Ims Magazine Fall 2016

IMS MAGAZINE THINK.LEARN.DISCOVER.

FALL 2016

ENGINEERING and MEDICINE 3D PRINTING

Revolutionizing Medicine Layer by Layer

THE ROAD TO REJUVENATION Stem Cell Therapy As a Treatment for Aging

TARGETED RADIATION As a Therapy for Cervical Cancer

Student-led initiative

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 1

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IN THIS ISSUE Letter from the Editors............................... 4 Director’s Message.................................... 5 Commentary............................................... 6 Twitter Feature........................................... 7 Feature: Engineering and Medicine........... 8 Special BMC Feature............................... 22 Viewpoint................................................. 24 Faculty Spotlight...................................... 26 Student Spotlight..................................... 28 Future Directions...................................... 30 Travel Bites............................................... 32 IMS Events............................................... 34 Book Reviews........................................... 38

MAGAZINE STAFF EDITORS-IN-CHIEF

Kasey Hemington Rebecca Ruddy

EXECUTIVE EDITORS

Anna Badner Ekaterina An Meital Yerushalmi Petri Takkala Sarah Peters

JOURNALISTS & EDITORS

Alexandra Mogadam Adam Betel Arunima Kapoor Beatrice Ballarin Danielle Cha Gaayathiri Jegatheeswaran Jabir Mohamed Jessie Lim Jonathon Chio Joshua Lipszyc Melissa Galati Mirkamal Tolend Muahtashim Mian Rachel Dragas Shokoufeh Yaseri Usman Saeed Vanessa Rojas Luengas Yekta Dowlati

DESIGN EDITORS

Christine P’ng Judy Rubin Lauren Huff Midori Nediger Ursula Florjanczyk

SOCIAL MEDIA & WEB EXECUTIVES

Beatrice Ballarin Fadl Nabbouh Tahani Baakdhah

SPONSOR EXECUTIVES

Antigona Ulndreaj Carina Freitas

PHOTOGRAPHERS

Ekaterina An Chung Ho Leung Fadl Nabbouh Meital Yerushalmi Pratiek Matkar Tahani Baakdhah

the many faces of BIOMEDICAL ENGINEERING Materials

Tissue Engineering This field focuses on constructing devices and materials to ameliorate tissue repair and regeneration.

Professor Milica Radisic created a biocompatible scaffold that can imitate real cardiac muscle fibre growth and contraction.

Medicine

Nanotechnology and Neural Systems Nanotechnology

Regenerative Medicine

This field focuses on engineering conducted with materials at the nanoscale (1 billionth of a meter).

This field aims to rejuvenate, replace, or regenerate cells, tissues, or organs to re-establish function.

Clinical Medicine

Neural and Sensory Systems

This field involves creating new materials for use in tissue engineering, and stem cell and drug delivery.

Clinical engineers work to design technologies, devices, and strategies for individuals living with disability, chronic disease, or injuries.

This field is at the intersection of engineering, physics, neuroscience, and mathematics that works to develop brain-computer interface systems, cognitive computers, and neural prosthetics.

8

Dr. Geoff Fernie has invented numerous assistive devices, from mobility products to non-slip winter footwear as well as improving accessibility policies.

This field involves the use of computer technology in management of biological information, such as genetic sequences or cell populations.

Human Genome Project

Professor Molly Shoichet and her lab are leading the way in developing nanoparticle drug delivery systems. They engineer biomaterials to develop safer and more effective cancer therapies.

Medicine by Design is a leading initiative in the field of regenerative medicine at the University of Toronto. It is funded by a $114 million federal grant from the Canada First Research Excellence Fund and brings together the best regenerative medicine and cell therapy researchers.

Biomaterials

Professor Alison McGuigan and her colleagues have developed a way to grow cancer cells in a rolled-up sheet to imitate the 3D structure of real tumors.

Bioinformatics

Professor Ofer Levi at the University of Toronto, and his students, developed a new cost-effective, neural imaging system.

Bioinformatics played a huge role in the Human Genome Project, the largest collaborative biological project to date, with 20 research teams making up the International Human Genome Sequencing Consortium.

However, the actual sequencing took place in a number of centers and universities in the United States, United Kingdom, France, Germany, Japan, and China.

The Human Genome Project determined the DNA sequence of the entire euchromatic human genome using DNA samples from several volunteers recruited through numerous collaborating labs.

FEATURE INFOGRAPHIC

By Judy Rubin

Copyright © 2016 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.

The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.

Cover Art

By Ursula Florjanczyk MScBMC Candidate “I chose to model a steampunk kidney to represent medicine and engineering. I find the steampunk an instantly recognizable, and visually catching style.”

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 3

LETTER FROM THE EDITORS

Letter

FROM THE

Editors

KASEY HEMINGTON (left) REBECCA RUDDY (right) Editors-in-Chief, IMS Magazine

T

echnology has become so ubiquitous in our everyday lives that sometimes, we take it for granted. It is important to take a step back and consider all of the ways in which technology continues to improve our daily lives. In medical research, technology and engineering are being leveraged in innovative and life-changing ways that have revolutionized the field.

In this Fall 2016 issue of the IMS Magazine, we explore the topic of engineering and technology in the medical research field. Many incredible researchers in IMS are incorporating cutting edge technologies in order to propel their research even further. We have featured Dr. Molly Shoichet and her exceptional work using hydrogels for drug delivery, as well as Dr. Ren-Ke Li, highlighted for his work using stem cells to combat age-related illness. Our team also spoke to Dr. William Song about using technology to improve radiotherapy for cervical cancer and Dr. Victor Yang to hear insights on improved 3D surgical navigation tools.

This issue also features the work of talented IMS undergraduate students, following our annual Summer Undergraduate Research Program writing contest. Congratulations to Thenuka Thanabalasingam and Ellen Wu on your winning articles and on your fascinating summer research projects. In addition to highlighting IMS research, in this issue we explore life after IMS by catching up with recent alumni and revealing their post-graduate pursuits. Finally, our book reviews feature exciting reads that might interest you for some much needed down time.

We would like to take this opportunity to express how honoured we feel to be selected as the new Editors-in-Chief of the IMS Magazine. Since starting with the magazine as journalists in 2013, we have greatly appreciated the opportunity to meet incredible scientists and delve into the ground-breaking research that occurs in IMS. As Editors-in-Chief, it has been a truly wonderful experience thus far working with such enthusiastic and passionate journalists, photographers, and executive members. We are extremely grateful for all of the guidance we’ve received from everyone at IMS and from the outgoing Editor-in-Chief, Annette Ye.

Kasey Hemington & Rebecca Ruddy Editors-in-Chief, IMS Magazine 4 | IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE

Photo by Meytal Yerushalmi

We are excited to share our newest issue with you. Happy reading!

DIRECTOR'S MESSAGE

Director's message

Photo by Tahani Baakdhah

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

elcome to another issue of the IMS Magazine, featuring engineering in medicine. This issue draws on the multidisciplinary strengths of the IMS, highlighting the work of University of Toronto IMS faculty Dr. William Song, Dr. Victor Yang, and Dr. Ren-Ke Li. Dr. Molly Schoichet of the Chemistry Department and Dr. Neil Fleshner of the Department of Surgery are also featured. I hope readers will enjoy learning about this rapidly growing area and the innovative research taking place at the intersection of medicine and engineering.

Fall has brought another exciting start to a new academic year here at the IMS. We are looking forward to hosting the annual Ori Rotstein Lecture in translational research on October 13th. This year’s lecture will be given by Dr. Peter Liu, Chief Scientific Officer and Vice President of Research at the University of Ottawa Heart Institute, and Professor of Medicine at the University of Ottawa. The title of the lecture is ‘Evolution of Biomarker Discovery: Challenges, Opportunities and Approaches’. A panel discussion on innovations and commercialization for cardiovascular disease will follow the lecture. We look forward to interacting with the IMS community at this highly anticipated event.

I would like to extend congratulations to Annette Ye, former IMS Magazine Editor-inChief, who stepped down from her position following the publication of the Summer 2016 issue, in preparation for her graduation from the IMS PhD program. Thank you Annette for your dedication to producing a publication that inspires students, staff, and faculty alike.

We now welcome new IMS Magazine co-Editors-in-Chief, Rebecca Ruddy and Kasey Hemington. Congratulations on the Fall 2016 issue, and we look forward to future issues.

The IMS Magazine has been a tremendous success and is just one of the many wonderful, student-led initiatives that make the IMS a very special institute. I look forward to reading about research conducted by our faculty and students that is bridging the gap between medicine and engineering in this Fall 2016 issue.

On behalf of everyone at the IMS, I wish you a terrific 2016-2017 academic year.

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

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 5

COMMENTARY

SLEEP IN GRAD SCHOOL

(OR LACK THEREOF)

By Amol Rao MSc Candidate in Department of Mechanical and Industrial Engineering, Faculty of Applied Sciences and Engineering, University of Toronto

T

he IMS Magazine recently conducted a Graduate Student Sleep Survey as part of a feature on sleep. The results, which can be seen in infographic format in the Summer 2016 issue, are quite concerning. Approximately 40% of respondents were unsatisfied or very unsatisfied with the quality of their sleep. A similar percentage were unhappy with the amount of time they sleep. If the survey respondents are any indication, there could be 6,800 grad students at U of T who are unhappy with their sleep.

Of those who were unsatisfied with their sleep quality, only 5% have consulted a sleep specialist and about 20% have tried OTC sleep medication—numbers that are similar for those satisfied with their sleep. This suggests that unhappy sleepers don’t generally seek treatment. A possible explanation is that poor sleep is considered normal or unavoidable due to external requirements. Most commonly mentioned reasons for poor sleep are: stress, work, schedule, and lack of exercise.

Poor sleep can have significant consequences for an individual’s well being.

From reduced cognitive function, memory and recall to altered mood and behavior; over time chronic sleep problems have been linked with increased risk of obesity, stroke, hypertension, and a weakened immune system.1 Those who experience poor quality sleep are encouraged to seek out and employ strategies and tactics to improve their sleep or consult a specialist.

Artificial Light at Night Time: A Potential Contributor to Sleep Problems Most respondents expressed the wish to go to bed earlier; however, one commonly cited barrier to an early bedtime was maintaining a regular sleep schedule while balancing a heavy workload. For most students, this means completing work on a computer in the evening hours.

For a long time, it was thought that nighttime light was inconsequential to our sleep. However, over the past 20 years many studies have demonstrated that exposure to light in the evening hours disrupts circadian rhythms by suppressing the production of melatonin.2 This in turn makes it more difficult to fall asleep and wake on a regular schedule. The disruption is intensity and wavelength dependent, with high energy blue light being the most disruptive.2 In addition, light emitting electronic devices have become almost ubiquitous in the last ten years. At a 2012 Annual Meeting, the American Medical Association (AMA) voted to adopt a position statement recognizing that ‘exposure to excessive light at night, including use of various electronic media can disrupt sleep or exacerbate sleep disorders…’3 So what is a hard working grad student to do? Ideally, lights should be dimmed and use of electronic devices minimized in the hours before bedtime. Since this isn’t possible for most, the use of free software such as f.lux or Apple’s Nightshift which

6 | IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE

reduce light related disruption should be seriously considered. Alternatively, several studies have shown that selectively filtering the most harmful element of lighting, i.e. blue light in the evening hours, can help improve sleep.4,5 Orange light bulbs and blue light filtering eyewear are both commercially available. Given the increasing attention being paid to sleep from tech startups to lighting companies there is hope that restful sleep is just around the corner. Until then, it’s off to Tim Hortons.

Amol Rao is the co-founder of www.BlueBlockGlasses.com. His team helps people learn about and mitigate the impacts associated with evening light exposure. If you’re interested in learning more or want to drop a line, please send an email to amol.rao@mail.utoronto.ca.

References 1. Driver H, Gottschalk R, Hussain M, et al. Insomnia in Adults and Children. The Youthdale Series. Joli Joco Publications Inc.; 2012 2. Reiter RJ, Tan DX, Korkmaz A, et al. Light at night, chronodisruption, melatonin suppression, and cancer risk : a review. Crit Rev Oncog. 2007 Dec; 13(4):303-28.

3. American Medical Association (AMA). Report 4 of The Council on Science and Public Health (A-12) on Light Pollution : Adverse Health Effects of Nighttime Lighting; 2012 4. Pauley M. Lighting for the human circadian clock : recent research indicates that lighting has become a public health issue. Med hypotheses 2004; 63(4): 588-96 5. Burkhart K, Phelps JR. Amber lenses to block blue light and improve sleep: a randomized trial. Chronobiol Int. 2009 Dec; 26 (8): 1602-12

TWITTER FEATURE

#MultipleSclerosis

#dementia IMS Magazine

IMS Magazine

@IMSMagazine

@IMSMagazine

#Dementia is not a normal part of #Aging. #IMSMagaine #Think #Learn #Discover 13 Sep 2016

Did you know that #women are twice as likely to get #MultipleSclerosis than men? #Think #Learn #Discover #IMSMagazine 9 Sep 2016

O U R MO S T P O P U LA R

Tweets #concussion

#mentalhealth IMS Magazine

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#PhD Training Around the #World: Are all degrees made equal? by @AnnaBadner #UofT @PhDForum #graduatestudents 25 Jul 2016

#PhD IMS Magazine @IMSMagazine

Head trauma injury account for 30% #TBI #IMSMagazine #Think #Learn #Discover 9 Sep 2016

Old #drugs and new tricks: Repurposing drugs to treat #psychiatric disorders #mentalhealth #depression #UofTMed 3 Aug 2016

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 7

FEATURE

the many faces of Materials

Tissue Engineering This field focuses on constructing devices and materials to ameliorate tissue repair and regeneration.

Professor Milica Radisic created a biocompatible scaffold that can imitate real cardiac muscle fibre growth and contraction.

Medicine

Regenerative Medicine This field aims to rejuvenate, replace, or regenerate cells, tissues, or organs to re-establish function.

