IMS Magazine Fall 2014

IMSMAGAZINE THINK, LEARN, DISCOVER

FALL 2014

FEATURE: ORGAN TRANSPLANTATION Innovations, ethics, perspectives

THE BIG THREE BOYCOTT Why big-time researchers are criticizing elite journals

THE IMPOSTER PHENOMENON Self doubt? You are not alone.

1 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

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IN THIS ISSUE CANADIAN TRANSPLANT STATISTICS Commentary.........................................4-5

SHORTEST & LONGEST WAITLIST TIMES IN CANADA

IN CANADA

2,124 ORGANS WERE TRANSPLANTED IN 2012

4,500 CANADIANS ARE AWAITING ORGAN TRANSPLANT

ONTARIO, CANADA: A WORLD LEADER IN TRANSPLANTATION

TORONTO

The world’s first transplant was performed at the Toronto General Hospital.

TRANSPLANTATION SUCCESS RATES ARE EXCELLENT In 2009, 15,000

Feature.............................................14-21

ORGAN DONOR RATES AMONG

$250,000

KIDNEY TRANSPLANT ($20,000)

over 5 years

USA

SPAIN

DONORS

DONORS

DONORS

PER

1,000,000

$21 MILLION

KIDNEY TRANSPLANTS saved the health care system $800 million.

COSTS SAVINGS OTHER ORGANS

HEMODIALYSIS TREATMENT ($50,000)

CANADA

WHAT ARE WE DOING ABOUT IT?

80-95%

Between of patients are doing well one year after their organ transplant.

Overall, transplant recipients enjoy an excellent quality of life and are able to work, attend scool, travel, & play sports.

to Canadian Blood Services to improve Since 2008, Health Canada has given the Canadian donation and transplantation system.

Feature 75

$76 MILLION

The Canadian Institutes of Health Research invested over in research between 2006 and 2012. Initiated the Canadian National Transplant Research Program.

KIDNEYS

They hope to increase:

%

MOST COMMON ORGAN TRANSPLANT

organ & tissue donation current survival rates recipient quality of life

Organ Transplantation

MEDICATION ($10,000)

p.12

Book Reviews...................................30-31

EDITOR IN CHIEF

Behind the Scenes...........................32-33

MANAGING EDITORS

Special Article..................................34-36

EXECUTIVE EDITORS

Ask the Experts......................................37 JOURNALISTS & EDITORS

Diversions..............................................39

DESIGN EDITORS

PHOTOGRAPHERS

PROMO & ADVERTISING

Adam Santoro Nancy Butcher Anna Podnos Annette Ye Sarah Gagliano Susy Lam Winny Li Anna Badner Brittany Campbell Chelsea Lowther Danielle Cha Joshua Lipszyc Kasey Hemington Katherine Schwenger Natasha Jawa Rebecca Ruddy Yekta Dowlati Cassandra Cetlin Natalie Cormier Naveen Devasagayam Ashley Hui Jerry Won Chung Ho Leung Laura Feldcamp Matthew Wu Leon Parsaud Gray Moonon

IMSMAGAZINE Cover design by Cassandra Cetlin & Jerry Won THINK, LEARN, DISCOVER

FALL 2014

Feature Infographic by Naveen Devasagayam, & Ashley Hui

FEATURE: ORGAN TRANSPLANTATION Innovations, ethics, perspectives

THE BIG THREE BOYCOTT Why big-time researchers are criticizing elite journals

THE IMPOSTER PHENOMENON Self doubt? You are not alone.

Student-led initiative

3 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

CANADA HAS THE

WORST INDUSTRIALIZED COUNTRIES 13 20 31

MAGAZINE STAFF

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.

75 PEOPLE

SINCE 2003

REGISTERED ORGAN & TISSUE DONORS

Close-up...........................................28-29

Copyright © 2014 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.

REGISTER TO DO N AT E YOU COULD SAVE UP TO 8 LIVES AND IMPROVE THE QUALITY OF LIFE FOR AS MANY AS

RECEIVED LIFESAVING ORGAN TRANSPLANT

%

The world’s first transplant was performed at the Toronto General Hospital.

Viewpoint........................................ 22-27

Natalie Venier p. 26

5.5 YEARS

10,039

15

1983 SINGLE LUNG 1986 DOUBLE LUNG

Director’s Message...............................13

Spotlight

5.2 YEARS

IN ONTARIO

Farewell Dr. Kaplan..........................10-11

Past Events............................................38

2.0 YEARS

TODAY

Letter from the Editor..............................7 News & Views.....................................8-9

NOVA SCOTIA MANITOBA BRITISH COLUMBIA

PEOPLE

COMMEN COMMENTARY Science: the long game.

Adam Santoro

A

ctive readers of scientific journalism no doubt smell the stench of rot on the scientific publication system. The Economist put out two outstanding articles, “How Science Goes Wrong” and “Trouble at the Lab,” discussing the problems scientists face with data replication;1,2 Nobel winner Randy Schekman is boycotting top scientific journals Nature, Science, and Cell because of their focus on sexy results instead of “good science”;3 and countless blog posts from wellknown and anonymous scientists alike express similar distress about this broken system.

The Economist articles outlined some scary truths about the current state of science.1,2 Researchers at Amgen, a multinational biopharmaceutical company, could only replicate 6 out of 53 major cancer research studies. Approximately 80 000 patients were involved in retracted clinical trials. Negative results account for an increasingly lower proportion of reported findings (now at 14%). The list goes on.

There are a number of theories as to why the publication system is so flawed, with careerism being near the top (see our previous article “Publish or Perish” by Amanda Ali); with so much pressure to produce high impact research, scientists shoot for the moon with fantastical studies that promise “paradigm-shifting” results, or even worse, they may outright fabricate data. Of course, if one does enough fantastical experiments, statistics dictates that one is bound to produce a false positive. With such an emphasis on high impact data the foundations of the scientific method start to shake. Who is going to, or even wants to perform simple, yet necessary replication studies? Who can publish negative results in any sort of meaningful fashion these days?

Blame can goes the other way too, with the

peer-review system being put in the spotlight. As reported in the Economist, a biologist at Harvard submitted a fabricated article to over 300 journals; 157 journals fell into his trap and accepted it.1 A former editor of the British Medical Journal (BMJ) submitted an article with deliberate mistakes to over 200 regular editors at BMJ. None of them could pick out all the mistakes, with most editors just spotting out a small fraction of them.

The problems of the publication system also extend beyond the scientific enterprise and into the general public. Associated news releases promote a non-scientific way of knowing. Unique and “ground-breaking” experiments are published constantly in top tier journals and are reported in newspapers and websites worldwide as norm-shattering results. “What we thought we knew about X but were wrong!” Should we really be telling the public that the scientific community is making overreaching conclusions from single papers? What happened to independent replication, and placement of hypotheses into an already established framework of knowledge?

It is difficult to come up with solutions to these problems, and many of the best solutions would be essentially impossible to implement. A simple improvement could be a double blind submission process whereby reviewers do not see the names of the authors, and vice versa. This can potentially alleviate any biases that exist; big labs should not always publish in top-tier journals because of the name of the principal investigator, the data should instead speak for itself (which, admittedly, it more often does). A study that is not blind and is submitted to a journal is harshly critiqued by reviewers. It baffles me as to why we accept a lack of blindness in the review system.

In a completely ideal world (read: impossible to implement), I would like to see the following system in place: a centralized data repository, including both positive and negative results. I am unsure as to whether

4 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

data should be presented void of origination, because let’s face it, we can be more confident in data produced by some labs more than others. Papers would then consist of mini-analyses of the data (and not necessarily the data originating from your lab). For example, I can access the database, see a few experiments that were deposited by different labs, and write a paper assessing the validity of a hypothesis based on the data. With this approach it would be unwise to accept a hypothesis and write about it if there is only one experiment addressing it, and so papers would be fewer in number and more impactful in nature. By separating the data from the origin we take a more objective stance on the process and we let the data itself, not the intents and biases of the experimenter, to do the hard work in pushing scientific progress. To take things a step further, a necessary component of completing a Ph.D. could be the replication of data in the system and a deposit of the confirmed results (or negative results). This would promote replication of data and the publishing of negative results, all while instilling the importance of these processes into the young minds of future scientists. I don’t see any reason as to why a Ph.D. student today would want to perform a replication study, and all of us are unfortunately left without an outlet to publish negative data and simply have to shrug our shoulders and move on when they are produced.

This idea is by no means flawless, and the problems with it are numerous. For example, we lose our measuring stick for evaluating scientists, there are disincentives to actually produce the data since there is a lack of ownership over it, there would be extremely difficulty organization issues, and we would lose the ability to pursue a beautiful scientific story (perhaps the best part of doing science is having an idea-your own idea−and living it through). However, I think we would be better off dealing with these technical and egoistic problems than with the problems of our current situation, which challenge the very foundations of the

NTARY scientific process.

Science, as a way of knowing, should, and does, demand respect. Science as an epistemology is not broken, and is still the best (and only way) in which we acquire truths about the natural world. We must remember that science is a long game, and given enough time, bad hypotheses and poorly collected data will be filtered out.

Likewise, we should embrace the scientific process and incorporate its strengths into our publication system. Data should be accumulated–over time, and repeated many times–before we accept hypotheses and publish grand proclamations. We may have to come up with new ways of assessing individual scientific prowess and we may deal with huge difficulties in organization, but I take these as challenges to produce a better system, not simply problems that we have to overcome.

References 1. Anonymous. Problems with scientific research: How science goes wrong. http://www.economist.com/news/leaders/21588069-scientificresearch-has-changed-world-now-it-needs-change-itself-how-sciencegoes-wrong (accessed January 10, 2014).

2. Anonymous. Unreliable research: Trouble at the lab. http://www. economist.com/news/briefing/21588057-scientists-think-science-selfcorrecting-alarming-degree-it-not-trouble (accessed January 10, 2014).

3. Ian Sample. Nobel winner declares boycott of top science journals. http://www.theguardian.com/science/2013/dec/09/nobel-winner-boycott-science-journals (accessed January 10, 2014).cott-science-journals

COMMENTARY IMS magazine: New leadership, more support, can they do it?

Brittany Campbell

S

ince its conception in 2010, the IMS magazine has become well known in the University of Toronto.

The original team worked extremely hard to bring it together, and now, four years later, these individuals are moving on to bigger and better prospects. Some may see this as an inconvenience, as it coincides with the time where interest in the IMS magazine from staff and students has peaked. I see it as an exciting time. All eyes are on the ‘new kids on the block.’

If the magazine wants to keep improving, they have to maintain the momentum they already have. The magazine has represented the graduate department so well as a student-run initiative, and the ‘adults’ are eager to be involved. The staff at the IMS are now looking at us and asking where we are going to go, and how we are going to integrate ourselves into the greater goals of the department as a whole.

definitely prove advantageous for both the magazine, and the department. Now that we have their attention, we have to stand up and push the magazine to new heights.

There are many ideas flying around: adding a podcast supplement, improving the website, showcasing articles on the new IMS website that will be launched soon. These are all great ideas in theory that could really widen the audience. The magazine already has a problem with dissemination of hard copies, so these ideas help reach readers in places where their attention is already focused, online. But it will take hours of commitment and hard work.

As busy graduate students who write for fun, the magazine team is now under a pressure that has never existed before. This can push them in one of two ways. They can either come together with a newfound persistence, demanding more commitment for everyone involved, or the students will be overwhelmed with deadlines and the passion for writing will be forgotten. Only time will tell if enough students see the potential in this publication to see it really thrive.

This is beneficial because it allows the publication to act more cooperatively with the departmental executives, which can

(accessed January 10, 2014).

Call for Articles The IMS Magazine is looking for scientific content to post on the IMS Magazine website. Whether you are a current blogger looking to cross-post your scientific musings, or are just looking to get your ideas out there on our platform, your submissions are welcome. Submissions are expected to be approximately 800 words in length (with considerable leeway) and priority will be given to individuals who comment and report on IMS specific issues (i.e. research in the department, conferences, general scientific issues that affect the IMS faculty and students, etc.) although viewpoints and commentaries are also welcome. Send an email to theimsmagazine@gmail.com for more information.

