Xu
Mingyao Liu, MD, MSc Director, Institute of Medical Science, University of Toronto Professor, Department of Surgery, and Physiology, Faculty of Medicine, University of Toronto Senior Scientist, Toronto General Research Institute, University Health Network IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 23
A BREATH OF
Dr. Chung-Wai Chow An interview with
Chung-Wai Chow, MD, PhD, FRCPC
Staff Physician, University Health Network Scientist, Toronto General Hospital Research Institute Assistant Professor, Dalla Lana School of Public Health, University of Toronto Member, Institute of Medical Science Photo by Sepehr Salehi
By Ekaterina An
s a lung transplant physician, Dr. Chung-Wai Chow sees, first-hand, the harmful effects of air pollution on her patients. Her dual role as both a clinician and a scientist allows her to tackle this problem from both basic science and clinical research perspectives. Dr. Chow’s research is centered around the key theme of using clinical and animal models to understand the effects of environmental air pollution on respiratory health. I recently had the chance to sit down with Dr. Chow to discuss her research. Exposure to air pollution is linked to
a number of lung diseases, including asthma, chronic obstructive pulmonary disease, and chronic organ rejection in lung transplant patients. However, the specific underlying biological mechanisms are still unclear. “A lot of underlying lung disease is due to the modulation of the immune system and its abnormal regulation. There is a lot of epidemiological data that links air pollution to poor health outcomes. Of course, pollution changes over time and geographical location. But when you look at the data on the whole, there is an underlying theme of inflammation. So one of the things I’m really interested in is
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trying to figure out what actually regulates this inflammatory response”, explains Dr. Chow. Traditionally, experimental models of the effects of air pollution on respiratory health involved exposing model organisms or cell lines to specific pollutants from a certain geographical location, or direct emissions from car engines. However, as with all scientific models, these are not always an accurate reflection of the circumstances of exposure in real life. “One of the criticisms of experimental models is that researchers use very high
FEATURE concentrations of pollutants—they do not use realistic amounts. Further, animals and cells are exposed to only one or two pollutants at a time, even though we know that when humans are exposed to environmental pollutants, this is not the case,” says Dr. Chow. In order to address some of these shortcomings, Dr. Chow and her team partnered with Dr. Arthur Chan, a chemical engineer at the University of Toronto, to build a simulation system that allows mice to be exposed to different concentrations and combinations of pollutants that the researchers wish to examine. “We can actually titrate the type of pollutants to reflect pollutants found in Toronto, Mumbai, or Beijing, which is really exciting. This system is also great because one of the other challenges to doing this type of research is that experimental human exposures are difficult to do, and even with mouse exposures, most animal facilities will only allow you to take the mice out once. So another advantage of our system is that it is fairly small and portable—about the size of a mini-fridge—so we are able to do the experiments inside the animal facility. This allows us to have repeated exposures over
are still seeing the same inflammatory response. The lung is the only organ, with the exception of skin, that is continuously exposed to the environment. So there must be something in the pollutants that is triggering this ongoing inflammatory response.” To that end, Dr. Chow is currently conducting a Canadian Institutes of Health Research (CIHR)-funded study that aims to examine the effects of traffic-related air pollutants on lung transplant patients using personal pollution monitoring. “We go into the homes of newly transplanted patients and leave a whole bunch of air pollution monitors in place. We coordinate this monitoring period with dates when the patients are regularly giving samples—blood, urine, and lung lavage fluid—as part of their routine post-transplant care. This allows us to obtain samples without having to inconvenience the patients. The idea is that, at the end of all this, we will look at specific pollutants that are actually taken up in the body, and correlate them to those identified from the personal pollution monitors. The hypothesis is that whatever you absorb is what causes problems,” says Dr. Chow. The personal pollution monitoring that is
I hope that these findings will impact not only lung transplant patients, but the population as a whole, because we can go back to the pollutants in our studies and identify the source of these emissions.”
time in a way that mimics typical human exposure situations,” says Dr. Chow. “This type of repeated-exposure system is one of only two in North America.” However, Dr. Chow’s research extends beyond animal models. Dr. Chow says, “On the human, clinical side, I’m a lung transplant doctor. And recently, there has been a lot of evidence, from both our centre and a larger European study, which links exposure to air pollution to chronic lung rejection. Now, what is interesting about this is that the pollutants in Toronto differ from those in Europe. However, we
carried out is impressively thorough, given the difficulties of measuring all of the pollutants that individuals may be exposed to on a daily basis. The home monitoring system consists of a small, rolling suitcase that is outfitted with several monitors to collect particulate matter of different sizes, as well as semi-volatile organic carbons which are often found in car emissions and household products. Participants are also provided with a personal pollution monitoring device that they carry with them, although this is often challenging as they are recovering from their transplant surgery, acknowledges Dr. Chow.
When asked about the future directions of her research, Dr. Chow states that she hopes to integrate both her basic science and clinical research findings. “We’re hoping that with the collection of the biological samples from patients and from the experimental animals, we will be able to develop a biosignature of different inflammatory biomarkers of people who are at increased risk of inflammation. [Then], you can screen for that signature to identify those who are at risk and think about mitigation strategies. For example, making sure homes are well vacuumed and that there is good air exchange. These are also the people whom you might want to treat earlier, if there is any clinical sign of decline in lung function or immunologic response. This could be helpful in transplant medicine in particular as abnormal findings do not always warrant treatment,” explains Dr. Chow. Taking her research a step further, Dr. Chow says, “I hope that these findings will impact not only lung transplant patients, but the population as a whole, because we can go back to the pollutants in our studies and identify the source of these emissions. And then [we can] ask: can we bring in regulation to limit these emissions?” More recently, Drs. Chow and Chan were awarded a second CIHR grant to specifically assess the long-term effects of air pollutants resulting from the Alberta wildfire. The unique ongoing collaborations of these two University of Toronto researchers will allow them to evaluate the physico-chemical properties of the wildfire pollutants (Dr. Chan) and correlate biological responses to these pollutants in studies using cell and animal models (Dr. Chow). Given the clear link between environmental air pollution and lung disease, Dr. Chow’s research could go a long way towards improving care for lung transplant patients. With the launch of the Alberta wildfires project in the summer of 2017, her findings are expected to be applied to other vulnerable populations, as well as inform policy-makers and improve public health regulations around the emission of harmful particulate matter. The balance of basic science and clinical research that Dr. Chow has achieved in her work can help us all breathe a little easier.