Medicine by Design is a leading initiative in the field of regenerative medicine at the University of Toronto. It is funded by a $114 million federal grant from the Canada First Research Excellence Fund and brings together the best regenerative medicine and cell therapy researchers.

Biomaterials

Clinical Medicine

This field involves creating new materials for use in tissue engineering, and stem cell and drug delivery.

Clinical engineers work to design technologies, devices, and strategies for individuals living with disability, chronic disease, or injuries.

Professor Alison McGuigan and her colleagues have developed a way to grow cancer cells in a rolled-up sheet to imitate the 3D structure of real tumors.

8 | IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE

Dr. Geoff Fernie has invented numerous assistive devices, from mobility products to non-slip winter footwear as well as improving accessibility policies.

FEATURE

BIOMEDICAL ENGINEERING Nanotechnology and Neural Systems Nanotechnology This field focuses on engineering conducted with materials at the nanoscale (1 billionth of a meter).

Professor Molly Shoichet and her lab are leading the way in developing nanoparticle drug delivery systems. They engineer biomaterials to develop safer and more effective cancer therapies.

Neural and Sensory Systems This field is at the intersection of engineering, physics, neuroscience, and mathematics that works to develop brain-computer interface systems, cognitive computers, and neural prosthetics.

Professor Ofer Levi at the University of Toronto, and his students, developed a new cost-effective, neural imaging system.

Bioinformatics

This field involves the use of computer technology in management of biological information, such as genetic sequences or cell populations.

Human Genome Project Bioinformatics played a huge role in the Human Genome Project, the largest collaborative biological project to date, with 20 research teams making up the International Human Genome Sequencing Consortium.

However, the actual sequencing took place in a number of centers and universities in the United States, United Kingdom, France, Germany, Japan, and China.

The Human Genome Project determined the DNA sequence of the entire euchromatic human genome using DNA samples from several volunteers recruited through numerous collaborating labs.

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 9

FEATURE

PROTEIN DELIVERY:

Thinking outside the nanoparticle

By Malgosia Pakulska & Molly Shoichet

I

t started with an odd result, as interesting discoveries often do.

A “huh” moment that got the wheels turning.

My colleague Irja Elliott Donaghue, a fellow PhD student in the Shoichet lab at the University of Toronto, had been encapsulating a therapeutic protein, neurotrophic factor 3 (NT-3), in polymeric nanoparticles composed of poly(lactic-co-glycolic acid) (PLGA).

By embedding those NT-3-loaded nanoparticles in a water swollen material called a hydrogel (think soft jello), she could control NT-3 release. But the release profile she obtained was not ideal–not enough NT-3 was coming out in the first few days.

After some discussion, the proposed solution was to mix some free, unencapsulated NT-3 directly into the hydrogel. This seemed like a logical solution; proteins diffuse out of hydrogels very quickly due to their high water content. But it didn’t work. Instead, the protein release profile remained unchanged whether the NT-3 was completely encapsulated within the PLGA nanoparticles or whether some NT-3 was encapsulated and some was freely dispersed in the hydrogel.

Malgosia Pakulska, PhD Research Associate, Shoichet lab, Department of Chemical Engineering & Applied Chemistry, University of Toronto Science Communication Specialist, Research2Reality

Huh. This was especially surprising because researchers have been encapsulating drugs in polymeric nanoparticles for several decades and, if anything, they usually have the opposite problem.

Burst release

10 | IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE

Molly Shoichet, PhD, FRSC, O. Ont. Professor, Chemical Engineering & Applied Chemistry, University of Toronto Professor, Chemistry, University of Toronto Professor, Biomaterials & Biochemical Engineering, University of Toronto Tier 1 Canada Research Chair

Photos by Tahani Baakdhah

One of the first studies to use PLGA nanoparticles for drug delivery was back in 1981.1 Robert Gurny and colleagues showed that encapsulating testosterone in PLGA nanoparticles decreased its release rate by more than ten-fold compared to the conventional oil-based formula. Despite this, encapsulated testosterone still had a rapid, “burst” release over the first 12-24 hours, before it slowed down.

The authors attributed this “burst” release to drug that wasn’t well encapsulated, but rather stuck to the nanoparticle surface. Since then, many papers about PLGA nanoparticles for drug delivery have been published, several devoted to overcoming this burst release and achieving a constant release profile.

FEATURE In the Shoichet lab, we have been using PLGA nanoparticles in controlled drug release applications for two decades. One of the drug delivery systems we have designed is composed of PLGA nanoparticles dispersed in a hyaluronan (HA) methylcellulose (MC) hydrogel (HAMC).2 HA is shear thinning, allowing the gel to flow through fine gauge needles, while MC is inverse thermogelling, providing in situ gelation at body temperature. The hydrogel vehicle creates a depot of particles at the injection site, allowing them to degrade and release the encapsulated proteins locally over time. Embedding PLGA nanoparticles in HAMC has always attenuated the initial burst release,3 but not to the extent we were seeing now.

Encapsulation free While we were frustrated that our seemingly simple solution did not work, we were also curious. How could this be happening? We decided to go to the extreme: put all the NT-3 directly into the hydrogel with blank PLGA nanoparticles– that is don’t encapsulate any of it. Still, the release profile of NT-3 from the hydrogel remained unchanged whether or not it was encapsulated.

“It was definitely surprising! I needed to repeat the experiment to feel confident it was a real result,” laughs Elliott Donaghue, now a Commercialization Analyst at the Centre for Commercialization of Regenerative Medicine. But even after many replicates, the results stayed the same.

This was a big deal. “Not needing encapsulation reduces the loss of protein activity and more importantly simplifies the ability to control release rate,” says Professor Michael Sefton, a leading biomedical engineer at the University of Toronto who was not involved in the project.

For protein therapeutics, the encapsulation process itself can be very damaging.

Sonication, organic solvents, freeze-drying—none of these things are good for protein structure which is so important for function. By skipping the encapsulation altogether, we can protect the fragile protein.

At the time, I was working on the controlled release of stromal cell derived factor 1α (SDF) to promote stem cell migration after spinal cord injury. Fascinatingly, I saw the same thing with SDF: the SDF release profile was slow and linear whether it was encapsulated in PLGA nanoparticles or simply mixed into the hydrogel with blank PLGA nanoparticles. Another PhD student in the lab, Jaclyn Obermeyer, was working on the controlled release of brain derived neurotrophic factor (BDNF) to promote tissue regeneration after stroke. She also observed that the release rate of BDNF was independent of encapsulation, but the presence of the PLGA nanoparticles in the hydrogel was still necessary.

PLGA nanoparticles,5 but no one ever thought to skip encapsulation altogether.

Similarly, PLGA nanoparticles have previously been exploited for surface loading of positively charged drugs, but in these cases, there was a very high concentration of protein which saturated the particle surface and masked the magnitude of the effect.6 Encapsulation in PLGA nanoparticles was a breakthrough for controlled drug release, but when it comes to proteins, it may be time to think outside the nanoparticle.

We spent the next several months trying to figure out why this was happening and how we could control it.

“It wasn’t just one protein that could use this encapsulation-free system, but many proteins that had some similar properties.

Those similarities helped us uncover the mechanism behind the release,” explains Elliott Donaghue.

It turns out NT-3, SDF, and BDNF are all positively charged at physiological pH while PLGA nanoparticles have a negative surface charge. When Anup Tuladhar, another PhD student in the Shoichet lab, tried to control the release of erythropoietin (EPO) using this same strategy, it didn’t work – EPO is negatively charged at physiological pH. By changing the pH of the hydrogel and the salt concentration, we strengthened the theory that release was governed by electrostatic adsorption of the positively charged proteins to the negatively charged surface of the particles.4 We could control the release rate by modifying the available surface area for adsorption through the particle size or concentration, or by modifying the strength of the interaction through the hydrogel pH. In hindsight, it seems so simple. The saying “opposites attract” is something you learn with magnets in elementary school; yet, in over 35 years of PLGA research, no one had taken full advantage of this phenomenon. But the clues were out there.

Past studies investigated the effect of charge interactions on drug release from

The “huh” moment. The release profile of (A) protein encapsulated in PLGA nanoparticles dispersed in a hydrogel was virtually identical to that of (B) protein dispersed in a hydrogel with empty PLGA nanoparticles.

References 1. Gurny R, Peppas NA, Harrington DD, et al. Development of biodegradable and injectable latices for controlled release of potent drugs.

Drug development and Industrial Pharmacy 1981; 7(1):1-25.

2. Baumann DB, Kang CE, Stanwick JC, et al. An injectable drug delivery platform for sustained combination therapy. Journal of Controlled Release 2009;138: 205-13.

3. Stanwick JC, Baumann MD, Shoichet MS. Enhanced neurotrophin-3 bioactivity and release from a nanoparticle-loaded composite hydrogel. Journal of Controlled Release 2012;160: 666-75.

4. Pakulska MM, Elliott Donaghue I, Obermeyer JM, et al. Encapsulation-free controlled release: electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles. Science Advances 2016; 2: e1600519.

5. Balmert SC, Zmolek AC, Glowacki AJ, et al. Positive Charge of “Sticky” Peptides and Proteins Impedes Release From Negatively Charged PLGA Matrices. J Mater Chem B Mater Biol Med. 2015; 3(23):4723-4734.

6. Cai C, Bakowsky U, Rytting E, et al. Charged nanoparticles as protein delivery systems: A feasibility study using lysozyme as model protein. Eur. J. Pharm. Biopharm. 2008; 61: 31–42.

Disclaimer This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Pakulska M, Donaghue IE, Obermeyer JM et al. Encapsulation-free controlled release: Electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles. Science Advances 2016;2(5): e1600519.

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 11

FEATURE

TARGETED RADIATION THERAPY

for CERVICAL

CANCER: the journey from bench to bedside

By Ekaterina An

S

itting behind two large, sleek monitors in an airy office in the T wing of the Odette Cancer Centre, Dr. William Song guides me through a PowerPoint presentation detailing a novel radiotherapy applicator that allows for targeted radiation treatment of cervical cancer. As images of cervical tumours slide across the screen, Dr. Song’s passion for his work is evident. Having earned his Ph.D. in medical physics from the University of Western Ontario, Dr. Song specializes in radiation oncology physics. Radiation therapy, which uses targeted and regulated radiation doses to kill cancer cells,1 is one of the three primary modalities involved in the treatment of cancer. The goal of radiation therapy is to maximize the radiation dose delivered to the tumour, while minimizing the radiation exposure to the rest of the body. This radiation dose can be delivered externally or internally.1 External delivery involves the use of a linear accelerator to deliver megavoltage x-rays (x-rays with energy that is about an order of magnitude greater than that of x-rays used for imaging) to a particular location in the body, while internal delivery of radiation therapy (brachytherapy), the original technique of radiotherapy, involves a surgical delivery of a radioactive source directly to the cancer tissue. Today, radiotherapy is highly computerized and involves an interdisciplinary team of radiation oncologists, dosimetrists (professionals responsible for treatment planning), radiation therapists, and medical physicists.

primarily includes teaching, administrative work, and research. One of his current major research projects is dedicated to improving the delivery of brachytherapy for cervical cancer. The current method of delivery involves the insertion of an applicator, called a tandem, through the endocervical canal. Then, Iridium-192, a tiny, high-activity radioactive source, is pushed into the tandem. “The problem with the current technology,” explains Dr. Song, “is that the source itself gives you isotropic radiation, meaning uniform radiation everywhere. So I thought, wouldn’t it be better if you direct the beam to conform to individual patient anatomy?” This is exactly what Dr. Song’s research aims to do. The idea behind his research is relatively simple: to improve the directionality of the radiation beam emanating from the radioactive source.

This concept, termed Direction Modulated Brachytherapy (DMBT), described the use of a novel applicator to tailor the delivered

In his role as head of the Medical Physics Department at the Sunnybrook Health Sciences Centre, Dr. Song’s job profile 12 | IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE

dose of radiation to the tumour volume, while minimizing damage to surrounding organs. “The applicator is very thin, around 6mm in thickness. But the source itself is only 1mm thick, so there is a lot of wasted space, even though it is already a small applicator” says Dr. Song. “So why don’t we fit in a very high density metal alloy in the applicator and cut out holes to place the source in there? That way, we get a directional radiation beam” (Figure 1).

Preliminary treatment-planning studies have shown that the use of Dr. Song’s novel DMBT applicator results in a decrease in “spillage radiation”—the amount of radiation that damages healthy tissues instead of the tumour (Figure 2). “Minimizing the radiation spillage will really minimize very nasty side effects,” explains Dr. Song.

Despite the promising results of the new applicator, a number of obstacles must be overcome before it can be implemented clinically. “In medicine, even if you have

Figure 1. The proposed DMBT-concept tandem applicator design. A (a) standard plastic tandem and (b) DMBT tandem cross-section with 6 peripheral holes carved out of a nonmagnetic tungsten alloy rod of 5.4-mm diameter, housed by a thin plastic sheath with 0.3mm wall thickness. (c) A successfully machined-to-specifications tungsten alloy piece to demonstrate the manufacturability of the applicator.

The Monte Carlo simulated isodose distributions of an 192Ir source inside a (d) standard tandem and a (e) DMBT tandem. (f) An artistic rendering of the concept applicator in full assembly.

FEATURE

Photo by Ekaterina An

William Song, PhD Scientist, Physical Sciences, Odette Cancer Research Program, Sunnybrook Research Institute Head, Department of Medical Physics, Sunnybrook Health Sciences Center Associate Professor, Institute of Medical Science, University of Toronto Associate Professor, Department of Radiation Oncology, University of Toronto Associate Professor, Institute of Medical Science, University of Toronto

the most definite advantage of a new technology, it is very difficult to implement it because physicians are used to doing things a certain way. There needs to be momentum,” says Dr. Song. Another challenge lies in the fact that the current technology is designed to work within a very well-established system. “Because this is a non-conventional way of delivering treatment, the conventional planning system will need to be redesigned.

