IMS Magazine Spring/Summer 2018

IMS MAGAZINE THINK. LEARN. DISCOVER.

SUMMER 2018

RARE DISEASES OUT OF SIGHT, OUT OF MIND

The strugles to fund treatments for rare diseases

FUTURE OF RADIOLOGY

How AI and big data are shaping the field

LET’S TALK SCIENCE Social media and science come together

Student-led initiative IMS MAGAZINE SUMMER 2018 RARE DISEASES 1

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

MAGAZINE STAFF

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

EDITORS-IN-CHIEF

Anna Badner Lindsay Caldarone

EXECUTIVE EDITORS

Beatrice Ballarin Jonathon Chio Meital Yerushalmi Natalie Osborne

JOURNALISTS & EDITORS

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

DESIGN EDITORS

Amanda Miller Chelsea Canlas Jerry Gu Lisa Qiu Patricia Nguyen

PHOTOGRAPHERS

Grace Jacobs Krystal Jacques Iris Xu Mikaeel Valli

SOCIAL MEDIA TEAM

Tahani Baakdhah Louise Pei

SPONSORSHIP TEAM

Carina Freitas

Commentary............................................... 7 Retrospective............................................. 8 Feature..................................................... 12 BMC Feature............................................ 24 Viewpoint................................................. 26 Faculty Spotlight...................................... 32 Future Directions ..................................... 36 Travel Bites............................................... 38 Past Events............................................... 39 Book Review............................................ 42

1. World Health Organization. (1997). Elimination and Eradication of Diseases, with Special Reference to Measles and Tuberculosis.

THE LAST MILE IS

2. https://www.cdc.gov/measles 3. De Serres, G., et al. (2015). Measles in Canada Between 2002 and 2013. Open Forum Infections Diseases. 2(2).

4. https://rarediseases.info.nih.gov/ 5. World Health Organization. (2018). Measles. http://www.who.int/news-room/fact-sheets/detail/measles

THE LONGEST

6. Orenstein, W., Seib, K. (2014). Mounting a Good Offense against Measles. NEJM. 371(18):1661-1663

7. Seither, R., Et al. (2014). Vaccination Coverage Among Children in Kindergarten - United States, 2013-14 School Year. Morbidity and Mortality Weekly Report, Centers for Disease Control and Prevention.

8. Hall, V., Et al. (2017). Measles Outbreak - Minnesota April-May 2017. Morbidity and Mortality Weekly Report, Centers for Disease Control and Prevention.

9. World Health Organization. (2018). Europe observes a 4-fild Increase in Measles Cases in 2017 Compared to Previous Year. http://www.euro.who.int/en/media-centre/sections/press-releases/2018/europe-observes-a-4-fold-increase-in-measles-cases-in-2017-compared-to-previous-year 10. European Centre for Disease Prevention and Control. (2018). Measles Outbreaks Still Ongoing in 2018 and Fatalities Reported from Four Countries. https://ecdc.europa.eu/en/news-events/measles-out-

when rare disease make a comeback

breaks-still-ongoing-2018-and-fatalities-reported-four-countries 11. World Health Organization. (2017). Fact Sheets on Sustainable Development Goals: Helath Targets - Measles and Rubella.

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WHO European Region reports a rebound in Measles in 20179

Romania (5224) Rest of EU/EEA

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Incidence of reported measles cases breakdown by country in 201710

Germany (906)

Measles Incidence in the EU/EEA

Greece (1398)

35000

Italy (4978) 30000

20 out of 27 92-94% estimated threshold in vaccine coverage needed for herd immunity against Measles6

Kansas

86.5

85.3

81.7

Arkansas

Pennsylvania

Colorado

Measles Incidence in the US and Canada

2014 US outbreak mostly accounted for by unvaccinated individuals of the Amish community in Ohio 2

Number of reported Measles cases

800 700 600

Measles declared eliminated in the US and Canada 2,3

65 of 118 confirmed reported cases due to low MMR vaccination coverage amongst Somali-Americans because of perceived increased rates of autism 8

500 400 300

EU countries were below second vaccination targets10

87%%

25000

Lowest estimated rates of MMR coverage in the US 7

Number of reported Measles cases

86.9

of reported 2017 measles cases were unvaccinated individuals10

20000

15000

WHY

10000

hasn’t measles been eliminated in Europe?11

Lack of immunization program commitment Vaccine hesitancy Vaccine refusal

5000

Non-compliance

200

Gaps in surveillance and reporting

100

Parental resistance about the MMR vaccine due to false linkage to autism

Canada US

0

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

0 2010 2011 2012 2013 2014 2015 2016 2017

Year

10

Keith Colaco Krystal Jacques Maryam Bagherzadeh Melissa Galati Mikaael Valli Mirkamal Tolend Mohammed Zavvarian Parita Shah Parnian Pardis Pontius Tang Priscilla Chan Priya Makhijani Ranya Barayan Rehnuma Islam Sarasa Tohyama Tamadher Alghamdi Usman Saaed Yekta Dowlati Yena Lee Yousef Manialawy Yvonne Bach

Religious obligation and/or philosophical beliefs

Year

FEATURE INFOGRAPHIC

By Lisa Qiu MScBMC Candidate

Copyright Š 2018 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 Patricia Nguyen MScBMC Candidate

IMS MAGAZINE SUMMER 2018 RARE DISEASES 3

LETTER FROM THE EDITORS

LETTER FROM THE

H

Photo by Krystal Jacques-Smith

EDITORS

oping to offer a unique perspective into the research conducted at the Institute of Medical Science (IMS), this combined Spring/Summer issue of the IMS Magazine focuses on Rare Diseases. As a result, we highlight a broad spectrum of faculty members investigating a range of uncommon conditions. Specifically, Dr. Mohammad Reza Akbari discusses distinct Mendelian genetic mutations within the Iranian population and Dr. James Eubanks explains advances in Rett Syndrome. There is also a piece on trigeminal neuralgia (TN), dubbed the “suicide disease”, with Dr. Mogjie Hodaie as well as an interview with Dr. Manuel Carcao on hemophilia and other rare bleeding disorders. Further, Dr. Elise Héon describes the genetic basis for retinal dystrophies and Dr. Neal Sondheimer comments on mitochondrial DNA mutations.

We are also excited to share Faculty Spotlight articles on Dr. Dafna Gladman, who was recently awarded the prestigious Carol Nachman Prize for her important work in rheumatology, as well as Dr. Alan Moody and recent developments in medical imaging.

We also cover the IMS Student Association’s (IMSSA) participation in the “World’s Largest Photo Awareness Campaign”, supporting the Centre for Addiction and Mental Health (CAMH), and Purple Day for epilepsy awareness. There are also thought-provoking Viewpoint articles on science communication and the Ontario electoral race, as well as two insightful book reviews. Importantly, as a part of the IMS 50th Anniversary Retrospective series, we are thrilled to include an article about Dr. Jack Laidlaw–one of the founders of the IMS–with a commentary from Dr. Allan Kaplan.

Finally, we would like to announce that this is the last IMS Magazine issue with us as co-Editors-in-Chief. We are especially grateful for our wonderful team of talented journalists, editors, designers, and photographers, whose continuous hard work and creativity has made this issue possible. We would also like to thank Dr. Mingyao Liu and the IMS for their constant support.

We hope you enjoy this issue, and would love to hear any questions, comments, thoughts or feedback that you may have. Please feel free to email us, visit our website (www.imsmagazine.com), or reach out to us in person.

Happy Reading!

Anna Badner

Lindsay Caldarone

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

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

4 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

DIRECTOR’S MESSAGE

DIRECTOR’S MESSAGE

W Photo by Tahani Baakdhah

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

ith the temperatures rising and days growing longer, I invite you to read the Summer 2018 issue of the IMS Magazine. The focus is on Rare Diseases, and we are able to delve into this rapidly evolving world through interviews with many esteemed IMS faculty. The feature articles in this issue present discussions with Dr. Mohammad Reza Akbari, Dr. James He Eubanks, Dr. Mogjie Hodaie, Dr. Manuel Carcao, Dr. Elise Heon, Dr. Andrea Boggild, and Dr. Neal Sondheimer.

This issue also highlights the work of Dr. Allen Moody and Dr. Dafna Gladman in the Faculty Spotlight articles. The Student Spotlight is on Dr. Wenjun Xu, an IMS alumnus and current post-doctoral fellow. There are a number of interesting Viewpoint articles written by the IMS Magazine journalists, on topics ranging from computer brain interface to the funding of tropical diseases.

The IMS Magazine Retrospective series continues, with an article on Dr. Jack Laidlaw.

I encourage you to take part in the IMS 50th Anniversary celebrations that will be occurring in October, and to continue to learn more about the history of the IMS! The IMS recently celebrated the annual IMS Scientific Day, a chance for students to showcase their research. I would like to congratulate everyone who participated, and especially the students and faculty who received awards.

Finally, I wish to congratulate the Anna Badner and Lindsay Caldarone on this issue and on their time as Co-Editors-in-Chief for the IMS Magazine. I look forward to working with Chantel Kowalchuk and Priscilla Chan as they take on this leadership role moving forward. And, of course, I would like to congratulate the entire IMS Magazine team on their hard work in producing another thoughtful issue.

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

IMS MAGAZINE SUMMER 2018 RARE DISEASES 5

PAGE HEADER

6 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

COMMENTARY

Putting Nutrition in the

Gutter

(literally)

By Krystal Jacques-Smith

T

he last IMS Magazine issue highlighted research on the metabolic mechanisms and treatment of diabetes. However, a discussion about Type 2 diabetes is not complete without consideration for lifestyle and diet. While physicians often recommend dietary changes as part of the treatment plan for diabetic patients, the central role of nutrition and lifestyle in this disease has not been represented fully in mainstream medicine, medical school teachings, and medical research.1 Our busy lives, hidden ingredients and obscure labelling of food items, and the powerful marketing of the food industry make it difficult to make healthy dietary choices. Unsustainable fads and dietary myths, including calorie counting for weight loss2 and the notion that all fat is bad,3 are popular despite being unsubstantiated. Can scientific research untangle the complex link between nutrition and diabetes?

Controversially, it is common for food industries to fund, and therefore introduce the possibility of bias in nutrition research. For example, shortly after the correlation between sucrose consumption and coronary heart disease (CHD) was published in the 1950’s, the Sugar Research Foundation (founded by Kellogg’s) sponsored its first CHD project that published data identifying fat and cholesterol as the dietary culprits of CHD while downplaying sucrose consumption as a risk factor.4 What is more, the authors of the CHD project did not disclose the conflict of interest (COI) arising from Kellogg’s funding, a large manufacturer of breakfast cereal. Similarly, the National Dairy Council funded research that led to an article that showed that those who consumed a high dairy or high fat meat

diet had higher levels of HDLs (the “good” cholesterol) compared to those consuming low-fat diets, such as diets containing mostly high carbohydrate diets,3 hinting that high fat animal-based diets are superior to other diet types. However, given this COI, the study design and specific contents of each diet may have been tailored to produce the results they obtained.

Studies without COIs have found a direct link between processed meats and Type 2 diabetes,5 as well as cancer.6,7,8 Further, scientific evidence suggests that plantbased diets or a diet that minimizes processed food consumption reduces the risk of cardiovascular disease,9 dementia,10 and diabetes,11 to name a few. Anecdotally, many individuals have successfully weaned off their long-list of medications to control diabetes and other diseases by adopting a plant-based diet. Nevertheless, the close relationship between pharmaceutical companies and medical organizations, including pharmaceutical company funding toward research and targeted education on drugs,12 highly encourages the medical field to emphasize drug treatments rather than preventative medicine.

every day, “Let food be thy medicine, and medicine be thy food (Hippocrates).”

1. Schoettler CL, Lee JN, Ireland KA, et al. A Novel Method of Increasing Medical Student Nutrition Areness and Education. J Biomed Edu. 2015; 2015, Article ID 784042, 8 pages.

2. Thomas DM, Martin CK, Lettieri S, et al. Can a weight loss of one pound a week be achieved with a 3500-kcal deficit? Commentary on a commonly accepted rule. Int J Obes (Lond). 2013;37(12):1611– 161.

3. Thorning TK, Raziani F, Bendsen, NT et al. Diets with high-fat cheese, high-fat meat, or carbohydrate on cardiovascular risk markers in overweight postmenopausal women: a randomized crossover trial. AJCN. 2015;102(3):573–581.

4. Kearns CE, Schmidt LA, Glantz SA. Sugar Industry and Coronary Heart Disease Research: A Historical Analysis of Internal Industry Documents. JAMA Intern Med. 2016;176(11):1680-1685.

5. Pan A, Sun Q, Bernstein AM, Manson JE, Willett WC, Hu FB. Changes in red meat consumption and subsequent risk of type 2 diabetes mellitus: three cohorts of US men and women. JAMA internal medicine. 2013 Jul 22;173(14):1328-35.

6. Stefani E, Boffetta P, Ronco AL, et al. Processed meat consumption and risk of cancer: a multisite case–control study in Uruguay. Br J Cancer. 2015;107(9):1584–1588.

7. Pearson H. Red meat strongly linked to cancer. Nature [Internet].

2005 Jan 11 [Cited 2018 April 28]; Available from: https://www. nature.com/news/2005/050110/full/news050110-7.html.

8. Gilsing AM, Schouten LJ, Goldbohm RA, et al. Vegetarianism, low meat consumption and the risk of colorectal cancer in a population based cohort study. Sci Rep. 2015;5:13484. doi:10.1038/srep13484.

9. Hu FB. Plant-based foods and prevention of cardiovascular disease: an overview. AJCN. 2013;78(3):544S–551.

10. Zheng F, Yan L, Yang Z, et al. HbA 1c, diabetes and cognitive decline: the English Longitudinal Study of Ageing. Diabetologia.

2018 Apr 1;61(4):839-48.

11. McMacken M, Shah S. A plant-based diet for the prevention and treatment of type 2 diabetes. Journal of geriatric cardiology: JGC. 2017 May;14(5):342 12. Wendy Glauser. Pharma influence widespread at medical schools: study. CMAJ 2013;185: 1121–1122.

13. What the health. (2017). (film) Directed by K. Anderson and K. Kuhn. United States: A.U.M. Films and Media.

Documentaries like What the Health, recently featured on Netflix, delve into detail regarding some of the overarching themes discussed here.13 However, one of the critiques of the film is downplaying the role of sugar in optimal heath. Chronic overconsumption of simple carbohydrates leads to chronic insulin spiking, and therefore, insulin resistance–which progresses to Type 2 diabetes. In addition to being mindful of diet, reducing feeding frequency will give the body a rest from insulin and prevent insulin resistance.

Perhaps we should remind ourselves IMS MAGAZINE SUMMER 2018 RARE DISEASES 7

RETROSPECTIVE

Establishing the Foundation for Medical Research

Dr. John (Jack) Coleman Laidlaw 8 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

RETROSPECTIVE

Courtesy of UofT Faculty of Medicine Courtesy of UofT Archives

Jack Laidlaw as a medical student at UofT

By Anna Badner

D

r. John (Jack) Coleman Laidlaw was a practicing Endocrinologist, Emeritus Professor in the Department of Medicine at the University of Toronto, advisor to World Health Organization, and among many others, an innovative force in graduate education.

Coinciding with the start of World War II, Dr. Laidlaw, at age 16, began his medical training at the University of Toronto (UofT) in September 1939. Not only was this an important time in history, but also a revolutionary period of change in the field of medicine. At the forefront of the antibiotic era, doctors were only beginning to gain widespread access to penicillin, driving greater emphasis on research and innovation in patient care. This heightened exposure to scientific promise was the foundation for Dr. Laidlaw’s extraordinary career and vision for clinical investigation.