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TRANSLATIONAL RESE Learning in the Real-World Classroom for the Greater Good
By Tazeen Qureshi
Image by Lauren Huff
f you ask any budding medical student why they decided to study medicine, the answers you receive will likely sound similar: to help people. But every future physician, often a few years into clinical training, realizes that although medical training provides professionals with the skills needed to perform procedures, order work-ups, and prescribe treatments, the â&#x20AC;&#x2DC;greater goodâ&#x20AC;&#x2122; can get lost in the details of perfect sutures, saline infusions, and sphygmomanometer measurements. Medicine is as much an art as it
is a science; however, the artistic component is being increasingly cropped out of medicine. The science of medicine cannot be sustained without the creativity that makes us human. The emerging discipline of translational research can fill this void. Translational research is defined as the process of moving information from bench to bedside. In other words, it is the progression of basic science discoveries to clinical trials which, in cases where the discoveries come to fruition and affect policy
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change, can produce tangible benefits for the population at large. These definitions, unfortunately, fail to accurately portray the translational research process. It is not a linear process; rather, it is cyclical and iterative. The outcome in one phase can affect the outcome of other phases in the translational continuum by providing valuable insights that inform further research and application. The students in the Translational Research Program at the University of Toronto are
SEARCH PROGRAM learning a new approach to translation in health sciences called translational thinking, which represents a hybrid of scientific methods and design thinking. This conceptual process involves discovering needs, defining problems, exploring the problem space and scanning the environment, and finally, validating problems. The ideation stage is where possible solutions are discussed, followed by implementation and evaluation of those solutions. The premise of helping humans lead a better, healthier life using recent and emerging scientific discoveries is the cornerstone of the discipline of translational research. To achieve this goal, healthcare professionals must connect with their patients (or users) to understand the true nature of their needs. One need can be the result of a hundred different problems and can have a thousand solutions. For instance, we assume that every cancer patient wants to live longer and find a cure for their cancer. While this may be true for many, it might not represent everyone’s need. Some could simply want a better quality of life for their remaining days. Thus, the assessment of needs and problem space exploration are critical steps in the process of translation. These steps delineate the most important and pressing problems facing communities. Design methods, like empathy mapping, and qualitative research methods such as focus groups, surveys, and interviews are valuable tools to use in the process of evaluating needs.
The complexity of the translational process necessitates the use of multiple skills. Translational building blocks include biomedical research and clinical research, intellectual property laws, funding, regulatory and legal issues, ethical considerations, communication skills, and the so-called “soft skills” which include collaboration and networking. Clearly, the spectrum of translation is broad, and no one is expected to take on every role. Instead, health translators are ‘super collaborators’ or facilitators. Collaboration with multiple disciplines lies at the heart of translation. A translational research team must be multidimensional. It has the room for a multitude of professionals including scientists, physicians, lawyers, business professionals, engineers and designers, IT specialists, policy makers, and analysts. Translational research advocates for a holistic approach to healthcare. Humans live in a world where they interact with one another and their environments; thus, translation cannot take place entirely in the confines of a lab. It happens in the world, and therefore must be learned in the world. As an applied science, it is learned by experiencing the field first-hand. To gain this real-world experience, the Translational Research Program students recently collaborated with St. Joseph’s Health Centre, Toronto, to provide them with possible ways to achieve certain strategic initiatives. This collaborative project
provided the opportunity to practice each step of the translational thinking model, from assessing the needs of various stakeholder groups at the hospital, to engineering and presenting solutions. The students examined issues that are generalizable to any healthcare setting, including mobilizing in-patients, ensuring efficient patient flow through the hospital, effective use of Patient and Family Advisors (PFAs) to achieve patient-centred care, and rehabilitation of mental health patients in the community. This experience served as a “real-world classroom” for the students and helped them think translationally to build their repertoire of translation skills. It also demonstrated that discovering needs and finding problems is not straightforward; rather, it is an iterative process. People tend to become fixated on solutions even before exploring the underlying problem, which can be a hindrance in devising a sustainable solution. It also revealed certain barriers to collaboration, including constraints of time, space, and differences of opinions and ideas. The world of translation is growing, and so are the challenges that come with it. Therefore, it is imperative to train individuals and promote the development of special skills that foster collaboration. This will facilitate the creation and realization of tangible applications of discovery science, and will curb the loss of knowledge in the process of translation.
The science of medicine cannot be sustained without the creativity that makes us human.” IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 27
Student spotlight on
degree in neuroscience with double minors in bioethics and physiology at Trinity College at the U of T, Katie was encouraged to pursue graduate studies by her teaching assistant and Trinity College Academic Don, Dr. Massieh Moayedi. After discussing her research interests, Dr. Moayedi (now an assistant professor in the Department of Dentistry at the U of T) introduced her to Dr. Downar. At the time, Dr. Downar was a new faculty member who was just opening his lab at Toronto Western Hospital (TWH). Katie completed a 4th year work-study project with the lab, began her MSc, and subsequently transferred into the PhD program. “What I liked initially about Dr. Downar’s lab was its small size. I would be one of the first graduate students and I appreciated having the opportunity to work with someone quite closely,” Katie says. “In retrospect, it’s been really interesting to watch the lab develop and grow, so that one day if I hopefully start my own lab, I have a good model to work from.”
Katie Dunlop, PhD Candidate Supervisor: Dr. Jonathan Downar By Natalie Osborne
Photo by Katie Dunlop
s a Vanier scholar with multiple awards and publications to her name, Katie Dunlop’s young academic career as a fourth-year Institute of Medical Science (IMS) PhD student under Dr. Jonathan Downar’s supervision has already hit many high notes. But Katie might have just as easily been hitting high notes on the stage as a classical soprano singer. After attending a performing arts
high school where she majored in musical theatre, Katie first considered studying vocal performance at the University of Toronto (U of T). However, a grade 12 chemistry project on neurotransmitters sparked her passion for neuroscience, which she has pursued enthusiastically ever since. After completing her undergraduate
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The Downar lab specializes in a non-invasive brain stimulation technique known as repetitive transcranial magnetic stimulation (rTMS). This technique applies magnetic pulses to specific brain regions thought to be involved in psychiatric illness to help them regain healthy activity patterns. The Canadian Network for Mood and Anxiety Treatments recommends rTMS as an alternative for patients who haven’t responded to first-line treatments such as medication or cognitive-behavioural therapy. Katie studies rTMS treatment in multiple psychiatric populations, including those with eating disorders, obsessive-compulsive disorder (OCD), and depression. Using rTMS, she targets the dorsomedial prefrontal cortex and the anterior cingulate cortex, regions implicated in a wide range of psychiatric disorders.1 To understand the effects of rTMS on brain function as a whole, Katie uses resting state functional magnetic resonance imaging (rs-fMRI). This measures brain activity while a person is ‘at rest’; in other words, awake but not
engaged in a specific cognitive task. She examines certain characteristics of the resting brain state to explore two main questions. First, why do some psychiatric patients respond to rTMS treatment while others do not? To answer this, Katie is looking for a reliable neural biomarker that can predict an individual’s response (or non-response) to rTMS treatment across different psychiatric diagnoses. This could help clinicians determine which patients are most likely to benefit from rTMS. Katie’s second question involves treatment-related changes in brain activity: “How [can] we use rs-fMRI to model what a favourable response to rTMS looks like in the brain?” Katie explains. “…When patients do get better, what about their brains are changing to accompany the improvement in their symptoms?”
Medicine in January 2017.5
So far, Katie has examined resting state brain activity correlates of rTMS treatment in bulimia nervosa and obsessive-compulsive disorder patient groups.2,3,4 Now, she is conducting a triple-blind randomized control trial in depressed patients, comparing two types of rTMS treatment (excitatory and inhibitory) with a sham condition. She is also collecting psychometric and behavioural data and combining it with rs-fMRI to examine the the effect of different treatments on clinical outcomes, and to look for reliable biomarkers of positive response in depressed patients whose symptoms improve after rTMS.
Katie still finds time to nurture her passion for music and singing, now in the deeper tones of an alto, as a member of the Massey College choir (where she is also a non-resident Junior Fellow). She has performed in several musicals, including one of her all-time Broadway favourites, “Into the Woods.”