Everyone involved in brachytherapy treatment will need to relearn how to use this technology and get comfortable with the clinical dose that is achieved,” he explains. Furthermore, clinical trials using Dr. Song’s new applicator have yet to be conducted, so a tangible benefit to patient outcomes is unconfirmed. Despite the numerous challenges facing Dr. Song and his research team, he remains optimistic.

“I believe in it—the idea is so simple to begin with. I know that to get to commercialization and implementation of this

technology is difficult, but I believe that it can benefit patients. It’s a massive undertaking, but that is research,” he says with a laugh.

In contrast to the cumbersome process of clinically adopting a new technology, the field of medical physics is dynamic and constantly evolving. “There are so many innovations happening that it is very difficult now for anybody to wrap their head around overall trends anymore. It is a very dynamic and very challenging field to stay in and maintain your knowledge,” explains Dr. Song. Nevertheless, his enthusiasm for medical physics is evident throughout our interview: “You are right in the middle of it—there are all these technologies that are being invented and it is your role to translate them into clinic. It is very challenging but at the same time very rewarding.” His role as a medical physicist also extends beyond simply researching and inventing novel technologies; Dr.

Figure 2. Two clinical cases demonstrating the benefits of the DMBT technology. HRCTV is the tumor volume, and bladder and rectum are two typical organs we need to spare from radiation damage. The dotted and solid red lines represent the prescribed radiation dose distribution delivered by the Standard (Figure 1a) and DMBT (Figure 1b) tandem applicators, respectively. As can be seen, the dose distribution resulting from the DMBT applicator conforms more tightly around the tumor volume, resulting in fewer side effects.

Song must collaborate extensively with other medical and industry professionals to bring research (including his) from the bench to the bedside. “There is a very close relationship between radiation oncologists, medical physicists, and industry.

Technological innovations come from academic centres, led by medical physicists.

Then you work with industry—you lure in their money, technology, and collaboration. Once you commercialize the product, you collaborate with physicians because they need to understand the technology,” describes Dr. Song. The considerable skills and knowledge required to successfully develop and implement novel technologies take time to refine. As for Dr. Song’s advice to young medical physicists, “All this knowledge has to be matured in order for you to benefit patients. So it may take ten years to get here, but it is very gratifying at the end. You just have to do it properly.”

Those looking to find more information on Dr. Song’s research endeavours should visit his profile on the Sunnybrook Research Institute webpage: http://sunnybrook.ca/research/team/member. asp?t=13&m=546&page=530

References 1. Overview - Radiation Oncology - Mayo Clinic [Internet]. Mayoclinic.org. 2016 [cited 25 August 2016]. Available from: http://www. mayoclinic.org/departments-centers/radiation-oncology/sections/ overview/ovc-20188591?mc_id=google&campaign=15982288&geo=9000967&kw=radiation%20oncology&ad=64414561468&network=g&sitetarget=&adgroup=18262261708&extension=&target=kwd-129865102&matchtype=e&device=c&account=2349750037&placementsite=minnesota&gclid=COudge7Jis8CFQlkhgodrjgE0Q

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 13

FEATURE

engineering WHEN

MEETS

MEDICINE Drs. Yang and Guha discuss the beauty and potential of surgery navigation systems to improve patient outcome.

By Jonathon Chio

D

uring any surgical procedure, accuracy is of the essence.

Greater surgical accuracy can reduce intra-operative complications and improve patient recovery. The need for accuracy provides impetus and rationale for developing and using 3-dimensional (3D) intra-operative navigation systems.

However, these aids can introduce error during surgery and potentially backfire, undermining their original purpose. In Dr. Victor Yang’s laboratory, clinicians and engineers work synergistically to refine these 3D navigation systems. One of his surgeon-scientist trainees, Dr. Daipayan Guha, leads a project focused on ameliorating a specific navigation system and implementing it into the clinical setting.

I’ve had the pleasure of interviewing both Drs. Guha and Yang to gain their insight into the future of surgical navigation technology.

Please describe your research background, education, and pastime interests.

Dr. Guha: I am currently a neurosurgery resident at Sunnybrook Hospital and conducting research at Dr. Victor Yang’s

“

laboratory. The work contributes towards my Master of Science degree, which I am pursuing through the surgeon-scientist program offered at the University of Toronto. During my undergraduate education (Laboratory Medicine and Pathobiology Program, medical school) at the University of Toronto, I conducted basic science research focusing on inflammatory mechanisms and vascular biology.

To balance out the stress in my academic training, I play a variety of sports during my leisure time. Depending on the season, these activities include badminton, tennis, biking, triathlons, and downhill skiing.

Of all scientific fields, why did you decide to pursue research in the development of advanced 3D optical imaging systems for surgical navigation?

Dr. Guha: Most of my prior research experience was in basic sciences. Although basic molecular and cellular biology provide the foundation for subsequent clinical work, multiple factors steered me away from further pursuing it. With bench-top research, the timeline to practical clinical impact is often lengthy, and sometimes not

The main goal of 3D navigation systems is to increase surgical precision.”

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achieved at all. At the other extreme of the spectrum, prospective clinical trials often provide definitive evidence to guide a particular therapy, but many clinical research avenues mine existing datasets retrospectively without adding to our fundamental understanding. With a desire to achieve a balance between the fundamental basic science and pure clinical extremes of the academic spectrum, I joined Dr. Yang’s laboratory. Here, I assist in developing new surgery navigation systems and devising strategies to implement them successfully in the clinic.

With our targeted audience coming from many different scientific fields, please describe your research in advanced 3D optical imaging systems for surgical navigation in lay terms.

Dr. Guha: My project focuses on determining mechanisms of error found in 3D surgery navigation systems; specifically, optical surface imaging (OSI) for intraoperative navigation. Surgery navigation systems have existed for a long time.

They use information of patient anatomy obtained from preoperative scans to generate a model that directs surgeons to perform necessary procedures. Creating these models is a time consuming process, as it requires calibration using 60 to 80 points which are manually picked by the surgeon. However, 3D maps are essential, as they allow for subsurface structures to be observed. With OSI, a visual bar code pattern is projected onto the body and the anatomy is rapidly mapped based on the reflected signals. Relative to traditional methods (manual point picking from

preoperative imaging, or intraoperative XR/CT scanning), OSI is superior in terms of speed and patient safety. It generates accurate maps 100 times faster and eliminates the need for harmful radiation.

The main goal of 3D navigation systems is to increase surgical precision. This is necessary, as surgical errors can cause both acute (e.g. hitting underlying blood vessels and nerves) and chronic (e.g. uneven biomechanical stress that cause eventual failure of hardware constructs) problems.

As the 3D map is based on landmarks, changes in body position after calibration create inaccuracy. Hence, another aspect of my work is to quantify how and when inaccuracies in registration and navigation may occur, and educate surgeons on recognizing when the system can be inaccurate and how to fix these issues.

What are the goals of analyzing the clinical and engineering accuracy of 3D navigation systems?

Dr. Guha: The goal of my project, and overall mandate of Dr. Yang’s laboratory, is to demonstrate that the novel navigation systems allow surgery to be done faster without sacrificing quality, accuracy, and patient recovery. As both Dr. Yang and I are neurosurgeons, we aspire to demonstrate the utility of these systems in brain and spinal surgeries, and increase the uptake in these fields. This can subsequently create opportunities for using these technologies in other fields, such as otolaryngology, orthopaedic, and extremity surgeries.

What are some challenges that you have faced in your career as a researcher?

Dr. Yang: As my laboratory specializes in the area between basic and clinical sciences, major obstacles include knowledge translation and implementation of novel technology into the system. Many factors must be overcome prior to success. These include convincing fellow surgeons to adapt your technology and overcome the associated learning curve.

In addition, the end goal is to make my technology widely available to general public. However, this will involve an expensive commercialization process with medical device companies. It is very challenging to alleviate or lower the costs

of the commercialization process, such that the end product can still be afforded by patients from all socioeconomic backgrounds. Last but not least, it is essential to maintain a balance between having a strong belief in your work and being flexible and receptive to ideas from others on where your technology can be used.

What are some of the future directions that your laboratory will be embarking on?

Daipayan Guha, MD

Dr. Yang: My laboratory combines the strengths of both engineers and clinician-scientists. While engineers can construct fantastic apparatuses, they may not be patient friendly. The opposite is true as well. As the principal investigator, I envision a grand plan where all navigation systems and modalities converge and work synergistically as one suite capable of tracking, navigating, and delivering therapy. As all navigation systems inherently carry flaws, we hope the systems can compensate for each other and ultimately increase ability to deliver and monitor therapy to ensure better patient outcomes.

PGY-4 Neurosurgery Resident, University of Toronto MSc Candidate, Institute of Medical Science, University of Toronto

What advice do you have to give to potential graduate students interested in your field of research, or research in general?

Dr. Yang: For incoming graduate students interested in my field of research (or in joining my lab), it is essential to learn cooperation and collaboration skills. This is readily needed, as developing surgical navigation systems require experts from engineering and biological/medical backgrounds. Both groups of individuals need to combine their expertise in order to construct fantastic apparatuses that are patient friendly.

Victor Yang, MD, PhD Senior Scientist, Physical Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute Neurosurgeon, Sunnybrook Health Sciences Centre Associate Professor, Institute of Medical Sciences, University of Toronto

Furthermore, prior to joining a laboratory, incoming graduate students should evaluate how the projects are coordinated.

Often, the projects are either run individually by members or led by the entire team, which works in an organic manner. The former style is important for a graduate student to be successful and innovative, as a collaborative environment will allow a graduate student to not be bound by previous education. Instead, students will have freedom to explore new grounds and make greater impact.

Associate Professor of Surgery, Faculty of Medicine, University of Toronto Associate Professor, Electrical and Computer Engineering, University of Toronto Associate Professor, Electrical and Computer Engineering, Ryerson University Adjunct Professor, Medical Physics, Ryerson University Canada Research Chair in Biophotonics and Bioengineering, Tier 2

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 15

Photo by Drs. Yang and Guha

FEATURE

FEATURE

the road to

REJUVENATION Stem Cell Therapy as a Treatment for Aging

By Ren-Ke Li, MD, PhD and Stephanie Wales Tobin, PhD Faculty affiliations: Ren-Ke Li, MD, PhD Senior Scientist, Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network Professor, Division of Cardiovascualr Surgery, Department of Surgery, University of Toronto Professor, Laboratory Medicine & Pathobiology, University of Toronto Associate Professor, Institute of Medical Science, University of Toronto

Stephanie Wales Tobin, PhD Postdoctoral Fellow, Li Lab

A

ging is an inevitable event for all of us, but disease and illness may not have to come with it. Muscle weakness, deficits in cognitive function, and heart disease will develop as we age and medical research must address these age-related issues for several reasons. First, deterioration of our physical fitness and memory negatively impacts one’s quality of life. Therefore, although people are living longer, they may not be living comfortably.

Additionally, as our elderly population increases, the cost required to treat age-associated illnesses places a growing burden on our healthcare system. Nearly 75% of adults over the age of 65 have at least one chronic illness, such as heart disease, arthritis, or diabetes.1 Currently 15% of Canadians are over 65 years of age and this population cohort accounts for 45% of Canada’s healthcare budget.2 However, in 2036 it is predicted that a quarter of Canada’s population will be over 65, putting considerable pressure on our healthcare budget.3 What contributes to aging and how can we reverse it? Aging is a complex event that has multiple contributing factors including genetics, nutrition, and level of physical activity. Stem cells have received considerable attention due to their potential anti-aging effects such as the promotion of tissue repair and organ regeneration.

Adults possess tissue-resident multipotent stem cells which proliferate and differentiate into specialized cell types. For example, stem cells play an important role in the

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cardiovascular system. After a heart attack, or myocardial infarction (MI), stem cells from the bone marrow or blood migrate to the heart, and differentiate into different cell types that may limit cardiac cell death, promote oxygen delivery (angiogenesis), or aid in debris clearance and scar formation.4 These processes are important for efficient healing. With age, however, healing is incomplete because of tissue-resident stem cell death and senescence.5 To circumvent the problems caused by faulty repair mechanisms, researchers have turned to stem cell therapy. The fundamental principle that stem cell therapy can restore function to diseased tissue has been confirmed by several groups. In the late 1990s, our research team initiated a cell therapy program to isolate stem cells from tissue in animal models of disease. After expansion, stem cells were implanted into injured tissue which promoted organ repair.6 Unfortunately, this technique showed limited benefit in clinical applications.4 One major difference between the animal models and human trials was that the human stem cell donor was considerably older than the animal equivalent. Following this, we completed cell transplantation studies in rodents and confirmed that stem cell age negatively correlates with heart function after MI.7 The molecular consequences of aged stem cells include reduced proliferative, angiogenic, and myogenic potential.8, 9 Based on these studies, further investigation into the molecular basis of rejuvenation is required.

FEATURE

To evaluate novel methods which may benefit the aged population our lab uses two streams of cell therapy to study cardiovascular aging in mice: cell transplantation and bone marrow reconstitution (systemic replacement of bone marrow).

We are interested in differences between the young and aged microenvironment mediated by cytokines, angiogenic signals, and growth factors and how cell therapy can alter these properties to rejuvenate the aged niche. We would also like to understand the cell fate decisions of bone marrow cells as they migrate to the heart, and how this may change with age. To answer these questions we are using a combination of cell and molecular biology tools. Young bone marrow is isolated from mice whose cells express green fluorescent protein (GFP), and reconstituted into older mice. We can then visualize the location and shape of GFP+ cells to determine where and when they migrate

“

to the heart or other tissues such as the brain and muscle. Interestingly we have observed a preservation of heart function in aged mice reconstituted with young bone marrow via activation of endogenous repair mechanisms.10 To understand these changes in more detail, we are also using microarray analysis to identify differentially expressed genes. Understanding alterations in gene expression caused by young to old bone marrow reconstitution may help to identify key changes associated with aging and treatment of age-related disease.