In his own words, “Science makes all the difference… But to have the science without the human warmth is just not good enough”.1 Innovators have the potential to identify limitations and implement strategic

Drs. Jack Laidlaw and Catharine Whiteside at Dean’s Alumni Awards on November 3rd, 2014

solutions. Accordingly, recognizing the obstructive detachment between basic biological research and clinical application, Dr. Laidlaw sought to create a pioneering interdisciplinary graduate program at the UofT. He wanted Medical Doctorate (MD) degree graduates to have access to graduate level courses in biology, thereby learning proper research methodology and setting a higher standard for translational work. This vision was shared by Dr. Ernest McCulloch and, together, they co-founded the Institute of Medical Science (IMS).

Currently one the of the biggest graduate departments at the University of Toronto, with over 600 faculty and 500 students, the IMS was initially met with considerable scrutiny and skepticism. The traditional model of research training received by MD graduate students consisted of yearlong apprenticeships, without advanced course requirements or critical evaluation. As a result, the IMS, which offered more structured training, was thought to be unnecessary. Yet, their patience and perseverance paid off when the IMS was approved as a graduate unit of the School of Graduate Studies (SGS) in 1967 and Dr. Laidlaw served as the founding Director from 1967 to 1975.

Although his main interests were in treating patients and training the next generation of clinician investigators, Dr. Laidlaw was also a highly respected researcher in endocrinology. His research career began with a Masters (Toronto, 1947) and a PhD (London, 1950) in Biochemistry, followed by further training at Harvard University. During his scientific endeavours, Dr. Laidlaw tackled subjects ranging from steroids, the adrenal gland and high blood pressure. This work, along-side his advocacy for research education, led him to be named to the Order of Canada in 2003, receive an honorary Doctor of Science from McMaster University in 2004 and a Lifetime Achievement Award from the UofT Faculty of Medicine in 2014. The annual IMS Scientific Day manuscript prize is also named in his honour.

In 2015, Jack passed away at the age of 94.

He will continue to be remembered for his medical career, advocacy for clinical research, and important vision for clinical investigation in the 21st century.

References:

1. 1https://www.thestar.com/news/gta/2012/09/16/u_of_ts_faculty_of_medicine_celebrates_125_years.html

IMS MAGAZINE SUMMER 2018 RARE DISEASES 9

INFOGRAPHIC

THE LAST MILE IS

THE LONGEST

when rare diseases make a comeback

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92-94% estimated threshold in vaccine coverage needed for herd immunity against Measles6

86.9

86.5

85.3

81.7

Kansas

Arkansas

Pennsylvania

Colorado

Lowest estimated rates of MMR coverage in the US 7

Measles Incidence in the US and Canada

2014 US outbreak mostly accounted for by unvaccinated individuals of the Amish community in Ohio 2

Number of reported Measles cases

800 700 600

Measles declared eliminated in the US and Canada 2,3

65 of 118 confirmed reported cases due to low MMR vaccination coverage amongst Somali-Americans because of perceived increased rates of autism 8

500 400 300 200 100

Canada US

0

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

10 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

Year

INFOGRAPHIC

1. World Health Organization. (1997). Elimination and Eradication of Diseases, with Special Reference to Measles and Tuberculosis.

2. https://www.cdc.gov/measles 3. De Serres, G., et al. (2015). Measles in Canada Between 2002 and 2013. Open Forum Infections Diseases. 2(2).

4. https://rarediseases.info.nih.gov/ 5. World Health Organization. (2018). Measles. http://www.who.int/news-room/fact-sheets/detail/measles 6. Orenstein, W., Seib, K. (2014). Mounting a Good Offense against Measles. NEJM. 371(18):1661-1663

7. Seither, R., Et al. (2014). Vaccination Coverage Among Children in Kindergarten - United States, 2013-14 School Year. Morbidity and Mortality Weekly Report, Centers for Disease Control and Prevention.

8. Hall, V., Et al. (2017). Measles Outbreak - Minnesota April-May 2017. Morbidity and Mortality Weekly Report, Centers for Disease Control and Prevention.

9. World Health Organization. (2018). Europe observes a 4-fild Increase in Measles Cases in 2017 Compared to Previous Year. http://www.euro.who.int/en/media-centre/sections/press-releases/2018/europe-observes-a-4-fold-increase-in-measles-cases-in-2017-compared-to-previous-year 10. European Centre for Disease Prevention and Control. (2018). Measles Outbreaks Still Ongoing in 2018 and Fatalities Reported from Four Countries. https://ecdc.europa.eu/en/news-events/measles-outbreaks-still-ongoing-2018-and-fatalities-reported-four-countries 11. World Health Organization. (2017). Fact Sheets on Sustainable Development Goals: Helath Targets - Measles and Rubella.

WHO European Region reports a rebound in Measles in 20179

Romania (5224) Rest of EU/EEA

Incidence of reported measles cases breakdown by country in 201710

Germany (906)

Measles Incidence in the EU/EEA

Greece (1398)

35000

Italy (4978) 30000

20 out of 27

87%%

25000

Number of reported Measles cases

EU countries were below second vaccination targets10

of reported 2017 measles cases were unvaccinated individuals10

20000

15000

WHY

10000

hasn’t measles been eliminated in Europe?11

Lack of immunization program commitment Vaccine hesitancy Vaccine refusal

5000

Non-compliance Gaps in surveillance and reporting Parental resistance about the MMR vaccine due to false linkage to autism

0 2010 2011 2012 2013 2014 2015 2016 2017

Year

Religious obligation and/or philosophical beliefs IMS MAGAZINE SUMMER 2018 RARE DISEASES 11

FEATURE

Understanding How Cancer Research Led to The Study of Rare Mendelian Disorders Within the Iranian Population By: Maryam Bagherzadeh

T

he human genome contains over 20,000 genes that serve as a blueprint for all the proteins that make us into who we are. A single mutation in any of these genes can result in disease. Rare diseases caused by a highly penetrant mutation in a single gene are referred to as “Mendelian disorders”. They are rare in the general population, but some of them are over-represented in other populations. For example, some rare Mendelian disorders inherited recessively are concentrated in certain populations within the Middle East. It was actually these disorders that caught the attention of Dr. Mohammad Reza Akbari, a molecular geneticist working at Women’s College Research Institute at Women’s College Hospital.

“As a person that has been born and raised in Iran, I have seen how some of these recessive Mendelian disorders impact peoples’ lives as well as the lives of their loved ones. For this reason, I have always been greatly interested in conducting research in this field, specifically studying recessive Mendelian disorders in this population,” explains Dr. Akbari.

Dr. Akbari and his collaborators have developed a targeted gene-sequencing panel for 26 Mendelian disorders in Iran, which includes over 650 genes. They use this panel to examine the genetic basis of patients with phenotypes that can be categorized into any of the 26 Mendelian disorders. So far, they have tested over 300 patients with a success rate of over 70% for finding the causal 12 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

genetic mutation for the patients.

Dr. Akbari is an assistant professor at the Dalla Lana School of Public Health in the division of Epidemiology, and an associate member of the IMS at the University of Toronto. His main research focus is on cancer genetics, and he only began studying rare Mendelian disorders in 2010 because of a project on the etiology of esophageal cancer. Dr. Akbari and his colleagues found that mutations in a group of genes, named Fanconi Anemia genes,

studying were from the North-East of Iran, a population named Turkmen. This population has one of the highest incidence rates for esophageal cancer worldwide, and as a result, we hypothesized that there may be a genetic basis for this disease, ” Dr. Akari explained. “But our literature search for more information on the Fanconi Anemia genes mutated within Iranian population was very inconclusive. Therefore, we decided that in order to gain more information on the role of Fanconi Anemia genes in relation to esophegal cancer, we first needed to

“As a person that has been born and raised in Iran, I have seen how some of these recessive Mendelian disorders impact peoples’ lives as well as the lives of their loved ones.” are associated with an increased risk of being diagnosed with esophageal cancer.

Fanconi Anemia is a rare mendelian disorder, which annually impacts three out of every one million live births.

“The groups of patients that we were

do a thorough study on the genes that are involved in the Fanconi Anemia phenotype in the Iranian population.”

Inspired by this project, Dr. Akbari began to research other rare Mendelian disorders within the Iranian population via a

FEATURE collaboration with Dr. Hossein Najmabadi at University of Social Welfare and Rehabilitation in Tehran. These conditions are rare worldwide, but more common in the Middle Eastern populations, potentially due to the prevalence of consanguineous marriages (the marriage between family relatives, such as first cousins). Some examples include muscular dystrophy, retinitis pigmentosa (which results in hereditary blindness), albinism, and bardet-biedl syndrome (a genetic disorder that has an impact on multiple body systems, such as hypogonadism and renal failure).

Dr. Akbari is also studying families with currently unknown genetic disorders. For example, he and his collaborators recently conducted a linkage study on a family with a mysterious auto-inflammatory skin disorder. A linkage study is a method used for genetic mapping, which examines the tendency for genes or genetic markers to be inherited together due to their close location on a chromosome. Although this disorder has not been previously defined, it has a dominant mode of inheritance in this specific family. Dr. Akbari and his collaborators were able to come up with several regions in the genome that could account for this disease. They also conducted next generation sequencing on those regions, leading them to find that the gene called NCSTN was mutated, and accounted for the auto-inflammatory skin phenotype in the family.

While studying rare Mendelian disorders in Iran, Dr. Akbari and his colleagues conducted whole-exome sequencing, hoping to investigate the genetic basis of these diseases. One of the first steps after sequencing the genome is to filter out the genetic variants that are commonly seen in the general population, and therefore very unlikely to be the causative variants for disease. However, the human genome databases that were available at the time were mostly specific to Caucasian, African and East Asian populations. Although the recent 1,000 Genome Project has over 26 different populations in its database, it does not include Middle Eastern populations.

Dr. Akbari explained how this was very problematic for their research on the Iranian population. “At that time, my collaborators and I concluded that if we wanted to continue our work in identifying

Courtesy of Dr. Akbari

DR. MOHAMMAD R. AKBARI, MD, PhD Assistant professor at the Institute of Medical Science and Dalla Lana School of Public Health genes for some of the new phenotypes that we were seeing in Iran, we had to develop our own human genome variations database specific to the population of Iran.

Based on that, we came up with a human genome database, which I named Iranome.

For this project, we conducted wholeexome sequencing on 800 individuals representing eight different ethnic groups that live in Iran, including Persians, Turks, Lors, Turkmen, Baluches, Kurds, Arabs, and a population who live in the Persian Gulf Islands.”

who reside in the North West of Iran share a common genetic basis with people from Azerbaijan and Turkey. Therefore, clinicians, scientists and the general population from the Middle East can take advantage of Iranome by using ethnicityspecific variants found in this database during genetic analysis.

To find out more about Iranome, visit: http://www.iranome.com/.

Importantly, although this project was conducted specifically for Iran’s population, the populations listed are representative of about half a billion people who live in the Middle East. For example, Turkmens who live in the North East of Iran are genetically similar to the Torkmenstan’s population, and the Turks IMS MAGAZINE SUMMER 2018 RARE DISEASES 13

FEATURE DR. JAMES EUBANKS, PhD Senior Scientist at Krembil Research Institute of UH, Divison Head of Genetics and Development Program, Professor in Department of Surgery at University of Toronto (cross-appointed in Institute of Medical Science and Department of Physiology)

Photo by: Krystal Jacques-Smith

Rett Syndrome: MeCP2-deficiency and the Potential for Reversibility By: Parnian Pardis

I

magine your daughter playing in the sandbox one day, laughing and having fun with her brother. Only two days later, your whole world turns upside down: suddenly, your daughter is unable to walk or communicate properly. The onset of Rett syndrome has occurred, a rare disorder which several University of Toronto (UofT) researchers believe may be reverseable.

One in every 10,000 girls suffer from this X-linked progressive neurodevelopmental disorder, for which symptoms do not arise until 6-18 months of age.1 Girls are suddenly confronted with developmental stagnation and the onset of symptoms including, but not limited to: loss of communication and motor skills; abnormal hand or eye movements; seizures; and irregular heartbeats.1 While Rett syndrome was recognized in 1983 and mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) were identified as its cause in 1999,2 this disorder does not yet have a cure nor an effective treatment. Dr. James Eubanks, a 14 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

Senior Scientist at the Krembil Research Institute of the University Health Network, wants to fill this gap.

Dr. Eubanks received his Doctoral degree at the University of California (UC), San Diego in 1991. Following his postdoctoral training at the Salk institute and Duke University, Dr. Eubanks came to Toronto and was hired as an assistant professor at the University of Toronto in 1994. He now serves as Division Head of the Genetics and Development Program at the Krembil Research Institute and a Professor in the Department of Surgery at the University of Toronto. Dr. Eubanks also holds crossappointments in the Institute of Medical Science and Department of Physiology.

Dr. Eubanks was interested in the influence of genes and gene products that have a significant function in early brain development. He used MeCP2 as a reference sample while investigating the potential role of specific methyl DNAbinding factors in influencing brain sensitivity in epilepsy and stroke. The

discovery in 1999 that identified MecP2 as cause of Rett syndrome2 led Dr. Eubanks to focus on understanding the impact of MeCP2 on brain development and function, as well as the consequences of its absence on brain activity.

To paraphrase a colleague, Dr. Janine LaSalle from UC Davis, Dr. Eubanks likened the brain to a huge orchestra and MeCP2 to its conductor. Members of the orchestra may be able to play their instruments when the conductor is absent, but we cannot actually hear the melody.

So, we can’t appreciate the music. MeCP2 thus governs nervous system activity to generate a homeostatic balance and keep the system in normal tolerance range.

With this understanding, it is clear that future advancements targeting MeCP2 deficiency in mice are crucial to improve the quality of lives of patients with Rett syndrome, and ideally, to eradicate the syndrome as a whole.

Dr. Eubanks and his team have started to think about how to rescue the phenotype

FEATURE of MeCP2-deficient mice. Fortunately, a colleague in Scotland had generated a number of mutant mouse lines that either 1) completely lacked MeCP2, or 2) expressed an allele to allow a silent MeCP2 to be reactivated using a Cre-lox system. To identify whether therapeutic improvement was possible in patients with Rett syndrome, Dr. Eubanks’ team devised strategies to reactivate the non-functional MeCP2 gene in these genetic models at very symptomatic stages of development, and conducted subsequent behavioral

with something different, and that’s what we’re doing now,” Dr. Eubanks explained.

There are several paths to make these findings clinically relevant. Ideally, researchers can identify the cure, the “moonshot” drug that can restore MeCP2 functionality. Dr. Eubanks acknowledges the possibility of this based on the type of mutation present. For example, in the case of a nonsense mutation, a mistake in the genetic sequence for the MECP2 results in a premature termination codon and

“You can’t do it all—you’d like to do it all—but you really have to do what you think is best and most likely to give returns now.” analyses. “To our pleasure, and somewhat surprise, the mice got a lot better.

Dramatically better,” said Dr. Eubanks.

Videos of a mouse prior to, and three months after, MeCP2 reactivation demonstrated exactly this improvement.

Pre-treatment, the mouse moved with difficulty, experienced seizures and tremor, and had trouble breathing. Three months later, the diagnosis of that same mouse was remarkably improved. The mouse still experienced a hobble while walking, but could now move freely and lived on average three times longer than its untreated litter mates. The previously attenuated cognitive abilities in this mouse had recovered to levels found in wildtype mice. Previous groups in Scotland had shown positive outcomes following reintroduction of the non-functional MeCP2 gene at less symptomatic stages, but this finding was the first indication that the problems associated with several neural systems could be rescued and set the foundation for why Dr. Eubanks thinks Rett Syndrome is reversible.