5 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

We encourage our readers to send their feedback, comments, questions, corrections, and letters to the editor to theimsmagazine@gmail.com

theimsmazagine @gmail.com

@IMSMagazine

!

CONNECT WITH US!

? facebook.com/ groups/imsmagazine

imsmagazine.com

Please also visit us at imsmagazine.com.

Engage in dialogue with fellow IMS students and faculty, and even post your own article to our website. We are always looking for IMS student journalists to contribute to our content, whether they wish to discuss new research around the IMS, or wish to comment on a controversial topic in science and scientific training.

Stem Cell Research

WE DO THAT ADVERTISEMENT

Explore Graduate Education with

The Institute of Medical Science For more information about our graduate programs visit our website at: http://www.ims.utoronto.ca

Learn. Discover. Apply.

6 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

LETTER FROM THE EDITOR

Adam Santoro Editor-In-Chief

Adam Santoro is a fourth year graduate student in the IMS studying memory consolidation under the supervision of Dr. Paul Frankland at The Hospital for Sick Children.

Letter from the Editor T ransplantation success rates are generally excellent , with

80-95% of patients successfully recovering one year after their transplant .

Overall, transplant recipients enjoy an excellent quality of life and soon attend work and school, travel, and play sports. Yet, approximately 2 000 organ transplants are performed per year, with roughly 4 500 people still waiting. Every year people die waiting for an organ, and as our population gets older, the situation may get worse. The Canadian Institutes of Health Research invested over $76 million in research linked to transplantation between 2006 and 2012. The institutes recently launched the Canadian National Transplant Research Program, which aims to increase donations of organs and tissues, improve survival rates, and enhance the quality of life of organ recipients. This issue of the IMS Magazine covers many facets of organ transplantation, and proudly features Drs. Shef Keshavjee, Reg Gorczynski, Vivek Rao, and Linda Wright. Additionally, we hear the personal stories of an organ donor and recipient.

This issue also features a number of viewpoint articles, as Anna Badner discusses a recent trend towards boycotting the “Big Three” science journals, Susy Lam explores the juxtaposition of doctors and judges in medical decision making, and Nicole Liscio talks about chronic self-doubt, or Imposter Syndrome.

We also get a chance to hear from Natalie Venier, the magazine’s creator and former Editor-in-Chief, as she takes a break from writing her thesis to give us an inside look at the origins of the magazine.

I would like to thank the entire IMS department, and especially Dr. Allan Kaplan, for their ongoing support. Everyone at the IMS Magazine sends their best wishes to Dr. Kaplan in his new position, and is excited to welcome Dr. Mingyao Liu as the new interim Director of the IMS. Lastly, the magazine would not exist without the excellent contributions from our entire magazine committee, from the enriching content provided by our journalists, to the attentive editing of our editors, to the magnificent design by the design team. Like always, we strongly encourage feedback—whether by email, through our website www.imsmagazine.com, or in person.

Enjoy!

Adam Santoro Editor-In-Chief, IMS Magazine 7 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

NEWS & VIEWS June 9 th • IMS PhD convocation ceremony at 2:30pm 12 th • IMS MSc convocation ceremony at 2:30 pm 30 th • University closed for Presidential Day

July 1 st • University closed for Canada Day 31 th • Institute of Medical Science Students’ Association (IMSSA) Roots and Rhythms

August 4 th • University closed for Civic Holiday 11 th • Student course registration for fall session begins 13 th • Summer Undergraduate Research Program Research Day featuring keynote speaker Dr. Shaf Keshavjee

September 1 st • University closed for Labour Day 15 th • Final date for PhD students to upload post defense completed thesis to SGS online repository to avoid fee charges for 2014 - 2015

November 13 th SAVE THE DATE • Ori Rotstein Lecture in Translational Research

8 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

NEWS & VIEWS

ANNOUNCEMENTS DOCTORAL COMPLETION AWARD Are you a PhD candidate outside the funded cohort, within the time-limit for your degree and in good academic standing? If so, you may be eligible for a Doctoral Completion Award to help you complete your studies. Students must meet with a graduate coordinator in order to determine eligibility for the award. To make an appointment, please contact Hazel Pollard at hazel. pollard@utoronto.ca For general inquiries, please contact Kaki Narh Blackwood at sf. medscience@utoronto.ca.

UPCOMING AWARDS It is never too early to start thinking about applying for awards. The Canada Graduate Scholarships - Masters (which covers CIHR, NSERC and SSHRC), the Vanier Canada Graduate Scholarships, and NSERC Doctoral Awards competitions will be opening in Fall 2014. Announcements will be sent via email and posted on the IMS homepage.

For further details about these and all other awards offered in the University, please visit www.sgs.utoronto.ca – Current Students – Financing Your Graduate Education – Scholarships & Awards.

FOR FACULTY RECRUITING STUDENTS Faculty members looking to supervise new students may submit recruitment requests to be posted on the IMS website. Please contact Kaki Narh Blackwood at sf.medscience@utoronto.ca

IMS WEBSITE The IMS is pleased to announce the unveiling of their new website slated for summer 2014. Michelle Rosen, IMS Curriculum and Communications Coordinator along with Joseph Ferenbok, Director Translational Research Program, have been spearheading this long overdue makeover to the IMS website. Michelle and Joseph have partnered with advertising company Tenzing

2014 SCIENTIFIC DAY IN NUMBERS 170+ ATTENDEES

to build a website that is visually appealing and user friendly with an emphasis on narrative rather than text. Above all, the new website will be an essential resource for students, alumni, faculty and the broader scientific community. Here are some of the things you can look forward to:

130 POSTER SUBMISSIONS

9 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

MOBILE READY: It will respond to your mobile device and tablet, making information accessible and designed just for your device.

SOCIAL MEDIA: You’ll be able to follow on Twitter, join the Facebook page or connect on LinkedIn. THEMES & PLATFORMS TOOL: Are you looking for a PAC member, or ways to collaborate with other faculty? This is the search tool for you.

ONLINE COMMUNITIES: Access to online communities that will give students and faculty opportunity to collaborate and connect. Look out for the new website soon!

LAIDLAW GRAND PRIZE WINNERS

14

LAIDLAW MANUSCRIPT JUDGES

30 POSTER JUDGES

SHORT-LISTED LAIDLAW PRESENTERS

6

17 STUDENT VOLUNTEERS

2

16 LAIDLAW MANUSCRIPT JUDGES

2 POSTER GRAND PRIZE WINNERS

Farewell Dr. Kaplan!

IMS Director (2011-2014)

Farewell to Dr.Kaplan, IMS Director from 20112014, as he transitions onto a new role as Vice-Dean, Graduate and Life Sciences Education (GLSE). Dr. Allan Kaplan is a Senior Clinician/Scientist, Chief of Research at the Center for Addiction and Mental Health in Toronto, and Vice Chair for Research and Professor in the Department of Psychiatry, University of Toronto. His dedication and efforts as Director of the Institute of Medical Science left a lasting impact on the graduate unit in the Faculty of Medicine. The IMS Magazine appreciates your unwavering support over the past years, and wishes you all the best!

10 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

11 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

ADVERTISEMENT

12 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

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

Director’s Message: IMS Magazine

A

s Interim Director of the Institute of Medical Science (IMS), I would like to congratulate the IMS Magazine for addressing the innovative and sometimes difficult subject of transplantation. In my own area of research, I am challenged daily by the complex and exciting science that surrounds advances in acute lung injury and transplantation. As a senior scientist with the world renowned Multi-organ Transplant Centre in Toronto, I have seen the positive impact of clinical research on patients and the larger research community.

A discussion of transplantation inherently calls us to examine the translational nature of the subject. In this issue, authors address a wide range of issues from the ethical dilemmas surrounding organ transplantation to personal stories of organ donation. Transplantation is transformative, not only for patients but also for the clinicians and scientists who strive for a deeper understanding of the topic to help improve outcomes for patients and their families.

I would also like to take this opportunity to congratulate Dr. Allan Kaplan in his new role as Vice-Dean, Graduate and Life Sciences beginning July 1, 2014. I have had the privilege of working with Dr. Kaplan as Associate Director in the IMS, and during this time witnessed his unfaltering leadership in guiding academic and research excellence. We will continue to prioritize engagement with our faculty and students, recognize excellence in student and faculty achievement, develop meaningful and rich curriculum, and recruit a diverse and intelligent student body.

On Thursday, May 22nd the IMS held its annual Scientific Day. There were over 170 attendees with 130 student poster presentations.

We were honoured to have Dr. James P. Landers give the Bernard Langer Plenary Address on “Rapid and Affordable Microfluidic Systems for Genetic Analysis: Are We on Track for the Personalized Medicine Era?” A big thank you to all the students, staff, and faculty who made this happen!

The IMS is also looking forward to launching a brand new website this fall! The site will feature a great new look while being engaging and accessible. Personalized faculty and student profiles, online communities, and a social media presence are just some of the things to look forward to!

Wishing you a wonderful fall!

Mingyao Liu Interim Director Institute of Medical Science 13 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

CANADIAN TRANSPLANT IN CANADA

2,124 ORGANS WERE TRANSPLANTED IN 2012

IN ONTARIO

ONTARIO, CANADA:

TORONTO

A WORLD LEADER IN TRANSPLANTATION

15

RECEIVED LIFESAVING ORGAN TRANSPLANT

%

The world’s first transplant was performed at the Toronto General Hospital.

The world’s first transplant was performed at the Toronto General Hospital.

TRANSPLANTATION SUCCESS RATES ARE EXCELLENT

Between of patients are doing well one year after their organ transplant.

Overall, transplant recipients enjoy an excellent quality of life and are able to work, attend scool, travel, & play sports.

80-95%

KIDNEY TRANSPLANTS saved the health care system $800 million.

COSTS SAVINGS OTHER ORGANS

HEMODIALYSIS TREATMENT ($50,000)

KIDNEY TRANSPLANT ($20,000) MEDICATION ($10,000) ORGAN TRANSPLANTATION 14 | IMS MAGAZINE FALL 2014

SINCE 2003

REGISTERED ORGAN & TISSUE DONORS

1983 SINGLE LUNG 1986 DOUBLE LUNG

In 2009, 15,000

10,039

$250,000 over 5 years

KIDNEYS

75

%

MOST COMMON ORGAN TRANSPLANT

STATISTICS SHORTEST & LONGEST WAITLIST TIMES IN CANADA

NOVA SCOTIA MANITOBA BRITISH COLUMBIA

2.0 YEARS 5.2 YEARS 5.5 YEARS

TODAY

4,500 CANADIANS ARE AWAITING ORGAN TRANSPLANT

REGISTER TO DO N AT E YOU COULD SAVE UP TO 8 LIVES AND IMPROVE THE QUALITY OF LIFE FOR AS MANY AS

CANADA HAS THE

WORST INDUSTRIALIZED COUNTRIES 13 20 31 ORGAN DONOR RATES AMONG

CANADA

USA

SPAIN

DONORS

DONORS

DONORS

PER

75 PEOPLE

1,000,000

WHAT ARE WE DOING ABOUT IT? $21 MILLION

to Canadian Blood Services to improve Since 2008, Health Canada has given the Canadian donation and transplantation system.

$76 MILLION

The Canadian Institutes of Health Research invested over in research between 2006 and 2012. Initiated the Canadian National Transplant Research Program.

They hope to increase:

organ & tissue donation current survival rates recipient quality of life

15 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

PEOPLE

FEATURE

Organ Donation and Transplantation Ethics: New Developments Daniel Z. Buchman MSW, RSW, PhD & Linda Wright, Director of Bioethics, University Health Network

T

he ethical issues in organ and tissue donation

and transplantation are often in the news, as we debate fair, reasonable, and respectful ways to find and distribute this scarce life-saving resource. Global developments in donation and transplantation technology, policy, and law have raised new ethical issues, including the use of social media, transplant tourism, incentives for donation, vascular composite allografts (VCA), and innovations in organ donation from living donors. Transplant centres, which strive to enable life-extending and -saving transplants, are often on the front line in deciding how to respond to these new situations. Two very topical issues are VCA–which is not done in Canada yet but has been performed elsewhere–and social media, which have become an integral part of daily life and force us to address new situations in our healthcare.