With longer life expectancies, chronic age-related illness will continue to be a problem. Treatment of diseases using stem cell therapies remains an attractive method to aid in tissue repair since it holds the possibility of complete tissue rejuvenation. Studies that we and others have done using various cell therapies to treat

Although people are living longer, they may not be living comfortably.�

cardiovascular disease demonstrate the importance of secreted signaling molecules in endogenous repair of tissue. Using cell and molecular biology techniques in vivo, we hope to identify new mechanisms that may be investigated to limit the damage that may occur to various organs to improve our quality of life.

References 1. Canadian Institute for Health Information. Seniors and the Health Care System: What Is the Impact of Multiple Chronic Conditions?

[Internet]. 2011. Available from: https://secure.cihi.ca/free_products/air-chronic_disease_aib_en.pdf.

2. Association CM. Health and Health Care for an Aging Population: Policy Summary of The Canadian Medical Association [Internet].

2013. Available from: https://www.cma.ca/Assets/assets-library/ document/en/advocacy/policy-research/CMA_Policy_Health_and_ Health_Care_for_an_Aging-Population_PD14-03-e.pdf.

3. Canadian Institute for Health Information. National Health Expenditure Trends 1975 to 2015 [Internet]. 2015. Available from: https://secure.cihi.ca/free_products/nhex_trends_narrative_report_2015_en.pdf.

4. Nguyen PK, Rhee JW, Wu JC. Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review. JAMA Cardiol 2016 Aug 24.

5. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy.

Nat Med 2015 Dec;21(12):1424-1435.

6. Li RK, Jia ZQ, Weisel RD, et al. Cardiomyocyte transplantation improves heart function. Ann Thorac Surg 1996 Sep;62(3):654-660; discussion 660-651.

7. Zhang H, Fazel S, Tian H, et al. Increasing donor age adversely impacts beneficial effects of bone marrow but not smooth muscle myocardial cell therapy. Am J Physiol Heart Circ Physiol 2005 Nov;289(5):H2089-2096.

8. Zhuo Y, Li SH, Chen MS, et al. Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: combined consequences for cell therapy in older recipients. J Thorac Cardiovasc Surg 2010 May;139(5):1286-1294, 1294 e1281-1282.

9. Brunt KR, Zhang Y, Mihic A, et al. Role of WNT/beta-catenin signaling in rejuvenating myogenic differentiation of aged mesenchymal stem cells from cardiac patients. Am J Pathol 2012 Dec;181(6):2067-2078.

10. Li SH, Sun Z, Brunt KR, et al. Reconstitution of aged bone marrow with young cells repopulates cardiac-resident bone marrow-derived progenitor cells and prevents cardiac dysfunction after a myocardial infarction. Eur Heart J 2013 Apr;34(15):1157-1167.

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FEATURE

3D PRINTING Revolutionizing Medicine Layer by Layer

By Sarah Peters Johannes Gutenberg’s printing press revolutionized the 15th century world, generating a surge of knowledge dissemination and an unrivaled acceleration of literacy.1 Five hundred years later, an American engineer named Charles Hull developed prototypes of the three-dimensional (3D) printer—a device that has analogously transformed commercial production, medical innovation, and scientific problem-solving.2 3D printing works through additive manufacturing, a process that builds objects layer by layer. Hull’s original design used acrylic liquid that solidified upon exposure to UV laser light; today’s printers utilize similar principles (see Box 1).2,3 As the technology’s popularity continues to rise, printing materials are becoming cheaper and more accessible: for example, open-source websites provide free downloadable printing codes and templates for plastic-based inks, and the University of Toronto’s ‘MADLab’ in Gerstein Library offers resources, training, and printing space for students. As an industry, 3D printing has an estimated worth of $700 million; over the next decade, this value is

expected to balloon to almost $8 billion, of which one-quarter will be dedicated to medical innovation.4 Innovation has a tendency to transform the way we think. In the 15th century, the advent of accessible printed language was an incredible tool for those attempting to circulate literary, philosophical, or scientific ideas. Similarly, 3D printing has added to the toolbox of problem-solvers— particularly those in medicine. Farrokh Mansouri, a PhD candidate in a joint program with the Institute of Medical Science (IMS) and the Institute of Biomaterial and Biomedical Engineering (IBBME), explained that the highly interdisciplinary nature of science often necessitates an engineering approach.

“Engineering skills may not be the most useful skills when working on the frontlines of healthcare, but they are no doubt some of the most important skills when it comes to [the] development and creation of novel medical technologies.” Indeed, medical applications of 3D printing are leading the charge in revolutionizing health delivery, education, and discovery.5

BOX 1: Varieties of 3D printing •

• •

Selective Laser Sintering (SLS) uses a laser to draw patterns in a powdered material. Areas traced with the laser are fused together to build one layer; next, more powder is added, and the process repeats to build the next layer.

This technique is commonly used to produce metal or ceramic objects.5 Thermal inkjet printing, more common in ‘bioprinting’ and tissue construction, relies on the principles of electromagnetics to deposit substrate droplets based on digital blueprints.5 Fused deposition modeling is a cheaper and more accessible technique that heats plastic and redistributes it into thin layers. The printhead is similar to that of a traditional ink printer, but it moves along both axes of a 2D plane to ‘draw’ each layer of the printed object.5

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In a world of increasing complexity, personalized medicine is a solution for outdated ‘one-size-fits-all’ approaches to diagnostic care. 3D printing is moving us even closer to this idealized reality: orthodontics (e.g., Invisalign), prosthetics, and orthopedic braces can now be easily customized for any individual.2 Increasingly affordable material means that individualized device production remains cost-effective, and devices can even be designed, produced, and fitted in the same office.5 Importantly, such customized equipment likely improves recovery time and implant success.6,7 Recently, the US Food and Drug Administration (FDA) approved the first 3D printed pill.8 Its benefits derive from the printer’s ability to tailor precise medication dosages and pill shapes. Research from University College London suggests that the surface-to-area ratio of pills modulates drug release more powerfully than surface area alone. Based on this principle, pills can be printed with varying geometries—for example, pyramidal or spherical—to tightly regulate the medication’s absorption.8 An engineer himself, Farrokh agrees that 3D printing provides quick and economic solutions to problems with personalized care: “Medical devices are only manufactured in a limited number of sizes and designs with the idea that they should fit all patients… With the use of 3D printing, you can manufacture medical equipment that is customized to the patient’s need.” To put his beliefs into practice, Farrokh has been developing software that can automatically print personalized headsets for patients undergoing brain stimulation to help navigate precise treatment targets in the cortex.

FEATURE Farrokh Mansouri and one of the 3D printers that he uses to develop personalized headsets for brain stimulation patients.

Medical innovations of 3D printing also raise interesting ethical questions, including matters of intellectual property and safety. Some have compared open-source printing templates to music streaming websites that bring benefit to the consumer but no profit to the producer. Additionally, the availability of 3D scanning, a technique that creates printing templates by scanning the dimensions of existing objects, could result in duplication of protected material that otherwise could not be copied.14

Photo by Arsalan Mir-Moghtadaei

Furthermore, modern medical devices are deemed to be safe based on tightly centralized manufacturing regulations; if devices can be developed anywhere there is a printer, such safety guidelines may be more difficult to enforce.14 In spite of these challenges, Farrokh sees 3D printing following a similar trajectory as traditional paper printers, with homes and office boasting the technology in coming years for everyday use.

Hand-in-hand with innovations in medical treatment are applications to medical education for both students and patients.

Physicians use 3D printers to create personalized, realistic models of patient anatomy that can be used for surgical planning and practice.9 Such printouts also allow surgeons to provide interactive explanations to their patients.9 Other researchers have developed biomaterials that enable the printing of human tissues for testing purposes. Jennifer Lewis, a scientist at Harvard University, created what she has deemed “fugitive ink.”2 The solid material is used as a substrate to print patterns of vasculature within a tissue matrix; when the tissue has finished printing, the sample is cooled and the ink liquefies.2 Suctioning the ink from the sample leaves a tissue sample with working vasculature that often continues to develop independently.2 Current implementations aside, 3D printing is paving the way for innovative medical discoveries.10 Experimentations of in situ printing, which allows realtime printing of implants or organs into the body during medical procedures,

demonstrate that the deposition of biological materials such as cells and growth factors can be precisely controlled through 3D printing instructions.11 In addition to smaller cell layers, some believe that eventually, this technology will allow researchers to create entire organs. Such advancement would not only alleviate organ shortages required for transplantation, but would likely result in more successful outcomes since the printed organs would be grown using a patient’s own cells and body materials.12 Clearly, 3D printing offers unmatched opportunities for therapeutic innovation; however, some caution that these exciting advances possess a hidden host of regulatory and legal challenges.13 First, printing may not be as simple as it sounds: “Although 3D printing prices are decreasing, the process of 3D printing is very time consuming. Even for most experienced users, the design has to go through many trials and iterations before a good prototype can be printed,” Farrokh says. “I think development of better tools to optimize this process may speed the adoption of 3D printing.”

“I encourage all students to take advantage of these facilities and consider using 3D printing for their projects,” he advises. It is likely that as new technologies rise in familiarity, so will the implementation of creative printing innovations; someday soon, the familiarity of refined medical 3D printing may make personalized medicine—and some pills—easier to swallow.

References 1. Palermo E. Who invented the printing press? Live Science. Online; 2014 Feb 25.

2. Groopman J. Print Thyself. The New Yorker. Online; 2014 Nov 24.

3. Hull C. Apparatus for production of three-dimensional object by stereolithography. U.S. Patent 4,575,330. 1986.

4. Wohlers Associates. What is 3D printing? Wohler’s Report 2013.

5. Ventola CL. Medical applications for 3D printing: current and projected uses. Pharmacy and Therapeutics. 2014;39(10):704-711.

6. Ursan I, Chieu L, Pierce A. Three-dimensional drug printing: a structured review. J Am Pharm Assoc. 2013;53(2):136-144.

7. Mertz L. Dream it, design it, print it in 3D: What can 3D printing do for you? IEEE Pulse. 2013;4(6):15-21.

8. Wainwright O. The first 3D-printed pill opens up a world of downloadable medicine. The Guardian, 2015 Aug 5.

9. Sagan A. Will 3D printers, bioprinters change the future of surgery?

CBCnews, Technology & Science, 2015.

10. Ozbolat IT, Yu Y. Bioprinting toward organ fabrication: challenges and future trends. IEEE Trans Biomed Eng. 2013;60(3):691-699.

11. Cui X, Boland T, D’Lima DD, et al. Thermal inkjet printing in tissue engineering and regenerative medicine. Recent Pat Drug Deliv Formul. 2012;6(2):149-155.

12. Schubert C, van Langeveld MC, Donoso LA. Innovations in 3D printing: a 3D overview from optics to organs. The British journal of opthamology. 2014;98:159-161.

13. Banks J. Adding value in additive manufacturing: Researchers in the United Kingdom and Europe look to 3D printing for customization.

IEEE Pulse. 2013;4(6):22-26.

14. Neely EL. The risks of revolution: ethical dilemmas in 3D printing from a US perspective. Science and engineering ethics. 2015;doi: 10.1007/s11948-015-9707-4.

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FEATURE

The Next

By Adam Betel

I

n late September, the US Food and Drug Administration (FDA) approved the first automated blood glucose monitor and insulin pump system to help automate blood glucose regulation for individuals with diabetes. The device, developed by Medtronic, a medical device company based in Ireland, has demonstrated promise in recent clinical trials.

According to the Summary of Safety And Effectiveness Data (SSED) made available by the FDA, the device has shown reasonable assurance of effectiveness to automatically adjust basal insulin rates based on continuous glucose monitor sensor values. This means that, in addition to tremendously easing the burden of diabetes management for individuals living with the disease, researchers will now have access to much more data which could potentially contribute to finding a cure in the future.1 The device, branded the MiniMed 670G System, has three main components: the continuous glucose monitor (CGM), an insulin pump, and the modulator (which can be an app on your cell phone). These three parts work together to function as

a ‘hybrid’ automatic system. “Hybrid,” in this instance, refers to the semi-automatic functioning of the device as individuals using it will still be required to manually enter relevant data, such as the amount of carbohydrates to be consumed during a meal. This allows the modulator to calibrate and adjust the amount of insulin it will release through the pump.2

“

This can provide the next step in long-term care for patients with diabetes and help to minimize potential complications.”

The CGM monitors the glucose values by measuring the glucose level in the subcutaneous interstitial fluid in the abdomen.

This works to provide glucose trend information, while the glucose meter, which has been conventionally used on its own, provides the user with immediate glucose levels in their whole blood. The blood glucose monitor is necessary to work in addition to the interstitial monitor because individuals with diabetes still must “bolus”

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prior to eating and adjust their insulin delivery when doing exercise. The two avenues for measuring glucose provide the user with greater control in maintaining steady blood glucose levels, as opposed to fluctuations which can be frequent while using conventional methods, depending on the individual.1

Overall, people with diabetes will benefit from this device because it can help provide individuals with a greater degree of confidence that they will not approach potentially dangerously high or low blood sugar levels. In the long term, this can provide the next step in long-term care for patients with diabetes and help to minimize potential complications that can arise later in life. According to Medtronic, the device is expected to become available

FEATURE

Step

in Diabetes Management

An illustration of the closed-loop insulin delivery system. Depicted on the individual is the glucose sensor, modulator, and the insulin pump.3 References in the spring of 2017. The gap in time between FDA approval and market arises because the FDA prioritized the device’s approval due to its potential to benefit public health. Cost estimates for the device range from $6,000 to $9,000.

Psychologically, this will contribute

greatest to ease the burden of living with diabetes, which most commonly requires taking only whole blood samples numerous times a day and either injecting or pumping insulin to level the fluctuations of blood glucose.

1. U.S. Food and Drug Adinistration. PMA P160017: FDA Summary of Safety and Effectiveness Data (SSED). Silver Spring, MD: U.S. Food and Drug Administration; 2016 p. 75.

2. What is the pancreas? What is an artificial pancreas device system?

[Internet]. Fda.gov. 2016 [cited 1 October 2016]. Available from: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/HomeHealthandConsumer/ConsumerProducts/ArtificialPancreas/ucm259548.htm 3. Elleri D, Dunger D, Hovorka R. Closed-loop insulin delivery for treatment of type 1 diabetes. BMC Medicine. 2011;9(1).