“We should be able to develop something that can have a similar effect in patients as what we see in mice. The unfortunate part is that the strategies used in mice have no clinical applicability—you can’t make that system in patients. So we have to come up

halts protein synthesis. However, effective drugs will trick the cell to skip over a nonsense mutation and reach the end of the normal protein coding sequence.

Searching for a drug with high fidelity and low toxicity, Dr. Eubanks and Principal Investigator, Dr. Alan Kozikowski, from StarWise Therapeutics, have received a Small Business Innovation research grant to experiment with this further.

The second approach is pharmacological therapy—targeting deficits that have already been identified as a consequence of MeCP2 deficiency. Dr. Natasha Shulyakova did exactly this. During her doctoral training with Dr. Eubanks, she questioned whether absence of MeCP2 causes increased oxidative stress in the neural system, and whether too much reactive oxygen species has progressive deteriorative consequences. In vitro, she was able to show that an antioxidative strategy implemented to improve mitochondrial efficiency decreases the level of oxidative stress and helps restore diminished ATP levels.

social interactive behavior improved.

Their epilepsy activity didn’t change, so it didn’t help everything, but it helped a number of these properties,” remarked Dr. Eubanks. Gathering interest, Dr. Shulyakova and Dr. Eubanks worked with a team to take her results and put them into a clinical trial. Two years later, having completed all regulatory requirements and manufacturing the necessary cocktail, recruitment for this clinical trial commenced in April of 2018.

Finally, gene editing, gene therapy, and X chromosome reactivation can play a large role with further developments in technology. Coupling these techniques, mutations have been corrected in cultured cells. The difficulty that remains is translating these findings in vivo.

Ultimately, “you can’t do it all—you’d like to do it all—but you really have to do what you think is best and most likely to give returns now. And let basic science identify the things that will give returns tomorrow,” says Dr. Eubanks.

Funding from CIHR, Ontario Brain Institute, Epilepsy Canada and the Canadian CDKL5 Network allows Dr. Eubanks to actively pursue the ideals of the Institute of Medical Science—bench to bedside. While he may have a lot of ideas, Dr. Eubanks humbly recognizes students as the driving force for his ongoing studies.

“Often, it’s the job of the student to show what isn’t going to work… something that may not be recognized is how important the ‘it didn’t work’ turns out to be for me sitting here. It’s frustrating for the student, but in many ways [it’s] essential for sculpting what is the right direction ,” says Dr. Eubanks.

References 1. Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56(3):422-437.

2. Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185-188.

Taking her findings one step further, this same antioxidative “cocktail” significantly improved various performance indications in MeCP2-deficient mice.

“They had better ambulatory activity, their balance was a bit better, and their IMS MAGAZINE SUMMER 2018 RARE DISEASES 15

FEATURE

‘Suicide Disease’ ‘Suicide Disease’ The ‘Suicide Disease’:

An Interview with Dr. Mojgan Hodaie By: Akshayan Vimalanathan

Photo by: Grace Jacobs

T

rigeminal neuralgia (TN) was historically dubbed the ‘suicide disease’ because many individuals with the condition developed suicidal tendencies, preferring death over the pain.

Arguably considered the most painful condition known to humankind, TN is a rare chronic pain disorder characterized by sporadic episodes of severe facial pain originating from the trigeminal nerve (CN-V). These episodes occur suddenly and spontaneously, lasting anywhere from a few seconds to a few minutes. According to the National Institute of Health, the disorder affects approximately 12 out of every 100,000 people per year.1 As a staff neurosurgeon at Toronto Western Hospital with clinical expertise in neuropathic pain, Dr. Mojgan Hodaie witnesses first-hand the debilitating nature of TN. Her dual role as a clinician-scientist allows her to address the welfare of people suffering with TN from both fronts.

Dr. Hodaie is a professor in the Department of Surgery at the University of Toronto (UofT) and a scientist at the Krembil Research Institute. She completed her neurosurgery residency and fellowship in stereotactic and functional neurosurgery at the UofT. With a special focus in neuropathic pain, she developed a particular interest in TN. “One [area] that was very attractive to me, within the field of functional neurosurgery, was pain. Pain is a peculiar thing, as it’s a shared human experience that is generally thought of as subjective, therefore difficult to understand and make sense of. We can think of pain as an entity onto itself that involves the whole central nervous system (CNS) and is very complex, [but] are there also ways where we can think of pain as essentially a surgical problem? And that was, I think, one of the most fascinating 16 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

DR. MOJGAN HODAIE, MSc, MD Scientist, Krembil Research Institute Affiliated Faculty, Techna Institute for the Advancement of Technology for Health (Techna) Associate Professor of Surgery, Faculty of Medicine, University of Toronto things for me,” says Dr. Hodaie.

Classical TN is the result of a blood vessel pressing against the trigeminal nerve as it exits the brain stem, causing neurovascular compression of the nerve.

The pulsating blood vessel rubs on the nerve and can slowly wear away the myelin sheath protecting it, creating small pockets of focal demyelination. This produces subsequent crosstalk between sensory and pain fibers, leading the brain

to misinterpret mild facial sensations as stabbing pain. TN has drawn comparisons to the feeling of being electrocuted. “[Patients] describe it as a 10,000-volt electric surge,” reveals Dr. Hodaie.

Interestingly, the attacks are triggered by very innocuous activities such as touching the face, eating, talking, or even being exposed to the wind.1 To combat these triggers, patients will often avoid these daily activities entirely, becoming very emaciated and socially withdrawn.

FEATURE

“I think our work has been the first instance where a measure of objectivity was introduced in studying this pain syndrome.”

Fortunately for people suffering with TN, surgical options exist which offer long-term pain relief. For those who are otherwise physically healthy, microvascular decompression is the preferred surgical treatment. The procedure involves entering the brain through a small incision behind the ear, locating the trigeminal nerve, and lifting the offending vessel off the nerve so that a piece of shredded Teflon can be placed in between.

As Dr. Hodaie explains it, “We need to put something that cushions the nerve and dampens the pressure of the blood beating within the vessel. We need that something to be inert, so it doesn’t cause an inflammatory reaction. The best candidate that we have is just a piece of shredded Teflon, [which is] like a white sponge.”

However, for those who are physically ill, have additional risks for surgery, or are older in age, microvascular decompression can be potentially dangerous. In these cases, Gamma Knife radiosurgery is recommended. By directing highly focused beams of radiation at the site where the trigeminal nerve exits the brainstem, the procedure creates a lesion on the nerve that disrupts sensory signal transmission to the brain.1 In most cases, surgical treatments provide complete relief from pain. However, interestingly, the pain reoccurs for select individuals. At present, it is not understood why such individual differences exist in response to treatment.

Dr. Hodaie and her team are exploring ways to use advanced brain imaging to help improve neurosurgical outcomes for patients, and to better understand TN. She has already made notable contributions to the field of functional neurosurgery, pinpointing key neuroanatomical signatures in TN and introducing imaging adjuncts that inform surgical diagnosis and treatment.

“Uniformly, the way TN has been studied is by way of clinical studies, purely relying on the subjective reports of patients.

I think our work has been the first instance where a measure of objectivity was introduced in studying this pain syndrome,” says Dr. Hodaie.

Using diffusion tensor imaging/ tractography, Dr. Hodaie’s lab has identified imaging correlates specific to TN, which serve as adjuncts to clinical data. “What we’re able to find is essentially a signature of pain that is left on the trigeminal nerve. If you look at the nerve microstructure, there are specific areas where we see distinct structural changes.

It indicates, potentially, a nerve that is very much compressed. Without advanced MR imaging, tiny details like this get missed. And so, [having] this measure of objectivity and having real imaging modalities [to] study a condition that has been forever subjective… that really, I think, is my greatest contribution.”

Another aspect of Dr. Hodaie’s work focuses on understanding how the presence of pain impacts the CNS in its entirety. How is neuropathic pain, particularly TN, represented in the brain?

Are there gray and white matter CNS changes associated with TN? These are fundamental questions that Dr. Hodaie attempts to address using structural imaging techniques like cortical thickness analysis and voxel-based morphometry.

The thickness of the cerebral cortex and the pattern of cortical folds provide valuable information for understanding disease progression, for identifying affected brain regions, and possibly for assessing treatment.2 By looking into CNSrelated features of TN that until now were entirely unknown, she hopes to delineate the role they play in the ongoing nature of this pain.

points out, “We found, in fact, that there were changes not only restricted to the trigeminal area, but very much within the brain–in the cortex, in the subcortical gray, and in the white matter. And these were primarily in areas that are important for the modulation and perception of pain.

It is quite possible that two patients that are identical in terms of neurovascular compression can [experience] different kinds of pain because of the CNS topdown modulation effect of that pain.”

When asked what inspires her research, Dr. Hodaie recalls a defining moment in her career: “As a resident, I had the unique blessing of meeting one of the fathers of functional neurosurgery, Ron Tasker. I distinctly remember we were having a session with [him] and one of the questions that I asked was, ‘Will there be an opportunity one day in which we can think of pain in an objective manner and not always as a subjective problem?’

He shared some very clear and tangible ideas about pain that I found extremely interesting. That session and that question has stayed with me and has really formulated a lot of my research.”

While there are still many unanswered questions regarding TN, Dr. Hodaie is optimistic about the current progress of the field, “We hope that in the near future, the imaging capabilities we have developed will help us predict who will respond well to treatment and allow us to establish a personalized medical approach.”

References 1. Trigeminal Neuralgia Fact Sheet [Internet]. National Institute of Neurological Disorders and Stroke. U.S. Department of Health and Human Services; 2013 [cited 2018 May 3]. Available from: https:// www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/FactSheets/Trigeminal-Neuralgia-Fact-Sheet 2. Hutton C, Vita ED, Ashburner J, Deichmann R, Turner R. Voxel-based cortical thickness measurements in MRI. NeuroImage.

2008 May;40(4):1701–10.

Speaking on her findings, Dr. Hodaie IMS MAGAZINE SUMMER 2018 RARE DISEASES 17

FEATURE

Successes in Rare Bleeding Disorders: Hemophilia and Others Courtesy of Dr. Caraco

By: Erika Opingari

A

cure for hemophilia is in the near future. A seemingly surreal statement to write and read, but a welcomed prospect nonetheless.

Hemophilia A and B are rare X-linked bleeding disorders caused by genetic mutations leading to respective deficiencies in the blood-clotting proteins, factor VIII (FVIII) and factor IX (FIX).

As an X-linked disorder, hemophilia is mainly a disease affecting males with a prevalence of one in 5,000 and one in 1,0000 females, respectively. Yet there are estimated to be two or three times as many women who are carriers of a hemophilia mutation–20-30% of these women also suffer from excessive bleeding. A life-long condition usually recognized in childhood, the severity of hemophilia reflects the degree of factor deficiency. Fortunately, over the years, therapy for hemophilia has decreased mortality rates and improved patient outcomes.

To provide an expert review and discuss the trajectory of hemophilia treatment and care practices is Dr. Manuel Carcao, a Clinician Investigator in the Division of Haematology/Oncology at The Hospital for Sick Children. Dr. Carcao completed his medical training at the University of Toronto, after which he completed fellowships in pediatric hematology/ oncology and hemostasis before joining 18 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

DR. MANUEL CARCAO Clinician Investigator, Division of Haematology/Oncology (Department of Paediatrics); Senior Associate Scientist, Child Health Evaluative Sciences, SickKids; Professor of Paediatrics, University of Toronto both institutes as faculty. Alongside his clinical practice, Dr. Carcao conducts both basic science and clinical research into congenital bleeding disorders, including hemophilia, von Willebrand disease, as well as rare inherited coagulation and platelet disorders, such as Glanzmann thrombasthenia.

Bleeding disorders typically occur due to a deficiency of a certain protein in the coagulation cascade. For a clot to form, there are a series of interconnected steps involving platelets and coagulation factors (factors I to XIII) which result in the formation of strong fibrinplatelet matrices. When one of the coagulation factors is absent (i.e. severe hemophilia) or reduced (i.e. mild/ moderate hemophilia), the process is disrupted, thereby preventing proper clot formation and increasing the risk of bleeding. Conventional management of bleeding disorders has been the replacement of the missing factor through intravenous injection. In the 1960s, when factor replacement therapy began for hemophilia, the products that existed were all plasma-derived factor concentrates prepared by obtaining and pooling blood from thousands or tens of thousands of donors. While this was effective, the potential for contamination was not fully appreciated at the time. Unfortunately, in the 1980s a disaster occurred when

virtually all plasma-derived factor concentrates were contaminated with HIV. As a result, thousands of individuals with hemophilia and other bleeding disorders contracted HIV. “This tragedy resulted in a tremendous drive to shift hemophilia therapies towards genetically engineered recombinant factors,” says Dr. Carcao, “and by the 1990s, this was successfully translated into practice.”

While recombinant factors have drastically changed outcomes for patients with hemophilia, there remain many challenges with the administration of these products, particularly in children. Factor products must be given intravenously and, due to short half-lives in the bloodstream, must be given frequently–sometimes several times a week. To address these issues, extended half-life recombinant factor products have been developed and implemented to reduce the frequency of injections and to improve quality of life. However, many patients with hemophilia may also develop inhibitors (neutralizing antibodies) against the infused factor during treatment. The development of inhibitors diminishes the benefits of the treatment and complicates the management of these patients, as the immune system will destroy the factor upon its infusion. Consequently, such patients have traditionally had the worst outcomes.

Still, hemophilia research continues to push

FEATURE the boundaries and improve treatment options. Dr. Carcao explains that the next wave of change in hemophilia involves non-factor therapies, which will replace the function of certain factors, in particular FVIII. Non-factor therapies have the advantage of being able to be administered subcutaneously and infrequently–weekly or even monthly, thus facilitating the administration and accessibility of treatment for patients. Non-factor therapies can also be used in patients with inhibitors and can provide these patients with comparable treatment efficacy to that of patients without inhibitors.

Almost unbelievably, Dr. Carcao says we are close to the point of curing hemophilia.

bleeding disorders require further attention.

Although the development of recombinant factors to treat other, rarer bleeding disorders would be greatly beneficial, there has been much less fervor to pursue this research. Dr. Carcao explains that because the market for very rare diseases is much smaller, pharmaceutical companies do not invest as many resources towards the costly development of products for these rare conditions.

Alongside his clinical work, Dr. Carcao is also involved with his colleagues Drs. Walter Kahr, Victor Blanchette and Margaret Rand, in basic laboratory research of congenital and acquired coagulation (e.g. von Willebrand disease, Factor XIII deficiency, anti-plasmin

Figure 1: Coagulation cascade. Picture adapted from Colman R.W. (2006)1.

He predicts that in just ten years from now, hemophilia patients will no longer require regular therapies with either intravenous factor infusions or non-factor therapies.

Instead, they will be treated, or even cured with gene editing and gene therapy.

Many studies are investigating the role of gene therapy in fixing factor deficiencies, which will allow patients to endogenously produce all the necessary factors.

Evidently, hemophilia management has dramatically changed over the decades and is expected to keep changing. “We’ve generally in the past, never talked about curing a genetic disorder,” says Dr. Carcao, “and now many clinical trials are doing just that.”

While hemophilia has taken great strides in research and treatment, other rare congenital

deficiency) and platelet disorders (e.g.