VCA Donation and Transplantation VCA include face, limb, and keratolimbal transplantation. They differ from other organ transplants in two important ways.

First, the transplanted body part is external, visible, and touchable, which may raise issues of personal identity and bodily integrity for the recipient. Ethical issues associat-

ed with identity have also been observed in such as Hélène Campbell’s campaign to ensolid organ transplant recipients also. Sec- courage people to consider organ donation, ond, the body part is not needed to save a which garnered attention from celebrities life, unlike heart, lung, or liver transplants. Justin Bieber and Ellen DeGeneres. This However, a person who is missing two drew a lot of media space and led a large hands could find much greater utility with number of people to sign their donor cards.

At the same time, a hand transplant. Consequently, the risk-bene- Social media provide several social media enable fit ratio for the recipient opportunities for people, in- people to find each is different (e.g. limb re- cluding finding living donors other by sharing stocipients need to balance through Internet websites, and ries. Anonymity of donor famthe risks of immunotherraising awareness of the need deceased ilies and transplant apy against the option recipients may be of a prosthesis). Limb for organs. and face transplants can reduce suffering, threatened when people share news, bringenhance quality of life, and improve sen- ing either positive or unwelcome outcomes. sation and functionality. Ethical issues to Websites where those who need organs can consider include the possibility of a recipi- post their stories in the hope of finding a ent becoming known to the deceased donor living kidney donor offer important opporfamily, who may wish to revisit a part of the tunities for people who do not have a living donor’s body (e.g. a parent could hold their donor among family members or friends. child’s hand again). Ethical issues include However, problems may arise for both the balancing the potential benefit of the VCA recipient and the potential donor. People to the recipient against asking donors and who respond by offering a kidney may not have a good understanding of what is intheir families to donate these body parts. volved in donation and can find themselves Social Media drawn into an arrangement that they ultiSocial media provide several opportuni- mately do not like. Recipients need to be ties for people, including finding wary of accepting a kidney from a stranger living donors through Internet whose expectations of the newfound relawebsites, and raising awareness tionship may not match their own. Transof the need for organs. Some plant centres perform vigorous evaluations initiatives have been very of potential living donors and their recipappropriate and suc- ients to ensure that ethical standards are cessful, met. In particular, they aim to ensure that all living donors are acting voluntarily and are making donation decisions based on accurate information.

Transplantation enables life. Ethical issues challenge us to find acceptable ways to enable responsible innovation through thoughtful analysis and creativity.

16 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

Illustration by Natalie Cormier

Conclusion

Improving the results of heart transplantation: The role of NRF-2 Hiroyuki Kawajiri, MD Arash Ghashghai, H.BSc Laura Tumiati, H.BSc Vivek Rao, MD, PhD, FRCS(C), F.A.H.A

T

he prevalence of heart failure has been in-

Photo by Chung Ho Leung

creasing worldwide. Although many treatment approaches have been developed, heart transplantation remains the best option for end-stage heart failure patients. However, donor scarcity is still an unsolved issue, and physicians are sometimes forced to enlarge the donor pool by accepting marginal organs, which include organs from elderly or ill patients. Damage caused to organ tissue when the blood supply is returned after being deprived of oxygen, known as ischemia reperfusion injury, is the major factor complicating heart transplantation. It causes various disease processes including inflammation, apoptosis and acceleration of allograft (organ or tissue transplant from the same species) rejection, or chronic allograft dysfunction.

Since marginal organs are maximally prone to ischemia reperfusion injury-mediated 1

Figure 1. Murine neck heart transplantation model

Vivek Rao

Division of Cardiovascular Surgery, Toronto General Hospital University Health Network, University of Toronto

damage,2 strategies that reduce ischemia reperfusion injury will significantly improve short- and long-term graft function and survival in these extended criteria cases and may be a potential solution for the donor scarcity issue.

Cardiac allograft vasculopathy (CAV), a form of chronic rejection that narrows the blood vessels of the transplanted heart is the most important cause of long-term morbidity in heart transplantation, in addition to malignancy. CAV is detectable by angiography in 8% of survivors within the first year, in 32% within the first five years, and in 43% within the first eight years after heart transplantation.3 The pathogenesis for the development of CAV involves immune and non-immune mediated mechanisms that lead to endothelial cell injury, followed by intimal hyperplasia, vascular remodeling, and subsequent coronary stenosis.4,5 Although many non-immune pathogenic factors contribute to the development of CAV, ischemia reperfusion injury has been shown to have an important impact.6,7 The use of immunosuppressive drugs, namely cyclosporine, has been also incriminated in the development of CAV.8 Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that binds to the antioxidant response elements of genes encoding certain antioxidant enzymes, such as superoxide dismutase, and plays a key role in cellular defense against oxidative stress by enhancing the removal of cytotoxic electrophiles or reactive oxygen species.9 In addition to protection against oxidative stress, recent studies have suggested that Nrf2 responds to pro-inflammatory stimuli and rescues cells andtissues from inflammatory injuries.

Several pro-inflammatory cytokines such

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as tumor necrosis factor-alpha, interleukin (IL)-1, IL-2, IL-6, and IL-12 are overproduced when redox-sensitive nuclear factor-kB (NF-kB) is activated by oxidative stress. Reactive oxygen species generated by these cytokines can further induce NF-kB activation and overproduce these cytokines. This vicious cycle of oxidative stress and overproduction of pro-inflammatory cytokines can be disintegrated by activation of Nrf2.

Since oxidative stress and following inflammation plays a critical role in mediating cellular apoptosis and tissue injury during ischemia reperfusion injury, we hypothesized that Nrf2 acts to protect the donor heart from ischemia reperfusion injury and following CAV in heart transplantation. In an in vitro study, we showed that cyclosporine decreased the Nrf2 nuclear/cytosol ratio, Nrf2 phosphorylation, and superoxide dismutase activity, which were rescued by the Nrf2 inducer, tert-Butylhydroquinone (tBHQ). Using rats, we then showed that cyclosporine exposure impaired endothelial function, which was also rescued by tBHQ. These results suggested that cyclosporine-mediated endothelial dysfunction, as it pertains to CAV, may be related to Nrf2.

We then extended our experiments to Nrf2 knockout mice and our unique murine neck heart transplantation model (Figure 1). We stored the donor heart in cold solution for two hours to induce ischemia reperfusion injury before transplant. The knock out donor heart function assessed by echocardiography after 24 hours was significantly impaired compared with wild-type donor hearts. We have also shown that the Nrf2 inducer sulforaphane prevented donor hearts from ischemia

FEATURE reperfusion injury in wild-type. However, this protective effect was absent in mice.

These results suggested that Nrf2 protects against ischemia reperfusion injury in heart transplantation, and the Nrf2 inducer sulforaphane may represent novel therapy to prevent ischemia reperfusion injury in heart transplantation. Now we are planning a chronic rejection murine heart transplantation study to explore the role of Nrf2 in the development of CAV. We believe that our results are novel and highlight the protective role of the transcription factor Nrf2 against ischemia

reperfusion injury and cardiac allograft vasculopathy in heart transplantation. We continue to investigate methods to help solve clinical issues surrounding heart transplantation and improve both short and long term outcomes.

References 1. Barker WH, Mullooly JP, Getchell W. Changing incidence and survival for heart failure in a well-defined older population, 1970-1974 and 1990-1994. Circulation. 2006;113: 799-805.

2. Subramaniam K. Early graft failure after heart transplantation: prevention and treatment. Int Anesthesiol Clin. 2012;50: 202-27.

3. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-third official

adult heart transplantation report: 2006. J Heart Lung Transplant.

2006;25:869-79.

4. Ramzy D, Rao V, Brahm J, et al. Cardiac allograft vasculopathy: a review. Can J Surg. 2005;48: 319.

5. Libby P, Tanaka H. The pathogenesis of coronary arteriosclerosis (‘‘chronic rejection’’) in transplanted hearts. Clin Transplant. 1994;8: 313.

6. Murata S, Miniati DN, Kown MH, et al. Superoxide dismutase mimetic M40401 reduces ischemia-reperfusion injury and graft coronary artery disease in rodent cardiac allografts. Transplantation.

2004;78:1166-71.

7. Tanaka M, Mokhtari G, Terry R, et al. Prolonged cold ischemia in rat cardiac allografts promotes ischemia-reperfusion injury and the development of graft coronary artery disease in a linear fashion. J Heart Lung Transplant. 2005;24:1906-14.

8. Jeanmart H, Malo O, Nickner C et al. Comparative study of CSA and FK506 versus newer immunosuppressive drugs MMF and rapamycin on coronary endothelial function in vitro. J Heart Lung Transplant.

2001;20:235.

9. Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol. 2004;37:139-43

Shaf Keshavjee, MD, MSc, FRCSC, FACS

Senior Scientist Division of Experimental Therapeutics Respiratory & Critical Care Toronto General Research Institute (TGRI) Clinical Studies Resource Centre Member

Ex-Vivo Lung Perfusion: A model for medical innovation

By Brittany Campbell

W

hen Dr. Shaf Keshavjee completed his Master’s degree with the Institute of Medical Science (IMS) in 1989, he began weaving one of the most seamless blends of medicine, research, and innovation that the University Health Network (UHN) has seen yet.

Lung transplantation, at the time, was only six years old. It was costly, dangerous, and often ineffective. The donated lungs themselves were often in poorer shape than the clinical eye could recognize, with no better way to assess them. Today, we can treat damaged lungs before they reach their re-

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cipient. The advances that have come from the UHN’s transplant research is now leading the world not only in science, but also in innovation and business prospects.

After publishing his first of over 300 publications on how to preserve lungs from the standard six to twelve hours, Dr. Keshavjee

FEATURE embarked on an endeavor to increase the proportion of suitable lungs available to patients. Completing the Surgeon Scientist Training Program at the University of Toronto allowed him to experience real clinical problems that accompanied the average lung transplantation and address them in the laboratory. “The first steps in turning around a difficult, seemingly impossible clinical problem is to do whatever you can to make a new treatment possible,” he explains. A major problem was that many of the already limited donor lungs were physiologically unsuitable for transplant. Donated lungs can be infected with pneumonia, harbour blood clots, or demonstrate poor function. The standard method of cold static lung preservation slows the rate of the lung’s metabolism to 5%, slowing the dying process, but it does not allow surgeons to address lung quality before the lung is sewn into the recipient. The introduction of normothermic ex-vivo lung perfusion (EVLP) on human lungs in 20081 by Dr. Keshavjee and colleagues would change the way clinicians around the world contend with these issues.

EVLP is a technique that involves taking the chilled donor lung and connecting it to a perfusion circuit that allows the lung to function outside the body. The lung is kept at a physiological temperature inside a specially designed, dome-shaped plastic chamber. There are various tubings and filters surrounding the chamber, designed to assess some aspect of lung function or to deliver medications that combat infection.

“The lung is at 37°C, living, breathing, me-

No one has ever been able to watch a lung in action outside of the body before, much less have a team of doctors tend to the organ itself, preparing it for transplantation. tabolizing…” he tells me enthusiastically. A carefully mixed solution called the ‘perfusate’ is adjusted for the correct pH, bicarbonate and glucose concentrations, akin to what our own bodies do with our blood, before entering through the tube connected to the pulmonary artery.2 No one has ever been able to watch a lung in action outside of the body before, much less have a team of doctors tend to the organ itself, prepar-

ing it for transplantation.

A successful lung perfusion can last for up to 12 hours. In this time, common issues like the deflation of alveoli or the presence of toxic waste products, are addressed.

Transplant surgeons have realized that they can now operate with more confidence regarding their outcomes, and EVLP is spreading across the United States and Europe.

Dr. Keshavjee credits the cutting-edge facilities at the Toronto General Hospital at UHN to allow his team to be the first in the world to successfully transfer EVLP from pig and rat models to routine human use.

The impeccable standards of both clinical care and research upheld by the institution creates an environment that facilitates this level of originality and resourcefulness.

“My colleagues at places like Harvard and Stanford are often really surprised to see what we have here. Our facilities are among the best in the world.”