One of the reasons Katie was attracted to graduate work in the IMS was the Downar lab’s unique access to hundreds of clinical patients who are referred each year, which allows her to collect a large amount of data very quickly. It was this volume of data that led to the opportunity to participate in a large, international collaboration headed by Cornell University’s Dr. Conor Liston. Dr. Liston and colleagues combined data from over 1,000 depressed patients from multiple sites, including Dr. Downar’s lab at TWH. Katie’s own contributions to the project earned her authorship on the resulting paper, “Resting-state connectivity biomarkers define neurophysiological subtypes of depression,” published in Nature
In addition to her PhD project, Katie is engaged in multiple extracurricular activities. She sits on the U of T’s governing council as a co-opted member of the University Affairs Board. She also organizes Krembil Neuroscience’s “Neuroimaging Rounds,” a weekly meeting that brings in visiting scientists to talk about their work, allows graduate students to share their results with faculty, and promotes discussion on new advances in the field. In 2015, Katie organized a local “Brainhack” as part of Cameron Craddock’s larger global BrainHack EDT.6 Brainhack brings together researchers from multiple disciplines to come up with creative solutions to specific challenges in neuroscience.
When asked how she maintains this worklife balance, Katie remarks, “I think you can be successful and still have a life, you just have to try to be efficient with your time. If you think about it, without distractions like your phone or Facebook, you can get more done in four hours than you might have in a ten hour day.” Although, she laughingly admits, she is on Facebook quite a lot. Katie is a Canadian Institutes of Health Research Vanier scholar, but remembers how she almost didn’t apply for the award. Uncertain about her undergraduate grades and told that students in their transfer year from MSc to PhD never get the award, she almost let apprehension hold her back. However, encouragement from her advisor and support from her referees convinced her to apply with one week left. After a long and anxious wait, she was thrilled to learn she had won.
This experience illustrates the most important lesson Katie has learned in grad school, and the advice she would give to new students: don’t be afraid to take every opportunity that’s given to you. “If you’re being offered something that will look good in a grant application or lead to a publication, just go for it! Try your best and see if it works, that’s all anyone can ask,” says Katie. “If it doesn’t work out that’s okay too; you learn what you can do better and try for the next thing.” What’s next for Katie? She plans on finishing her PhD next year and is currently deciding between medical school and postdoctoral studies. Her love of research has her exploring international post-doc positions, where she may continue with neuroimaging or switch gears into working in affective psychology or with non-human models. Alternatively, everyone from her mother to her family doctor is encouraging her to pursue her interest in psychiatry, where she would like to combine clinical work with a resident research fellowship. Either way, Katie knows she would like to keep her connection to neuroscience, and she specially values her interactions with patients. “I really like this field because it’s interesting, very broad, and really human,” Katie says. “You’re really getting to know someone, and I love that every single person is different.” References 1. Goodkind M, Eickhoff SB, Oathes DJ, et al. Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry. 2015;72(4):305-315. 2. Downer J, Geraci J, Salomons TV, et al. Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression. Biol Psychiatry. 2014;76(3):176-185. 3. Dunlop K, Woodside B, Lam E, et al. Increases in frontostriatal connectivity are associated with response to dorsomedial repetitive transcranial magnetic stimulation in refractory binge/purge behaviours. Neuroimage Clin. 2015;8:611-618. 4. Dunlop K, Woodside B, Olmsted M, et al. Reductions in cortical-striatal hyperconnectivity accompany successful treatment of obsessive-compulsive disorder with dorsomedial prefrontal rTMS. Neuropsychopharmacology. 2016;41(5):1395-1403. 5. Drysdale AT, Grosenick L, Downar J, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nature Medicine. 2017;23(1):28-38. 6. Craddock CR, Marquilies AD, Bellec P, et al. Brainhack: a collaborative workshop for the open neuroscience community. GigaScience. 2016;5:16.
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Master of Science in
Posterior Gluteal Region
Ryan Park, 1T8 Ryan has a background in Biochemistry and Biochemical Engineering from the University of Maryland, Baltimore County, and traditional art from the Schuler School of Fine Arts. His favourite medium is oil painting, and these days he mainly uses pencil, brush pen and watercolor, with some experimentation with ZBrush and Cinema4D. In all of his illustrations, Ryan focuses on developing clear and thoughtful visual storytelling. More of his work can be found at https://ryantjpark.artstation.com/projects/XxWLa. 30 | IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE
Amanda Miller, 1T8 As a first year student in the Biomedical Communications Masterâ&#x20AC;&#x2122;s Program, Amanda is currently collaborating with researchers in the Department of Immunology to create an illustration about the etiological factors that contribute to colorectal cancer. In the past, Amanda has served as an illustrator for a mutation research lab at the University of Minnesota, creating didactic images to support their research. Her interests are in the application of augmented and virtual reality, simulation, and 3D printing technology to aid the public in understanding complex scientific concepts and procedures. More of her work can be found at her website, www.amandamariemiller.com. IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 31
good, THE bad, AND THE
Could genetically modified organisms be the answer to world hunger and malnutrition? By Archita Srinath
lip through a menu at any restaurant and their options are garnished with symbols representing a variety of dietary restrictions. Organic! Gluten free! Vegan! The options seem to be endless, and cater to the needs of many different diets. Many restaurants across the globe tend to update their menus and grocery store shelves according to the latest trends in food consumption. When food abundance and affordability are relatively insignificant, it is easy to take it for granted. We often forget that eating nutrient rich food is necessary for basic survival. The World Food Programme (WFP) estimates that 795 million people on this planet—1 in every 9—cannot afford adequate food for survival.1 A theoretical solution to this devastating issue comes from exciting advances in agricultural biotechnology and genetics: the development of genetically modified organisms (GMOs).2 However, GMO foods have been a hot topic for debate as the public opinion of GMO safety seems to greatly differ from that of scientists. A survey conducted by the American Association for the Advancement of Science (AAAS) found that over 88% of scientists viewed GMO foods to be safe, whereas only 38% of the general public shared this opinion.3 The broadcasting of distorted information misrepresentative of good scientific research has led to these opinions spreading to developing nations.2 Take Chipotle Mexican Grill, for example: in 2013, they were the first major restaurant chain to inform customers which foods were made
using ingredients from GMOs, and to further move towards a GMO-free menu.4 Even though this decision only further divided public and scientific opinion, it was still deemed a wise business decision.3 Wealthier nations have the luxury of choice—if you hate the taste of spinach, you can get your iron from red meats. Or, if you choose to follow a vegetarian diet, you can substitute tofu for chicken. This is not afforded by people living in countries that are prone to drought, poverty, conflict, and disease. Nutrient-rich food is scarce in many places, and people must eat to survive above all else. More importantly, anti-GMO propaganda in places that have strong export relationships with these countries prevents the distribution of this life-saving technology to those who would benefit most.2 So, what are GMOs? GMOs are crops or animals with artificially-introduced changes in their DNA that do not occur through normal mating or genetic recombination.4 In this manner, it is possible to take desirable genes from one species and transfer them to another to obtain a certain trait or characteristic. Modifications are made to sustain increased nutrient profiles, resistance to pathogens, herbicides, and severe weather conditions like drought and floods.4 Two common genetic techniques are used to modify the genome: the use of Agrobacterium tumefaciens, and a gene gun. Agrobacterium tumefaciens is a