Glanzmann thrombasthenia (GT), MYH9 macrothrombocytopenia, and gray platelet syndrome). Being in such a multicultural city such as Toronto, Dr. Carcao and his colleagues encounter a much larger prevalence of patients with these extremely rare bleeding disorders compared to other centers. Consequently, The Hospital for Sick Children sees a larger number of patients with disorders such as type 3 Von Willebrand disease, GT and Factor XIII deficiency than any other North American center.

individuals worldwide, making it much rarer than hemophilia. Consequently, GT has not seen the same trajectory in medical advancement as has hemophilia. While patients with GT have normal platelet counts, their platelets are dysfunctional, resulting in uncontrolled bleeding.

Therefore, they often require platelet transfusions to prevent or stop bleeding.

Transfusing patients with GT is unique in that it is the only situation where patients with normal platelet counts are routinely transfused with platelets. The uniqueness and the ramifications of this situation was not fully appreciated prior to the work completed by Dr. Carcao and his colleagues.

Dr. Carcao and colleagues showed that in patients with GT, the healthy transfused platelets are completely overpowered by the native dysfunctional platelets, which remain in the majority. Competition between the native malfunctioning platelets and the healthy transfused platelets reduces the expected benefits of a platelet transfusion. Therefore, patients with GT require higher levels of transfused platelets than normal in order to achieve therapeutic goals. This important finding will modify practice, thereby improving the treatment of patients with GT. It is due to the dedicated work of investigators, like Dr. Carcao and his colleagues, that we continue to make advancements in medicine and change the story of patients with rare diseases. Curing hemophilia is hopefully just the beginning of this story.

References 1. Colman RW. Are hemostasis and thrombosis two sides of the same coin? J Exp Med. 2006; 203(3):493-495.

GT is a severe, autosomal recessive bleeding disorder caused by a quantitative or qualitative defect of platelet membrane glycoprotein IIb-IIIa, a fibrinogen receptor required for platelet aggregation. It is estimated to affect one in one million IMS MAGAZINE SUMMER 2018 RARE DISEASES 19

FEATURE

al Clarity Striving for Visual in the Genomic Era By: Ranya Barayan, Anjali Vig

I

nherited retinal dystrophies are genetically heterogeneous blinding disorders characterized by progressive retinal degeneration (RD). RD affects approximately one in 3,000 individuals and can manifest itself at various ages with variable severity and inheritance.1 Using genetic testing, mutations have been identified in over 200 genes, but these account for at most 60% of cases.2,3 There are only a few common variants which have been found to influence inherited RD and almost all causal mutations are rare.1 As there is no cure for RD, there is a strong incentive to understand its genetic basis to develop therapies that can slow or prevent vision loss, generate better diagnostic tools, and improve quality of life.

To learn about the advances that have been made to better our understanding of RD pathogenesis, we sat down with Dr. Elise Héon, member of the Institute of Medical Science and professor of Ophthalmology with the department of Ophthalmology and Vision Sciences at the University of Toronto. She is also a staff ophthalmologist and director of the Ocular Genetics Program at the Hospital for Sick Children.

This program is unique in Canada and one of only a few in the world. Her clinical work focuses on the management of hereditary eye diseases, which include hereditary cancer (retinoblastoma) and other non-cancerous blinding conditions such as retinitis pigmentosa (RP). In addition to her teaching and clinical responsibilities, Dr. Héon is a ClinicianScientist in the field of Ocular Genetics, and a Senior Associate Scientist at The Hospital for Sick Children Research Institute in the program of Genetics and Genomics Biology. Her laboratory is involved in the genetic analysis of inherited eye disorders with a focus on retinal dystrophies.

Dr. Héon specialized in ophthalmology in medical school at Sherbrooke University, where she quickly became bored with 20 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

the routine training in cataract surgery.

She describes what first inspired her to study rare diseases. “I had encountered a case of rare disease as a resident which, unlike common diseases, could not be treated with prescription-based medicine or surgery, and it was really sad that these patients could not be treated,” Dr. Héon explains. “I believe that there is always a solution. Just because we currently don’t have something that “fits”, it doesn’t mean that a solution doesn’t exist—that there is no hope.”

For this reason, she came to the University of Toronto in 1991 to complete her fellowship with Dr. Maria Musarella, who fostered her interest in the genetics of inherited eye diseases. At that time, only two genes were known: rhodopsin (RHO) and retinal degeneration slow (RDS). If someone found a mutation in a different phenotype, it automatically meant that

many cases, the lowest hanging fruit have already been picked, which requires her lab to confront conventional thinking. One of her main projects involves interpreting Whole Genome Sequencing (WGS) data from patients with inherited retinal disease where no disease-causing mutations have been identified by “standard of care” genetic testing. This testing does not fully exploit coding and non-coding regions of the genome, whereas WGS provides the opportunity to dig into these previously unexplored areas. It also gives deeper insight into how phenomena such as transposable DNA elements like retrotransposons, copy number variations, and regulatory elements can influence inherited retinal disease.

However, analyzing WGS data can be challenging because of the immense quantity of information that is produced.

Dr. Héon and her lab are continuously

“It is a very emotional process when someone learns that it is likely that their vision will decrease.” they had to be wrong, because at that time it was thought that one gene “clearly” meant one phenotype. Not long after, there was a major shift in the whole paradigm of understanding diseases. The ability to clinically phenotype patients expanded as the technical tools continued to improve.

Therefore, ophthalmology was in a unique position to phenotype quite precisely. Now, the exact structure and function of over 200 genes have been well-documented.

Dr. Héon’s work focuses on identifying the underlying genetic mechanisms of a variety of inherited ocular diseases. In

learning how to best interpret this data.

She emphasizes the importance of collaboration by highlighting that her work is made possible through a collaborative and multidisciplinary approach to research, with a strong network including bioinformatics, epigenetics, cellular biology, structural biology and imaging.

As a part of the WGS project, Dr. Héon’s group is interested in identifying and validating the role that putative diseasecausing variants in regulatory and intergenic regions of the genome play in RD. So far, there has only been one

FEATURE association of variants in regulatory regions to retinal degeneration,4 making this an exciting opportunity to highlight the role of regulatory regions in RD. The project will help lay the foundation for future gene discovery and variant interpretation for individuals with unknown causes of RD. “It is a very emotional process when someone learns that it is likely that their vision will decrease. When patients do not know what they have, they feel alone,” says Dr. Héon. “Providing patients with ‘their gene’ or the variant that is responsible for their RD is an important step in helping them feel less alone. It is important to always find options for the patient, and when patients know that you are trying to make a difference, they trust you.”

To maintain that trust, Dr. Héon stresses the importance of realistic scientific communication that does not overhype the implications of scientific results or provide false hope “Otherwise, donors and patients will not trust scientists anymore and the whole system will be at a loss,” she explains. “Playing ‘hero race’ is a big mistake, because at the end of the day it’s about the patient and the people who may benefit from the research.”

Although there are still many unanswered questions about the genetic and mechanistic characteristics of RD, there are also several exciting applications in the field. Studying the eye has a unique advantage for developing therapies because it is accessible and immune privileged.5 This means that experiments and tests can be conducted on it without affecting other parts of the body.

One promising area is gene therapy, where healthy genes are transplanted into cells to replace defective genes. The first gene replacement therapy trial for retinal degeneration was successfully completed and the product has been approved by the FDA.6 Specifically, RPE65-associated Leber’s congenital amaurosis was treated by means of subretinal delivery of recombinant adeno-associated virus (rAAV2) vectors carrying the human RPE65 complementary DNA. The treatment improved visual sensitivity for one to three years. However, after this time visual sensitivity declined.6 Future research should focus on improving the longevity of these therapeutic effects.

With the rapidly evolving era of precision medicine—there may be a future in which many of the genetic causes of inherited

Photo by: Iris Xu

retinal diseases have been identified.

Importantly, the molecular mechanisms underlying disease progression will also be better defined, making it possible to develop potential therapeutic interventions—such as targeted therapy aimed at slowing down the degenerative process. Factors such as the age of the patient, stage of disease, type of mutation, and patient reported outcome measures will be taken into consideration when establishing future personalized gene and stem cell therapies.

Dr. Elise Héon left us with some words of wisdom: “For young women and men pursuing careers in medicine and/ or research: stand tall and do your job, live with integrity—even in times of adversity, and acknowledge that you have strengths and share them with others. Do not be opposed to acknowledging your weaknesses; instead, seek out the necessary resources to help manage them. Take pride in your vulnerabilities which make you who you are; recognize that it is never really just about you—appreciate your supportive environment. Find a mentor to refer to for advice and guidance. Do not refrain from speaking up, and never tolerate disrespectful interactions—do not let that negative energy get to you! Finally, do what you enjoy so that you smile in the morning and feel proud at night.”

References 1. Wright, F. A. et al. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nature Reviews 11, 273-284, doi:10.1038/nrg2717 (2010).

2. Nishiguchi, K. M. et al. Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. Proc Natl Acad Sci U S A 110, 16139-16144, doi:1308243110[pii]10.1073/pnas.1308243110 (2013).

3. Guo, Y. et al. Advantage of Whole Exome Sequencing over Allele-specific and Targeted Segment Sequencing, in Detection of Novel TULP1 Mutation in Leber Congenital Amaurosis. Ophthalmic Genet, doi:10.3109/13816810.2014.886269 (2015).

4. Small, K. W. et al. North Carolina Macular Dystrophy is caused by dysregulation of the retinal transcription factor PRDM13. Ophthalmology 123(1), 9-18, doi:10.1016/j.ophtha.2015.10.006 (2016).

5. Zhou, R. and Caspi R. R. Ocular immune privilege. F1000 Biol Rep, doi:10.3410/B2-3 (2010).

6. Wright, A. F. Long term effects of retinal gene therapy in childhood blindness. N engl J Med, doi: 10.1056/NEJMe1503419 (2015).

DR. ELISE HÉON, MD, FRCS(C) Professor, Department of Ophthalmology and Vision Science at University of Toronto IMS MAGAZINE SUMMER 2018 RARE DISEASES 21

FEATURE

Unraveling Mitochondrial Mysteries: An Interview with Dr. Neal Sondheimer

Photo by: Krystal Jacques-Smith

By: Yousef Manialawy

W

hen people hear the word ‘genetics’, their minds often turn to the DNA residing in the nucleus of virtually every cell in the body, having gradually evolved after being passed down through countless generations.

However, there also exists an often-overlooked evolutionary partner of the nuclear genome: mitochondrial DNA (mtDNA).

Unlike its nuclear equivalent, mtDNA is exclusively inherited from the mother (i.e. matrilineally). Moreover, with only 13 protein-coding genes, the mitochondrial genome is dwarfed by the 20,000 or so protein-coding genes that make up the nuclear genome.1 Despite this, the pivotal role of mitochondria as the main energy source for the cell means that even minor disruptions of its tiny genome can have huge implications on human health. As a mitochondrial researcher and paediatric geneticist at SickKids hospital, Dr. Neal Sondheimer is a leading figure in the pursuit of novel 22 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

DR. NEAL SONDHEIMER The Hospital for Sick Children – Staff Physician, Clinical and Metabolic Genetics The Peter Gilgan Centre (SickKids) – Associate Scientist, Genetics & Genome Biology University of Toronto – Assistant Professor, Department of Paediatrics

techniques to characterize and treat diseases linked to mitochondrial mutations.

Dr. Sondheimer completed an MD/PhD at the University of Chicago, followed by clinical training in paediatrics, genetics and clinical biochemistry at the Children’s Hospital of Philadelphia before eventually joining SickKids in 2015. His interest in mitochondrial genetics stemmed from his experience working with patients who had rare mitochondrial mutations, and how their problems differed from those seen in patients affected by nuclear-encoded disorders. Dr. Sondheimer confesses that his interest is also largely due to his longstanding fascination with rare topics in biology. “In graduate school I worked on prion biology, so my joke is always that I’m the only geneticist who is terrified of the nuclear genome because I’ve always worked on stuff that causes phenotypes but is not subject to Mendelian inheritance.”

Dr. Sondheimer’s current research revolves around the inheritance of mtDNA in disease

and its interaction with nuclear DNA to produce distinct phenotypes. One aim of his work is to identify a method to manipulate mitochondrial heteroplasmy–the balance of different mtDNA variants within the same cell. Unlike the nuclear genome, thousands of independent copies of mtDNA exist across the mitochondrial population of the cell, and a certain percentage of those copies may carry pathogenic variants. The ratio of pathogenic to healthy mtDNA can drift and manifest into a disease phenotype if it gets too high. “We’re trying to understand if we can use a sort of structural cue within the mtDNA as a selective filter to block the replication of mutated mtDNA and allow the replication of the good mtDNA,” he explains.

Dr. Sondheimer has also recently published a study outlining a system to quantitatively evaluate how mtDNA fits into the context of nuclear genomes, and how this might relate to preterm birth.2 He explains that, whereas nuclear DNA from both parents forms new combinations in an individual, their mtDNA is fixed based

FEATURE

“Because of the way mtDNA is inherited, there actually may be a consequence to having your nuclear DNA drift too far away from it.” on their maternal ancestry. The study suggests that as the two have co-evolved over many generations, rapidly changing nuclear DNA in increasingly diverse populations might be disrupting crosstalk with mtDNA, potentially causing increased rates of preterm birth.

“If you look back a thousand years ago, people were born, lived and died in the same location and there was no opportunity for mitochondrial and nuclear polymorphisms to diverge. Now people are extremely mobile and have children with people of different backgrounds. Because of the way mtDNA is inherited, there actually may be a consequence to having your nuclear DNA drift too far away from it.”

Dr. Sondheimer is currently attempting to develop an animal model to demonstrate this, but researching mitochondrial genetics presents some unique challenges.

Unfortunately, there is currently no way to make a specific, targeted mutation in mtDNA–a technique that is a cornerstone of nuclear genetic research. To study mtDNA mutations, mitochondria have to be taken from patients and transferred into tumor cell lines, which comes at the cost of losing nuclear-mitochondrial interactions.

The elusive nature of mitochondrial mutations also poses a challenge in the clinic. “For example, when we have a family who’s had a child with an inherited nuclear disorder like phenylketonuria, we can tell them the exact probability of having another affected child–it’s 25 percent. But for mtDNA, there are no firm rules like that,” he explains.

As it stands, the challenge of mitochondrial research means that effective long-term solutions for patients with mitochondrial disease simply do not

exist. However, Dr. Sondheimer remains hopeful that these solutions are over the horizon in clinical care. “For very severe nuclear disorders we can use in vitro fertilization to help people not have an affected child, and that’s something that is just on the cusp of being possible for mitochondrial disease. Take a healthy egg [containing healthy mitochondria], remove its nucleus and stick the embryo’s nucleus in it. It’s called mitochondrial replacement therapy.”

Due to the novelty of the therapy, the procedure currently remains illegal in Canada and much of the world. Although the UK was the first to approve the therapy in 2015, the first announcement of the birth of a so-called ‘three person baby’ emerged the following year under more controversial circumstances. Being illegal in the US, a couple and their medical team travelled to Mexico to perform the procedure in an attempt to prevent their child from inheriting Leigh syndrome, a severe neurodegenerative disorder linked to mitochondrial mutations in approximately a quarter of cases.3 The experimental nature of the treatment and the controversy surrounding selective genetics has led many to question the approach. However, Dr. Sondheimer believes that the therapy is indeed the way forward.

mitochondrial DNA, that’s all anybody wants.” However, while he approves of the method, he takes issue with the aforementioned case. “It wasn’t done in a very regulated fashion, so I think there’s a lot of concerns because there are possibilities for abuse. In England there are groups who are doing it under appropriate supervision for the right reasons, and they’re picking the right patients and that’s what I think should be introduced in Canada.”