The UHN has a history of changing medical practices. Dr. Keshavjee credits the “research machine” for turning heparin, insulin, and pacemakers into world firsts. “Our first goal is to make things possible. We fundraise and apply for many grants in order to see our ideas first come to fruition.”

New techniques are, indeed, cost-intensive, which is why the research has to be goal-directed and show potential for ‘deliverables.’ “Money in, money out” he explains.

As surgeon-in-chief, he looks to recruit the best talent; people who can design research questions to both help patients and be competitive on the market, so that the research discoveries can then turn around and fund themselves. “Once we’ve made a discovery, we protect our intellectual property,” he explains. When that is done, medical discoveries can be turned into business opportunities that will generate the income for further investigations. EVLP, in this respect, is a success story.

You cannot miss the sparkle in his eye, as Dr. Keshavjee pulls out his iPhone and shows me photos of a half-constructed building.

“We started Perfusix in Canada at UHN a year ago, now this is Perfusix USA Inc., the first ‘lung hospital’ in the world,” he divulges, “I am watching it being built in real time.” The building is a rehabilitation centre—not for people, but for donated lungs.

In the near future, lungs that are removed

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from donors will be shipped to Perfusix to undergo EVLP before being shipped to the hospital of the chosen recipient. This soonto-be three storey facility in Silver Spring, Maryland is the world’s first commercial provider of rehabilitated lungs using EVLP, with the intention of expanding to other organs once the techniques are in place.

The culmination of years of research and collaboration that has earned Dr. Keshavjee the Order of Ontario and two Queen’s Jubilee medals has officially crossed over

As surgeon-in-chief, he looks to recruit the best talent; people who can design research questions to both help patients and be competitive on the market, so that the research discoveries can then turn around and fund themselves. from research bench to the clinic and then to the business world. It is truly the cause of a paradigm shift in the field. It begs the question, with this technique available, how can a surgeon justify transplanting a lung that has not been through EVLP? It almost sounds too risky.

As both Chief Scientific Officer of Perfusix and a prominent clinician, Dr. Keshavjee is enthusiastic about what this means for the future of his patients. Perfusix’s website states its vision: “No patient should die waiting for a new organ.” The technique upon which Perfusix is centred around has already demonstrated its capacity to improve outcomes on a case-by-case basis, and now it is poised to affect the lives of thousands. “I am doing things now that did not even exist when I was student, or even during my training,” he tells me. “That’s where research brings the excitement into my life.”

References: 1. Cypel M, Yeung JC, Hirayama S, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant.

2008;27(12):1319-25.

2. Raemdonck DV, Neyrinck A, Cypel M, et al. Ex-vivo lung perfusion.

Transplant Int. 2014; doi:10.1111/tri.12317

FEATURE

Laura Slade, MD

Resident in Psychiatry University of Toronto

A Family Journey to Transplant

J

ust over two years ago, our family was given the biggest gift anyone can receive. My dad was given a second chance at life. Yet all the while, another family out there was facing a tremendous loss of their own. In April 2012 following over four months of waiting in the hospital on supportive treatment, my dad finally got his heart transplant.

It is hard to capture into words the many years of uncertainty and struggle that our family went through on the road to transplant, let alone a few. For a long time, I prepared myself for the very real possibility that my dad may not survive until a transplant was available. I still vividly recall my first year medical school lecture on heart failure where a graph depicting ‘survival versus time’ made this reality all too clear. While trying to remain positive, I had to also be realistic that my dad may not get to walk me down the aisle or meet his future grandchildren.

All that being said, my dad was championed by his entire team of physicians, nurse practitioners, and coordinators as part of his journey to transplant. When his heart failure became severe, he was hospitalized and cared for by the wonderful nursing team at Toronto General Hospital (TGH). They made it their collective goal to keep him as healthy as possible until a donor heart was found. Unfortunately,

the nature of his cardiomyopathy meant that beyond an implantable defibrillator, surgical interventions (such as ventricular assist devices) to bridge him to transplant were not ideal. They worked toward the goal for Dad to just have one surgery — the transplant if at all possible.

“

Not a day goes by that our family doesn’t think of, and honour the life of our donor and the donor’s family. We celebrate the anniversary of Dad’s transplant with the TGH team as well as the family and

This day that we were celebrating the chance at a new life for my dad was also a day that somewhere, another family was grieving the loss of their loved one.

Following roughly nine months on the official heart transplant list, and over four months in hospital waiting, the call came in the early hours of the morning. A donor heart had been found.

We descended upon the hospital shortly after 3 am to spend time together as the preoperative preparations were made.

Dad was cool, calm, and collected. He was ready. As his surgeon and anaesthesiologist wheeled him toward the operating room, Dad hummed the lyrics to “Centerfield” by John Fogerty: “Put me in coach, I’m ready to play today.”

Four hours. Four hours was all it took for the surgery to be done. The wait was not easy. My mom and sister kept busy,

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cleaning up Dad’s room on the fifth floor, which by now had accumulated quite a lot of cards, magazines, and books from visiting family and friends. I spent the majority of the time calling and emailing our family members. The time passed remarkably quickly, all things considered. Soon enough, we were able to pay a brief visit to Dad in the Cardiovascular Intensive Care Unit. Medical school had prepared me for the image of him, minimally conscious, with many drains, tubes, and IVs running out of his body. However, what I wasn’t prepared for was the overwhelming feeling of love. We didn’t know a single thing about Dad’s donor, except that it was a young person from elsewhere in the province. Despite not having a name or face to put to the donor heart, I felt a powerful sense of connectedness, and above all, love. Our family had always recognized the awful reality that for a heart to become available, someone’s life would come to an end. Usually, it is someone fairly young, and frequently someone who had an accident. This day that we were celebrating the chance at a new life for my dad was also a day that somewhere, another family was grieving the loss of their loved one.

friends who stood behind us. Dad attends meetings with his fellow “Heartlinks” members as well as organ donation awareness groups to spread the much needed word about signing up on BeADonor.ca.

In closing, I would like to say thank you to those of you reading who have already given your consent for organ donation. To those of you who have not signed up on BeADonor.ca yet, but do indeed wish to be an organ donor, please consider doing this today. You could save the life of someone amazing like my dad.

FEATURE

CD200:CD200R Interaction in Organ Transplantation Reg Gorczynski, BA, PhD, MD

Senior Scientist, University Health Network Professor, Department of Medicine, University of Toronto

Organ transplantation remains the treatment of choice for end organ failure associated with a number of clinical disease entities. The development of artificial organs—or the promise of stem cell technology to render transplantation an obsolete methodology—remains a still-distant objective. While limitation of organ supply has encouraged the development of techniques for live donor transplantation, the fact that a foreign graft will be recognized by the recipient immune system and will generate a potent rejection response, is still a key obstacle to long-term graft acceptance. Currently, the only suitable option to counter rejection is the ongoing use of immunosuppressive drugs, which, in turn, is associated with three major unwanted side effects, namely: drug toxicity, opportunistic infection, and malign ancy.

It has been the immunologist’s “dream” that uncovering mechanism(s) that could induce specific tolerance to foreign grafts, presumably through processes akin to those by which we are naturally tolerant of our own self tissues, would overcome the need for non-specific immunosuppressive drugs and provide the long-sought after breakthrough for transplantologists.

Basic immunology research over the past decades has established a framework by which we can understand how T cells (thought to be the main “culprit” in initiating rejection responses) are activated, and in turn regulated. From this body of knowledge, new efforts have been developed to combat rejection which have built upon the ideas about attenuation of signals leading to T cell priming (i.e. blockade of

effective antigen presentation; suppression of costimulatory signals; neutralization of cytokine growth signals; and/or fostering the activation and expansion regulatory T cells). Many of these approaches are in the throes of clinical trial, or indeed are already incorporated into more novel regimens for patient treatment post engraftment.

Our own laboratory’s efforts have centered around improving our understanding of the actions of a novel molecule, CD200, increased expression of which we showed many years ago could suppress immune inflammation and foster enhanced organ allograft survival following interaction with the inhibitory receptor, CD200R1. Using genetically constructed mice over-expressing CD200 (CD200tg), or lacking either CD200 or its receptor (CD200-/-, CD200R1-/-), along with gene expression profiling of accepted grafts in CD200tg animals and immunohistology, we concluded that important mechanism(s) implicated in CD200-mediated increased graft survival involved increased infiltration of Foxp3+ regulatory T cells (Treg) and non-degranulating myeloid cells (MCs) in the graft. Despite this, however, indefinite allograft survival of the most vigorously rejected grafts was not seen for all recipients, and tolerance was not being achieved.

In models based on studies of natural neonatal tolerance in mice, an embryonic (immature) immune system encountering (allo)antigen develops “true tolerance”.

In these scenarios we and others showed several decades ago that grafts expressing

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the same antigens applied to adults treated as neonates are permanently accepted, without the concomitant non-specific immune hyporesponsiveness, which often accompanies adult allogeneic bone marrow transplantation. Again, Treg are implicated in graft survival in such neonatal tolerance models. In our most recent studies we examined whether mice receiving transplants under cover of rapamycin as immunosuppressant, and subsequently receiving autologous marrow transplants after drug-induced myeloablation (using busulphan and cyclophosphamide), would become tolerant to allografts such that following marrow regeneration, long-term graft survival would be possible in the absence of exogenous immunosuppression.

Using this protocol in CD200tg animals, a state of true tolerance develops in mice, and is associated with marked graft infiltration with Foxp3+ Tregs. We anticipate a similar regimen could be of use in clinical transplantation.

VIEWPOINT

SELF DOUBT? YOU ARE NOT ALONE The Impostor Phenomenon

Nicole Liscio

I

f you have ever found yourself with an eerily simi-

lar internal dialogue, do not worry; you are not the only one. I have come to understand, both through personal reflection and discussions with others, that this style of thinking is more prevalent than I had previously realized. It became amusingly clear when colleagues asked about my recent Master’s defense. My response? “It was okay. I felt like I could have answered the questions better. I just don’t do well in oral exams.” There was confusion written all over their faces, and who could blame them? I had swiftly and single-handedly just transformed one of my most proud accomplishments—the successful defense of a Master’s thesis—into something resem-

bling an apology. Apart from showcasing my Canadiana, it got me thinking: why do so many perfectly capable and intelligent people feel like they just do not measure up?

In 1978, psychologists Pauline Clance and Suzanne Imes first documented what they coined the Impostor Phenomenon (IP), an effect that occurs when high achievers chronically doubt their own abilities and fear that others will discover that they are intellectual frauds.1 Those that experience IP often attribute their successes to external factors, like luck or circumstance, and have trouble truly believing that their own acumen and competence are behind such

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accomplishments. What is so curious is that the stark reality is often far from it.

Take, for example, Dr. Cherry Murray, a Massachusetts Institute of Technology-educated Professor of Physics, and the current Dean of the Harvard School of Engineering and Applied Scievnces. In addition to having published over 75 papers, she holds two patents, has served on over 80 national and international scientific committees, and has garnered numerous accolades over the course of her academic and professional career. In spite of this impressive list of accomplishments, she still admits to feeling overcome with the sense of being a fraud or a phony. “Do I ever think I’m not qualified?” she says, “All the time.”2 This skewed self-perception is usually observed in those who have no obvious reason to feel this way. These people often share common characteristics: they are highly educated, hold positions of power, have been awarded for their intellect, and

Photo courtesy of iStockphoto.com

“

It must be pure luck that I got that award. I do not have enough data to be able to produce a good lecture. I am just not cut out for this type of work. I will never be as successful as my colleagues. Am I really qualified for this?

VIEWPOINT have been given the “smart and successful” stamp of approval by society’s standards.

Why, then, is this self-imposed feeling of inadequacy and fear of failure so persistent and pervasive in some of us, when all evidence points to the likelihood of our future success? Why can we not look at our track record and foreshadow a positive outcome?

Why do we give ourselves a hard time emotionally, when really, it would be easier, less anxiety-provoking, and more effective to simply pat ourselves on the back and be our own cheering squad?