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bacterium which naturally transfers DNA to plants. The desired gene can be transferred into the bacterium, which will then infect the plant cells and subsequently transfer the gene to the crop.5 The gene gun shoots nanometer-sized particles that are coated with DNA into the plant cell. Either of these techniques can yield cells in crops with the artificially-introduced modification, and grown plants can then express the desired trait.5 The very first GMO food that was approved for human consumption was the Flavr Savr tomato. Its DNA was altered to delay ripening to successfully prolong shelf life.6 A famous example of a pathogen-resistant GMO food is the papaya ringspot virus (PRSV) resistant papaya. PRSV severely threatened the booming Hawaiian papaya industry in the mid-1990s.7 The yearly supply of papaya had decreased from 53 million pounds in 1992 to 26 million pounds in 1998. It was only when the transgenic PRSV resistant papaya was introduced to the farms in 2001 that the population rebounded, saving the industry from complete disaster.7 How can GMO foods aid world hunger? The main reasons for famine include drought, floods, poverty, and war.8 The observation that people are eating does not mean that they have access to nutrient-rich food. Simply put, food does not always mean “good” food. Many people suffer from micronutrient deficiencies. This leads to weakening of the immune system that increases susceptibility to diseases and eventually death. Some common deficiencies that incur serious medical consequences include iron, iodine, vitamin A, and folate.8 In 1999, biologists Inge Potrykus and Peter Beyer set out to tackle this problem.2 These researchers genetically modified the part of the rice crop that is eaten—the seeds—to produce beta-carotene, a precursor for vitamin A, and termed the GMO rice as “Golden Rice.”2 Beta-carotene is naturally converted to vitamin A in our bodies. This finding could single handedly alleviate vitamin A deficiency-associated blindness, immunodeficiency, and death.2 Golden rice has received the prestigious Patents for Humanity award and has a petition signed by 121 Nobel laureates supporting its distribution. Even Pope Francis gave his
VIEWPOINT personal blessings to this effort!10 Sadly, due to strong opposition by anti-GMO activists, this life-saving invention is still under development.10 In recent history, drought gripped Somalia in 2010-2012 and caused mass famine events that led to 260,000 deaths, including 133,000 children under the age of five. People were forced to flee their homes in search of food.11 According to the WFP, drought is the most common cause of food shortages in the world.8 In order to circumvent periods of decreased water availability, the pro-GMO company Monasato created DroughtGard, a variety of corn that remains viable during water shortages.12 Other efforts to create crops that are resistant to drought are also underway, applying the technology to soy bean, rice and wheat. A “resurrection” plant called Myrothamnus flabellifolius is also being studied in South Africa. Its nickname originates from its ability to revive its dead leaves very quickly when rain finally comes.12 Scientists are hoping that this provides further clues to developing drought-resistant crops.12 Poverty-associated starvation is a vicious cycle. Without food, people get ill and are unable to work, and without work, food cannot be afforded. Malnourished children often grow up to be adults who earn low incomes.9 Also, people in developing countries may not be able to afford the fertilizers, herbicides, or tools required for prosperous farming.9 Pathogen and
Artwork by Lisa Qiu
herbicide-resistant GMO crops can increase crop yield, thereby producing more food per dollar spent. Dr. Richard Roberts wrote an article in the Boston Globe and Mail calling anti-GMO propaganda a “crime against humanity.”2 He expressed that Europe viewed the introduction of GMOs into their market as a money grab by American companies. Vocal political opposition began to spread, and these misleading ideas about GMOs’ safety were engrained.2 Strict regulations were imposed on GMO crops in Europe, and these ideas leached into countries that are in desperate need of this technology.2 An example of this hostility was seen when Zambia refused donations of GMO grain from other countries, despite widespread food shortages.13 UN officials criticized the country’s leaders of starving their people to death. As a humanitarian and a scientist in training, I must agree with Dr. Roberts. The finest scientific minds and institutions have deemed GMOs to be safe for human consumption by basing their claims on high-quality studies. In May 2016, one of the most extensive studies conducted on this topic was published by the prestigious National Academies of Science, Engineering, and Medicine. It unmistakeably stated: “There is no substantiated evidence that foods from [genetically engineered] crops were less safe than foods from non-GE crops.”14 The potential of GMOs and related agricultural
research is vast and this article has only provided a few examples. I implore you to do your own research by reading the scientific literature and conversing with experts in the field. When evidence-based research cumulatively supports this stance, it is unethical to spread false propaganda backed by a Google search. Ultimately, it is both public opinion and policy that affect those in need.
Artist’s Statement Food insecurity, severe hunger, and malnutrition remain predominant issues that plague a significant part of the developing world, often due to poverty, droughts, floods, and conflict. GMO foods can provide improved nutrition, increased crop yield, and decreased costs for fertilizers and herbicides. These factors, in the absence of corporate barriers, can alleviate some problems faced by victims of world hunger. - Lisa Qiu References 1. World Food Programme [homepage on the Internet]. Rome: World Food Programme; c2017. Available from: http://www1.wfp.org/ zero-hunger. 2. Roberts R. GMOs are a key tool to addressing global hunger. The Boston Globe. 2014 May 23. Available from: https://www.bostonglobe.com/opinion/2014/05/23/gmos-are-key-tool-addressingglobal-hunger/SPlNunvLl5WjovCpXvsihJ/story.html. 3. Schwartz D. GMO debate shows big opinion gap between scientists, public over safety. CBC News. 2015 May 19;Technology and Science. Available from: http://www.cbc.ca/news/technology/gmodebate-shows-big-opinion-gap-between-scientists-public-oversafety-1.3011371 4. World Health Organization [homepage on the Internet]. Available from: http://www.who.int/foodsafety/areas_work/food-technology/ faq-genetically-modified-food/en/ 5. Dielh P. Can genetically modified food feed the world? The Balance. 2016 October 16. Available from: https://www.thebalance.com/ can-genetically-modified-food-feed-the-world-375634 6. Powell C. How to make a GMO. Science In the News. 2015 August 9. Available from: http://sitn.hms.harvard.edu/flash/2015/how-tomake-a-gmo/. 7. Gonsalves C, Lee DR, Gonsalves D. Transgenic virus-resistant papaya: the Hawaiian ‘rainbow’ was rapidly adopted by farmers and is of major importance in Hawaii today. The American Phytopathological Society. 2004; doi:10.1094/APSnetFeature-2004-0804. 8. Centers for Disease Control and Prevention. International micronutrient malnutrition prevention and control (IMMPaCt). Available from: https://www.cdc.gov/immpact/micronutrients/. 9. World Food Programme [homepage on the Internet]. Rome: World Food Programme; c2013. Available from: https://www.wfp.org/ stories/what-causes-hunger. 10. Golden Rice Project. C2005-2016. Golden Rice Humanitarian Board. Available from: http://www.goldenrice.org/. 11. Somalia famine ‘killed 260,000 people’. BBC News. 2013 May 2. Available from: http://www.bbc.com/news/world-africa-22380352. 12. Weiser M. Scientists think GMO crops may help us deal with climate change. PRI. 2016 Jan 13. Available from: https://www.pri. org/stories/2016-01-13/researchers-around-world-are-exploringhow-gmo-technology-might-boost-food. 13. Gershon L. GMOs, inequality and world hunger. JStor Daily. 2015 February 27. Available from: https://daily.jstor.org/gmos-inequality-world-hunger/. 14. Lynas M. GMO safety debate is over. Cornell Alliance for Science. 2016 May 23. Available from: http://allianceforscience.cornell.edu/ blog/mark-lynas/gmo-safety-debate-over.