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SPECIAL BMC FEATURE

Master of Science in

BIOMEDICAL COMMUNICATIONS

Kaia Chessen, IT7

As a student in the Biomedical Communications Masters Program, Kaia is working in conjunction with researchers in the Department of Immunology to create a 3D animation informing the public about recent findings and potential therapies stemming from macrophage research. Recently, she worked at the PATH headquarters in Seattle to create didactic visuals about new global health technologies, treatments, and modes of prevention, targeting audiences around the world. Her interests are in promoting healthy decision-making using visual design, and translating complex scientific concepts into engaging narratives. She also plays the cello and writes short stories and comics. More of her work can be found at www.kaiachessen.com.

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SPECIAL BMC FEATURE

Ruth Chang, IT7 As a student in the animation stream of the Biomedical Communications Master’s program, Ruth is currently collaborating with the Women’s College Hospital to produce 3D visualizations and learning modules on the intersection between obesity and mental illness. Over the summer, she worked at the National Institute of Medicine in Washington, DC to draw illustrations for the U.S. government’s Genetics Home Reference website. Her interests lie in visual storytelling, patient education, and usability design. She is also a fan of birds, brains, and baked goods.

More of her work can be found at www.ruthchangvisuals.com

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 23

VIEWPOINT

FROM MEDICINE TO SPORT: AN EVOLUTION OF DOPING

By Jonathon Chio and Fadl Nabbouh Introduction

With this issue of the IMS Magazine featuring a focus on engineering and medicine, and the Rio 2016 Summer Olympics just behind us, a relevant topic for discussion is doping. Defined as the use of synthetic technology to supplement training and biology in order to create an unfair field competition, doping is an increasingly popular though controversial—means to succeed in sport.1 In this article, we will address the early history of doping, the various existing technologies, and the social stigma associated with its use.

History of doping and its contributing factors

According to the Olympic Creed, “the important thing in the (Olympic) Games is not winning, but taking part. The essential thing is not conquering, but fighting well.”2 Canadian philosopher Bernard Suits describes athletes as manifestations of the lusory attitude. In this mindset, individuals voluntarily play a game where they attempt to overcome obstacles to achieve a specific goal.3 While both Bernard Suits and the Olympic Creed describe sports as a noble endeavour, this poorly reflects the reality of competitive sport.2 In fact, the negative side of competition results from various contributing factors, such as the redefinition of an athletic build and the media’s spotlight on fame and fortune.

In the early to middle 20th century, the average body type was thought to be best for all athletic activities. However, science has revealed that genes (and physical traits) have a tremendous influence on how individuals respond to training.

Prominent examples include a diminutive stature for diving, or a combination of long arms and short legs for swimming. This body type’s success was made apparent by Michael Phelps’ great Olympic achievement as the most decorated swimmer in Olympic history.4 Baseball players with 20/12, rather than 20/20 vision, have an advantage by better learning visual cues to predict projectile motion of the ball.

Genetic advantages are also rampant among Olympians. Eero Mantyranta, a

decorated Olympic Finnish cross-country skier, was born with an endogenous mutation in his EPO receptors that allows his body to produce 50% more red blood cells after EPO stimulation. This increased his oxygen carrying capacity by 50%, giving him an advantage in long distance, endurance sports and making him one of the most successful cross-country skiers in Finnish history.1,5 These results have prompted countries to identify future athletes by screening for unique and advantageous physiological traits. Overall, presence of rare gene mutations and physiques shed light on the reasons to dope.

Most importantly, it begs to question of whether a level playing field exists.

Further encouraging the cheating atmosphere in sport is the media spotlight on fame and fortune, which persuades athletes and coaches to develop a mentality of “winning at all costs. ” The aforementioned reasons create a strong temptation for some athletes to dope.2 This is starkly revealed in a Sports Illustrated interview, where Olympic athletes were asked: 1. "If you were given a performance enhancing substance and you would not be caught and win, would you take it?"

2. "If you were given a performance enhancing substance and you would not be caught, win all competitions for 5 years, then die, would you take it?"

To the first question, 98% of the athletes responded "Yes", while more than 50% said "Yes" to the second question. Furthermore, in a study conducted by Takahashi and colleagues on university students partaking in physical activity, 20% indicated they would dope, given the chance to win a gold medal. They also indicated that they’d still use the drug even if they only lived for 5 years afterwards.5 It is clear that the media’s focus on fame and fortune has pushed athletes to seek performance-enhancing drugs.

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Different doping techniques, detection, and side effects

Interestingly, despite massive media attention, doping isn’t unique to modern day athletic competitions. Dating back to 776 BC, various herbs were used by ancient Greek athletes and Roman gladiators for their stimulant and analgesic effects.

Within the vast array of technology currently available, doping can be divided into three broad techniques:3,7 1. Medical doping: administration of foreign substances to an individual in order to stimulate physical and psychological strength 2. Surgical doping: undergoing of elective surgery for performance enhancing reasons 3. Gene doping: non-therapeutic usage of cells, genes, genetic elements, or modulation of gene expression in order to have capacity to enhance performance Medical doping is often the method of choice. Applied substances can range from anabolic steroids, to EPO, and even human growth hormone (HGH). Synthesized by kidneys in response to low blood oxygenation, EPO has been administered medically to anemic patients following kidney failure and chemotherapy.8 Similarly, HGH is a naturally occurring hormone produced by the anterior pituitary gland and used medically for its anti-apoptotic as well as mitogenic properties. Athletes often self-administer these biomolecules prior to or after competition in order to gain competitive edge or expedite recovery, respectively.

Surgical doping is another way athletes can enhance performance. This is particularly common in baseball among pitchers following elbow injuries. An ulnar collateral ligament (UCL) reconstruction (Tommy John surgery)3,9 is generally the procedure of choice, and this has the effect of reverting injury to elbow ligaments by replacing the damaged UCL with a tendon from elsewhere in the body.9 Repetitive stress of the throwing motion causes stretch and tear damage on the pitcher’s UCL; ultimately decreasing their performance.

Replacing the damaged UCL is able to help pitchers return to pre-injury levels of performance and hence, enhance longevity

VIEWPOINT of the pitchers’ careers. Another type of surgery common among baseball players is vision enhancing eye surgery, which is performed because of the advantages conferred by better vision.

A method that has attracted considerable interest in recent years is gene doping, a technique originally based on artificial gene expression to treat degenerative conditions.7 However, given the current state of technology, the putative benefits of gene doping have not been observed in humans despite successes in pre-clinical animal models. For example, insulin growth factor-1 (IGF-1) has been shown to treat a murine model of Duchenne Muscular Dystrophy (DMD)—a sex-linked genetic disorder where loss of muscle fibers lead to muscle dysfunction—by alleviating severity and increasing muscle mass by 40%. Another example is delivery of peroxisome proliferator activated receptor- delta (PPAR-δ) to prevent loss of type I muscle fibers in obese and type II diabetic patients.10 However, as PPAR-δ is a fat-burning protein, mice with PPAR-δ injection ran twice the distance relative to wildtype littermates.11 With such a wide array of gene doping possibilities, we will likely be hearing more about this method in the coming years.

Overall, it is clear that there is much controversy surrounding the practice of doping. While there are medical benefits to all the techniques mentioned above, it begs to ask where to draw the line between surgeries and performance-enhancing biological molecules that enable expedited recovery, and those that also enhance athlete performance.

Efforts from anti-doping agencies

Created in 1999, the World Anti-Doping Agency (WADA) is the preeminent international organization in eliminating the practice of doping.7 The original goal of WADA was to “promote, coordinate and monitor the fight against doping,” but with the advances in technology, they have now expanded to include monitoring against “compounds and/or methods that enhance oxygen delivery and growth, gene and cellular technologies applied to doping and miscellaneous projects related to the list of prohibited substances.”7,12 EPO’s ability to bolster oxygen delivery has led athletes to abuse various commercially available

forms of recombinant EPO (Epoetin alpha, Epoetin beta, Darbepoetin alpha).

Similarly, HGH’s ability to increase muscle mass have prompted athletes to use it for non-medical purposes. To test for EPO and HGH abuse, WADA has formulated various assays that work by detecting the different biochemical properties between endogenous and recombinant molecules or measuring the pharmacological endpoints of action. For example, EPO abuse can be detected by differentiating between endogenous and recombinant EPO based on glycosylation patterns. Effects of HGH are mediated through IGF-1 and hence, HGH abuse can be identified by abnormally high levels of IGF-1.

Conclusion

Stigma of doping

References

Heavy stigma surrounds athletes from multiple sporting communities who practice doping. Regardless of whether their doping practice continues, these athletes have eternally tarnished their reputation once caught. They are viewed as cheaters and alienated by the sporting community, and to a lesser extent, the public. Further, legislative bodies usually punish athletes caught doping by banning them from competitions or stripping their titles. Examples include high profile baseball players, such as Barry Bonds, Alex Rodriguez, Manny Ramirez and Roger Clemens.12 In cycling, Lance Armstrong, who was once considered the greatest cyclist of all-time, had his titles removed due to his doping infractions.13 Most recently, the Russian government and sport agency caused great controversy when they were found to be falsifying drug test results of their Olympic athletes during the 2014 Sochi Olympics and the 2015 season. This provided impetus for the International Olympic Committee to ban all Russian Paralympic athletes from competing at the 2016 games and empowered individual sporting federations to ban athletes from the Olympic Games. Over 100 Russian athletes were banned from the Olympic Games due to doping and falsifying tests allegations.14 In a feud that made international news, Australian swimmer Mark Horton criticized a Chinese rival, Sun Yang, who had previously been caught doping.15 The doping controversy was highlighted during the 2016 Olympic Games, showing that international athletic communities, as well as individual athletes, will unapologetically alienate dopers.

As doping becomes increasingly regarded as an opportunity to succeed in sports, an ever-growing population of athletes may consider abusing performance-enhancing drugs. While the majority of the sporting community agrees that doping is wrong, some would still consider doing it; even with awful side effects and negative consequences. Playing a game of cat and mouse, WADA has implemented multiple measures and rules to eliminate the future of doping in sports. Ultimately, they aim to ensure success is obtained through practice, which at the end of the day, truly reflects the noble means of sport and competition.

1. Epstein D. Magic Blood and Carbon-Fiber Legs at the Brave New Olympics [Internet]. Scientific American. 2016 [cited 10 September 2016]. Available from: http://www.scientificamerican.com/article/ magic-blood-and-carbon-fiber-legs-at-the-brave-new-olympics/ 2. Baron D, Martin D, Samir M. Doping in sports and its spread to at-risk populations: an international review. World Psychiatry 2007 [Internet]. 2016 [cited 10 September 2016];6(2):118-123. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219897/ 3. Scientific American. Big Bang of Body Types: Sports Science at the Olympics and beyond [Internet]. 2016 [cited 10 September 2016]. Available from: http://www.scientificamerican.com/podcast/ episode/big-bang-of-body-types-sports-science-at-the-olympicsand-beyond/ 4. Hadhazy, A. What Makes Michael Phelps so Good? [Internet].

Scientificamerican.com 2008 [cited 18 September 2016]. Available from: http://www.scientificamerican.com/article/what-makes-michael-phelps-so-good1/ 5. de la Chapelle A, Traskelin A, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proceedings of the National Academy of Sciences.

1993;90(10):4495-4499.

6. Yukitoshi Tatsugi M. Investigation of the Attitudes of Japanese Physical Educational University Students toward Doping in Sports.

Journal of Sports Medicine & Doping Studies. 2013;03(01).

7. Pray L. Gene Therapy in Sports: Gene Doping | Learn Science at Scitable [Internet]. Nature.com. 2016 [cited 10 September 2016].

Available from: http://www.nature.com/scitable/topicpage/sportsgene-doping-and-wada-764.

8. Azzazy H, Mansour M, Christenson R. Doping in the recombinant era: Strategies and counterstrategies. Clinical Biochemistry.

2005;38(11):959-965.

9. Noe A. Is It Fair For Baseball To Reject Drugs But Embrace Surgery?

[Internet]. NPR.org. 2013 [cited 15 September 2016]. Available from: http://www.npr.org/sections/13.7/2013/07/25/205513618/isit-fair-for-baseball-to-reject-drugs-but-embrace-surgery 10. Scott W, Stevens J, Binder-Macleod S. Human Skeletal Muscle Fiber Type Classifications. Physical Therapy [Internet]. 2016 [cited 10 September 2016];81(11):1810-1816. Available from: http://ptjournal.apta.org/content/81/11/1810.long 11. Wang Y, Zhang C, Yu R, Cho H, Nelson M, Bayuga-Ocampo C et al. Regulation of Muscle Fiber Type and Running Endurance by PPARδ. PLoS Biology. 2004;2(10):e294.

12. Noto D. MLB: 5 Players Who Will Be Remembered for Drug Scandals [Internet]. The Cheat Sheet. 2016 [cited 10 September 2016].

Available from: http://www.cheatsheet.com/sports/5-top-mlb-players-involved-in-doping-scandals.html/?a=viewall 13. Wilson J. Lance Armstrong's doping drugs - CNN.com [Internet].

Lance Armstrong's doping drugs. 2016 [cited 10 September 2016].

Available from: http://www.cnn.com/2013/01/15/health/armstrong-ped-explainer/ 14. Furlong C. Decision of the IOC Executive Board concerning the participation of Russian athletes in the Olympic Games Rio 2016 [Internet]. International Olympic Committee. 2016 [cited 10 September 2016]. Available from: https://www.olympic.org/news/ decision-of-the-ioc-executive-board-concerning-the-participationof-russian-athletes-in-the-olympic-games-rio-2016 15. Shih G. Australian, Chinese swim officials tangle amid doping feud [Internet]. Summergames.ap.org. 2016 [cited 10 September 2016].

Available from: http://summergames.ap.org/article/australian-chinese-swim-officials-tangle-amid-doping-feud.