One possible explanation stems from the value we place on intelligence, competence, and ability. Many of us who feel like intellectual impostors—especially graduate students and postdoctoral fellows—have extensive educational and life experiences behind us. We thrive on being highly skilled, acquiring knowledge, and thinking critically, and we place these attributes in high esteem. As children, it is likely that our parents instilled in us that above all else, a good education was the foundation for our future success. Maybe we performed well in school and were rewarded and valued for being bright. This reinforcement may have unwittingly given rise to overwhelming feelings of self-doubt and phoniness when the pattern of good grades did not follow in graduate school, and when—bewilderingly—it was not effortless to excel at a new job.

It could help shed light on why so many post-secondary students suffer from perfectionism, especially in the physical and life sciences.3 Conscientiousness and attention to detail that served us so well in elementary and high school suddenly seems like a great weight on our shoulders, slowing us down and impeding the completion of the simplest of tasks. The need to meet and surpass our own outlandishly high standards can be all-consuming, not to mention that the tedious nature of producing flawless work, ironically, makes efficiency a non-option. Inefficient work is unacceptable work, we say to ourselves. We proceed to delve deeper into perfecting our work output. It becomes a bleak, bleak cycle that is difficult to break out of without changing that internal dialogue.

It is clear that the impostor effect occurs at least in part to fulfill the basic social needs we have of being accepted and feeling valued. Enhancing our social support network

and sense of belonging are factors such as emotional support, affirmation, informational assistance, intimacy, comfort, and affection. In one study of 247 volunteer undergraduates (134 women, 113 men), Hale et al. showed that a sense of belonging was the only variable that could directly predict physical health outcomes, indicating that our social support can actually affect our well-being.3 Although the imposter phenomenon may ply a person with extra stress, for the most part, goals are achieved in the end.

This begs the question: If these feelings do not affect actual success, why should we care? As was alluded to earlier, it is not so much that success is fully halted; rather, it is stunted. Those that are too preoccupied with self-doubt have less time to focus on reaching lofty goals, and may instead settle for achievements that are low-risk.4 What fuels these chronic thought patterns?

Realistically, there are not nearly enough situations in the academic life of a student where making one mistake (or even a few of them!) will lead to catastrophic results and life-changing outcomes. Consider that it is not the fear of being wrong so much as it is the utter terror at the thought of being ostracized from a community. For example, if we were to answer a question incorrectly in front of a group of our colleagues, peers, and revered faculty, we would look foolish and feel humiliated. “They will form an opinion about our aptitude that will depreciate our feelings of self-worth! They will have finally realized we do not belong!”

So, before an answer is even attempted, we have: weighed the pros and cons; decidedly erred on the side of caution; and quashed all potential for a fruitful exchange.

Research suggests that people experiencing IP may even exhibit symptoms that are similar to those suffering from a mild depressive disorder. However, because impostors are constantly such harsh self-critics, they may not realize that their symptoms may be depressive.5 Such severe perfectionism is a trait that has been shown to be associated with increased anxiety and distress amongst individuals. Results of a study of 477 medical, dental, nursing and pharmacy students (224 men, 253 women) showed that a higher than expected percentage of students (27.5%) were experiencing psychiatric levels of distress.6 Within the sample population, these feelings of distress,

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perfectionism, and IP were shown to have strong associations, and that they were better than other variables at predicting mental well-being and adjustment.

The researchers also noted that women typically reported greater impostor-like feelings than men. This is not that surprising, especially since women are more likely to value “social belonging.”4 In fields like science, that have been historically male-dominated, it is also understandable that women may experience more feelings of inadequacy, even though there are now more women in science and engineering than ever before.

A little self-doubt can often be a good thing; it can keep your ego in check and help you produce quality work with care and attention to detail. However, when negative feelings begin to overstay and take up permanent residency, the long-term results can be debilitating. Instead of focusing on weaknesses, it might be good practice to highlight strengths and review the evidence that proves your potential for future success. The comfort of a strong social support network can also help alleviate any impostor feelings, but ultimately, changing these perceptions needs to come from within. As difficult as it may be, sometimes you just need to give yourself a break. After all, you do deserve it.

References: 1. Clance PR, Imes SA. The impostor phenomenon in high achieving women: Dynamics and therapeutic intervention. Psychotherapy: Theory, Research & Practice 1978;15(3):241-247.

2. Kaplan K. Unmasking the impostor. Nature 2009;459:468-469.

Hale CJ, Hannum JW, Espelage DL. Social support and physical health: The importance of belonging. Journal of American College Health 2005;53(6):276-284.

3. Clance PR, O’Toole MA. The impostor phenomenon: An internal barrier to empowerment and achievement. Women & Therapy 1987;6(3):51-64.

4. McGregor LN, Gee DE, Posey KE. I feel like a fraud and it depresses me: The relation between the impostor phenomenon and depression.

Social Behavior and Personality 2008;36(1):43-48.

5. Henning K, Sydney E, Shaw D. Perfectionism, the impostor phenomenon and psychological adjustment in medical, dental, nursing and pharmacy students. Medical Education 1998;32(5):456-464.

FEATURE

MD vs. JD: Doctors and Judges in Medical Decisions Who Should Have the Last Say?

By Susy Lam

“Rules are meant to be broken.”

This saying was brought to light through a recent matter in which rules were called into question: Sarah Murnaghan’s court case publicized controversial policies in organ donation in the United States, calling into question the fairness of organ donation policies where young children are involved. The big question is: should expert medical opinion prevail, or should the law?

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Photo courtesy of http://www.freeimages.com

T

ure and urgently required a double lung the patient’s age and size. For transplant transplant. However, paediatric lungs were patients younger than 12—of which there in shortage at the time, and Sarah fell short are 55 nationally, compared with about 1 of the age requirement set by the Organ 800 adults—the LAS is not used. Instead, Procurement and Transplantation Network patients are broken into “Priority 1” and (OPTN)—she had to be at least 12 years “Priority 2”, known as the Under 12 Rule. old to be prioritized Paediatric patients are not for a pair of adult Paediatric patients are not pri- prioritized using the LAS lungs. Waiting for because there is oritized using the LAS algorithm algorithm a rare paediatric no available evidence that lung donation, and because there is no available demonstrates that a simibeing at the bottom evidence that demonstrates lar allocation system is efSarah Murnaghan was a 10-year old girl, of the adult lung that a similar allocation system fective for this age group. plagued transplant list, is effective for this age group.

It is this difference in alby cystic m i n i m i z e d location practices that has fibrosis The big question is: Should exSarah’s hopes been deemed “discrimina(CF)—a pert medical opinion prevail, or for surviving this deadly disease. tory.” chronic, should the law?

The algorithm used to prioritize adult Eventually, the Murnaghans initiated a naeventupatients for lung transplants is the tion-wide campaign, claiming that this rule ally fatal disease. CF is a genetic disorder associated Lung Allocation Score (LAS). Lung trans- was discriminatory against their daughter, with dysfunctional chloride channels that plant candidates older than 12 are assigned and they won a temporary restraining orleads to mucus accumulation in the lungs. a LAS based on a complex mathematical der from the courts. A restraining order is Sarah eventually went into respiratory fail- formula, which takes into consideration a form of court order that requires a party hey say,

VIEWPOINT to do, or to refrain from doing, certain acts. Dr. Art Caplan, of the New York University again. Ultimately, what could end up hapThis meant that the OPTN’s Under 12 Rule Langone Medical Center, echoes this opinpening is that doctors are unable to treat would temporarily have no effect on Sarah, ion. It may be easier to find a pair of adult patients in objective and unbiased ways and she would qualify to be considered for vs. paediatric lungs to transplant to chilbecause of the perceived “unfairness” of the adult lungs. dren, but is very difficult to policies by which their decisions are made, The ruling get any good lung donor due resulting in detrimental patient In essence, allowing the courts to to factors including smoking, potentially concluded outcomes. that the Un- make decisions that go against asthma, air pollution, and the The focus should not be on rule-bending, der 12 Rule medical advisement might ulti- immense fragility of lungs. but rather on revamping the policies as a “d i s c r i m i - mately harm paediatric patients In fact, Sarah Murnaghan’s first step to take in order to improve the nates against in the long-term, due to the risks body rejected the first pair of OPTN’s donor allocation strategies. OPTN c h i l d r e n of transplant rejection and the lungs she received, putting is currently reviewing its policies, so perhaps and serves the young girl in a dangerous a better strategy will soon be developed to challenge of finding suitable no purpose, medical state. From an ethical better allocate organs such that donor-reis arbitrary, adult organs for children. standpoint, if an organ is concipient matches are maximized, to augcapricious, tinually rejected ment patient and an abuse and the patient’s survival, and The focus should not be on of discretion.” The OPTN was required to condition worsens, the patient minimize enter a fake birthday for Sarah under the may end up unnecessarily en- rule-bending, but rather on remedical risk. waitlist for adult lungs, tricking the system during prolonged suffering. In vamping the policies as a first Judges should into thinking she was 12 years old. This essence, allowing the courts to step to take in order to improve not always raised Sarah to the top of the recipient list. make decisions that go against the OPTN’s donor allocation have the final Since Sarah’s case, 11 additional paediatric medical advisement might ulsay in medistrategies. patients have been allowed to override the timately harm paediatric pacal decisions system to enlist for adult lung transplants in tients in the long-term, due for patients. a similar fashion. to the risks of transplant rejection and the Through these court-based decisions, the challenge of finding suitable adult organs Three pertinent questions arise from this patient and their family may indeed gain a for children. issue: (1) Is it fair that children under 12 false sense of comfort, but the patient may years of age be bumped up on the list above If allowing patients to override the Under suffer in the long-term. In the end, medical hundreds of thousands of other patients in 12 Rule can potentially be harmful, should expertise should win—marginally. desperate need of a lung transplant? (2) Is judges be allowed to supersede medical deit safe that a child receives an adult lung, cisions? Of course, it is understandable that from a medical perspective? (3) Should out of purely good intentions, parents will medical opinion prevail, or do everyshould the judicial officials be thing possiable to trump doctors to over- If the policy seems to be unfair or ble to fight rule seemingly discriminatory is lacking in some way, it is not for what they decisions? always in the patient’s best inter- believe is fair and right for If a decision is backed up by est to ask a judge to overrule a their child. relevant medical evidence, policy-based medical decision. If Overturning then it should not be deemed rules can be bent once, they most a seemingly discriminatory. Several experts unjust polcertainly can be bent again. in medicine, law, and ethics icy would support the Under 12 policy, indeed comstating that overruling the Unfort parents, der 12 policy unfairly brought Sarah and helping them to believe that their child will other young patients to the top of the list, survive and be well. However, perhaps it is while other older recipients had to wait lonequally important to consider the rationale ger. behind creating policies and rules in sciWhile parental concern for a child’s health ence and medicine in the first place. Poliand wellbeing is often the motivator for cies were put into place in order to render pursuing legal action in cases such as these, the system more efficient, fair, and safe. If medical complications can be overlooked the policy seems to be unfair or is lacking when decisions are not made objectively. in some way, it is not always in the patient’s Dr. Cronin, a transplant surgeon, states best interest to ask a judge to overrule a polthat adult organs are generally not suitable icy-based medical decision. If rules can be for children, for a combination of reasons. bent once, they most certainly can be bent 25 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

The Growing Big Three Boycott

By Anna Badner

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Photo courtesy of http://www.freeimages.com

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Na- is biologist Dr. Randy Scheckman, 2013 ty. One major concern, which Sheckman ture, Cell, or Science is considered Nobel Laureate in Physiology or Medi- touched upon, is the widespread use of the Impact the golden ticket to a successful cine. Upon receiving the Nobel Prize, Scheckman wrote a brief Factor as science career. From superior job opporcommentary in The Guarda measure Thus, in recognizing the mistunities to more successful grants, a paper in these journals is definite boost to any ian2 describing the damaging leading influence of the Impact of research scientist’s reputation–a token of true scien- effects of “glamour journals.” Factor, scientists across various quality and productivitific ability. Exceedingly competitive, these In the article, he compares disciplines are voicing a call for Nature, Cell, and Science to ty. Derived top tier journals reject more than 90% of change. high-end fashion brands, highfrom citamanuscripts they receive and continue to 1 lighting that their main aim is tions to all have growing submission rates. There are to sell subscriptions and not to display the articles in a specific journal, the Impact approximately 10 000 submissions per year most important research.