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ORGAN GROWTH in a
human-pig chimera Ethical Questions in a New Era of Science By Hira Raheel and Meital Yerushalmi
entaurs, fauns, sphinges, minotaurs, and mermaids—mythological human-animal hybrids have captivated the human imagination since ancient times. For millennia, stories have portrayed their world of enchantment and mystery, inspiring allure and fascination. Nevertheless, these fantastical creatures have also evoked abhorrence and fear of the unknown by virtue of their enigmatic and unnatural attributes. It comes as no surprise, then, that a similar response surfaced when news emerged of scientists bringing human-animal hybrids to life for the growth of organs for xenotransplantation. Scientists have long been interested in the possibility of real-life human-animal hybrids, also known as genetic chimeras. Earlier this year, a groundbreaking discovery published in Cell brought this topic to the headlines of popular media outlets, with intriguing captions such as “Humanpig ‘chimera embryos’ pave way to growing organs for transplants.”1 Unsurprisingly, the topic has attracted a growing public attention to genetic chimeras, particularly due to their potential to revolutionize the field of organ transplantation. The publication, “Interspecies chimerism with mammalian pluripotent stem cells,” demonstrated that pluripotent stem
cells (PSCs) from one species could be integrated into another species at the blastocyst stage of development.1 While the media highlighted human-pig chimeras, the paper primarily focused on a ratmouse chimera.2 By injecting embryonic PSCs of one species into the blastocyst of another, researchers were able to grow a rat pancreas, heart, and eyes in a developing mouse, thereby providing a proof-ofconcept that functional tissues can be derived via interspecies blastocyst complementation.3 Importantly, the researchers were also able to cultivate human cells and tissues in early-stage pig and cattle embryos, marking the first step toward animal-based generation of human organs for transplantation.
mutant strains. To bypass the reliance on knockout animals, the group utilized the CRISPR-Cas9 technology, harnessed for genome engineering in mouse models, for targeted genome editing directly in the host zygote. Specifically, they employed the technology to introduce a gene mutation that disables the development of a specific organ of interest. In doing so, they established the interspecies blastocyst complementation system, a strategy used to induce organ-specific chimerism through the injection of PSCs into an organogenesis-disabled host blastocyst. Notwithstanding the importance of the study’s results, its robust and innovative methodology garnered recognition among the scientific community.
Despite recently growing public interest in the topic, the concept of generating chimeras through blastocyst complementation is not unique to this study. Preceding it were two other groups whose mouse-rat and porcine-porcine pancreatic chimeras were presented in 2010 and 2013, respectively.4 These studies obtained mutant blastocysts from existing lines of the knockout animals, generated through the labour- and time-intensive process of gene targeting in germ-line-competent embryonic stem cells.2,4 Nevertheless, the present study has come a long way in its methodology of blastocyst complementation, as it is distinct from its predecessors by way of non-dependence on existent
In a fundamental experiment of this study, researchers knocked out the Pdx1 gene— essential for pancreatic development—in mice by co-injecting Cas9 mRNA and Pdx1 single-guide RNA (sgRNA) into the mouse zygotes.2 Stated simply, the sgRNA guides the Cas9 nuclease to a specific genomic locus according to its sequence. The Cas9 nuclease then cuts the DNA at the target location, thereby disabling the function of the gene of interest. This experiment generated apancreatic mice— that is, mice lacking a pancreas while other internal organs appear normal—which only survived a few days after birth. After proving the functionality of their zygotic knockout mice, the authors demonstrated
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Artwork by Nancy Ji
that simultaneous injection of the Cas9 mRNA and Pdx1 sgRNA with rat PSCs resulted in a mouse-rat chimera with a viable pancreas.2 The resulting chimeric animal lived to adulthood (seven months) while maintaining normal glucose levels in response to glucose loading, a measure of pancreatic function. In addition to pancreatic chimeras, the publication presents data regarding heart and eye rat-mouse chimeras generated through a similar methodology, and confirms the existence of such chimeras for other organs, albeit without supporting data.2 In this study, the use of CRISPR-Cas9 genome editing was limited to the generation of rodent chimeras, as it has not yet been well-established for larger animal knockouts.2 Instead, the researchers resorted to injecting the inner cell mass of pig and cattle blastocysts with different types of human induced PSCs (hiPSCs), a type of PSC that can be generated directly from adult cells.2 This method of chimera generation was shown to have poor efficiency, as very few pig embryos successfully exhibited chimerism with hiPSCs. Even among the successful pig-human chimeras, numerous embryos showed abnormalities in growth and size.2 Evidently, the generation of functional humanized chimeras is in its infancy, as acknowledged by study’s authors.2 Nevertheless, it is only a matter of time
until the CRISPR-Cas9 technology becomes available for larger animals and, possibly, humans. At that point, the blastocyst complementation method, used for rodent chimeras in this study, may be used to develop viable chimeras for human organs, likely within a porcine host.2 Given its homology to humans in organ size, anatomy, and physiology, the pig host holds the greatest potential of a model organism for producing organs functional for human transplantation. The medical benefits of animal-human chimeras are far-reaching, and include: a better understanding of human embryogenesis; more reliable, animal-based pharmaceutical tests prior to human trials; and a framework for studying the onset and progression of human diseases in vivo.2 Above all, the study’s preliminary results raise the possibility of xeno-generating transplantable human tissues and organs, thereby helping to address the global shortage of organ donors. Notwithstanding the contribution of this cutting-edge research to science and medicine, the issue of harvesting human organs from animals raises various moral and ethical concerns. Owing to its controversial nature, this study has raised important questions for bioethicists, and has faced fierce opposition on numerous fronts including opponents of stem cell research, various religious groups, and animal rights advocates.3,5 In fact, perhaps
the most contentious issue at hand is the exploitation of animals, which could be used, manipulated, and sacrificed to harvest human organs. Within this publication alone, more than 2000 pig embryos were used, in addition to rodent and cattle embryos.2 Notably, such human-animal chimeras may suffer from other health issues, secondary to the cultivation of foreign organs within them. Considering all of the above, and as young and passionate medical science researchers, we believe that the work presented here is at the forefront of life-saving stem cell research, and therefore must be continued. That said, we must implement care and dignity in the treatment of animals involved in future studies, and strive to maintain the highest degree of ethical standards when employing animals as tools for our own potential benefit.
References 1. The Associated Press. Human-pig ‘chimera embryos’ pave way to growing organs for transplants. 2017 Jan 26. Available from: http:// www.cbc.ca/news/technology/human-pig-embryos-growing-organs-transplants-1.3953451. 2. Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, et al. Interspecies Chimerism with Mammalian Pluripotent Stem Cells. Cell. 2017;168, 473-486. 3. Shepherd J. Why We Need to Discuss the Ethics of Creating Human-Pig Chimeras. Newsweek [newspaper on the Internet]. 2017 Feb 14 [cited 2017 Mar 2]. Available from: <http://www.newsweek. com/pigs-chimeras-human-organs-stem-cells-556721>. 4. Nagashima H. & Matsunari H. Growing human organs in pigs-A dream or reality? Theriogenology. 2016;86, 422-426, . 5. Marino L. We’ve created human-pig chimeras — but we haven’t weighed the ethics. [document on the Internet]. STAT; 2017 Jan 26 [cited 2017 Mar 2]. Available from: <https://www.statnews. com/2017/01/26/chimera-humans-animals-ethics/>.
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Driving Under the Influence of
Is Canada ready?