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FACULTY SPOTLIGHT

Spotlight on:

Dr. Neil Fleshner

By Melissa Galati

P

rostate cancer, the most common type of cancer in Canadian men, has been deemed a “silent killer” in light of its commonly asymptomatic presentation. Dr. Neil Fleshner, a uro-oncologic surgeon at University Health Network (UHN), has dedicated his life to improving the treatment and prevention of this common malignancy. A leading expert in the prevention of early-stage disease

progression, Dr. Fleshner shared with the IMS Magazine his journey through the field of urology, focus on prostate cancer, and his team’s strides toward disease prevention.

Dr. Fleshner was born and raised in Montreal. His motivation to pursue medicine as a career stemmed in part from the death of his grandmother, who passed

away from pancreatic cancer when he was young. After completing his medical education at the University of Toronto, he began the internship year, aspiring to become a medical oncologist. However, he soon realized that he was drawn more to the procedural aspects of surgery, rather than internal medicine. “I started thinking about what interesting cancer fields are procedural, and landed on urology because of the nature of the cancers.” According to Dr. Flesher, 23% of human cancers are urological, and these malignancies have a wide “cancer portfolio.”

Photo by Pratiek Matkar

Dr. Fleshner then spent three years completing his oncology training at Memorial Sloan Kettering Cancer Center in New York, and concomitantly obtained a Master of Public Health (MPH) from Columbia University. Discussing his interest in epidemiology, he elaborates: “I never really felt I had the right mindset for wet lab research.

On the other hand, I knew I wanted to have an impact. Around the same time, it hit me that parts of our disease models were wrong. It was always about treating disease and I was turned on by the idea of preventing disease… Epidemiology is really about what causes diseases and how to prevent them.” From that point on, Dr. Fleshner focused his energy on the emerging field of prostate cancer prevention.

Neil Fleshner, MD, PhD, FRCSC

Division of Urology, University Health Network Department of Surgery, University of Toronto 26 | IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE

Research on the impact of lifestyle on health and disease has revolutionized prostate cancer research in the past two decades. “One of the most interesting aspects of what I’ve done is [try] to get men interested in men’s health issues.”

Women, he says, are much better at prioritizing and monitoring their own health than men. “It’s this idea of macho-provider.

Men are conditioned not to complain about aches and pains; to ‘bring home the

“

FACULTY SPOTLIGHT

[Patients are] excited because they make it threeand-a-half years. My part of the disease is ten years.

If I can have the same impact, I can get the [patient] five or seven years as opposed to months.”

bacon.’ We need to culturally change men that way… not only about prostate cancer, but about their health in general.” He adds that much of his work has involved investigating causes of prostate cancer. Poor eating and inactivity, two aspects of the “Western lifestyle,” are some of the biggest driving agents of prostate cancer. “It comes full circle. If we can get men to look after their eating habits and their exercise, this would [help prevent] prostate cancer.” Dr. Fleshner is pleased to share that many of his patients have become involved in this movement.

Given Dr. Fleshner’s expertise in prevention, I wondered what his thoughts are on the recent—and somewhat controversial—recommendations for prostate cancer screening. The Canadian Task Force on Preventative Health Care advised against Prostate-Specific Antigen (PSA) testing, the gold standard for early prostate cancer detection, due to a high rate of false positives. “I think the recommendations came from a flawed mindset. We know without a doubt that by catching elevated PSA levels early in life, we can lower the rate of death from prostate cancer. The question becomes, at what cost—financially and also [in terms of] quality of life for men.

I think the best solution is what we do now, which is surveillance. We aggressively find prostate cancers but only treat the bad ones and continue to monitor the [benign] ones. This wasn’t even taken into account when they did the task force.” Dr. Fleshner also notes that new biomarkers and imaging tests on the horizon will make monitoring less invasive and more informative.

Today, prevention is still one of Dr. Fleshner’s main areas of work, but he also devotes time to biobanking patient

samples and studying prostate cancer metabolism. Biobanking is the storage of biological samples—in this case human samples—for future research purposes. Dr. Fleshner has been a leader in generating the world’s largest genitourinary biobank, with approximately 1 million specimens, which facilitates extensive research by him and his collaborators. In addition to collaborating with many wet labs, he also examines patient outcomes, epidemiology, and health services.

Further to lifestyle factors, metabolism also plays an integral role in prostate cancer. Dr. Fleshner explains that prostate cancers use carbon differently from most cancers, taking advantage of oxidative phosphorylation rather than glycolysis. As a result, certain compounds like fludeoxyglucose (FDG), used as a radioactive glucose uptake marker in positron emission tomography (PET) scans, cannot be used in prostate cancer imaging. “We’re trying to see if we can exploit this [unique metabolic property].” To investigate potential therapeutic avenues, much of Dr. Fleshner’s work centres around metformin, a drug commonly used to control blood sugar in diabetes. “I think it has a phenomenal potential in early-stage prostate cancer.”

In addition to its therapeutic potential, the drug seems to delay disease progression at its early stages—a particular area of Dr. Fleshner’s research interests. “Most people are doing research in end-of-life prostate cancer. I’m interested in the early part. The problem is that the end-of-life with prostate cancer is [only] a three-year period.” Dr. Fleshner comments that those who focus on end-of-life disease are only able to extend a patient’s life by months.

“They’re excited because they make it

three-and-a-half years. My part of the disease is ten years. If I can have the same impact, I can get the [patient] five or seven years as opposed to months. Very little research is placed there. It’s challenging to do trials because the time is long— most grant cycles are [only] three to five years.” But Dr. Fleshner is optimistic. “I lead a Canadian-wide network with basic scientists here… and collaborators across the country. We have a five year, $5 million project to look at prostate cancer metabolism and how we can both understand it and take advantage of it.”

After many years in his field, I wondered what aspects of Dr. Fleshner’s work he is most passionate about today. “For me, the most exciting thing [about research] is getting a new project together and executing and analysing a new data set.” However, the most rewarding part of his job, Dr. Fleshner maintains, is seeing patients in the clinic. “I also love a challenging operative case, where I can really concentrate for hours on one little task.” When I asked him if he listens to music while he operates, Dr. Fleshner grinned, “Always. I play Metallica.”

With regard to guidance for graduate students, Dr. Fleshner’s advice is simple: “Choose something you love.” If you’re doing something you love, he reasons, then it’s not work. “Don’t go where the money is. You don’t have to choose a ‘hot topic’ just because it’s hot.”

Finally, he cautions, “Not all research pans out. Research is this search for the truth and it doesn’t guarantee a good outcome from your work. But that doesn’t make the work not useful. You learn a lot on the way.

You become a much more critical thinker.

That’s the big one from my point of view.”

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 27

STUDENT SPOTLIGHT

Student Spotlight:

The Raw Data Podcast Team Photo by Anna Badner

By Anna Badner

The Team:

Richie Jeremian (3rd year PhD, Dr. Art Petronis, CAMH; favourite podcast: Marc Maron Podcast) Jabir Mohamed (2nd year MSc, Dr. McIntyre Burnham, MSB; favourite podcast: The Smart Passive Income) Ekaterina An (2nd year MSc, Dr. Gary Rodin, PMH; favourite podcast: The Bugle) Alexandra Mogadam (2nd year MSc, Dr. Elizabeth Pang, SickKids; favourite podcast: 99% Invisible) Melissa Galati (2nd year MSc, Dr. Uri Tabori, SickKids; favourite podcast: Gilmore Guys) Romina Nejad (2nd year MSc, Dr. Gelareh Zadeh, MaRS; favourite podcast: Radiolab)

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STUDENT SPOTLIGHT

T

he Institute of Medical Science (IMS) has over 600 faculty members and 550 students studying a diverse range of subjects in various research intuitions around the city. With this wide spectrum of student experiences, it can be fairly difficult to engage and foster community throughout the department.

For these reasons, Richie Jeremian, who is currently in the third year of his PhD studies, devised an innovative project that would showcase IMS investigators and their research. “Since everyone is

“

Together, with a common goal, they filmed a few trial interviews. Although the pair had originally planned to produce short (60-90 second) edited videos for the Spotlight project, the trial contained a fluid dialogue that had naturally stemmed from the interview questions. Moreover, while listening back to the audio recordings, Richie noticed that the conversations were “pretty interesting” and “would work really well as a podcast.” In addition to discussing their research, the investigators reflected on their experiences and life in

it is more than just science talk,” clarifies Alex, “we also chat with students and collaborators.” Each season consists of 24 episodes and the first was released this fall. Equipped with Hart House rental gear and smartphone accessory microphones, the podcast interviews usually take place in faculty offices and videos are recorded at the SickKids’ Peter Gilgan Centre for Research and Learning gallery. Overall, the Raw Data team hopes to offer science students insight into the graduate school experience and research environment.

The Raw Data team hopes to offer science students insight into the graduate school experience and research environment.”

located in different hospitals, we often lose people to their labs,” Richie sighed, “I wanted to help unite IMS students and faculty.” Initially dubbed Spotlight, the initiative was designed to introduce faculty members to current and prospective students in the form of short video interviews. Through involvement with the IMS Student, Alumni, and Faculty Engagement (SAFE) Committee, Richie was able to secure departmental support and the resources necessary to get the project started. He was also introduced to filmmaking hobbyist Jabir Mohamed, now a second year MSc student with an impressive repertoire of video-editing expertise. At the time, Jabir had been looking for a supervisor with the IMS and felt that a more comprehensive look at faculty members would help with this selection process. “I wanted to learn more about the people behind the science than what a few keywords about their research interests offered,” explained Jabir.

academia. Recognizing that this could be of significant interest to other students, Richie and Jabir decided to keep the audio archives for what would later become the Raw Data podcast.

They also hope that the content can help incoming students make decisions about selecting supervisors and committee advisors.

In its current form, the Raw Data podcast team is made up of six student volunteers; specifically Richie Jeremian, Jabir Mohamed, Ekaterina An, Alexandra Mogadam, Melissa Galati, and Romina Nejad. Ekaterina joined the group through her involvement with the SAFE Committee, while Alex, Melissa, and Romina were recruited through the IMS Students’ Association. “For me, it’s a creative outlet and great way to get involved,” described Romina. The Raw Data episodes, each approximately 30-45 minutes long, are organized into monthly themes and released on the second and fourth Friday of every month. Guided by the graduate coordinators, the team tries to highlight new faculty and the most influential researchers from the department. “But

During our interview with the Raw Data team, they radiated with enthusiasm.

Their passion was evident in the way they explained the details of past interviews and imminent plans for the podcast. “We want this to get as big as it can,” declared Richie. From discussions on science engagement and professional development to neurotrauma and lung injury, the podcast will definitely keep us in the loop.

Most importantly, it is obvious that the Raw Data team has a lot of fun working together and, as a result of quick graduate student turnover, the team is always looking for more members to join for the next season. If interested, details can be found on their website (http://rawdataims.com/), Facebook (@rawdataims), or on iTunes.

Until next time, as they say in the podcast, “keep it raw.”

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 29

FUTURE DIRECTIONS

SARAH

GAGLIANO: A Biomedical Genetics Research Aficionado

By Petri Takkala

S

Photo by CanGrad Studios

arah Gagliano, PhD, is a postdoctoral fellow at the University of Michigan in Ann Arbor working with Drs. Gonçalo Abecasis and Michael Boehnke.

Her work aims to identify novel genetic risk variants for multifactorial diseases, especially disorders affecting the brain, such as bipolar disease and schizophrenia.

The susceptibility to develop neurological and psychiatric diseases is known to depend on the interaction between genes and the environment. To disentangle this interaction, Sarah is using data from a population with a higher incidence of bipolar disorder and schizophrenia, and for other phenotypes, such as cardiovascular traits. She has data from a relatively isolated population in Sardinia, Italy, where the population and environment are relatively constant. She is using a biostatistics approach to identify novel genetic risk variants for multifactorial diseases, and employing machine-learning algorithms to model and investigate the genomic contribution to phenotypic traits in these diseases.

Initially trained in biochemistry and human biology as an undergraduate student at the University of Toronto, Sarah remained in Toronto to complete her PhD in statistical genetics at the Institute of Medical Science. While working in the labs of Drs. Jo Knight and James Kennedy, Sarah completed her PhD on “In silico Prioritization of Genetic Risk Variants

Using Functional Genomic Information.”

Genomic annotations ascribe biological information about the regulation of the protein product of a coding region. By using functional annotation data, she was able to cross-examine and identify risk variants causing diseases affecting the brain and immune system. Sarah looked at DNA sequence data and annotations in genomic information for histone modifications and enzymatic sites, but found that a lot of risk variants are in non-coding regions of DNA, which agreed with results from the literature. These variants are difficult to interpret and require more functional annotation data, better lab techniques, and tissue specific information to identify, but are of vital importance to understanding the genetic contribution to disease.

At the end of her PhD, Sarah was awarded a prestigious Weston Brain Institute international fellowship to work in Dr. Michael Weale’s lab at King’s College London to use her statistical genetics approach to identify novel risk factors for Parkinson’s disease and to investigate the heritability of neurodegenerative diseases. Using tissue-specific functional genomic annotation data, she found that Alzheimer’s disease heritability comes from variants in the genome with regulatory roles in immune cells— specifically T and B lymphocytes and other immune cells, which are responsible for the adaptive and innate immune

30 | IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE

responses. Sarah’s work has contributed to our recent understanding of Alzheimer’s disease being an autoimmune disease.

As an already very accomplished genetics researcher with a global presence, Sarah continues to be focused on her research and blossoming academic career. Her future research goals include further investigating how phenotype is affected by variants in non-coding regions of DNA. A lot of risk factors are known to reside in non-coding regions of the genome, but identifying these risk variants is more difficult than in coding regions due to their more subtle association with gene function. However, with sufficiently annotated genome data from tissue relevant to the phenotype of interest, Sarah hopes to be able to employ her statistical tools to disentangle the interaction between genes and their environment, and the relationship between genotype and phenotype in multifactorial diseases affecting the brain.