Marketing their Factor was originally established

by Thomfor Nature and more than 12 000 for Sci1 product with the ploy of Imson Reuters Corporation as a tool to help ence, which 3 pact Factor, Dr. Sheckman librarians identify journals to purchase. is definitely Marketing their product with the criticizes these journals for However, when applied by funding agentelling of the ploy of Impact Factor, Dr. Sheck- publishing only eye-catching cies, academic institutions, and other parincreasing competition man criticizes these journals for and provocative science in ties, the Impact Factor is often used as the primary parameter to evaluate an individand selectivi- publishing only eye-catching and “sexy subjects.” ual’s or an institution’s scientific contributy to publish. provocative science in “sexy subAlthough Dr. Sheckman’s tions. Meanwhile, scientists alike agree that Nevertheless, jects.” piece has received a fair share the Impact Factor does not appropriately despite the of criticism, including remeasure the quality of a sci entific article continuous marks of evident hypocrisy, nor does it reflect how influential the work growth in paper submissions, established it does bring attention to certain emerging is in the field.4 Thus, in recognizing the misscientists have begun to publically criticize problems within the scientific communileading influence of the Impact Factor, scithese elite journals. One notable example publication in the prestigious journals

VIEWPOINT entists across various disciplines are voicing a call for change.

matters, in India and China, researchers re- Dr. Eisen was easily able to identify some ceive financial incentives to publish in jour- truly appalling and erroneous papers to nals like be cleared by the apparently Nature, rigorous Nature and Science C e l l , Of even greater concern, these peer-review process. Furtheror Sci- increasingly demanding expectations more, if historically wrong e n c e . 1 may actually drive scientists to pubCell, Science, and Nature paSignifi- lish unreliable or faulty results. pers are not enough to highcant sallight this spectacle, the recent ary infiasco-involving allegation c re a s e s of fraudulent data (involving and cash rewards are offered to those that Stimulus-triggered acquisition of pluripget their work accepted in famous journals, otency cells, ie. STAP cells) in a published endorsing their country’s world-class stan- Nature paper may do the trick.12 dards.9 As the role of financial incentives in Although the future is of science is uncerany context raises certain ethical considertain, it is clear that in this new digital age ations, the major concern lies in how such the classical models of Impact Factor, jourmotivators may adversely affect science nal subscription and peer review are growquality. It is no surprise that the scientific ing out of date. It is time for scientists in process relies heavily on trust between colall stages of their careers to recognize these leagues and collaborators, and is based on flaws and work towards solutions. a silent commitment to research integrity.

Academia must play its part and begin to praise quality over quantity and scientific merit over Impact Factor.

At the 2012 Annual Meeting of The American Society for Cell Biology in San Francisco, an extensive group of editors and publishers of scholarly journals developed The San Francisco Declaration on Research Assessment (DORA), a set of recommendations for improving the way in which the quality of research output is evaluated.

With approximately 10 668 signers to date, many of which hold prestigious academic positions, DORA aims to have research assessed on its own merits. The document recommends that institutions and funding agencies weighs the “scientific content of a paper as much more important than publication metrics or the identity of the journal in which it was published.”5 Furthermore, the document reminds researchers to cite primary literature in which observations first give credit to the appropriate scientists rather than to temptation of citing reviews.

In addition to the positive reactions in academia, Thomson Reuters, Science,6 and Elsevier have all responded to DORA with Lastly, no commentary on scientific publirelative optimism. There is a definite con- cation and its big players can be complete sensus for change, but the leaders in scien- without discussion of the persistent contific entertroversy around open-access prise must Academia must play its part and (OA). While the fight is hontake re- begin to praise quality over quan- orable, OA has been blamed sponsibility causing a “wild west” effect tity and scientific merit over Impact for to transin science publishing. To those form the Factor. who remain unfamiliar with evaluation this phenomenon, an invesprocess. tigation by Science magazine (a subscription-based journal) showed that Another prominent critic of the system is a completely false cancer treatment paper theoretical physicist Dr. Peter Higgs, one of with meaningless data and significant erthe key researchers to predict the existence rors was accepted by approximately half of the Higgs boson. Despite his indisput(~150) of the OA scientific journals it had ably fundamental contributions to science, been submitted to, highlighting the deDr. Higgs has openly stated that he himself fective peer review process in online OA would not have been able to survive the expublishing.10 However, supporters and tremely competitive environment of modadvocates of OA have rebutted, stating ern academia.7 With growing productivity that, despite the growing number of onstandards, scientists are under continuous line journals (some of them unreliable), it pressure to publish frequently, especially in is the peer review process that is broken top tier journals. Of even greater concern, in subscription-based as well as OA pubthese increasingly demanding expectations lications.11 One especially vocal advocate may actually drive scientists to publish unreof OA publications and critic of the previliable or faulty results. A 2011 paper explorously mentioned Science magazine investiing journal retraction rates found a direct gative article is UC Berkeley biologist, Dr. correlation between retraction frequency Michael Eisen. A co-founder of the Public 8 and journal impact factors, suggesting that Library of Science (PLOS), Eisen is undethe disproportionally high payoff of glamniably invested in OA, and has repeatedly our journal publications may encourage refuted the illegitimacy claims of online scientists to inappropriately interpret and/ OA journals with accusations of hypocrisy. or present their data. Further complicating 27 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

References

1.Reich ES. Science publishing: The golden club. Nature. 2013; 502(7471): 291-293.

2. Scheckman R. How journals like Nature, Cell and Science are damaging science. The Guardian. 2013 Dec 9 [Cited 2014 April 20]. Available from: http://www.theguardian.com/commentisfree/2013/dec/09/howjournals-nature-science-cell-damage-science 3. Vanclay JK. Impact Factor: Outdated artefact or stepping-stone to journal certification. Scientometric. 2012; 92: 211-238.

4. The PLoS Medicine Editors. The impact factor game. PLoS Med. 2006; 3(6): e291.

5. Schmid SL. Beyond CVs and Impact Factors: An Employer’s Manifesto. Science Careers. 2013 Sept 3 [Cited 2014 April 20]. Available from: http://dx.doi.org/10.1126/science.caredit.a1300186 6. Alberts B. Impact factor distortions. Science. 2013; 340(6134): 787.

7. Aitkenhead D (2013). Peter Higgs: I wouldn’t be productive enough for today’s academic system. The Guardian. 2013 Dec 6 [Cited 2014 April 20]. Available from: http://www.theguardian.com/science/2013/ dec/06/peter-higgs-boson-academic-system 8. Fang FC & Casadevall A. Retracted science and the retraction index.

Infect Immun. 2011;79(10): 3855-9.

9. Wang NX. China’s chemists should avoid the Vanity Fair. Nature.

2011; 476(7360): 253.

10. Bohannon J. Who’s afraid of peer review? Science. 2013; 342(6154): 60-5.

11. Basken, Paul. Critics Say Sting on Open-Access Journals Misses Larger Point. The Chronicle of Higher Education. 2013 Oct 4 [Cited 2014 April 20]. Available from: http://chronicle.com/blogs/percolator/ critics-say-sting-on-open-access-journals-misses-larger-point/33559 12. Normile D. Stem cell research RIKEN panel finds misconduct in controversial paper. Science. 2014; 344 (6179): 23.

SPOTLIGHT WITH NATALIE VENIER IMS MAGAZINE FOUNDER

By Kasey Hemington

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Venier was surprised when I asked to interview her — the Institute of Medical Science (IMS) graduate student probably never expected to be featured in the very publication she founded three short years ago. The former Editor-in-Chief took a break from writing her PhD thesis on prostate cancer chemoprevention to reflect on the journey of the IMS Magazine. atalie

Venier recalls her first inspiration for the magazine: IMS Scientific Day, when she was struck by the breadth of the world-class research that goes on within the IMS. Recognizing a need to be more aware of the work of her colleagues, Venier set out to create a publication that would showcase and synthesize novel research findings of the IMS, with the hope that this might promote more interaction and collaboration. She brought her vision to Dr. Howard Mount, an IMS graduate coordinator, who recommended taking advantage of the unique diversity of IMS programs by involving Biomedical Communication Program students in design and layout. Since then, the IMS Magazine has

been the envy of other University of Toronto departments wishing to start their own magazine, and stunning visual appeal generated by the design team has certainly contributed.

After the meeting with Dr. Mount, Venier formed a committee of writers she considers integral to mobilizing the publication, including Avi Vandersluis, Nina Bahl (former Assistant Managing Editor) and Adam Santoro (current Editor-in-Chief). She developed a prototype for the first issue, laid everything out on the desk of then IMS director, Dr. Ori Rotstein, and held her breath. Fortunately, Dr. Rotstein was impressed by the quality of the publication and granted approval for printing of the inaugural issue.

Since this time, current IMS Director Dr. Allan Kaplan has also been incredibly supportive, and

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“

Venier enjoys reading article comment sections peppered with remarks from a wide range of IMS faculty members as well as the greater scientific community.

Starting up a student-run publication receiving thousands of views per issue, while in grad school, is no trivial task. Venier is grateful

Go for it! With graduate degrees, you have a lot of freedom to think critically about new ideas – you have to figure things out for yourself. As a student, you have access to so many resources. to her supportive supervisor, Dr. Vasundara Venkateswaran at Sunnybrook Health Science

SPOTLIGHT Centre, for allowing her to maintain a flexible schedule. Despite the challenge, Venier’s advice to students pursuing entrepreneurial passions is, “Go for it! With graduate degrees, you have a lot of freedom to think critically about new ideas — you have to figure things out for yourself.

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interview with Rebecca Skloot, author of ”The Secret Life of Henrietta Lacks”, conducted by Jennifer Rilstone, and one of the IMS Magazine’s most controversial articles by Amanda Ali, “Double Doctors, Double Trouble. ” Besides opportunities to interview distinguished scientists and network with the greater scientific community, Venier believes there are many other benefits for students working on the publication, commenting, “when you’re working on a graduate degree, you specialize in analytical skills – but writing and communicating to the lay public is important too […]. The magazine has given me the ability to communicate with many different people with diverse backgrounds for different reasons, whereas before, I communicated mostly to colleagues in my lab about my

I can reach out to any scientist in the world… and more times than not they will respond.

As a student, you have access to so many resources.” Venier elaborates, “I can reach out to any scientist in the world… and more times than not they will respond.” The magazine founder names several articles as highlights: an interview by Allison Rosen with Dr. Thomas Insel, Director of the National Institute of Mental Health, an

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specific research.”

When asked what the future holds after completing her PhD, Venier admits that working on the magazine has impacted her career path by allowing her to explore her passions. While she is looking at different opportunities, she tells me, “I believe that there is a need to communicate accurate and sound scientific data to the public in a way that is clear and comprehensive. I’m really interested in this type of science communication — whether it be print, electronic, or new age social media. I would definitely like to do something entrepreneurial in the future. The IMS Magazine has positively inspired me!”

I BELIEVE THAT THERE IS A NEED TO COMMUNICATE ACCURATE AND SOUND SCIENTIFIC DATA TO THE PUBLIC IN A WAY THAT IS CLEAR AND COMPREHENSIVE.

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BOOK REVIEWS

BOOK REVIEWS

Cognition in Major Depressive Disorder

by Roger S. McIntyre, Danielle Cha, Joanna K Soczynska, Oxford University Press. 2013. 128 pages

Review by Danielle Cha

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Major Depressive Disorder is a concise pocketbook that provides its readers with an articulate description of cognition (e.g., concentration, learning, memory, etc.) and its impact on individuals diagnosed with major depressive disorder. Ample research has demonstrated that mood disorders can lead to and manifest cognitive impairments (e.g., inability to think, trouble with memory, and lack of concentration).