By Benjamin Markowitz
s promised by Prime Minister Justin Trudeau, the recreational use of cannabis will be legalized in Canada during his time in office. With legalization comes the likely possibility of seeing a rise in drivers under the influence of cannabis. Using Colorado as an example, cannabis-related traffic deaths increased by 48% during the three years post-legalization (20132015) compared to the three years pre-legalization (2010-2012).1 Compared to other illicit drugs used in Canada, cannabis is the most common drug detected in drivers involved in fatal motor vehicle collisions.2 Both short and longterm exposure to cannabis can impair driving performance, but less is known about these effects in comparison to alcohol. This article explores recreational users’ perceptions on driving under the influence of cannabis, the link between tetrahydrocannabinol and driving performance, and the question of whether Canada’s current method for detecting impaired drivers is suitable for cannabis impairment.
Recreational user’s perceptions on driving under the influence of cannabis
In May 2016, a survey conducted by an auto insurance provider made the headlines of the National Post.3 Out of 300 Canadians who admitted to driving under the influence of cannabis (DUIC), about half of them did not perceive cannabis to impact their ability to drive safely.4 This is concerning when you consider that DUIC almost doubles the risk of a motor vehicle collision compared to driving sober.5 Perceiving that DUIC increases the risk for accidents has been shown to be an independent predictor of discouraging this behaviour.6 Due to the public focus on the risks of drunk driving, perceptions of the risks of DUIC may not be commonly shared amongst recreational cannabis users. Many advertisement campaigns have helped bring attention to drunk driving, but it is much harder to find anti-DUIC campaigns. Users may infer that DUIC is safer than driving while under the influence of alcohol because they hear much less about it. In 2010, 320 cannabis users took part in structured individual interviews about DUIC.6 The majority of these cannabis users (87%) agreed or strongly agreed with the statement, “You are more at risk of having an accident
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if you drive while feeling intoxicated by alcohol than if you drive while feeling intoxicated by cannabis.” In another study of regular users, 20 out of 23 interviewees thought they were less likely to be stopped by the police for driving high than driving drunk.7 Peer perceptions of DUIC can have an important impact on the driver’s perception. Regular recreational users who perceived few of their peers to disapprove of DUIC were associated with higher DUIC frequencies.8 Peer groups may be consciously aware of the need for designated drivers when engaging in social gatherings that involve alcohol, but they may not perceive the same need for cannabis.
What is known about the link between THC and driving performance? Tetradyrocannabinol (THC) is the active chemical found in recreationally consumed sources of cannabis. THC is known to exert its effects on the user through increasing GABA and dopamine activity. Currently, there is no legal limit set for THC while driving. The “Framework for the Legalization and Regulation of Cannabis in Canada”
Cannabis-related traffic deaths increased by 48% during the three years post-legalization.”
suggests that more scientific testing and epidemiological research needs to be performed in order to prove that a standardized limit should be enforced.9 In a study conducted by Drummer et al., almost 4,000 cases of fatally injured drivers were examined to assess the involvement of drugs in motor vehicle collisions.10 First, investigators classified drivers as being responsible or non-responsible for the collision. There was a significant increase in the adjusted odds ratio for collision responsibility (2.7) for drivers with any measurable blood THC in comparison to drug-free drivers. The odds ratio for responsibility increased to 6.6 for a THC concentration ≥ 5 ng/ml, which was comparable to the odds ratio for a 0.15% blood alcohol concentration. To experimentally test the effect of THC on components of driving performance, studies have used driving simulators and on-road tests. Low THC doses (13 and 17 mg) were found to produce significant and dose-dependent increases in reaction time for divided-attention tasks.11 Maintaining a correct road position has consistently been shown to be affected by THC, and there is a wide range of THC doses that can affect this behaviour.12 For example, doses from seven to 38 mg of THC have significantly increased the standard deviation of lateral road position when compared to placebo.13,14 Such a wide range encourages examination of variables other than dose that could be influencing the relationship between THC and driving performance. Two of these variables that seem to be especially relevant are frequency of cannabis use and the combination of THC and alcohol. It is possible that frequent users may develop a tolerance for THC, which could result in the same THC dose having less of an impact for frequent users versus occasional users.15 With regards to THC and alcohol, a study of 681 THCpositive drivers involved in fatal crashes revealed that >40% of them had blood
alcohol concentrations above the legal limit.16 This hints that their combined presence could be more influential on driving performance compared to either chemical alone.
Suitability of our current method for detection: Standardized Field Sobriety Tests If a police officer perceives that a driver is operating a vehicle while impaired, they may ask the driver to pull over and perform a series of tests.9 These are called Standardized Field Sobriety Tests (SFSTs) and include nystagmus tests, the walk and turn test (WAT), and the one leg stand test (OLS). Although SFSTs may be effective for detecting cannabis impairment, it is important to remember that they were initially developed for detecting alcohol impairment.17 The nystagmus tests include three types of eye examinations (horizontal gaze, vertical gaze, and convergence). When under the influence of alcohol, it is expected that drivers will exhibit impairment for all of these parameters. However, drivers under the influence of cannabis are not likely to show any signs of impairment in horizontal or vertical gaze. Interestingly, they only show a noticeable lack of convergence.18 The WAT helps the observer assess the driver’s balance and coordination. For the OLS, the observer is only focused on assessing the driver’s balance. An experimental study has revealed sensitivity for cannabis impairment detection using the OLS.19 In the same study, impairment was detected using the WAT only when alcohol was ingested in combination with cannabis. When taken as an overall performance score, the combined use of all three SFSTs has been shown to provide accurate detection in only 30% to 50% of individuals who are impaired only by cannabis.19, 20
Conclusion Driving under the influence of cannabis must move out of the shadow cast by driving under the influence of alcohol. Recreational users’ perceptions on the risk of driving under the influence of cannabis, and police officers’ techniques used to detect impaired drivers, can be influential targets for behavioural and policy interventions. In terms of objectively proving cannabis impairment, further investigation must be conducted to more deeply examine the link between THC and driving performance. References 1. Rocky Mountain High Intensity Drug Trafficking Area. The Legalization of Marijuana in Colorado: The impact. Colorado, Montana, Utah, and Wyoming (United States of America); Rocky Mountain High Intensity Drug Trafficking Area;2016. 2. Woodall KL, Chow BL, Lauwers A, et al. Toxicological findings in fatal motor vehicle collisions in Ontario, Canada: a one year study. J Forensic Sci. 2015;60(3):669-74. 3. Kirkey S. When is stoned too stoned? About half of Canadians who drive while high insist pot doesn’t impair them. National Post. 2016 May 17;http://news.nationalpost.com/news/canada/0518na-stoned. 4. State Farm Mutual Automobile Insurance Company;Desjardins Group. Canadian driving habits: 2016 driving Survey. State Farm Mutual Automobile Insurance Company;2016. 5. Asbridge M, Hayden JA, Cartwright JL. Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ. 2012;344:e536. 6. Swift W, Jones C, Donnelly N. Cannabis use while driving: a descriptive study of Australian cannabis users. Drug-Educ Prev Polic. 2010;17(5):573-86. 7. Terry P, Wright KA. Self-reported driving behaviour and attitudes towards driving under the influence of cannabis among three different user groups in England. Addict Behav. 2005;30:619-26. 8. Aston ER, Merrill JE, McCarthy DM, et al. Risk factors for driving after and during marijuana use. J Stud Alcohol Drugs. 2016;77:30916. 9. Health Canada, Government of Canada. A framework for the legalization and regulation of cannabis in Canada. Health Canada;2016. 10. Drummer OH, Gerostamoulos J, Batziris H, et al. The involvement of drugs in drivers of motor vehicles killed in Australian road traffic crashes. Accident Anal Prev. 2004;36:239-48. 11. Ronen A, Gershon P, Drobiner H. Effects of THC on driving performance, physiological state and subjective feelings relative to alcohol. Accid Anal Prev. 2008;40:926-34. 12. Hartman RL, Huestis MA. Cannabis effects on driving skills. Clin Chem. 2013;59:478-92. 13. Lamers CTJ, Ramaekers JG. Visual search and urban city driving under the influence of marijuana and alcohol. Hum Psychopharmacol. 2001;16:393-401. 14. Lenné MG, Dietze PM, Triggs TJ, et al. The effects of cannabis and alcohol on simulated arterial driving: influences of driving experience and task demand. Accid Anal Prev. 2010;42:859-66. 15. Khiabani HZ, Bramness JG, Bjorneboe A, et al. Relationship between THC concentration in blood and impairment in apprehended drivers. Traffic Inj Prev. 2006;7:111-6. 16. Laumon B, Gadegbeku B, Martin JL. Cannabis intoxication and fatal road crashes in France: population based case-control study. BMJ. 2005;331:1371. 17. Burns M, Moskowitz H. Psychophysical tests for DWI Arrest. U.S. Department of Transportation, National Traffic Safety Administration. Final Report, Publication No. DOT-HS-5-01242. 18. Declues K, Perez S, Figueroa A. A 2-year study of Δ 9-tetrahydrocannabinol concentrations in drivers: examining driving and field sobriety test performance. J Forensic Sci. 2016;61(6):1664-70. 19. Bosker WM, Theunissen EL, Conen S. A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid. Psychopharmacology (Berl). 2012;223:439-446. 20. Papafotiou K, Carter JD, Stough C. An evaluation of the sensitivity of the Standardised Field Sobrtiety Tests (SFSTs) to detect impairment due to marijuana intoxication. Psychopharmacology (Berl). 2005;180:107-114.