For students who intend to pursue a research career in academia, Sarah offers the following advice: publish your research, network at conferences, attend events where students can interact with potential PI’s, and manage stress by establishing a healthy work-life balance.

Labs in different countries have different resources, expectations, and work environments; be prepared to adapt and take advantage of new opportunities.

FUTURE DIRECTIONS

LIAM KAUFMAN MSc, IMS Alumnus

By Alexandra Mogadam

E

Photo by Meital Yerushalmi

veryone enjoys a good success story, especially when the person who achieves success is a dedicated and hard worker who started off where you, the reader, are currently standing.

Liam Kaufman is exactly that person in this story. Liam is the CEO of Winterlight Labs, a start-up research and development company advancing a cutting-edge software intended to aid in the early detection of Alzheimer’s Disease and other types of neurodegenerative disorders. Having graduated from the Institute of Medical Science (IMS) in 2008, Liam has spent the last eight years making a name for himself in Toronto’s tech and startup circles. With this issue of the IMS Magazine dedicated to Science and Engineering/Technology, Liam is the perfect fit for our ‘Future Directions’ section.

Early detection of cognitive decline, Liam explains, is currently the “holy grail” in neurodegenerative research. Winterlight Labs, co-founded by Liam and his three partners, strives to create a tool to do just that: facilitate early detection. By registering and analyzing a patient’s speech pattern, the software in its current form can discriminate with 85% accuracy between Alzheimer’s patients and control subjects. In essence, the software reliably

identifies subtle decreases in speech complexity and changes in acoustic patterns in the affected population, distinguishing them significantly from controls.

Following the analysis, the software calculates the likelihood that the tested subject has Alzheimer’s Disease. The value of this software lies in its ability to quantify lingual and cognitive declines, a potentially valuable clinical tool for medical professionals. Indeed, the Winterlight Labs team envisions the integration of this technology into mainstream healthcare. However, before this software can realize its clinical potential it must gain diagnostic validity, which requires longitudinal data demonstrating changes in speech patterns over time. Striving to advance their technology to the next level, the team is currently working on gathering such data to support the software’s validity.

While Liam has successfully found his place and calling in the tech and startup world, he did not start his graduate studies at IMS envisioning he would take this path. In fact, he was initially set on doing his Ph.D. with his then-supervisor, Dr. Sandra Black. Halfway through his Master’s, however, he began having doubts. He recalls one night in particular when he was working late to meet

a deadline and had a sudden moment of clarity: he realized that if he were to continue on with a Ph.D., it would involve many more similar nights, and he wasn’t sure that he had the passion to give it his all. He did, though, enjoy the programming and coding he did on the side during his Master’s. Perhaps owing to this interest, Liam had noticed that a lot of the technology used in neuroscientific research was rather rudimentary and in need of improvement, a goal he became interested in tackling. He vocalized these concerns to Dr. Black, who was very supportive and understanding. She even helped him gain contacts in the Department of Computer Science at the University of Toronto, where he obtained his HBSc following his Master’s at IMS. After various experiences in the tech world, including working for a mobile app development company and independently developing and launching his own app (‘Understoodit’), in 2015 Liam decided to turn back to his original field of interest: the interface between neuroscience and computer science. Shortly thereafter he met Dr. Frank Rudzicz, one of his co-founders at Winterlight Labs, and ever since Liam has been working alongside his team toward advancing how and when we diagnose neurodegenerative disorders.

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 31

TRAVEL BITES

Empathy, Evidence, and the EAPM

By Ekaterina An

W

alking into the venue of the annual European Association for Psychosomatic Medicine (EAPM) conference, I was unsure of what to expect at my first international conference. First of all, the definition of “psychosomatic medicine” was still unclear to me, despite the fact that I was set to present during one of the sessions at the conference. Second, the journey to the conference was rather stressful, and had made me apprehensive about what was to come. The meeting took place in a very unique location—Lulea, a small, quaint town in northern Sweden, located just beneath the Arctic Circle. The conference webpage had promised mild temperatures and sunny days, with nearly-perpetual daylight. Unfortunately, Swedish pilots went on strike in the days preceding the conference, which seriously complicated my travel plans. However, despite my trepidation over travel delays this visit was definitely worthwhile: the EAPM conference opened my eyes to psychosomatic medicine—an incredibly diverse, multidisciplinary field consisting of clinicians, researchers, and other health professionals dedicated to integrating and promoting somatic and mental health.

“

Lulea in the summertime. in the South London and Maudsley NHS Trust; Dr. Colin Shapiro, director of the Sleep and Alertness clinic at Toronto Western Hospital (whose sleep research was featured in our previous issue); and Dr. Michael Sharpe, professor of psychological

The EAPM conference opened my eyes to psychosomatic medicine.”

This year’s conference theme was “Transforming health through evidence and empathy,” a concept that was touched upon by all of the keynote speakers. This group included Sir Simon Wessely, professor of psychological medicine at King’s College, London and president of the Royal College Psychiatrists; Dr. Gary Rodin, professor of psychiatry and director of the Global Institute of Psychosocial, Palliative, and End-of-life Care at the University of Toronto (and my supervisor); Dr. Carmine Pariante, professor of biological psychiatry and consultant perinatal psychiatrist

medicine at Oxford University. While all speakers share a background in psychiatry, their diverse areas of research and clinical work reflect the heterogeneity of the field of psychosomatics. This diversity was further reflected in the conference program and its attendees, whose range of research and clinical expertise was impressively broad. The concurrent sessions offered a range from a master class in psychopharmacology to gender aspects in health and disease, to psychooncology. As a Master’s student in a research-based program, I was humbled to be one of the only

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non-clinician-scientists.

Despite feeling somewhat under-qualified to be presenting to such a diverse and accomplished group, I found the whole experience to be an incredible learning opportunity. While the field of psychology is often criticized for its lack of rigour and quantifiability, 1 the work that was presented at the EAPM conference provided solid evidence to the contrary. I attended talks that linked depression and anxiety to immune disorders, explored psychosocial and existential health issues among Syrian refugees in Istanbul, discussed psychiatric outcomes of transplant recipients, and taught healthcare professionals strategies to improve medical communication between physical and psychological health, and provided a unique opportunity to disseminate my own work in the field of psychosocial oncology to a diverse, international audience.

References 1. 1. http://blogs.scientificamerican.com/the-curious-wavefunction/ is-psychology-a- e2809creale2809d-science-does-it-really-matter/

SHOWCASE

Biomedical communications alumni showcase:

WALID AZIZ Walid Aziz, MScBMC 2011 www.walidaziz.com

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IMS EVENTS

Message from the SURP DIRECTOR

By Vasundara Venkateswaran, PhD

Associate Professor Department of Surgery, University of Toronto Director, Summer Undergraduate Research Program Graduate Coordinator Institute of Medical Science, University of Toronto Scientist, Division of Urology Sunnybrook Health Sciences Centre Email: vasundara.venkateswaran@sunnybrook.ca

A

Photos by Daniel Wesser and Oliver Salathiel

nother year has gone by, and the Summer Undergraduate Research Program (SURP) has been a great success—for the sixth year in a row! As with every year, this year we were fortunate to have excellent undergraduates who were highly motivated and engaged, both in the weekly lectures and at the research day. I am extremely pleased to be serving as the Director of SURP, and this has been a truly rewarding experience over the past six years. Each year has brought an even more exciting experience than the last and I am looking forward to upholding the standards, eminence, and success of this program in the years to come.

SURP is the largest summer research program at the University of Toronto, facilitated through the Institute of Medical Science. The program gives undergraduate and medical students an opportunity to acquire research knowledge and skills, inspiring them to pursue a career in translational research. Students participate in individual laboratory meetings, data analysis sessions, journal clubs, and appropriate clinical research rounds at the various affiliated teaching hospitals. This year 94 students were enrolled—both domestic and international. Students came from universities as far as Shandong in China,

while others came from right here at the University of Toronto.

The program commenced on June 1st, 2016 with an orientation session. During the course of the 12 week program, we offered a formal lecture series consisting of diverse research and practical skills presentations rendered by IMS faculty. This year our graduate students paired up with their supervisors to render the seminars; supervisors presented an overview of the research conducted and graduate students focused on their specific research topic.

This was an exciting opportunity for the summer students to interact with the faculty as well as engage with the graduate students to get insight into graduate education. The participation and interaction from the summer students was phenomenal.

The SURP concluded with the research day on August 17th, 2016. This was an all-day event providing students an opportunity to showcase their research findings through oral or poster presentations. All of the presentations were remarkable. One outstanding student from each group was awarded first place, and one was awarded an honorable mention. First place winners were presented with a book, Planning a

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Career in Biomedical and Life Sciences: Making Informed Choices by Dr. Avrum I. Gotlieb, as a token of their accomplishment. Honorable mentions received a certificate and distinction at the SURP awards ceremony. Awards and certificates were handed out to the students by Dr. Vasundara Venkateswaran, Director of SURP. It was rewarding to see students beam with excitement when they presented their research; the enthusiasm exhibited clearly demonstrated a productive summer experience in the laboratories or clinics. Students showcased their work with confidence and pride and responded well to the challenging questions posed by the judges. All students received a certification of participation on the successful completion of the summer program.

This is the 40th Summer Undergraduate Research day hosted by the Institute of Medical Science. As part of this day it was an honour to have with us Dr. Michael Farkouh to render the keynote address.

Dr. Farkouh is the Peter Munk Chair in Multinational Clinical Trials, University Health Network and Director of the Heart and Stroke / Richard Lewar Centre of Excellence in Cardiovascular Research.

IMS EVENTS He is Professor and Vice-Chair, Research, Department of Medicine at the University of Toronto. Prior to his current appointments, he served as the founding director of the Mount Sinai Cardiovascular Clinical Trials Unit in New York City. He has published over 200 papers largely on acute coronary syndromes and cardiovascular prevention and is internationally known for his work on the management of acute coronary syndromes in the emergency room. Numerous international residents and fellows have been mentored by Dr. Farkouh. He is currently the project officer for numerous clinical trials on questions related to diabetes and heart disease, including the NIH-sponsored FREEDOM trial. He chairs the committee on diabetes and heart disease at the Banting and Best Centre and at the University of Toronto.

Dr. Farkouh has received the Gold Medal from John Paul II Hospital in Krakow, was elected Teacher of the Year at the Mayo Clinic, and was awarded the Jan J. Kellermann Memorial Award from the International Academy of Cardiology. I take this opportunity to thank Dr. Farkouh for his captivating lecture, and for engaging the students in discussion.

All this would not have been made possible without the significant contribution by our IMS faculty who have not only supervised the students but also provided them with a stimulating environment, motivation, and guidance in their research. I would like to convey my sincere appreciation to our faculty who served as judges at the research day, as well as to the distinguished researchers and graduate students for presenting lectures at the weekly seminars. Special words of appreciation to our funders who helped make this program a grand success. Funding support was received from UROP, St. Michael’s Hospital, Department of Medicine, Department of Surgery, University Health Network, and Merck Canada Inc.. We appreciate Elena Gessas, Departmental Assistant, for her year-long efforts in coordinating this program and Ms. Kamila Lear, Business Officer, for her continued support.

On behalf of the faculty and staff at IMS, I would like to congratulate the summer students on their research achievements and wish them the very best in all their research endeavours!

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 35

IMS EVENTS

Healing Scars

A Novel Approach to Reducing Fibrosis in Progressive Cardio-Renal Disease

By Ellen Wu

“

There is something beautiful about all scars of whatever nature, ” Harry Crews once said, “[a] scar means the hurt is over, the wound is closed and healed, done with.”1 However, when scars are present in excess in the body, on some of our most vital organs, they no longer mark the healing of a wound but the beginning of a new trauma.

Excessive tissue scarring, known as fibrosis, exerts detrimental effects on multiple organs in the human body, including the kidney and the heart. The two organs’ pathologies are closely associated, therefore heart and kidney diseases are examined together, clinically and in research, as cardio-renal disease.2 In a range of progressive cardio-renal diseases such as diabetes and hypertension, excess extracellular matrix proteins accumulate in chronically injured tissues.2 This pathogenesis, known as cardio-renal fibrosis, can ultimately lead to end-stage renal failure, heart failure, and death.3 Cardio-renal fibrosis occurs after chronic tissue injury.2 In the kidney, resident cells become activated, synthesizing and releasing cytokines that promote systemic inflammation. Cytokines drive a chemical gradient that guides T cells and inflammatory macrophages to locations of injuries. This, in turn, drives the activation of inflammatory cells that release fibrogenic cytokines, eventually causing fibroblasts, mesangial cells, and tubular epithelial cells to continuously deposit extracellular matrix proteins such as collagen. Extracellular matrix deposition leads to tubular atrophy, capillary loss, and podocyte depletion in the kidney.4 Cardiac fibrosis has a similar pathogenesis where fibroblasts and related myofibroblasts produce extracellular matrix proteins that result in structural and functional damages such as decreased compliance and diastolic dysfunction.3 Normal wound healing has similar mechanisms as pathological fibrosis, where fibrogenic factors are released and fibroblasts are activated after acute injury.

However, in normal wound healing, the tissue is repaired structurally and functionally by regenerating tubules and remodeling matrix. This vital difference could be attributed to the extent of the injury. After an acute injury, the tissue is able to repair properly. When there are chronic injuries, presented in progressive diseases, the tissue experiences Smad antagonist loss and fibrogenic signal amplification, resulting in cardio-renal damages.5 While it is difficult to control the extent of an injury, controlling the release of growth factors and cytokines could regulate cellular responses. One of the most common growth factors studied in chronic diseases is transforming growth factor beta (TGF-β).6 TGF-β plays a key role in extracellular matrix production and was found to be upregulated in both animal models and humans with chronic cardio-renal diseases.4 Through type I and II transmembrane serine-threonine kinase receptors, TGF-β signaling activates Smad downstream mediators.7 TGF-β/ Smad signaling has been previously viewed as entirely phosphorylation-dependent, however, more recent investigations have shown that deacetylation also plays a pivotal role.8 Our research study explores the effect of TGF-β deacetylation in cardio-renal fibrosis. We used activating compounds of sirtuin 1 (SIRT1), a class III lysine deacetylase, which is more potent, specific and orally bioavailable compared to the relatively non-specific nutraceutical, resveratrol.9 In vivo, rats underwent subtotal nephrectomy (SNX), the gold standard to mimic chronic cardio-renal disease models. Their cardio-renal structures and functions were thoroughly assessed with glomerular filtration rate, urinary protein excretion, systolic blood pressure, left-ventricular pressure volume relationship measurements, and stained tissue analysis. The SNX rats that received SIRT1 activators showed significant improvement compared to the controls in all criteria mentioned above. In vitro, we performed PCR and used RPL13A housekeeping

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gene as a loading control to assess SIRT1 expression in human biopsy samples.