With much to discover, mitochondrial genetics undoubtedly remains an exciting frontier of research. It’s this drive that propels Dr. Sondheimer forward, and he believes this to be critical to the success of budding researchers. “The most important thing in all fields of science is to fundamentally be interested in the area that you’re working on. I think one of the things that’s helped me is that even on days, weeks, or even months where things are going badly, I at least realize that these are important problems that I want to resolve. And it helps me feel good about the things that I’m doing.”

References 1. Reference GH. What is mitochondrial DNA? [Internet]. Genetics Home Reference. [cited 2018 Apr 29]. Available from: https://ghr. nlm.nih.gov/primer/basics/mtdna 2. Crawford N, Prendergast D, Oehlert JW, et al. Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth. J Pediatr. 2018 Mar;194:40–46.e4.

3. Reference GH. Leigh syndrome [Internet]. Genetics Home Reference. [cited 2018 Apr 29]. Available from: https://ghr.nlm.nih.gov/ condition/leigh-syndrome

“Scientifically it’s essential, and I’m actually trying to work with folks in Canada to see if we can develop the technical means to do it but also to change the laws. I don’t see anything ethically wrong as a geneticist.

People who would like to use this method are trying to have healthy kids and their wishes are entirely inoffensive. We’re not recombining DNA, although ultimately the DNA for that child will come from three parents. It’s a healthy kid with normal IMS MAGAZINE SUMMER 2018 RARE DISEASES 23

BMC

Master of Science in

BIOMEDICAL COMMUNICATIONS 2018 VESALIUS TRUST AWARD WINNERS

Founded by the Association of Medical Illustrators, the Vesalius Trust recognizes exceptional graduate student research in health science visual communication in Canada and the US. Here, we highlight his year’s winning BMC Master’s Research Projects.

(FROM LEFT TO RIGHT) PATRICIA NGUYEN, NATIVIDAD CHEN, CHELSEA CANLAS Project Title: Kinundrum: A problem-based multimedia learning application for undergraduate kinesiology education Kinundrum is a web application designed as a supplementary learning resource for an undergraduate kinesiology anatomy course. Students work through lower limb biomechanics case studies at increasing levels of difficulty. Each case study is introduced with an animated injury scenario, after which students solve interactive problems accompanied by 3D models, animations, and illustrations of the affected anatomy.

Our primary goal is to engage students in deep, active learning of lower limb anatomy and foster a holistic understanding of structure function anatomical relationships.

Kinundrum is the first collaborative Master’s Research Project in the BMC program. Together we are co-designing the UX design, with Chelsea as the lead UI designer. She is developing design documentation to be shared with programmers during the implementation stage. Nati is the lead 2D animator, responsible for storyboarding and animating the introductory case injury scenarios. Patricia is the lead illustrator, spearheading the character designs and creation of the 3D anatomical models.

24 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

BMC

AILEEN LIN Vesalius Trust Research Grant Project Title: Perinatal Mental Health: Animations to educate pregnant and postpartum women about perinatal mental illness and treatment options Mental health issues are common during the perinatal period, but in spite of their prevalence, many women with perinatal mental illness remain undiagnosed and untreated. A number of barriers prevent these women from seeking help. The

most common barriers include a lack of knowledge about the conditions and their symptoms, and feelings of shame and stigma. I hope to address these barriers with my educational animations. These animations can help inform women who are undiagnosed, and encourage them to seek treatment. They can educate women who have already been diagnosed so they can be better informed and more involved in the decision-making process

for treatment. Furthermore, women can share the material with family and friends, which will help their social support circles become more knowledgeable and more understanding about their condition.

Results learned from creating this project can also be generalized to help inform the creation of sensitive and engaging educational material for similar audiences, such as women, mental health patients, new parents, or vulnerable populations.

understanding of the full extent of multiple traumatic brain injuries in a personal injury case. Advancements in medical imaging technology now allows for the use of 3D volumetric radiographs. Volumetric imaging provides more comprehensive information than 2D imaging (e.g. CT scans and MRIs), but is more complicated to interpret, especially for a non-medical audience. These radiographic images can

be enormously challenging for a judge and jury to understand. Therefore, the purpose of this visual research project is to create and evaluate a demonstrative evidence presentation that incorporates volumetric radiographic imaging, combined with three-dimensional anatomical models and animated sequences to improve juror understanding of complex medical information.

AMANDA MILLER Vesalian Scholar Project Title: Visual knowledge building and translation of volumetric radiographic imagery for dynamic 3D medical legal visualization The 3D medical legal animation I created is designed to support medical expert witness testimony and provide a judge and jury with an engaging, didactic, knowledge building experience to assist them in visualizing three-dimensionally, and enable

IMS MAGAZINE SUMMER 2018 RARE DISEASES 25

VIEWPOINT

Out of Sight, Out of Mind:

Funding for Rare Diseases By: Yvonne Bach and Parita Shah

A

bout one in 12 Canadians are affected by rare diseases, and two-thirds of these Canadians are children.1 Rare diseases are defined as “seriously debilitating or life-threatening conditions affecting fewer than five in 10,000 people”.2 Canada has recently made some advancements relating to the knowledge and treatment of rare diseases; however, considerable challenges still remain, ranging from inadequate scientific understanding and clinical expertise to drug availability and pricing.

Rigorous scientific research to improve our understanding of a disease requires funding and research participants, both of which are scarce for research in rare diseases. With respect to the availability of research funding, government agencies have a mandate “to improve public health”, 26 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

and so are less likely to favour preclinical and clinical research investigating uncommon conditions because it has a potential to influence a relatively small number of people, and thus they are likely to favour grants that address common conditions.3 The impact of research in rare diseases focuses on a small population, which makes it difficult for researchers in the field to secure funding.4, 5 In addition to the challenge of securing a grant, clinical researchers are faced with another obstacle: finding research participants. Given that rare disease populations are small, conducting a rigorous research through large randomized trials is often impractical.

However, Canada is probably one of the few developed countries in the world that has limited guidelines for providing care to individuals with rare diseases. Inadequate

resources could contribute to inconsistencies with treating rare diseases among academic scholars and clinicians. As a result, individuals with rare diseases may be at an increased risk of misdiagnoses, futile medical interventions, confusion, stigma, social isolation, and early preventable death. Fortunately, in 2012, Canada gained access to Orphanet, an online platform that offers peer-reviewed information on rare diseases from world experts. This tool not only allows clinicians to make informed decisions, but it could also allow patients and their families to gain a better understanding of their condition and actively engage in the decision-making process. Although this tool can help in making accurate diagnoses and care plans, Canada does not have readily accessible treatment options. If new and effective therapeutic interventions are found, families could still

VIEWPOINT face the financial hardship of treatment that isn’t subsidized by the government or medical insurance.

In Canada, the approval of drugs for rare diseases can take a long time, which contributes to unnecessary distress for both the patients and their families. For example, only 60% of the available treatments for rare diseases are accessible in Canada, and most get approved up to six years later than analogs in the US and Europe.1 Of the drugs available in Canada, most are so expensive that drug plans may refuse to cover the cost. Furthermore, patients requiring the remaining 40% of drugs not available domestically may have to travel outside of Canada, further adding to their financial expenses. Other options are to remain untreated—which could contribute to debilitating consequences for their physical and mental health—or opt out for other non-allopathic/homeopathic treatment options, which may or may not be effective in treating their condition.

Overall, practical treatment options for individuals with rare diseases are limited, even though our knowledge for these conditions has improved over the years.

Federal and provincial grants are not the only source that basic and clinical scientists rely on to conduct their research. Similar to most health care systems and research institutions, a large portion of their funding comes from private donors. Thus, it is up to the everyday people in our society to educate others and raise awareness on the scarcity of funding and support for people suffering from rare diseases. Although these patients and their families experience similar physical and mental burdens as those diagnosed with other life-threatening illnesses such as cancer or heart disease, it has been difficult to foster the same kind of attention from the public.

In recent years, social media has been the go-to platform for a myriad of important but overshadowed issues, including rare diseases. For instance, amyotrophic lateral sclerosis (ALS), a rare motor neuron disorder, caught international headlines when Pete Frates, a Boston College alumnus, was diagnosed with it, giving him only a few years left to live. In 2014, Pete and his friend, Pat Quinn, who also had ALS, took to social media to share their personal experiences and frustrations associated with the lack of funding in discovering

a cure for ALS, even though we have the technology to do so. The pair created the famous campaign known as the “Ice Bucket Challenge.”6, 7 The campaign went viral in the summer of 2014 when the world’s most influential leaders, politicians, athletes, and A-list celebrities (Former President George W. Bush, Lebron James, Justin Bieber, etc.) were seen being doused with a bucket full of icy cold water in support of the cause.

Soon enough, it was impossible to go on Facebook and Instagram without seeing your friend or colleague accepting the Ice Bucket Challenge.

disease and unclear connection between the act and cause, not to mention the amount of clean drinkable water that was used to complete the challenge (to which some participants responded by using rain water and even dirt). This presented a jolting realization that our society requires “exciting” and “fun” marketing campaigns to garner empathy and care for the suffering—how much knowledge and in-depth thought was given to ALS by the public?

Were the monetary donations generated from narcissistic intent or genuine concern for ALS and the future of health care?

The campaign proved to be an extraordinary feat; millions of dollars were raised for health and research organizations that focus on ALS and other degenerative neuromuscular disorders. Within one month of the Ice Bucket Challenge, the fundraising initiative had already generated $100 million USD for the American ALS Association.8 Canada also experienced a similar positive impact as a result of the campaign—$10 million CAD was raised for the ALS Society of Canada which was financially matched by the Brain Canada Foundation and Health Canada, for a total of $20 million CAD.9

And although those are valid and important concerns that would be better addressed by sociologists and marketing strategists, the awareness and funding that ALS generated would not have reached global recognition if it were not for the Ice Bucket Challenge. We should invest our time and energy in maintaining the momentum generated by this campaign and brainstorming strategies to produce a similar amount of support for the other 7000 known rare diseases in the world. The Ice Bucket Challenge was a momentous breakthrough for research in ALS and all rare diseases for that matter—but what happens when the bucket runs dry?

The tremendous surge of funding for ALS research was not raised in vain; in July 2016, the ALS Association announced that a fraction of the donations from the Ice Bucket Challenge was used to discover a new gene variant associated with ALS called NEK1 at the University of Massachusetts Medical School.10 No one can dispute the courage and determination of Frates, Quinn, and the many other advocates that helped inspire the entire world to join in on their fight. The campaign generated discussion, funding, and action in ways that a government cannot accomplish, simply because of their limited resources. The Ice Bucket Challenge was inspirational and instrumental to the progress of ALS research. However, it was also an eye-opener to the challenges that face all patients and families suffering from ALS or other rare diseases.

1. Canadian Organization for Rare Disorders (CORD). Now is the time: A strategy for rare diseases is a strategy for all Canadians; 2015.

2. The Canadian Institutes of Health Research (CIHR). Supporting cutting-edge rare disease research. Government of Canada; 2016.

3. Gupta S. Rare diseases: Canada’s “research orphans”. Open Medicine 2012;6(1):e23-e27.

4. Griggs RC, Batshaw M, Dunkle M, et al. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab 2009 Jan;96(1):20-26.

5. Lavandeira A. Orphan drugs: legal aspects, current situation.

Haemophilia 2002 May;8(3):194-198.

6. Goldberg, Eleanor (15 August 2014). “Meet The Guy Who Made ALS ‘Ice Bucket Challenge’ Go Viral”. Huffington Post. Retrieved 17 April 2018.

7. Cary, Billy (16 August 2014). “Reaction overwhelms Ice Bucket Challenge creator”. USA Today. Retrieved 17 April 2018.

8. “The ALS Association Expresses Sincere Gratitude to Over Three Million Donors”. The ALS Association. August 29, 2014. Retrieved 17 April 2018.

9. “ALS Canada awards $3 million for 12 new research projects to help make amyotrophic lateral sclerosis (ALS) a treatable, not terminal disease”. AMYOTROPHIC LATERAL SCLEROSIS SOCIETY OF CANADA. November 22, 2017. Retrieved 17 April 2018.

10. Kenna, K. P., Van Doormaal, P. T., Dekker, A. M., Ticozzi, N., Kenna, B. J., Diekstra, F. P., ... & Shatunov, A. (2016). NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature genetics, 48(9), 1037.

It is clear that funding from one sole source is insufficient and in recent years, the influence that social media holds has become a new platform for health advocacy. However, the Ice Bucket Challenge was not met unopposed; the campaign was criticized on its glamorization of a terminal IMS MAGAZINE SUMMER 2018 RARE DISEASES 27

VIEWPOINT

Turn ON Your Smartphone and

Let’s Talk Science By: Louise Pei and Beatrice Ballarin

T

oday, it is almost impossible to stay away from social media. Since the development of smartphones, it has become incredibly easy to connect to the web, anywhere, anytime. Whether it be Twitter, Facebook, or Instagram, there is no hiding. With this rise in social media platforms, their access, and usage, people have started using them as tools to show la bella vita—a mix of holiday pictures, exotic landscapes, and amazing food recipes. Yet, is there a way for scientists to use these platforms effectively? Here, we examine the history, current trends and potential of social media in science dissemination.

In addition to connecting with other researchers around the world, several scientists have chosen to use social media as a tool to engage with the public. These platforms can also provide a window into everyday research life, virtually bringing people inside their laboratories and sharing their ideas. For some, social media could also be seen as a unique opportunity to “reclaim” their identity and to change the stereotypes associated with the word “scientist”. Rather than portraying science as nerdy and complex, scientists wanted to reframe science as cool and accessible.

Thus, driving a new the era of “science communication”.

28 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

Importantly, science communication— defined as the act of sharing “scientia” (Latin for knowledge)—is nothing new.

Actually, in Ancient Greece, the sharing of knowledge took place in the main square, the agora, through the form of public debates. Unfortunately, this form of education and information dissemination was lost during Europe’s dark ages, where the majority of the population was left illiterate. Later, in 1456, thanks to the invention of the first printer by Johannes Gutenberg, knowledge slowly began to be shared again by means of printed text and manuscripts.

However, the high cost of printing made it difficult to distribute information widely and only centuries later, after the printing press revolution, could science sharing be made accessible and affordable again.

And so, it began in 1632 with Galileo Galilei. He first published “Dialogo sopra i massimi sistemi del mondo” (Dialogue concerning the two chief world system), a revolutionary book that attempted to change the dogma of the Earth being at the centre of the universe. Galileo chose to write it in Italian, when it was considered the language of the common people, as opposed to Latin, the official language of science and literacy. By doing so, he directed his book to the broader public, expanding his audience in support of his

revolutionary ideas.

Since this time, science communication has evolved and faced new challenges.

For the increasingly complex information hidden within convoluted manuscript figures, language alone is no longer enough to reach a large audience. For this reason, scientists must consider alternative platforms. Adding to this issue, tools for the distribution of information are changing rapidly, with resources such as newspapers and television losing popularity. Quick to adapt, scientists are beginning to use blog posts, YouTube videos, and Instagram pictures to share their daily lives and research ideas. Interestingly, a 2016 survey that sampled approximately 600 scientists found that Twitter was the most widely used sharing platform. It is easy to understand why—messages are short, sweet, and arguably promote the most audience-scientist interaction. Therefore, with increased unfiltered access to the public, scientists need to reconsider their responsibilities.

One of these main responsibilities will be to overcome the public’s mistrust of scientists and their research—a reality caused by decades of miscommunication.

One of the best examples of poor communication has been the issue of climate

VIEWPOINT

“The evolution of technology has brought us to where we no longer have to solely rely on traditional news outlets for the dissemination of scientific knowledge.” change. Sensationalisation, distortion, and misrepresentation of research findings has created a dichotomy in public opinion.