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The Master of Health Science in
Medical Radiation Sciences Program A conversation with Nicole Harnett By Lindsay Caldarone
he University of Toronto (U of T) is home to a unique graduate program, the Master of Health Science in Medical Radiation Sciences (MHScMRS). This professional program in the Institute of Medical Science, and offered in collaboration with the Department of Radiation Oncology, is novel in its goals as well as its curriculum. I was fortunate to have the opportunity to catch up with the Program Director, Nicole Harnett, and get the inside story of what the MHScMRS is all about. The idea for the MHScMRS stemmed from the development of a joint undergraduate program in radiation therapy, offered by the Michener Institute and U of T. Ms. Harnett was hired by the Michener Institute to implement this program, through which students would gain a Bachelor of Science from U of T and an Advanced Diploma from the Michener Institute. The undergraduate program was developed in response to a government mandate that a baccalaureate degree be required for radiation therapists in Ontario. However, creating the undergraduate program left Ms. Harnett with a burning question: “What’s next?” The idea of a graduate program in advanced radiation therapy was developed by Ms. Harnett and the late Dr. Pamela Catton, a radiation oncologist at Princess Margaret Hospital and Ms. Harnett’s partner at U of T. In 2004, Dr. Catton hired Ms. Harnett to build a professional
Master’s program in the Department of Radiation Oncology, “…in recognition of the fact that the profession was changing enormously, and we need[ed] to keep academic preparation up to speed.” As the MHScMRS developed, Ms. Harnett and the Ministry of Health were engaged in a complementary project: the development of advanced practice in radiation therapy. Together, they hoped to examine whether a higher-level practitioner could make the existing model of care more useful. The two projects “went hand in hand, and informed each other,” Ms. Harnett explains, and were “aligned, although they aren’t connected directly.” Through this multidisciplinary approach, Ms. Harnett and her colleagues developed the MHScMRS: a professional Master’s program, “targeted at expert professionals who have a lot of experience, but want to augment it with academic and theoretical underpinnings.” Ms. Harnett practiced radiation therapy for years and enthusiastically claims her clinical experience helped her “200%” in developing the MHScMRS program. The forward-thinking and clinicallyrooted ideology of its founders is reflected in the goal of the program, which, in Ms. Harnett’s words, is “to increase competence and functionality of radiation therapists, to add academic competence to existing practice, and to develop advanced techniques in their practice.” The program remains innovative as it
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adapts to the needs of students in a rapidly changing field. In 2015, approximately ten years after the inception of the MHScMRS program, a sort of “internal review” was held in which students, stakeholders, alumni, and prospective students were interviewed and their thoughts were collected, reflected upon, and put into action. “Not everyone was interested in advanced clinical practice. Some were interested in leadership and some in straight research,” Ms. Harnett reflects. Therefore, the curriculum was remodeled to reflect this and now includes three unique pathways for students: 1) the Research Pathway; 2) the Clinical Practice Pathway; and 3) the Professional Leadership Pathway. These pathways allow flexibility in personal customization of an overall experience to suit students’ professional interests. Incidentally, these three pathways reflect the initial goals of the program-to develop “clinical expertise, scholarly competence, and leadership.” Another innovative aspect of the curriculum is the requirement for students to have hands-on experience (e.g., through an internship, research, or clinical work). The students set specific goals to develop research, clinical, or professional leadership competencies, and are required to complete a certain number of hours under a supervisor or other leader in the field to gain practical skills to help them accomplish these goals. Furthermore, the program uses a “Blended
Delivery” approach to its teaching. “Ninety percent of the program is online,” Ms. Harnett explains, “which makes it possible for students in Edmonton and Halifax to be in class together.” Clearly, the MHScMRS program does not abide by the traditional, paper-reliant route of learning. Rather, students are actively online four to six hours per week with live and interactive lecture presentations from faculty, student-led discussion groups, and presentations to one another. Ms. Harnett and her team specifically ensure that screen time is “maximized” to facilitate debates, discussions, and critical thinking by assigning readings and discussion preparation to be done ahead of class. “[The students are] talking to each other all the time online,” says Ms. Harnett. “It’s very unique and the way of the future.” The opportunity to participate in a highquality professional Master’s program with the flexibility of an online classroom is an appealing prospect. When asked if the goal
is to take the program internationally— one student enrolled from Singapore—Ms. Harnett responds, with a laugh, “We’re going to take over the world! We would like to be the de facto program for anyone interested in advanced clinical practice [in radiation science].” The MHScMRS program receives a great deal of international interest, and “these programs are hard to come by,” Ms. Harnett points out. However, the MHScMRS program at U of T remains true to its specific goal of advancing radiation therapy practice, and only admits practicing radiation therapists. At the time of enrollment, most students have been out of school for about six to eight years. In this time, they have been “advancing themselves in the professional world,” whether through leadership positions, research projects, or other initiatives. Students may have different interests or specialties, but there is what Ms. Harnett calls a “common phenotype” to the student
body: they are self-directed, leading projects independently in their specific clinical environment. Ms. Harnett emphasizes that this program would not be possible without the Department of Radiation Oncology. The core faculty for the MHScMRS program come from the Department of Radiation Oncology, and Ms. Harnett explains that the Department’s “culture of learning and belief in inter-professional practice [is] at the crux [of the MHScMRS program]”. To illustrate, she points out that the MHScMRS program retains a small class size—usually about three or four students—and yet, thanks to the commitment and generosity of the Radiation Oncology faculty, the students can engage with world-renowned lecturers. The Department of Radiation Oncology provides an environment of interprofessional collaboration and innovation, and this way of thinking is what facilitates such a unique and successful program. IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 39
A Panel Event on Medical Assistance in Dying By Melissa Galati
n Tuesday February 21st, 2017, the Institute of Medical Science Students’ Association (IMSSA) hosted a panel event to discuss Medical Assistance in Dying (MAID) in Canada. The event covered the history of MAID, its moral and clinical relevance in our healthcare system, and its potential in the future. The evening kicked off with IMSSA’s Director of Academic Affairs, Nancy Liu, who welcomed the attendees and introduced the expert panelists: •
Dr. Isser Dubinsky: Professor at the Institute of Health Policy, Management and Evaluation at the University of Toronto, and Associate Director of Hay Group Health Care Consulting. Ms. Patricia Murphy-Kane: Clinical Nurse Specialist in Palliative Care at Princess Margaret Hospital and Clinical Appointee at the Lawrence S. Bloomberg Faculty of Nursing, University of Toronto. Mr. Robert (RJ) Edralin: Registered
Nurse in the Emergency Department and Clinical Care Coordinator in MAID at the University Health Network. •
Mr. Giles Scofield: Clinical Ethicist at the Centre for Clinical Ethics and Associate Clinical Professor in the Department of Family & Community Medicine at the University of Toronto.