However, there has been a paucity of research studies critically investigating the multifactorial effect impaired cognition has on individuals with major depressive disorder. These factors include, but are not limited to the individual’s social, work, or domestic circumstances. The enduring effects of cognitive dysfunction in major depressive disorder beyond resolution of the acute episode indicates that it may represent a trait/residual phenomenon in many individuals. The authors express the ignominious position of major depressive disorder as one of the world’s leading causes of disability and cognitive dysfunction as a principal cause of functional impairment. ognition in

Several significant points are posed in this pocketbook, bringing to light a perspective that encourages a greater focus on research and prospective treatment applications for a patient population characterized by cognitive impairments. Cognitive deficits are a focus of research for diverse patient populations — however, not all relate to mental illness — indicating that individuals may require different methods of trea tment and care. In medicine, particularly psychiatry, patients’ treatments are applied across a heterogeneous group (e.g., major depressive disorder) without considering potential stratification strategies that may improve treatment outcomes (e.g., inflammation status, metabolic comorbidity, etc.). It remains to be determined whether cognitive dysfunction is subserved by discrete neurobiological substrate(s) and/or if they overlap with substrate(s) implicated in other neuropsychiatric disorders. Moreover, further investigation evaluating the contribution of various effector systems and molecular pathways that converge across frequently comorbid conditions (e.g., major depressive disorder, diabetes mellitus type II, and Alzheimer’s Disease) may provide the basis for novel treatment avenues specific to ameliorating and preventing cognitive dysfunction.

Depressive symptoms have consistently been associated with de30 | IMS MAGAZINE FALL 2014 ORGAN TRANSPLANTATION

creased workplace productivity. However, therapeutic interventions specifically targeting cognitive dysfunction in major depressive disorder are not currently available due to insufficient information on the underlying neurobiological substrate(s) and/or circuits associated with the effects of this subjective complaint.

The hazards posed by cognitive impairments in major depressive disorder demonstrate the need to target cognition to better identify and treat, as well as prevent, reduce, and/or recover psychosocial function in individuals with major depressive disorder.

Available evidence provides the impetus to further refine potential mechanisms and molecular pathways subserving these disorders in order to more effectively treat these populations by aiming to reduce and prevent cognitive impairments. Several lines of evidence are brought forth in this pocketbook, encouraging novel treatment approaches and the pursuit of empirically-based, hypothesis-driven research. Questions regarding which treatment modalities, if any, are more effective in mitigating cognitive deficits, enhancing cognitive function, and/or preventing their occurrence in major depressive disorder remain unanswered. Cognition in Major Depressive Disorder uses available evidence to demonstrate the importance and need to explore the various facets of cognition and its subsequent deficits as a domain requiring further investigation in this heterogeneous clinical population.

Collectively, this pocketbook effectively introduces the concept of cognition to its readers and its relevance to major depressive disorder. The chapters are constructed in such a way that the principal ideas are easily accessible at the start of each chapter in the form of two or three bullet points that is then elaborated throughout each chapter. The headers for each chapter, followed by the key points, research gathered, and analyses are all essential and successfully portrayed. The chapters demonstrate a wide variety of perspectives when discussing cognition and cognitive deficits in major depressive disorder, highlighting their mediational contribution to psychosocial impairment in this clinical population.

The authors Dr. Roger S. McIntyre, Danielle S. Cha, and Joanna K. Soczynska exceeded expectations, providing an informative piece of work that represents a paramount exposition on the topic of cognition in major depressive disorder.

Still Alice

by Dr. Lisa Genova, Simon and Schuster. 2009. 320 pages

A

Review by Chelsea Lowther research on Alzheimer’s disease into the story line and is full of interesting information. Genova does an excellent job detailing the critical role genetic counselors are increasingly playing in the US (and Canadian) health care system. During the genetic counseling session, the readers learn that Alice carries a mutation in PS1 (the presenillin-1 gene), one of only three known susceptibility genes for early onset Alzheimer’s disease. The mutation is transmitted in an autosomal dominant fashion, meaning all of Alice’s children are at a 50% risk of inheriting the disease-causing mutation.

s a scientist in training I am acutely

aware that my single greatest asset is my mind. Everything we (academics) do on a daily basis requires Herculean cognitive effort.

Whether it is developing a study design, writing a grant proposal, or peer reviewing a manuscript, the hamster upstairs is usually in perpetual motion. I try to do my best to preserve the health of my brain– eat right, sleep, exercise–but what if my DNA is working against me?

In a too-close-for-comfort tale of a Harvard psychology professor with early onset Alzheimer’s disease we learn that a mutation in Dr. Alice Howland’s genetic code has slowly been damaging her most prized possession. Still Alice is a personal tale of one woman’s experience of Alzheimer’s disease and the unravelling of family dynamics that ensues.

I read enthusiastically to see how each of the three children would react to the genetic findings; I wanted to understand how they would grapple with the decision to get tested themselves. However, my curiosity was never satisfied and the issue was quickly swept under the rug. It is not clear whether this was an attempt to get the readers to explore their own personal beliefs about genetic testing or simply poor character development. The only purpose it served was to reconfirm that Lydia is indeed the family outcast as the only Howland child not to receive the genetic testing.

At fifty years of age and at the height of her academic career, Alice is a celebrated cognitive psychologist trained in linguistics. Alice and her husband John, also a HarGenova does an excellent job vard-employed scientist, have three grown children: Lydia, Anna, and detailing the critical role genetic Tom. The story focuses heavily on counselors are increasingly playthe strained relationship between ing in the US (and Canadian) Alice and Lydia, the so called health care system. black sheep of the family. Lydia is an aspiring actress living in Los Angeles and the only Howland child to not have pursued a college As Alice’s disease progresses, John is offered his dream job in degree. Ironically, Lydia is the first to attribute Alice’s increasingly New York City, several hours away from their Boston home. He frequent memory lapses to something larger than age-related foreventually decides to take the job and leaves his wife in Boston to getfulness. Alice’s cognitive decline begins insignificantly enough be cared for by his two daughters (Lydia has relocated back home) — a lost Blackberry charger, a forgotten word — and escalates in a swift decision that feels somewhat insincere. John is largely dramatically. Soon Alice is unable to remember the instructions portrayed as a self-absorbed scientist; however, there are affecto her favorite recipe or recognize her own neighborhood. tionate moments throughout the story that made me question the authenticity of his decisions. Overall, Still Alice does a good job Told as a first person narrative, author Dr. Lisa Genova (PhD) of communicating interesting research findings in the context of a gives the readers a candid look into the first-hand experience relatable story. of Alzheimer’s disease. As a Harvard trained neuroscientist it is obvious that Genova’s background has suited her well to write such a fictional tale. Still Alice incorporates “current” (circa 2008)

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SPOTLIGHT

SPOTLIGHT ON DR. VASUNDARA VENKATESWARAN

By Yekta Dowlati

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r. Vasundara Venkateswaran is a woman wearing many hats.

She is an associate professor in the Department of Surgery at the University of Toronto (U of T), a graduate coordinator and Chair of Graduate Admissions at the Institute of Medical Science (IMS), the Director of the IMS Summer Undergraduate Research Program (SURP), and a scientist in the Division of Urology at the Sunnybrook Health Sciences Centre.

Dr. Venkateswaran completed her double master’s degree in clinical biochemistry and Ph.D. in clinical biochemistry at the University of Madras in India in 1990.

Her Ph.D. studies focused on estrogen receptors in breast cancer. She explains, “I was fascinated particularly by clinical biochemistry because it talked about disease pathways and applications.” Her first postdoctoral fellowship was at Washington State University where she investigated the effect of growth factors on the development of breast cancer and how various types of breast cancer cells interact in the tumor environment. She then moved on

to take up her second training as a senior research associate, at the University of Kansas Medical Centre, where she investigated molecular mechanisms relating to physical therapy treatment such as the use of growth factors in repairing injured tendons.

After residing in the United States for approximately six years, she returned to India for a period of five years with her family, so that her only daughter could be exposed to and be part of the Indian culture. There she had a tenured position as an assistant professor and head of the Department of Biochemistry at the University of Madras.

In 1999, Dr. Venkateswaran and her family immigrated to Canada, and was recruited right away as a research fellow in January 2000, by Dr. Lawrence Klotz, an uro-oncologist at the Sunnybrook Health Sciences Centre. Dr. Venkateswaran was instrumental in setting up and managing the Prostate Cancer Research Laboratory at Sunnybrook. Following her extensive work on prostate cancer leading to publications in high impact journals, Dr. Venkateswaran

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was appointed as an assistant professor in the Department of Surgery and Scientist in the Division of Urology in 2003.

When Dr. Venkateswaran started working in prostate cancer research, she enjoyed the transition from breast cancer research into a different field, as she believes that the importance does not lie in a specific type of cancer but rather in the broader concept of cancer development. At that time, a landmark clinical trial (SELECT) testing the ability of vitamin E and selenium in preventing prostate cancer was taking place. In parallel Dr. Venkateswaran was interested in replicating these observations in a transgenic model that replicated the development of human prostate cancer beginning from early stage (microfocal) cancer to full blown neoplasia. Although the clinical trials were well underway, Dr. Venkateswaran had very intriguing findings and was the first to demonstrate the ineffectiveness of these compounds, with the findings being published in Cancer Research.

Consequently, different treatment

SPOTLIGHT strategies were being tested by Dr. Venkateswaran’s research group. It was noticed that a subset of patients undergoing androgen deprivation therapy as a treatment for prostate cancer developed hyperinsulinemia, which was being treated with the drug metformin. An increase in insulin levels was suspected to be causing an increase in the progression and aggressiveness of the cancer in patients. Another consequence of hyperinsulinemia was obesity. The results of a study led by Dr. Venkateswaran published in the Journal of the National Cancer Institute found that feeding a high carbohydrate diet to mice with prostate cancer caused an increase not only in their body weight and hyperinsulinemic state, but resulted in overall larger tumor size and aggressiveness as well.

She is now investigating if metformin can sensitize and improve the response of prostate cancer cells compared with conventional radiotherapy and chemotherapeutic drugs by eradicating tumor cells as well as cancer stem cells in the There was a tumors.

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program has expanded and she has created partnerships with international universities, obtaining funding for the students to conduct their research. She has been a member of IMS for nearly eight years. Dr. Venkateswaran’s involvement in the IMS has made her even more passionate about what she is doing. “It gives me a great sense of satisfaction in mentoring students and even more of a gratification when I see them come out of their tough times,” says Dr. Venkateswaran.

she is challenged by multiple tasks and has to juggle compared with times when she only has to focus on one single task.

Her third suggestion as a scientist is collaboration, “You tend to withhold information, because you are scared. You feel that somebody else will take away your idea. It’s so unfortunate. The scientific world has changed. There was a time that we were happy to discuss and share our work and the fear was not there. We were all able to enjoy the science and collaborate Dr. Venkateswaran acknowledges Dr. widely. Collaboration is also a key element Mary Seeman and Dr. Howard Mount as to success.” In the midst of all this, Dr. her mentors in helping her with transition- Venkateswaran says, “None of this would ing into her new roles at the IMS. Under be possible but for my loving family. The the leadership of Dr. Allan Kaplan, Dr. incredible support from my husband and Venkateswaran took on the responsibility daughter–they are the only family I have of a graduate coordinator and Chair of in Canada and they mean the world to me.

Graduate Admissions. Dr. Venkateswaran But now I have an extended family in IMS admits that she would do anything to and I love them dearly at a personal and make sure her students experience the professional level.” She further mentions, same excitement in research as she did, be “It is very important for anyone to have inner satisfaction. I want to live for people who want time that we were happy to discuss and share me to help and support them.” and the fear was not there. We were all able to

our work enjoy the science and collaborate widely. Collaboration is also a key element to success.

One of Dr. Venkateswaran’s graduate students is now studying if capsaicin (a compound found in chili pepper) can be considered as a novel radio-sensitizing and therapeutic agent in prostate cancer. As stated by Dr. Venkateswaran, “Diet alone is not the only player instrumental in prostate cancer progression. Other key player includes exercise. To sum, “lifestyle” as a whole has to be taken into consideration.”

Hence, other graduate students have focused on the effect of regular sustained aerobic exercise in conjunction with various dietary regimens on the inhibition of prostate cancer growth in mice.

In 2011, Dr. Venkateswaran was promoted to associate professor at U of T. Over the past three years, she has been a graduate coordinator tending to student affairs. In addition she has participated in graduate admissions for several years and presently chairs this very important committee at IMS. She has been the director of SURP, (one of the largest summer undergraduate research programs at the U of T) for nearly five years. Under her leadership, the SURP

successful, and achieve their dreams. She doesn’t believe in being a task master, but rather being a great mentor, “So I have to wear different hats and I love it. I have to be a mother, teacher, mentor, researcher, and counselor, but again it is the art of balancing.”