Advances in science communication can help solve this problem by providing a stronger understanding of unadulterated research and expressing its everyday relevance. More importantly, social media also provides an opportunity for conversation and discussion between scientists and the public. Therefore, through effective social media application, scientists can share findings with increased transparency and even build rapport with the public, potentially influencing project funding, whether it be by government or crowdsourcing (such as for the ALS campaign with the “Ice bucket challenge”).

Another important goal of science communication is to inspire the next generation of students, shaping the future of STEM. Therefore, these platforms are important in engaging and interacting with the younger public. During the early to mid 2000s, the only source of science

communication in schools was through guest speakers, which in and of itself was very rare. Now, we’ve entered an era of smartphones and tablets. Needless to say, this change in technology also brought upon a change in the way that we communicate with one another. Elementary school students are already familiar with the concept of being a world citizen; they choose what they want to be informed about, and they also actively pursue the kind of knowledge they are interested in.

This is a great opportunity to fully utilize the influence that these social media platforms have on the population to effectively increase science literacy.

While social media for science communication offers significant advantages, it is also important to note the limitations. It takes time to become established on these platforms and to develop a large subscriber network. Posts are very time-sensitive, easily missed unless they are released during peak hours. Above all, being in the public eye also means facing scrutiny and

criticism on a regular basis.

Nevertheless, science communication is an integral part of our culture. The evolution of technology has brought us to where we no longer have to solely rely on traditional news outlets for the dissemination of scientific knowledge. We can collectively agree that translating research into jargon-free content to a layperson is difficult, and scientists are not known to be the best communicators. Although social media usage has yet to be globally adopted, we see an increase in scientists using these platforms to teach others.

Proper science communication will result in numerous personal and professional benefits, and through the use of social media, today’s scientists can become even better educators.

IMS MAGAZINE SUMMER 2018 RARE DISEASES 29

VIEWPOINT

Healthcare and the

2018 Ontario Elections (please note that this article was written in advance of the election results)

By: Jonathon Chio

W

ith the Ontario 2018 election set to occur on June 7th, a change in leadership may take place, as major political parties (Progressive Conservatives led by Doug Ford and the New Democratic Party guided by Andrea Horwath) aim to take over from the Liberals, currently led by Kathleen Wynne. Recently, on behalf of Ms. Wynne, the Lieutenant Governor of Ontario delivered the Throne Speech. In this statement, the Liberal government outlined its next steps to build on the plan for fairness, healthcare, and opportunity within Ontario.1 As most of IMS Magazine readers have at least some healthcare background, many working in affiliated teaching hospitals, we felt it was appropriate to first provide a quick overview of how the Liberal party views the importance of healthcare in their election platform. We also evaluate the rationale supporting their 30 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

healthcare statements and examine how all the parties, hoping to earn Ontarian’s vote (and trust), have responded.

To open the new session of legislature, the Throne Speech titled, “A Plan for Care and Opportunity” mentioned the word “care” 62 times, specifically referring to healthcare, home care, long-term care, pharmacare, dental care, mental health, and childcare.2, 3 Through the Throne Speech, it is clear that the Liberals attempted to claim their stake, during the pre-election period, with an emphasis on improving healthcare quality. This focus is likely in response to results from a recent poll asking Ontarians about their top issues in this election.4 40% of voters identified healthcare as the most pressing issue, while “economy and jobs” and “lower taxes” received 35% and 34% of votes, respectively. It is well-established that our healthcare system and associated

universal medical coverage is a major part of our national identity and a source of pride.5 However, the poll results serve to be an alarming and nagging reminder that the Canadian healthcare system is flawed.

A central tenet of our imperfect healthcare system is the excessive wait times to see/ consult specialists and undergo diagnostic as well as surgical procedures.6 This was highlighted by the 27th annual waiting time survey conducted by the Fraser Institute. In this study, the academic group surveyed specialist physicians across 12 specialties (oncology, radiation oncology, internal medicine, urology, cardiovascular, orthopaedic surgery, neurosurgery, general surgery, otolaryngology, ophthalmology, gynaecology) and 10 provinces.

Between 2016 and 2017, the average wait times to consult specialists have increased from 9.4 to 10.2 weeks. Similarly, within the same period, the average wait times to

VIEWPOINT undergo procedures have lengthened from 10.2 to 10.9 weeks. Actual wait times also exceeded the clinically-reasonable wait times in 62% of comparisons, with the average expected and real wait times being 6.4 and 8.6 weeks. The national wait times for imaging technology (namely computer tomography (CT) scans, magnetic resonance imaging (MRI), and ultrasound) have generally stayed the same, going from 3.97, 11.1 and 4 weeks in 2016 to 4.1, 10.8 and 3.9 weeks in 2017. Ontario can take some solace, as its wait times to consult specialists and undergo procedures are 6.7 and 8.6 weeks respectively, both of which are below the nation’s average. Ontario wait times for imaging technology have largely remained unchanged; at 3, 6 and 2 weeks for CT, MRI and ultrasound. A summary of these values is given in the table below.

While one can argue that the increases are small, and hence not troubling, prolonged wait times have negative socioeconomic consequences. During their wait times, patients may be unable to work due to their physical conditions. The lack of income and decreased productivity hamper economic growth. Extended wait times may also decrease patient quality of life, as there is a higher likelihood of poor medical outcomes.6 Consequently, to avoid these negative effects, Ontario patients may seek medical help elsewhere.

This can explain why Ontario is the top province where patients travel abroad for treatment. In 2016, there were 26,513 patients who sought medical help outside of Canada, and the Ministry of Health spent $35 million to send patients to the United States for procedures.7 While Ontario tops the list for patients leaving to obtain medical assistance, it is important

to remember that wait times in Ontario are below the nation’s average. It is clear that the resentment towards the healthcare system can’t be solely explained by longer wait times. Nevertheless, the existence of this cause-and-effect relationship is undeniable. Interestingly, the Ontario Medical Association (OMA) is in midst of a campaign titled, “Not a second longer”.8 Through this campaign, the OMA calls for the provincial government to improve an underfunded healthcare system that is illsuited for a growing and aging population.

However, an even more troubling statistic is that with the current flaws, Ontario is the largest sub-sovereign debtor in the world, owing an excess of $300 billion and spending $11 billion annually to fund it.9 Understandably, healthcare is a major issue debated by all the political parties. As such, the Throne Speech indicated that the Liberal government (among other priorities) aims to: (1) reduce wait times for healthcare by increasing hospital operating budgets, (2) expand homecare to provide more services to seniors at home, and (3) make historical investments in mental health.1 This translates to a Liberal 2018 budget allocating $300 million to hire registered nurses for Ontario long term care facilities and $19 billion for hospital infrastructure and operations.10 However, these promises will push Ontario further into debt until 2025. Given that healthcare is the primary concern for majority of Ontarians, it will be of interest to observe how other parties will seek to obtain Ontarians’ votes and trust through making financial promises within context of a, hopefully, balanced budget.

influence the amount of debt incurred in the future. Based on the Throne Speech, the Liberals have begun the debate and discussion regarding Ontario healthcare. The responses from other parties to the Liberals’ platform, along with their own plans and promises, will be highly anticipated.

So, who will you vote for on June 7th, 2018?

1. Throne Speech Announces Major Investments Guided by a Commitment to Care and Creating Opportunity [Internet] Office of the premier: Ontario [cited 2018 April 22]; [about 2 screens]. Available from: https://news.ontario.ca/opo/en/2018/03/ throne-speech-announces-major-investments-guided-by-a-commitment-to-care-and-creating-opportunity.html 2. Editorial: Ontario throne speech – who cares? Oh, Wynne does. [Internet] Ottawa Citizen Editorial Board [cited 2018 April 22]; [about 2 screens]. Available from: http://ottawacitizen.com/opinion/editorials/editorial-ontario-throne-speech-who-cares-oh-wynne-does 3. Care and change: The messages driving Ontario’s 2018 election.

[Internet] Behind the numbers. [cited 2018 April 22]; [about 3 screens]. Available from: http://behindthenumbers.ca/2018/03/20/ care-change-messages-driving-ontarios-2018-election/ 4. Ontarians trust PCs with key election issues: Ipsos poll. [Internet] Global News. [cited 2018 April 22]; [about 1 screen]. Available from: https://globalnews.ca/news/4040177/ontarians-pcs-key-issues-ipsos/ 5. The ER waiting game. [Internet] Toronto Life. [cited 2018 April 22]; [about 1 screen]. Available from: https://torontolife.com/city/ er-waiting-game/ 6. Bacchus Barua (2017). Waiting Your Turn: Wait Times for Health Care in Canada, 2017 Report. Fraser Institute.

7. 63,000 Canadians left the country for medical treatment last year: Fraser Institute. [Internet] CTV News. [cited 2018 April 22]; [about 1 screen]. Available from: https://www.ctvnews.ca/health/63-000canadians-left-the-country-for-medical-treatment-last-year-fraserinstitute-1.3486635 8. Not A Second Longer Platform. [Internet] Ontario Medical Association. [cited 2018 April 22]; [about 1 screen]. Available from: http:// notasecondlonger.ca/platform/ 9. Ontario election will be won or lost on health care. [Internet] The Star. [cited 2018 April 22]; [about 1 screen]. Available from: https:// www.thestar.com/opinion/contributors/2018/03/25/ontario-election-will-be-won-or-lost-on-health-care.html 10. Ontario Liberals bet big on seniors’ care, drug and dental coverage in 2018 pre-election budget/ [Internet]. CBC News. [cited 2018 April 22]; [about 1 screen]. Available from: http://www.cbc.ca/news/ canada/toronto/ontario-liberals-budget-2018-1.4595213

Taken together, it is imperative for voters to maintain perspective of how promises made to improve healthcare will

Table 1: Comparison of wait times between 2016 and 2017 in Canada and Ontario for multiple categories of health care.

Canada Ontario

Year

Wait times (weeks) for seek specialist after referral

Wait times (weeks) to get procedure completed

Wait times (weeks) for CT scan

Wait times (weeks) for MRI

Wait times (weeks) for ultrasound

2016

9.4

10.6

3.7

11.1

4.0

2017

10.2

10.9

4.1

10.8

3.9

2016

7.2

8.4

3.0

6.0

2.0

2017

6.7

8.6

3.0

6.0

2.0

IMS MAGAZINE SUMMER 2018 RARE DISEASES 31

SPOTLIGHT

Spotlight on

Dr. Alan Moody Courtesy of Dr. Moody

Forecasting the Future of Radiology 32 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

By: Bowen Zhang

S

itting behind three large, sleek, vertically-oriented monitors in a neatly organized office on the 7th floor of Sunnybrook Health Science Centre, I had the unique opportunity to speak with Dr. Alan Moody, Chair of the Department of Medical Imaging at the University of Toronto, regarding the field of medical imaging and its future impact on healthcare. His journey in medical imaging began in 1986, as he earned his medical degree at the University of Oxford in the United Kingdom. After completing radiology residency training in London and a subsequent fellowship in Toronto, Dr. Moody became a senior lecturer at Leicester University. This was followed by a similar post at Nottingham University.

With these experiences, in 1998, he became the Chair of Academic Radiology

SPOTLIGHT DR. ALLAN MOODY, MBBS, FRCP, FRCP Senior scientist, Physical Sciences, Schulich Heart Research Program, Sunnybrook Research Institute Staff physician, Medical Imaging, Sunnybrook Health Sciences Centre Chair and Professor, Department of Medical Imaging, University of Toronto Associate Professor, Institute of Medical Science, School of Graduate Studies, University of Toronto Associate Professor, Department of Medical Biophysics, University of Toronto and Clinical Director of the Radiology Department at Queen’s Medical Centre in Nottingham. His prolific research profile and experience also contribute to him holding senior positions at various different academic and research institutions.

These roles include Radiologist-In-Chief at the Sunnybrook Health Science Centre, Senior Scientist at Sunnybrook Research Institute and Chair of the Department of Medical Imaging at the University of Toronto.

“Medical imaging is at the heart of modern medicine,” said Dr. Moody. When referring to black-and-white cross-sectional images scrolling across the screen, Dr. Moody exudes passion for medicine and radiology.

This is evident when he analyzes magnetic resonance images from an anonymized patient with late-stage atherosclerosis, “The marvellous thing about medical imaging is that we are able to diagnose and treat patients quickly and non-invasively.

Here [in this image], bright spots indicate bleeding inside the plaque. Therefore, this suggests that the patient is highly susceptible of having a stroke.”

When asked about the contributing factors that led to his decision of specializing in the field of diagnostic radiology, Dr. Moody reminisced, “I pursued radiology, because I trained at sites which were at the forefront of imaging innovations. At Atkinson Morley’s Hospital in London, I witnessed the creation of computed tomography (CT) and trained under pioneers of the field; Drs. Jamie Ambrose and Godfrey Hounsfield. While working at Royal Marsden Hospital, I had the great opportunity to be among one of the first teams to use magnetic resonance imaging in a clinical setting.”

Prior to the advent of CT in the 1970s, there was no method available to directly image the brain. Dr. Moody remarked, “We had very limited technologies. Plane X-ray films were used to highlight the

bony skull. To identify potential maladies inside a patient’s brain, angiography would indicate the presence of a late-stage tumour if the vasculature was displaced.

In air catholography, a lumbar puncture was performed to inject a large volume of air into the patient’s cerebrospinal fluid.

The patient was subsequently maneuvered for the air to travel to the ventricles.

Despite the procedure being crude, air catholography allowed us to observe the ventricles and discern growing tumours.

Nevertheless, patients dreaded the procedure and complained about its side effects, such as terrible headaches.”

When describing the invention and conception of CT, Dr. Moody claims that CT imaging has changed the landscape of diagnostic medicine and is the workhorse of diagnostic radiology. The evolution of CT imaging is remarkable, as the world’s first CT scanner at Atkinson Morley’s Hospital would take over two minutes to make one tomographic image and hours to fully map out the brain. If the patient sneezed, the process would have to re-start. However, the modern multidetector CT acquires multiple sub-millimeter spatial resolution slices. Processing speeds are reduced from hour to milliseconds.

Aside from medical imaging, Dr. Moody also comments on the potential of big data in healthcare. Dr. Moody says, “Big data is changing the way we learn, train and educate others. The medical world is sitting on a ‘gold mine’ of research fodder, which consists of numerous patient diagnostic images. Currently, many of the clinical images are used just once. By working cooperatively, clinicians and researchers could use these images to identify trends, correlations, and get new insights into health and disease.” With this vision for the future, Dr. Moody and his team have started a project called Medical image Network Enterprise (MiNE). This is a platform and electronic repository of anonymized clinical imaging data that could

be shared among physicians, researchers, and students. “The most difficult part is getting the ‘gold’ out, as these images belong to the patients. We have to ensure that the patients’ data are used securely and responsibly.”

In parallel to big data, the next technological revolution will be centered on artificial intelligence (AI) and machine learning. The waves of enthusiasm and optimism have successfully brought AI to the forefront of physicians’ imaginations. Dr. Moody regards that machines can potentially make medical diagnoses independently. He comments, “It’s not a question of if, it’s a question of when! AI and machine learning are on the horizon for medicine in general. Regardless of your speciality, if you access and use big data, you can expect AI to be part of your everyday practice. In radiology, we are in prime position to apply AI and machine learning techniques, as our content and medium are already digitized. By simultaneously enhancing workflow efficiency, patient care and throughput, these technologies offer a paradigm shift in how clinicians work.”

Today, one of the biggest challenges faced by physicians is the task of sifting through large volumes of patient information and determining what is clinically relevant.