What is MAID and what does Canadian legislation stipulate regarding MAID? In February 2015, the Supreme Court of Canada ruled that section 14 and paragraph 241(b) of the Criminal Code were unconstitutional because they prohibited physicians from assisting in the consensual death of another person. This ruling, Mr. Scofield pointed out, did not completely decriminalize assisted suicide; instead, it merely highlighted “exceptions to the rule.” Nearly a year and a half later, in June 2016, Bill C-14, legislation on medical assistance in dying, received royal assent. The legalization of MAID in Canada allows for aid in dying, either
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through prescription of lethal medication or through administration of medication. So, MAID is legal in Canada. Who is eligible? The discussion quickly moved from history to current clinical practices of MAID at the University Health Network (UHN). This, the panelists cautioned, is where MAID legislation becomes controversial. Mr. Edralin, who is the first ever MAID Clinical Care Coordinator, and Ms. Murphy-Kane took attendees through information that has been relayed to UHN employees. In order to be eligible for MAID, patients must: •
Be 18 years of age with decision making capacity.
Have health services funded by the government of Canada (e.g. OHIP).
Request MAID voluntarily.
Have informed consent for MAID.
Have a grievous and irremediable
PAST EVENTS medical condition. What is a grievous and irremediable medical condition? A patient’s medical condition meets MAID criteria if his or her illness is incurable, the patient has experienced an irreversible decline in capability, the patient is in intolerable physical pain or psychological suffering, and the patient’s natural death is reasonably foreseeable. Likely, you can appreciate that these guidelines leave a lot of room for interpretation. Whether or not a patient meets these conditions is determined on a case-by-case basis. At this time, care providers at the UHN will consider a patient’s request for MAID if their death is predicted within two years. But, who are we to determine when someone else’s life is over? Dr. Dubinsky shared a personal example to illustrate why this two-year time frame is unjust from the perspective of the patient. A friend of Dr. Dubinsky, who worked in media as a childhood educator, developed slow, progressive Amyotrophic Lateral Sclerosis (ALS). Although she would live for seven years, her life was over as soon as she was unable to do what she loved—educate. For this reason, the panelists stressed, patients and families need to be part of the discussion. Another controversy surrounding assisted dying is the exclusion of individuals with chronic psychiatric disorders. Given the absence of decision-making capacity that often exists in these cases, policy makers are reluctant to include this patient population, even when an individual would be considered lucid. Moreover, current legislation does not allow for advanced directives in care planning or Power of Attorney (PoA) to substitute for a patient’s lack of decision making capacity or ability to provide informed consent at a time when they meet the rest of the eligibility criteria. What is a typical timeline for MAID? Once a patient makes their request for assisted death, a three-step process occurs over a two-week period, where: 1) the clinical staff informs the Most Responsible [healthcare] Provider (MRP) of the patient’s decision, 2) the MRP and team perform assessment interviews to confirm patient eligibility and consent, and, finally, 3) the intervention is administered.
As with the eligibility requirements for MAID, there is much dispute regarding the way that assistance in dying is accomplished. Mr. Edralin comments that the purpose of the two-week process is to ensure that the patient’s request for MAID is sustained. Although there are individuals that opt-out during this two-week period, Ms. Murphy-Kane expressed that much of the feedback received from patients indicates they believe the process is too long. It can take a lot of courage for patients to express their wish so when they are put “on hold” or delayed in discussing their options until their next clinical visit, many feel neglected or altogether abandoned. “At the end of the day, the patient is still a person and they deserve to be talked to.” Ms. Murphy-Kane iterates that engaging in meaningful conversations with patients is beneficial to all parties. MAID is not offered on a list of “services” provided by the hospital; it is incredibly important to avoid jumping to assumptions regarding what patients want. It may be that they are simply wondering what their future holds, or what palliative care involves. Patients, Ms. Murphy-Kane states, have a way of telling you what they want to know. Determining this might involve rephrasing their question back to them or facilitating the conversation so they can better iterate their request. What happens at the time of the intervention? Attendees of the panel were interested in the day of the intervention itself. Mr. Edralin and Ms. Murphy-Kane explained that a private room is always secured for intervention administration. Friends and family may be present and some patients even request they have their pet with them. If family members plan to be present, the clinical team prepares them for what they are going to see, as many of them have never witnessed death before. Often, a spiritual care provider is present and will read a short prayer or poem. This practice has been especially helpful for staff, particularly those who have cared for the patient over a long period of time. When asked about the feedback the team has received at the time of the intervention, Ms. Murphy-Kane responds that patients and their families
are thankful; overall, the process is experienced positively, with the major recurring qualm being the perceived lengthiness of MAID delivery. Once again, amplifying the importance of including patients and families in the conversation can make the process of assisted death easier for all. “In an ideal world,” says Mr. Edralin, the Clinical Care Coordinator in MAID, “my job wouldn’t exist.” Much of Mr. Edralin’s job entails coordinating and organizing the MAID process. There is a strict protocol he must follow for all patients, with little room for deviation. In practical terms, this means confirming that patients meet the criteria for assisted death, ensuring all mandatory paperwork is completed correctly, and all relevant parties perform their responsibilities leading up to the scheduled intervention. Dr. Dubinsky adds that the real beneficiaries of MAID decriminalization are nurses and physicians, since the new laws lead to enhanced autonomy of medical professionals. Bill C-14, he points out, did not necessarily make assisted death easier for patients to undergo—in fact, many see it as simply another service they can request and subsequently be denied of. One major takeaway from the event was that panelists clearly agreed there is room for improvement when it comes to MAID. However, Dr. Scofield emphasized that what we are witnessing now with the introduction of MAID into our healthcare system is normal. New interventions start out with stringent protocols, allowing only a select group eligibility. As an intervention becomes more integrated into the system, these protocols loosen, and more patients will be able to request it. Overall, panelists seemed optimistic that tweaks to current practices could be expected. They continually referred to MAID as an “experiment”—one that Canadian health professionals are learning from. In a way, the real conversation has only just begun. Useful links for information on MAID: http://www.uhn.ca/ healthcareprofessionals/MAID http://www.dyingwithdignity.ca/ IMS MAGAZINE SPRING 2017 RESPIRATORY MEDICINE | 41
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