Dr. Venkateswaran’s belief is that if someone wants to do research, it’s not only about doing the research; but to ensure that they are enjoying what they are doing.

One should not miss the moment and that moment is today. She explains, “All students are stressed for sure, but I think you should enjoy what you are doing. It’s not about doing something; it’s about how well you want to do something and for sure enjoying it.”

Her second suggestion is that students need to interact, “They say they don’t have time, but you should create time. Time management is the key to your success.

The thing I have learned in life is the art of balancing.” Dr. Venkateswaran believes that she is personally more effective when

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Dr. Venkateswaran reflects on the difficult times of her graduate school, her unapproachable supervisor.

She now supervises graduate students, uro-oncology fellows, and postdoctoral students of her own. What she has learned from this is to be accessible and approachable to all students and to be available for them. She believes in giving students the freedom of thinking, the opportunity to express their ideas, and not forcing your ideas on them in order for them to be successful, “My role is not just being a supervisor, but also being a mentor. I want to give them free thinking and make them be independent. Because if you want them to become successful scientists, don’t force your ideas on them, train them to think independently.” She continues, “It is exactly like teaching your baby how to walk. I have to hold the hand of my students at first, but then let them go, so that they can start taking hold of themselves, but I am always there watching out for them.”

SPECIAL ARTICLE

Tiffany Chow, MD, MSc Senior Scientist Baycrest Health Sciences Rotman Research Institute Associate Professor of Neurology and Geriatic Psychiatry, University of Toronto Associate Member, Institute of Medical Science, University of Toronto

D

ave Sackett has advised that no one under age 40 should write a book. I took his intent well when I heard this: lay people read books to gain a perspective, to learn how someone else has solved problems, or come to important decisions. Until relatively recently, I had always assumed my association with books as an academic behavioural neurologist would be as a book editor or chapter author, not as an author of a book for lay readers.

But then opportunity knocked, while I was standing in a coat check line at a Toronto restaurant. Within five minutes of pleasant chitchat, I was invited by a literary agent to write a book on how I chose my subspecialty and was introduced to her buddy, Margaret Atwood (whole ‘nother story, best over a glass of wine). The agent, Beverley Slopen, was surprised that a lively young(!) person like me would choose to devote energy to research and clinical care of dementia, a topic that had horrified and depressed her.

Over a series of coffee chats, Beverley taught me crucial differences between the writing I’d been doing for work and writing for lay readers. We academicians never feature ourselves as characters or protagonists in

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our peer-reviewed journal articles. We demonstrate hypothesis-testing with positive results in order to publish in a high impact journal; the lay reader wants to see a story arc over which you realized you needed to make a change, were motivated to make that change, survived the change, then confirmed it was the right decision (or not).

“

Can you write about your life’s work at the “30 000 foot level”? It’s very challenging to convert the gory details of knowledge that has earned us our titles as experts into readable, understandable text, but that is exactly the mission at hand if you think your message is important enough to disseminate through trade press. One of the pillars of my success was that my message itself involved translation of knowledge to lay people. After a great deal of soul-searching, I finally heard Bev-

erley’s original question and realized that the reason I work in dementia is that I am not horrified and depressed by it; I find inspiration and incredibly diverse expressions of love and kindness in this work, and that is the vital story to broadcast. I was not being asked to boil my findings in neuroimaging and tracking of beh av i o u r a l disturbances into a primer for non-neurologists.

Rather, my task was to bring the heart and spirit of why I do this work into words.

One of the pillars of my success was that my message itself involved translation of knowledge to lay people.

Photo courtesy of http://www.freeimages.com

Neuroscientist, Reluctant Author

SPECIAL ARTICLE

I committed vacation time over about two and a half years and found it a terrific way to reflect on what I’ve seen, what I’ve done, what I’ve learned, and what I’ve taught. Many faculty happen across prior papers years later and wonder, “Who wrote that?”, or “Why did I go on so long?”, or “How did I get that past the reviewers?” Thanks to my literary agent and seasoned professional editors, I have no problem re-reading my book or excerpts during invited talks for lay audiences. I not only stand behind what I wrote, it has shaped me to practice what I preach more coherently, and I feel healthier now, physically and mentally, than before I started writing the book. I encourage each of you to answer the call if you have a story to tell.

Tiffany Chow is a senior scientist at the Baycrest Health Sciences Rotman Research Institute and an associate professor of Neurology and Geriatric Psychiatry at the University of Toronto. Her book, The Memory Clinic was published as a hard cover edition in 2013 and the paperback version launched in January 2014. Follow her on twitter: @tchowbella or see excerpts from the book at http://www.huffingtonpost.com/dr-tiffany-chow/

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SPECIAL TOPICS

CANCER COSTS ON THE RISE

CANCER IS EXPENSIVE Susy Lam

A

from the physical, spiritual, and emotional challenges cancer brings to patients and their loved ones, cancer also financially drains pockets. In the context of developing a cancer cure, two factors are crucial: efficacy and affordability. The Canadian Cancer Society quotes $2.6 billion dollars in direct health care costs, and $17.4 billion in wage-based productivity loss in 2000.1 Direct health costs are defined as the health expenditures of each patient, such as drug expenses and therapy fees, and wage-based productivity loss is defined as a productivity loss in the economy due to unexpected, premature deaths.1 side

Despite cancer already establishing itself as an expensive condition to research and to treat, there is evidence that these figures will continue to increase. In 2013, an article in Nature discussed new immunotherapies and their prospects to effectively target cancer.2 Immunotherapies are a class of drugs that modify aspects of a patient’s immune system, arming it to fight cancer, and are most efficacious when combined with other therapy types, such as radiation therapy or chemotherapy. The term for this is “combination therapy.” Yervoy, a new three-month “combination therapy,” has since been approved by the Food and Drug Administration and can potentially send cancer into remission for years.3 Despite an increased number of patients in remission from combination

therapy, however, the costs are far from ideal and patients are expected to be on the drug for years to come.3 Therefore, an appropriate question to ask at this point is the following: Is it economically wise to continue on this route to treat cancer, despite the escalating costs?

It is inevitable; for research and development are our only hopes to find a sound cure for cancer. Research costs have also risen in the recent years, even after adjusting for inflation. The average cost of developing a new drug skyrocketed from $318 million in 1991 to $802 million in 2001, and then to roughly $1.2 billion in 2011.4 Prescribing these drugs for a longer time in conjunction with other therapies will undoubtedly multiply the total costs for patients.

These costs further increase when retail and wholesale mark up their prices. The average annual cost in Canada for new drug therapies is $65 000–approximately the value of an average annual salary.5 In to our effort to cure cancer in patients, we are simultaneously hampering patients’ ability to afford these new drugs. The conundrum is clear.

Cancer is most expensive to treat at the late stages. One possible solution to the economic dilemma may be to develop and optimize more sensitive screening methods that detect cancer at the earlier stages, so health professionals can decide the severity of the cancer and when it is appropriate to intervene. In this way, a pro-active approach to treat cancer may be economically more feasible than treating more patients with advanced stage cancer through expensive therapies.

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In March 2013, Doug Easton from the University of Cambridge announced that their research team had discovered over 80 regions of the genome that greatly increased the risk of breast, prostate, and ovarian cancer.5-7 These findings will hopefully lead to the development of more effective screening for individuals. Implementation to more screening programs, as a result, may also help alleviate the financial burdens of patients and the nation in the long term.

Cancer is no longer an acute disease for health care providers; it is viewed as a chronic disease that requires expensive and sometimes multi-faceted approaches to control. With the increasing costs to engineer drugs for cancer, compounded by their sky-high market prices, it is wise that we ensure accessibility of screening tests for all individuals to prevent costly expenditures if they are diagnosed with late stage cancer. Two factors are crucial for the cancer cure: efficacy and affordability. It is with great hope that the time will come when both needs can be met.

References: 1. Canadian Cancer Society’s Advisory Committee on Cancer Statistics.

Canadian Cancer Statistics 2013. Toronto, ON: Canadian Cancer Society; 2013.

2. Ledford, H. Nature. May 2013. 497(544). doi:10.1038/497544a Link for Yervoy graph: <http://www.nature.com/polopoly_ fs/7.10768.1369754844!/image/ASCO-cancer-graph.jpg_gen/derivatives/fullsize/ASCO-cancer-graph.jpg> 3. Tufts Center for the Study of Drug Development. 2012. Outlook 2012. 1-12.

4. Canadian Cancer Society. Cancer Drug Access for Canadians. Sept 2009. i-39.

5. Ruark E, Seal S, McDonald H et al. Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. 2013. Nature Genetics. 45: 686-689.

6. Garcia-Closas, Couch FJ, Lindstrom S et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

2013. Nature Genetics. 45(4):392-398.

7. Michaildou K, Hall P, Gonzalez-Neira A et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. 2013. Nature Genetics. 45(4): 353-358.

ASK THE EXPERTS

FACULTY QUESTION Dear Experts, I am an assistant professor at the IMS. Am I eligible to supervise graduate students?

Eager Prof Dear E.P., It is your status within the School of Graduate students that determines your supervisor eligibility. If you have Associate Membership in the IMS, you can only supervise Masters students.

With a Full Membership, you can supervise both Masters and PhD students. If you have a restricted membership, depending on the terms, you probably cannot supervise at all. If you are an Associate Member seeking Full Membership, it is beneficial to get involved with the department (i.e., judge at IMS Scientific Day, join PAC committees, etc.) Good luck!

CURRENT STUDENTS

Dear Experts, I am third author on a manuscript that is ready for submission but feel I have contributed more work and deserve to be second author. What should I do?

Wrongly Credited Dear W.C., Ideally, authorship should be determined prior to drafting the manuscript, in which mutual agreement amongst all

Dear F.A., It can be quite difficult when entering IMS halfway through the school year. IMSSA holds meetings each week and anyone is welcome to attend. There are also site-based events such as board games or movie nights, in addition to departmental pub nights and career workshops.

Joining an IMS student-led group such as the IMS Magazine is also a great option. Lastly, the annual IMS Scientific Day in May is a fantastic way to meet other students!

PROSPECTIVE STUDENTS

ASK THE

Dear Experts, I’ve heard that it’s more advantageous to find a supervisor before applying/ entry into IMS and can better my admission chances. Is this true?

Curious Applicant

Dear C.A., While many students contact potential supervisors prior to submitting their application to IMS, it is not a requirement. In fact, most supervisors are reluctant to speak with students without an admissions offer from IMS. You should, however, have a clear idea of the subject areas you would be interested in. If you want to better the chances of working with your preferred supervisor, your best options are to apply early and obtain your own funding (CIHR, OGS).

EXPERTS

Dear Experts, I am attending an international conference next month and am feeling overwhelmed at the number of parallel sessions and poster presentations. Meanwhile, my lab mates have planned an afternoon off to sightsee. What should I expect out of the conference?

Conference Novice Dear C.N., It is always a good idea to speak with your supervisor regarding conference expectations.

The first couple days of the conference will be the busiest, so if you do want some downtime, plan it closer to the end. Attend a variety of oral presentations, keynote sessions, and posters. Of course, you won’t be able to attend all sessions (most of them run in parallel). Take notes, and try to capture one highlight for each of the days you’re there. Conferences are a great way to network and meet colleagues in your field so socials and sightseeing are highly encouraged!

authors should exist. In your case, meet with your supervisor and explain the situation. If it is still an issue, consult a graduate coordinator.

Dear Experts, I joined IMS in the January cohort and have not yet made any friends outside the lab. Where are all the IMS students hiding?

Feeling Alone

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EXPERT TIP Speak up. Don’t be afraid to consult others for help and advice.

PAST EVENTS

PAST EVENTS Summer Pub Night

Career Seminar Series

Roots & Rhythms

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DIVERSIONS

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READ IT ONLINE

IMSMAGAZINE http://issuu.com/imsmagazine www.facebook.com/groups/imsmagazine/

@IMSMagazine

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