With the advancement of AI technology, it will augment the ability of radiologists to find the crucial data they need in a concise, easily-digestible format.

Medical imaging is truly a vital element in modern-day clinical practice. It has and continues to evolve the way physicians diagnose and treat patients. Dr. Moody is among those excited by the opportunities to come, “I think the future for medical imaging is extremely bright; provided we seize the opportunity through research to help build the next generation of medical imaging innovations. This will allow us to play an ever-increasing role in patient management through diagnoses, treatments, and preventions.”

IMS MAGAZINE SUMMER 2018 RARE DISEASES 33

SPOTLIGHT

Spotlight on

Dr. Dafna Gladman Recognizing a Severely Overlooked Disease By: Cricia Rinchon

R

heumatology is the branch of medicine devoted to the diagnosis and treatment of musculoskeletal and systemic autoimmune diseases affecting joints, muscles, and bones, and which cause pain, swelling, stiffness, and deformities. Rheumatic disorders were originally attributed to humors (rheuma) as it was originally thought that a substance would flow, settle in joints, and cause arthritis. Today, we know that this is not the case—and, in hindsight, the notion seems almost humorous—but progress in medicine is impossible without scientists who have dared to challenge the status quo throughout history. Dr. Dafna Gladman is in her 40th year of studying a now world-renowned cohort of patients with psoriatic arthritis and has been recognized as this year’s recipient of the Carol Nachman Prize: the most prestigious international award for research in rheumatology that recognizes outstanding research and innovative achievements in the field. Dr. Gladman has dedicated most of her research career to psoriatic arthritis (PsA), an inflammatory joint disease associated with psoriasis. Ultimately, Dr. Gladman has made an unparalleled impact on the research of PsA and this article aims to explore how she earned this award through over 40 years of work as a rheumatologist, scientists, and pioneer.

1977: An Early Call.

Dr. Gladman was in her last year of specialization training when she was offered a staff rheumatologist appointment at 34 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

Women’s College Hospital. Her start date was originally set to July, but the Head of Dermatology asked if she would be willing to start early to do consultations for a newly established clinic, “The Psoriasis Education and Research Centre”, which had been running for approximately a year with almost 2,000 registered patients with psoriasis. Between March and July, she saw more than 40 patients with PsA, which was way beyond the number she had been exposed to throughout her training. As a result, Dr. Gladman quickly realized that PsA was a more common and severe disease than originally taught. Nevertheless, a trend cannot simply change commonplace convention—she knew she had to prove it.

1978: Developing an Assessment Protocol.

The first step Dr. Gladman took to investigate the incidence of PsA was to develop a protocol to evaluate patients in a standardized way. A year later, this protocol was implemented into the Women College Hospital’s Psoriasis Education and Research Centre. In the early days of her epidemiological endeavors, an encounter with a patient turned to be a pivotal moment for her research career. Within a period of three weeks after being admitted, the patient had developed a fused toe joint.

Dr. Gladman thought to herself, “well… if this is what happens then I better learn more about the disease!” and thus her mini-project turned into a journey now celebrating its 40th year.

1978: Establishing a Longitudinal Cohort.

At the time, longitudinal cohorts were not the norm. Dr. Gladman was warned about not getting funded or being able to pursue her research goals. However, she firmly believed one observation would not be enough to make a substantial impact and decided to begin following patients over time. Today, her clinic at Toronto Western Hospital has about 1,500 patients who are regularly evaluated in a meticulous and standardized format: clinical history, extensive physical examination, detailed treatment record, and x-rays every two years.

1987: Publishing and Improving Medicine.

Dr. Gladman and her colleagues followed 220 patients with PsA, collecting clinical, radiological, and biochemical data for ten years. They found polyarthritis was a more common presentation of the disease than was generally acknowledged at the time. Importantly, this frequency of deforming arthropathy (a disease of a joint) challenged the concept that PsA was a benign arthropathy.1 Dr. Gladman made suggestions to change the treatment plan for patients with PsA, making them more aggressive early in the course of the disease, as she found evidence of significant inflammation at first visit predicted progression of damage in the future.2 Moreover, Dr. Gladman and her collaborators found that patients with PsA had a higher mortality risk compared with the

SPOTLIGHT transfer in which the program investigators communicate research findings to patients and, together with program allied health professionals, teach them about the disease, its management, and things they can do for themselves.

Today: The Impact.

Dr. Dafna Gladman is undoubtedly a key player for progressing her discipline of rheumatology worldwide, and the impact of her decades of research is far-reaching. The Carol Nachman Prize serves to promote clinical, therapeutic, and experimental research and is one of rheumatology’s most prestigious international awards. While this award was granted in recognition of her extensive work in inflammatory arthritis, she is an expert in both systemic lupus erythematosus and psoriatic arthritis. Her work has an emphasis on database development, prognosis studies, genetic markers for disease susceptibility and expression, assessment instruments, and quality of life measures.

DR. DAFNA GLADMAN, MD, FRCSC Senior Scientist, Krembil Research Institute (Krembil) Deputy Director, Centre for Prognosis Studies in the Rheumatic Diseases (part of the UHN Arthritis and Autoimmunity Research Centre) Co-Director, Lupus Clinic, Toronto Western Hospital (TWH) Director, Psoriatic Arthritis Program, TWH Courtesy of Cricia Rinchon

general population, where the prognostic indicators for death are active and persistent joint inflammation.3

30% of patients would develop PsA within 15 years—a much higher percentage than originally thought.

2006: Establishing a Prospective Study.

At this point, the literature was quite varied on the prevalence of PsA. Therefore, Dr. Gladman decided to establish a prospective cohort, whereby patients only diagnosed with psoriasis were followed over time to find out how many develop arthritis and study the factors underlaying its development. To establish the cohort of psoriasis patients, her team requested referrals from colleagues in family medicine, dermatology, and even put ads in newspapers. To their surprise, 12% of recruited psoriasis patients already had arthritis and were therefore not eligible to join the cohort and were enrolled in the PsA cohort instead. Of the patients that were screened and successfully registered into the psoriasis cohort, the incidence of PsA was 2-3% per year. In other words,

Ongoing: Teaching Students.

Now, Dr. Gladman’s program is an esteemed avenue of education for medical and graduate students, medical and specialty residents, and postdoctoral fellows as well as research trainees. Many people from the University of Toronto, University of Waterloo, and University of Cambridge in England have received their Master’s or PhD degrees based on graduate work performed on her cohort. Her group collaborates with co-investigators at these universities to help develop new programs for data analysis. Furthermore, they have preceptorships where trainees come in and learn how to conduct both the joint and skin assessments. Finally, Dr. Gladman’s group at Toronto Western Hospital is passionate about patient education and hosts a symposium once a year for knowledge

Dr. Dafna Gladman is an internationally-renowned rheumatologist as an expert in systemic lupus erythematosus and psoriatic arthritis. She received her MD from the University of Toronto in 1971 and completed her post‐graduate training in Rheumatology at the University of Toronto.

She was a staff rheumatologist at Women’s College Hospital in Toronto from 1978 to 1990 and at the Wellesley Hospital from 1990 to 1995. Currently, she is a Professor of Medicine at the University of Toronto, and Senior Scientist at the Toronto Western Research Institute. She is Deputy Director of the Centre for Prognosis Studies in The Rheumatic Diseases, Director, Psoriatic Arthritis Program, University Health Network and Co‐Director of the University of Toronto Lupus Clinic.

1. Gladman DD, Shuckett R, Russell ML, Thorne JC, Schachter RK. Psoriatic arthritis (PSA)-an analysis of 220 patients. QJM: An International Journal of Medicine. 1987 Feb 1;62(2):127-41.

2. Gladman DD, Farewell VT, Nadeau C. Clinical indicators of progression in psoriatic arthritis: multivariate relative risk model. The Journal of Rheumatology. 1995 Apr;22(4):675-9.

IMS MAGAZINE SUMMER 2018 RARE DISEASES 35

FUTURE DIRECTIONS

Science of

Innovation Courtesy of Krystal Jacques-Smith

By: Rehnuma Islam

W

hile research entails exceling our knowledge, it also requires working with unpredictable outcomes and troubleshooting to obtain results that define a narrative. This ability to see things beyond what is apparent requires creativity. Therefore, being a scientist has allowed Dr. Wenjun Xu to become the forward-thinking trailblazer she is today. With a desire to solve an increasing number of problems, Dr. Xu has focused her energy towards innovative ideas in science and technology. As a result, she is currently one of many bringing forth solutions to large-scale global issues by brainstorming innovative ideas, right here at the University of Toronto (UofT).

Although business was important in the family, Dr. Xu took the unconventional route of completing a bachelor’s degree in forensics and biology. Further, while 36 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

attending a seminar course in undergrad, Dr. Xu found interest in the field of stem cell biology and pursued that interest by completing doctoral studies in the laboratory of Dr. Cindi Morshead. Her research focused on the effects of myelin basic protein in determining stem cell behaviour.

From the beginning, Dr. Xu displayed a willingness to perform academically, but also through extracurricular activities that would cater to her brewing interest in business. She quickly became involved with the IMS Magazine during the first year of her PhD, as an advertising manager. She further immersed herself in the world of business as a co-founder of two start-ups: an online skin-care retail store and an online platform for scientists to find resources and equipment at a discounted rate.

Finding the right tools to complete a research project can be challenging.

Scientists can spend days, weeks, and even months setting-up collaborations for access to the resources and equipment absent from their own laboratory.

Moreover, the costs of buying new reagents and/or necessary equipment can be impractical. For these reasons, Dr. Xu sought to find a solution to this paradigm. While completing her graduate studies, she partnered with a former colleague, and friend, Zhang Zoe Yi, to develop a platform called “Coolaborator”.

This platform allows researchers to share information about unused equipment, and surplus reagents, which may be sought by another lab. By creating a way to facilitate the reduction of waste within labs, and by driving down the cost of reagents, every researcher could benefit.

Her start-up gained momentum due to support from her supervisor, Dr. Cindi Morshead, and partners at the Faculty

FUTURE DIRECTIONS global management consulting firm, in partnership with the Globe and Mail and the Canadian Government. BCG wants to re-ignite discussions at the level of government, in boardrooms, and nationwide, around transformative ideas on Canadian infrastructure involving the latest technologies. Participants in this challenge put forth ideas to improve infrastructure on: transportation, energy, waste and water, utilities, and communications. These ideas are ranked based on public votes as well as expert judges, where the top 10 finalists pitch their idea to industry experts, academic partners, investors, and the government at the Canadian Transformational Infrastructure Summit in May 2018. The top two winners as well as the People’s Choice awardee, based on public vote, are given cash prizes.

of Medicine’s Health Innovation Hub (H2i). However, Dr. Xu quickly learned that a start-up only grows by catering to an audience. Importantly, the audience that showed interest in her product was investors outside of academia, such as the Chinese government and other industry partners. She also discovered that both industry professionals and scientific leaders require evidence-based as well as data-driven ideas. From her experience researching market-value, pitching Coolaborator and building an overall narrative, Dr. Xu would go on to greater challenges, specially by competing in the hugely competitive CanInfra Challenge.

The CanInfra Challenge is a six-month public competition seeking to inspire breakthrough innovative ideas that would improve Canadian infrastructure. This challenge was put forth by the Boston Consulting Group (BCG), a top tier

One of the key problems faced in Canada, is a lack of knowledge on the health of our water. Currently, the government is data-deficient on the quality of twothirds of Canadian sub-watersheds. As the second largest global consumer of water, Canadians need to make informed choices about the way water is managed. Dr. Xu brought together engineers, industry experts, and scientists to form a team that could enlighten the public as well as the government about the growing concerns regarding our fresh water. They also hoped to help raise awareness about the risks of a potential water shortage in Canada, if we continue to mismanage this most precious resource. The CanInfra Challenge was met with a creative solution, named the Canadian Advanced Hydrologic Network. Their team proposed customizing sensors, currently available on the market, which could obtain data on water level rises, changes in depth as well as flow of streams, and alterations in contaminants. By placing these sensors around watersheds that feed into larger bodies of water, data centers would gain remote-access information about the quality and quantity of water sources in Canada. A remote monitoring system could inform the government and public about the quality of our watersheds, allowing for better management policies. The Canadian Advanced Hydrologic Network proposal was selected by judges as one of the top 10 innovative ideas (out of 70+ proposals received across Canada)

and will go on to compete among the finalists in the CanInfra Challenge.

Ultimately, as intimidating as pursing a graduate degree alongside a start-up may be, Dr. Xu mentions, “[that] the most time-consuming part was coming to a decision to commit and to build a new idea, while being responsible to your teammates—this took me over a year to decide.” Most importantly, Dr. Xu’s entrepreneurial skills have grown with increased experience developing start-up platforms and increased exposure to the different facets of entrepreneurship. Her advice to students with an interest in building their own start-up is to “take it as an experience, whether you succeed or fail, it’s all an experience that we would never trade for anything else—you may not understand your skillset as a PhD until you apply it.” She advises students to be honest with their supervisors about wanting more than an academic career.

Further, the advice from experts at UofT provided her with a sense of security, as she mentions that “when we started CanInfra, we thought we can do whatever we want because, deep down, we were confident that UofT would provide exceptional resources compared to a smaller university.” Networking among peers is also important in finding the right group of people to work with. She credits the brilliant students at UofT, with whom she formed close ties, for allowing her team to make it to the final round in the CanInfra Challenge.

When discussing our graduate program, Dr. Xu believes that it equips students with fundamental transferable skills, such as resilience and a “can-do mentality”.

Taken together, she believes that industry finds graduate students attractive due to their rigorous analytical abilities, scepticism in the absence of hard evidence, and a knack for never giving up. Graduate programs need to “ensue confidence in our candidates” and then use those strengths to excel in other fields.

As Dr. Xu continues to make an impact around Canada, we hope to see more of her innovative ideas in the future.

IMS MAGAZINE SUMMER 2018 RARE DISEASES 37

TRAVEL BITES

Under the Tuscan Sun

Courtesy of Chantel Kowalchuk

By: Chantel Kowalchuk

I

left Toronto in the midst of an unexpected April snowstorm to enter 25 degrees of Tuscan sun in Florence, Italy. Avoiding that snow storm alone would have been enough to make attending the biannual Schizophrenia International Research Society Conference (SIRS2018) worth the nine-hour flight; however, SIRS2018 offered much more than a mere respite from Canadian winter. The conference involved expert discussions on topics from new therapies to biomarkers and genetics, providing symposiums for both basic researchers and clinicians. The attendees were schizophrenia researchers from all over the world, many of whom are leaders in the field I have frequently cited and whom have been crucial to my research. The poster sessions were my personal favourite, where nearly 100 people presented an extremely diverse array of data while gelato was served (yes, they provided gelato with lunch because Italy is a refined society).

The theme of SIRS2018 was Integrated Prevention and Treatment: Shifting the Way We Think. Although they were referring to a shift in thinking regarding schizophrenia, I returned from the conference with a shift in thinking about my research as whole. Research can be just as draining as it is exciting, and I frequently realize that issues, data, and statistics can be overwhelming. SIRS gave 38 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

me an opportunity to take a step back from my investigations and rediscover the big picture through interactions with enthusiastic, creative minds from all over the world in my field, but whom are performing vastly different studies. Such is the beauty of conference; it gives researchers—who are frequently isolated in labs eight hours a day—an opportunity to collaborate and share findings, create new ideas, and remind each other that we are in this up-and-down chaos of success and setbacks together. I now come back to my lab with a fresh perspective and renewed resolve for my research.