Patients with secondary focal glomerulosclerosis showed a significantly higher expression of SIRT1 gene compared to control patients.

Along with other recent studies, we have shown that deacetylation by SIRT1 could modify TGF-β’s signalling pathway in cardio-renal disease; SIRT1 activation is positively correlated with a reduction of fibrosis in chronic cardio-renal disease.

Despite our promising findings, many questions in regards to the mechanisms behind fibrosis remain unanswered.

While we have shown that deacetylation attenuates TGF-β induced fibrosis, some studies have shown the reverse where acetylation also reduces fibrogenesis.10 Our future studies will examine the effect of the summation of both acetylation and deacetylation in chronic cardio-renal disease.

Although it is every researcher and clinician’s intention to simply cure or heal a disease, many times the mechanism behind a small wound take years to discover, to understand, and eventually to heal. But Crews wasn’t entirely wrong; there is something beautiful behind all scars, and with every pain comes hope.

References 1. Crews H. Scar lover. New York: Touchstone; 1993.

2. Hundae A, McCullough PA. Cardiac and renal fibrosis in chronic cardiorenal syndromes. Nephron Clin Pract. 2014;127:106-112.

3. Krenning G, Zeisberg EM, Kalluri R. The origin of fibroblasts and mechanism of cardiac fibrosis. J Cell Physiol. 2010;225(3):631-637.

4. Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 2006;69(2):213-7.

5. Yang J, Zhang X, Li Y, et al. Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic kidney: an amplification mechanism for TGF-beta1 signaling. J Am Soc Nephrol.

2003;14(12):3167-77.

6. Finnson KW, McLean S, Di Guglielmo GM, et al. Dynamics of transforming growth factor beta signaling in wound healing and scarring. Adv Wound Care. 2013;2(5):195-214.

7. Böttinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol. 2002;13(10):2600-10.

8. Kume S, Haneda M, Kanasaki K, et al. SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation. J Biol Chem. 2007;282:151-158.

9. Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci. 2014;35:146-154.

10. Choi SY, Ryu Y, Kee HJ, et al. Tubastatin A suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes. Vascul Pharmacol. 2015;72:130-40.

IMS EVENTS

Taking Cues from the Brain

The Potential of the Neuronal Chemorepellent Slit in Treating Atherosclerosis

By Thenuka Thanabalasingam

C

ardiovascular disease, which often culminates in the increased incidence of heart attack or stroke, continues to be the primary cause of mortality worldwide, representing 28.2% of all deaths in 2013.1 Previously, scientists had characterized the underlying pathology of atherosclerosis as the simple build-up of cholesterol leading to vessel blockage. However, in recent years, our understanding of the dynamic pathophysiology has extended beyond this rudimentary model, and atherosclerosis is now recognized as a chronic inflammatory disease.

The multifaceted pathology begins with the retention of low-density lipoproteins (LDLs) in the arterial intima, where they are subject to enzymatic oxidation. The resulting oxidized-LDLs (ox-LDLs) are pro-inflammatory and induce epithelial expression of adhesion molecules and chemokines to recruit leukocytes into the lipid-rich subendothelial space.2 Although many inflammatory cells are involved, it is monocyte migration that is crucial to disease progression. Once recruited into the intima, monocytes differentiate into macrophages and initiate ox-LDL clearance via internalization of the immunogenic lipid particles.3 Incoming T lymphocytes perpetuate this process by secreting pro-inflammatory cytokines to enhance macrophage activation.2 With continuous rampant ox-LDL accumulation, macrophages become lipid-laden foam cells.

Eventually, their lipid-metabolizing machinery becomes saturated and fails to process the large intracellular pool of internalized lipids efficiently, leading to apoptotic cell death.

Typically, other macrophages within the atherosclerotic lesion would be responsible for removing these dead foam cells. However, since their own metabolism is dysregulated, these lesional macrophages fail to clear the apoptotic cells, leading to the release of cellular factors, such as matrix metalloproteinases (MMPs) into the extracellular space.4 The released MMPs, along with pro-inflammatory proteases secreted by activated T lymphocytes, degrade the fibrous cap encasing the atherosclerotic plaque. As this cap thins, patients become increasingly susceptible to plaque rupture and thrombosis, which

may manifest in heart attack or stroke.3-4 Currently, for patients diagnosed with atherosclerosis, curbing plaque growth and preventing rupture are key objectives in order to avoid vessel occlusion and subsequent tissue ischemia. Along with recommended lifestyle changes, patients are often prescribed statins to lower circulating cholesterol levels and, in severe cases, undergo invasive surgical procedures to relieve occlusion. However, given that the immune response is so critical to atherosclerosis, strategies that alleviate localized inflammation within the plaque may have significant therapeutic benefits.

The Slit family of secreted proteins was first discovered in the 1990s at the midline of the developing central nervous system (CNS) in Drosophila.5 When Slit binds to its receptor, Roundabout (Robo; expressed on neuronal growth cones), it directs axon-migration away from the midline, preventing inappropriate axonal crossing at the midline.5 Although the details of the Slit-Robo signalling cascade are largely unknown, the inactivation of local Rho GTPases has been identified as downstream to Slit-Robo binding. This inactivation of Rho GTPases impairs local remodelling of the actin cytoskeleton, consequentially curbing cell migration.6 In mammals, multiple isoforms of Slit and Robo exist. While mammalian Slit1 is expressed exclusively in the CNS, Slit2 and Slit3 are found in other tissue. Interestingly, Robo1 is expressed on the surface of several leukocytes, including macrophages,7 lymphocytes,8 and platelets.9 The Robinson Lab at the Hospital for Sick Children has demonstrated that Slit2 inhibits the chemotaxis of monocytes,7 even in the presence of various counteracting chemoattractants, including interleukin-8. Similiar observations have also been made in T lymphocytes. Slit-mediated inhibition of T lymphocyte migration was accompanied by an inactivation of Rho GTPases,8 as observed in neurons. These findings imply that Slit2 expression at the atherosclerotic lesion may curtail leukocyte recruitment (particularly

that of monocytes and T lymphocytes), resulting in reduced disease severity.

As previously described, Slit2’s effect of cell migration depends on the inactivation of Rho GTPases and the subsequent suppression of actin remodelling. Aside from cell migration, actin remodelling is a prerequisite for multiple cellular processes, including the internalization of ox-LDL by macrophages.10 This link recently prompted the Robinson Lab to assess the effect of Slit2 on ox-LDL uptake. We observed that Slit2-treated macrophages internalize less ox-LDL compared to untreated controls. This gives rise to the exciting possibility that Slit2 may not only inhibit monocyte migration into the atherosclerotic lesion, but it may also prevent any recruited macrophages from turning into deleterious foam cells.

Will Slit be the miracle drug in treating atherosclerosis? More research is definitely required to clearly elucidate the effects of Slit on the atherosclerotic pathophysiology as a whole and to address concerns regarding its in vivo use. However, Slit2’s ability to influence multiple leukocytes even in pro-inflammatory environments and to block several steps in disease progression makes it a promising therapeutic candidate.

References 1. Barquera S, Pedroz-Tobias A, Medina C et al. Global overview of the epidemiology of atherosclerotic cardiovascular disease. Arch Med Res. 2015;45(5):328-338.

2. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12(3):204-212.

3. Bobryshev YV. Monocyte Recruitment and foam cell formation in atherosclerosis. Micron. 2006;37(3):208-222.

4. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Bio. 2005;25(11):2255-64.

5. Kidd T, Bland KS, Goodman CS. Slit is the midline repellent for the Robo receptor in Drosophila. Cell. 1999;96(6):785-794.

6. Mukovozov IM, Robinson LA. Slit/Robo signaling: inhibition of direction leukocyte migration. In: Faraggi E, editor. Protein Structure. Intech, 2012; p. 309-334.

7. Mukovozov IM, Haung Y, Zhang Q et al. The neurorepellent Slit2 inhibits postadhesion stabilization of monocytes tethered to vascular endothelial cells. J Immunol. 2015;195(7): 3334-3344.

8. Prasad A, Qamri Z, Wu J et al. Slit-2/Robo-1 modulates the CXCL12/ CXCR4-induced chemotaxis of T cells. J Leukoc Biol. 2007;82(3):465-476.

9. Patel S, Huang YW, Reheman A et al. The cell motility modulator Slit2 is a potent inhibitor of platelet function. Circulation. 2012;126(11):1385-1395.

10. Collins RF, Touret N, Kuwata H et al. Uptake of oxLDL by CD36 occurs by an actin-dependent pathway distinct from macropinocytosis. J Biol Chem. 2009;284(44):30288-30297.

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BOOK REVIEWS

Outliers : The Story of Success Review by Beatrice Ballarin

W

hen Steve Jobs died in 2011, his biography was already written and ready to be published. The book that sold millions of copies worldwide describes the story of an underprivileged kid who was so brilliant and loved apples so much, that he created one of the first personal computer companies and named it Macintosh.

He was a self-made man. A man of the new millennium. He came from a family of little means, but despite his circumstances, he succeeded by inventing something valuable enough to make a difference on a global level. He represented the technological revolution that began in the sixties; Steve Jobs was a genius.

We’ve all heard the incredible stories of highly successful individuals. But what those stories don’t tell you are the circumstances that fostered that success: the historical and geographical contexts. In my experience, pure luck doesn’t exist.

There are only opportunities; if you’re brave and smart enough, you take them.

This is exactly what Malcolm Gladwell’s Outliers is about: the multi-millionaires who we continue to hear about are not true outliers. They are ambitious, they are smart, and they are brave. Luck is not enough. What those stories miss is the context and the power of cultural legacy.

Have you ever asked yourself: who was Steve Jobs’ neighbour before he became Steve Jobs? His name was Bill Hewlett.

Gladwell likens this to a situation in which you, the reader, come from an economically disadvantaged home, but next door to you lives Giorgio Armani, and he offers you a summer job in his fashion studio. What would you have done? This is what Gladwell asks.

The life of Steve Jobs is one of the many stories the book endeavours to analyze.

Outliers explores the success stories of numerous household names: Bill Gates, the giant of the computer industry, famous Canadian Hockey players, the Beatles and the 10,000-Hours Rule, and big law firms in New York. Gladwell

“

Who we are cannot be separated from where we're from.”

- Malcolm Gladwell, Outliers: The Story of Success

describes how Joe Flom, a Jewish kid without a college degree, became one of the most successful lawyers in the world; how two people with exceptional intelligence—Christopher Langan and J. Robert Oppenheimer—ended up living two very different lives; and how Korean airway companies were formed. In Outliers, Gladwell considers the factors that we believe contribute to success and breaks them apart. This is a book about the hidden power of legacy and culture-bond and how these factors shape the character and the mind-set of a person.

These traits, together with the critical

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opportunities that life gives, determine true success. This is the concept at the heart of Outliers, told through the stories of those who made it to the top.

I read this book during my summer holidays in Venice, and although everybody thought I was crazy for reading a book about statistics at the beach, don’t let the title mislead you; this book is about so much more. Perhaps one last take-home message from the book to encourage those of us in grad school: with hard work and passion, you can go far. Happy reading!

BOOK REVIEWS

Review by Antigona Ulndreaj

I

n Bold: How to Go Big, Create Wealth and Impact the World, the world’s most challenging problems are viewed as the biggest business opportunities. So, if you have solutions that will improve the world and want to become extraordinarily wealthy, this book is for you.

In the first chapter, the authors, Peter Diamandis and Steven Kotler, introduce exponential thinking as the cornerstone of large-scale impact. Although the human brain is hardwired to think linearly rather than exponentially, using case studies of companies that went extinct, the authors make the case that linearity can no longer serve the needs of an exponentially evolving world. Next, they explain the six progression stages of exponential technologies (i.e digitalization, deception, disruption, demonetization, dematerialization, and democratization), and bring examples of multi-million-dollar companies that leveraged these concepts.

The second chapter of the book focuses on the importance of having the right attitude and mindset to achieve exponential

success. Â The book delves into the traits of some of the most impactful entrepreneurs of our time, such as Larry Page, Elon Musk, and Jeff Bezos, and further conveys that vision, perseverance, aiming high, failing often, and taking well-calculated risks are some of the most important predictors of success. Citing scientific evidence, they further explain why money is not always the best motivator and how, by engaging certain environmental, psychological, and social triggers, one can maximize performance.

lastly, how to receive expert help from the crowd through incentive challenges.

However, having the right mental frameworks and implementing the concepts of exponential technology can only take an entrepreneur so far. Thus, in the third chapter, the authors talk about the immense power of the crowd and how to use it to skyrocket the potential of your ideas and broaden the impact of your enterprise. You will learn how to use crowdsourcing to have your ideas implemented in a fast, reliable, and inexpensive way. You will further read how to explore crowd-funding opportunities to raise money and materialize your ideas and

In summary, through a prism of realistic optimism, this book provides a complete roadmap that will inspire you to think big and create large-scale impact.

In closing their book, the authors acknowledge that malicious use of exponential technologies can endanger world peace and human freedom. Therefore, they emphasize that an exponentially evolving world needs bold leaders; ethical and visionary people who will ensure that exponential technologies will benefit everyone rather than be a privilege in the hands of the few.

IMS MAGAZINE FALL 2016 ENGINEERING AND MEDICINE | 39

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