Of course, the conference location was also a highlight of the experience. It was set in the heart of Florence at Firenze Fiera, with the backdrop of beautiful Rococo and Renaissance architecture among discussions on modern day scientific theory and techniques. The centrality of the location also made it easy to take a quick break from academics and stroll through cobblestone streets, take an espresso on a patio, or grab a gelato (daily gelato is a must in Italy—like I said, refined!). Florence also made it incredibly easy to network—a meal over wine and pasta is bound to result in fantastic conversations and helped me initiate potential collaborations to pursue.

Attending SIRS2018 in Florence was a

Courtesy of Chantel Kowalchuk

three-year goal in the making. As a firstyear graduate student, I saw my colleagues going to Florence and dreamed of the day when I could join them at one of the largest conferences in my field and in one of the most beautiful destinations imaginable.

Having had the opportunity to attend, my new target is SIRS2020. Until then, I’ll be practicing my Italian and dreaming of freshly made ravioli!

PAST EVENTS

Purple Day

2018

Courtesy of Anna Badner

By: Priscilla Chan

S

eizures are scary, but that doesn’t mean we have to be scared of them.

Over 500 million people live with epilepsy worldwide. For many of them, seizures are a reality they face regularly.

Individuals with epilepsy have the same abilities and intelligence as those without this neurological condition. However, the stigma and misconceptions associated with epilepsy continue to prevent these people from leading fulfilling lives. So, what can we do to help?

We can wear purple!

On March 26, 2018, members of the Toronto Western Hospital and Krembil Research Institute gathered to celebrate Purple Day. Founded in 2008, Purple Day is an international grassroots effort to raise awareness and dispel myths surrounding epilepsy with the hopes of providing a sense of community to people living with epilepsy. The fervour and commitment to community and outreach has been made possible by the work coming out of the Epilepsy Monitoring Unit and co-director of surgery program, Dr. Taufik A. Valiante and his team. This year’s event was bigger and better than ever before thanks to the efforts of nurse practitioners (Alina Mednikov and Darcia Paul), Epilepsy Foundation representative (Jonathan Lucas), Institute of Biomaterials and Biomedical Engineering PhD student (Chaim Katz), and IMS alumnus (Sumayya Mehmood).

Purple Day hosted representatives from Epilepsy Toronto and EpLink in order to educate the general public about the differences between epilepsy and seizures.

While seizures are independent events caused by sudden electrical activity in the brain, epilepsy is a neurological condition that is characterized by recurrent seizures. The most common types of seizures are convulsive in nature, but seizures can also mimic a momentary lapse in consciousness.

Attendees were given the chance to experience seizures characterized by a lapse of consciousness through a virtual reality simulation. UCB, a global biopharmaceutical company, allowed people to learn about epilepsy through the eyes of Jane, a young woman who developed epilepsy after suffering from a traumatic brain injury. By listening to her inner thoughts before, during, and after a seizure, individuals learned how seizures interrupt daily activities and affect patients emotionally.

Furthermore, Toronto Regional Police were also present to demonstrate how to appropriately respond to someone experiencing a seizure.

In addition to advocating for and bringing awareness to epilepsy, Purple Day was also a welcoming opportunity for researchers of the Krembil Research Institute to showcase their exciting and innovative research on epilepsy pathology and therapies. As strong believers in scientific outreach, Mehmood and her Neuron to Brain lab colleagues helped organize poster presentations so that the public could learn about the cutting-edge epilepsy research taking place in Toronto.

Liang Zhang and his students explained the strengths of using ischemia-induced models of epilepsy to explore antiepileptic therapies. Similarly, students from Dr. Peter Carlen’s lab explained how cerebral organoids could generate spontaneous electrical activity, which could lead to their use as an in vitro model of epilepsy.

These pre-clinical models of epilepsy show promise in expediting the discovery of not only seizure mechanisms, but also potential therapies. While most seizures can be controlled by medications and/or surgery, as many as 20 to 30% of cases are considered uncontrolled or intractable. To this end, colleagues of Dr. Taufik A. Valiante’s lab described how music could serve as a therapy for treatment-resistant forms of epilepsy.

One of the central objectives of Purple Day is to educate the public about epilepsy. But more importantly, the event now serves to establish connections between the research community and the individuals impacted by epilepsy. In Mehmood’s own words, “outreach and community involvement has been a central part of [my] research and it provides meaning to the research we all do.” This year’s event was certainly a success and we can’t wait to see how Purple Day will continue to grow. Until then, keep wearing purple!

Dr. James Eubanks’ lab shared their understanding of the link between epilepsy and Rett syndrome. Furthermore, Dr. IMS MAGAZINE SUMMER 2018 RARE DISEASES 39

PAST EVENTS

IMSSA Presents:

Courtesy of Louise Pei

One Brave Night

World’s Largest Photo Awareness Campaign By: Elizabeth Cho

M

ental illness affects one in five Canadians annually, and occurs ubiquitously in individuals from all socioeconomic backgrounds, ages, and levels of education. Over the years, many universities and colleges have stepped forward to implement mental health awareness campaigns and have brought forward considerable effort to remove stigmas surrounding mental health. These stigmas include unwarranted assumptions that individuals with mental health problems are dangerous and unpredictable. However, much of the conversation has been focused on undergraduate students, with virtually no dialogue regarding the graduate student population. A considerable proportion 40 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

of graduate students combat stress, anxiety, and emotional difficulties on a daily basis. These factors can negatively impact their daily life, sense of wellbeing, and academic performance. Although the reasons for heightened anxiety and stress are multifold, most common explanations include adaption into a new and unfamiliar environment that is largely disconnected from the larger campus community, an immense pressure to succeed academically, and increasing financial and familial burdens. As many graduate students feel overwhelmed, the lack of mental health support and community needs to be addressed. There is an impetus to build wider support networks among graduate communities

and create a platform for catalyzing ideas into action.

To tackle the issue of mental health among graduate students, members of the University of Toronto’s Institute of Medical Science Students Association (IMSSA) participated in One Brave Night (OBN). Founded by the Centre for Addiction and Mental Health (CAMH), this annual, nation-wide initiative provides the opportunity for teams or individual ambassadors to stay up one full night in order to reach out, share stories and instill hope for those troubled with mental illness. The first IMSSA coalition for OBN began in 2016, where the event at the time was called “Darkness to Light”.

PAST EVENTS studying for exams to find a way to destress.

She stated, “OBN had [everything] from happiness–not just words and figures–but also colors and expression. It was interesting to be part of something larger.” Katherine Schwenger, the brain behind IMSSA’s OBN, explained that “art is just a different medium for conversation.” Indeed, many participants were thoroughly involved in the process of creating a meaningful piece of art that contributed to an impactful endgoal project.

Courtesy of Louise Pei

In this event, graduate students within the Institute of Medical Science walked across the city throughout the night and showcased a creative improvised dance routine. A video was also made to capture this memorable event.

This year, OBN has set a new goal–to break the Guinness World record by holding the world’s largest photo awareness campaign.

The idea was spurred from “Beti Bachao, Beti Padhao”; a national art campaign held in Varanasi (India) that aims to generate awareness and improve welfare services for woman. “Beti Bachao, Beti Padhao” currently holds the world’s record for the greatest art campaign after accepting 302 out of 500 paintings themed around improving social welfare for girls, which are wholly produced by schoolchildren.

OBN aspires to break this world record with a target goal of 303 or more posters

to be produced and displayed across Toronto for the greater goal of engaging Torontonians in a conversation about mental health. Through this initiative, many advances in promoting mental wellness, destigmatizing the illness, and raising funds toward non-profit organizations will be accomplished.

The highlight of the event consisted of asking participants to illustrate a border describing what mental health means to them. Subsequently, the illustrated border and participant’s photo were merged by CAMH into a final poster. The posters were printed and posted around the city. OBN served to be a memorable way for students to showcase their artwork and freely express their thoughts about mental health.

Swapna Mylabathula, a PhD candidate and co-president of IMSSA, commented that it was an opportunity for students who were

This memorable event took place at five different locations around campus; CAMH, the Medical Science Building, Sidney Smith Hall Lobby, Grad Room, and Chestnut Residence. Over 300 participants (students, staff, faculty, and visitors) gathered together in an effort to end the stigma of mental health. This year, CAMH raised $704,525.63 in funding by allowing Canadians to step up and share their #OneBraveNight stories.

For more information on upcoming next year’s OBN, or to contact the organizers for more information, please visit: https://ims.utoronto.ca/event/ imssa-presents-worlds-largest-photoawareness-campaign/.

Courtesy of Louise Pei

IMS MAGAZINE SUMMER 2018 RARE DISEASES 41

BOOK REVIEW

A Brief History of Time

By Priya Makhijani

“We are lucky to live in an age in which we are still making discoveries.”

-Richard Feynman

D

r. Richard Feynman was a theoretical physicist who passed away a few months before Dr. Stephen Hawking’s highly acclaimed book, A Brief History of Time, was first published in 1988. Dr. Hawking, known for exploring the boundaries of general relativity and quantum mechanics, passed away only a few months ago, on the 14th of March 2018. His death marks the end of an important era of research in theoretical physics. But discovery will continue—as Dr. Hawking reasons in his book—because we have yet to uncover a unified theory that fully explains the nature our universe(s).

A Brief History of Time delves into the most mysterious questions—some that you may have grappled with yourself. For example, what caused the “big bang” and when exactly was it? When and how will the world end? Is the universe expanding?

Is time travel possible? Is there evidence of God? Within the first chapters, Hawking brings the lay reader to an understanding of the evolution of theoretical physics, from Galileo to Newton and Einstein—as well as each of their shortcomings. A Brief History of Time also highlights the sociopolitical context in which this research was conducted and exemplifies the power of public awareness of and participation in science.

A particularly remarkable model described 42 | IMS MAGAZINE SUMMER 2018 RARE DISEASES

in A Brief History of Time was one that proved our universe was expanding. With a simple 1920s telescope, Edwin Hubble collected significant data on the colour, composition and changing position of every star in the sky. Using this information, astronomers were able to calculate that stars from both our galaxy and others appeared red-shifted. Hawking further explains what this means. If a ray of light is emitted by an object approaching us, its wave crests are closer together and light appears on the blue end of the spectrum (smaller wavelength). However, when the object is moving away, its wave crests are farther apart and appear red-shifted (larger wavelength). This is the same Doppler Effect and is routinely used by police in radar guns to implicate speeding vehicles. When applied to stars appearing red-shifted, the Doppler Effect proves that our universe is expanding. According to Hawking, this was one of the great intellectual revolutions of the twentieth century.

With clarity and wit, Hawking goes on to review topics such as the nature of black holes, parallel universes, and time travel. In the concluding chapter, Hawking reminds the reader of incongruences in past and present theories and the need for a unified theory of physics. He ends with a surprising outlook on God. Hawking says, “The usual approach of science of constructing a mathematical model cannot answer the questions of why there should

be a universe for the model to describe.”

Hawking, however, was a self-proclaimed atheist.

As a biologist, I’ve always contended with the idea that physicists are the “superior” scientists. After all, they do complex mathematics, study space, and solve problems with implications in both the physical as well as metaphysical realms. However, in a swollen-headed effort to prove my significance as a biologist, I would like to point out that we are not simply looking for one theory. Biologists tease apart the many intricate mechanisms that life has evolved to defy entropy; molecular mechanisms that are very much outside our field of view at the nanoscopic scale. However, if we consider the efforts of biophysicists like Rosalind Franklin (DNA) and Carl Ludwig (blood pressure), it’s easy to appreciate that science is interdependent.

Stephen Hawking passed away at the age of 76 due to complications of Amyotrophic Lateral Sclerosis, surviving more than 50 years longer than his original prognosis. In a way, his life is a testament to how much progress both physics and medical science have made.

BOOK REVIEW

My review of

Lab Girl

By Beatrice Bellarin

B

y now you must have heard of Lab Girl. To mention a few, it’s won the National Bestseller, been nominated for The New York Times Notable Book, won the National Book Critics Circle Award for Autobiography, was named one of the best books of the year for The Washington post as well as TIME Magazine and the list goes on. I read it as soon as it was published a year ago. I was fascinated by the title: I am a girl, I work in a lab—it’s me, I had to read it. Lab Girl has its own character. It’s the equivalent for the field of botany as the famous Oliver Sacks’s essay is for neurology: a vocation to science. But what is it about Lab Girl that makes it so special?

Hope Jahren’s Lab Girl is a combination of scientific memoir and an ode to the discipline of paleobiology. It’s not just a simple biography, where the author traces back the origins of her love for science; the book is puzzled out through stories about the secret life of a plant, from a plant’s perspective. In Lab Girl, short essays about plant’s resilience and ingenuity interleaves personal anecdotes from Dr. Jahren’s scientific career. She explains the life cycle of trees and flowers and seeds discovering similarities between human life and a plant’s—the tenacity, creativity, flexibility and ability to adapt. Lab Girl discusses what it means to be a scientist, including both the joys of successful research and the craziness of long days full of experiments.

Being a Scientist is not just a profession, it becomes a passion and an identity, where the concept of work-life balance often gets lost.

Growing up in a Scandinavian family in freezing and rural Minnesota, Dr. Jahren describes her past through the sound of plants. Spending most of her youth in her father’s physics laboratory, she was introduced to the rituals of science early on, where she learned to embrace procedures and attention to details. Her stories

continue through her college and graduate school experiences, where she pursued a PhD at the University of California, Berkeley, and even later when she obtained her first teaching job and opened her first lab at the Georgia Institute of Technology.

She openly talks about the difficulties and stress of attaining grants to support her research, as well as how she was affected by mania-depression. Besides conveying both her devotion to her job and obsession with it, as a true workaholic, Lab Girl communicates the electric excitement that only a scientist can experience when discovering something new—something that nobody knew before. It captures the process of all the tedious work of gathering data, repeating experiments, the days and weeks of waiting and watching, the all-nighters protocols, as well as the hope and serendipity involved.

The issue of funding in academia set the tone of the book. At times finding money in science is harder than the actual science.

Especially when she opens her independent laboratory—her ultimate safe place where she can do what she loves with the people that she has chosen—yet her biggest concern is money. “Ask a science professor what she worries about,” Jahren invites her reader; it is not the fear of failure to reproduce past findings, nor the fear of negative data. According to Dr. Jahren, what keeps a professor up at night is money.

without her usual medications. To me she fears too often about her work-life balance.

Personally, I believe that if science is your true passion, it is hard to stay away from it. She makes a point to show that being a scientist is not an easy career choice—but is there any? She comes across as both a perfectionist and a workaholic. Even when she becomes an assistant professor she is on edge, always stressed, always sleepless and aware of failure. I wanted to shake her! Such a narrative doesn’t do any good for her or for the picture she creates of academia. This idea that you need to be pushed to the edge of reason to succeed is frightening. This “make it or break it” attitude is dangerous and false, especially because it leads to talented scientists turning away who fear they won’t be able to survive in such a competitive and harsh environment. Someone might even ask why would oneself go through so much pain? This is not how academia is, or at least it is not how academia should be.

This was not the Lab Girl I wanted to read about.

Lab Girl speaks to me as I am thriving to become a scientist myself. Who knew that the plants could be so interesting?!

Hopefully the next Lab Girl that will come along will have an easier time in becoming a scientist.

So why did I become discontent with Lab Girl at this point? Increasingly, I wished Dr. Jahren to be stronger than she was, to fight more for what she had, and to get less discouraged by the challenges she faced.

Simply put, I wanted to see a stronger and more confident figure. Although I appreciate how openly she talks about her mental disorder, describing it as a “great cosmic fire” that overtakes her during manic episodes and the uncertainties it causes when she has to navigate pregnancy IMS MAGAZINE SUMMER 2018 RARE DISEASES 43

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