Erin Howe

Researchers at the University of Toronto and partner hospitals have discovered a DNA repair mechanism that advances understanding of how human cells stay healthy – a finding that could lead to new treatments for cancer and premature aging.

The study, published in the journal Nature Structural and Molecular Biology, also sheds light on the mechanism of action of some existing chemotherapy drugs.

“We think this research solves the mystery of how DNA double-strand breaks and the nuclear envelope connect for repair in human cells,” said Karim Mekhail, co-principal investigator on the study and a professor of laboratory medicine and pathobiology in U of T’s Temerty Faculty of Medicine.

“It also makes many previously published discoveries in other organisms applicable in the context of human DNA repair, which should help science move even faster.”

DNA double-strand breaks arise when cells are exposed to radiation and chemicals, and through internal processes such as DNA replication. They are one of the most serious types of DNA damage because they can stall cell growth or put it in overdrive, promoting aging and cancer.

The new discovery, made in human cells and in collaboration with Razqallah Hakem – a senior scientist at UHN’s Princess Margaret Cancer Centre, University Health Network, and a professor in Temerty Medicine’s department of medical biophysics and department of laboratory medicine and pathobiology – extends prior research on DNA damage in yeast by Mekhail and other scientists.

In 2015, Mekhail and collaborators showed how motor proteins deep inside the nucleus of yeast cells transport double-strand breaks to “DNA hospital-like” protein complexes embedded in the nuclear envelope at the edge of the nucleus.

Other studies uncovered related mechanisms during DNA repair in flies and other organisms. However, scientists exploring similar mechanisms in human and other mammalian cells reported little to no DNA mobility for most breaks.

“We knew that nuclear envelope proteins were important for DNA repair across most of these organisms, so we wondered how to explain the limited mobility of damaged DNA in mammalian cells,” Mekhail says.

The answer is both surprising and elegant.

When DNA inside the nucleus of a human cell is damaged, a specific network of microtubule filaments forms in the cytoplasm around the nucleus and pushes on the nuclear envelope. This prompts the formation of tiny tubes, or tubules, which reach into the nucleus and catch most double-strand breaks.

“It’s like fingers pushing on a balloon,” says Mekhail. “When you squeeze a balloon, your fingers form tunnels in its structure, which forces some parts of the balloon’s exterior inside itself.”

Further research by the study authors detailed several aspects of this process. Enzymes called DNA damage response kinases and tubulin acetyltransferase are the master regulators of the process, and promote the formation of the tubules.

Enzymes deposit a chemical mark on a specific part of the microtubule filaments, which causes them to recruit tiny motor proteins and push on the nuclear envelope. Consequently, the repair-promoting protein complexes push the envelope deep into the nucleus, creating bridges to the DNA breaks.

“This ensures that the nucleus undergoes a form of reversible metamorphosis, allowing the envelope to temporarily infiltrate DNA throughout the nucleus, capturing and reconnecting broken DNA,” says Mekhail.

The findings have significant implications for some cancer treatments.

Normal cells use the nuclear envelope tubules to repair DNA, but cancer cells appear to need them more. To explore the mechanism's potential impact, the team analyzed data representing over 8,500 patients with various cancers. The need was visible in several cancers, including triple-negative breast cancer, which is highly aggressive.

“There is a huge effort to identify new therapeutic avenues for cancer patients, and this discovery is a big step forward,” says Hakem.

“Until now, scientists were unclear as to the relative impact of the nuclear envelope in the repair of damaged DNA in human cells. Our collaboration revealed that targeting factors that modulate the nuclear envelope for damaged DNA repair effectively restrains breast cancer development,” Hakem says.

In the aggressive triple-negative breast cancer, there are elevated levels of the tubules – likely because they have more DNA damage than normal cells. When the researchers knocked out the genes needed to control the tubules, cancer cells were less able to form tumours.

One medication used to treat triple-negative breast cancer is a class of drugs called PARP inhibitors. PARP is an enzyme that binds to damaged DNA and helps repair it. PARP inhibitors block the enzyme from performing repair, preventing the ends of a DNA double-strand break in cancer cells from reconnecting to one another.

The cancer cells end up joining two broken ends that are not part of the same pair. As more mismatched pairs are created, the resulting DNA structures become impossible for cells to copy and divide.

“Our study shows that the drug’s ability to trigger these mismatches relies on the tubules. When fewer tubules are present, cancer cells are more resistant to PARP inhibitors,” says Hakem.

Mekhail says the work underscores the importance of cross-disciplinary collaboration.

“The brain power behind every project is crucial. Every team member counts. Also, every right collaborator added to the research project is akin to earning another doctorate in a new specialty – it’s powerful,” he says.

Mekhail notes the discovery is also relevant to premature aging conditions like progeria. The rare genetic condition causes rapid aging within the first two decades of life, commonly leading to early death.

Progeria is linked to a gene coding for lamin A. Mutations in this gene reduce the rigidity of the nuclear envelope. The team found that expression of mutant lamin A is sufficient to induce the tubules, which DNA damaging agents further boosted. The team thinks that even weak pressure on the nuclear envelope spurs the creation of tubules in premature aging cells.

The findings suggest that in progeria, DNA repair may be compromised by the presence of too many or poorly regulated tubules. The study results also have implications for many other clinical conditions, Mekhail says.

“It’s exciting to think about where these findings will lead us next,” says Mekhail. “We have excellent colleagues and incredible trainees here at Temerty Medicine and in our partner hospitals. We’re already working toward following this discovery and using our work to create novel therapeutics.”

The research was supported by the Canadian Institutes of Health Research, Royal Society of Canada, U of T and Princess Margaret Hospital.

U of T grad seeks to make care for traumatic brain injury patients more equitable

Christopher.Sorensen — Fri, 09 Jun 2023 14:31:33 +0000

U of T grad seeks to make care for traumatic brain injury patients more equitable

Christopher.Sorensen Fri, 06/09/2023 - 10:31

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Samira Omar, who graduated with a PhD in rehabilitation sciences, studies institutional racism and its manifestations in traumatic brain injury rehabilitation research and practice (photo by Erin Howe)

Erin Howe

Topic

Our Community

Convocation 2023

Temerty Faculty of Medicine

Subheadline

Samira Omar's research was inspired by her experience caring for her brother

Samira Omar, who recently graduated with a PhD in rehabilitation sciences from the University of Toronto’s Temerty Faculty of Medicine, is driven by care and curiosity.

Her research lies at the intersection of equity, rehabilitation science and racism – with a focus on rehabilitation care for Black-identifying people with traumatic brain injuries (TBI).

Omar’s work is inspired by her experience caring for her brother, who experienced a traumatic brain injury nine years ago.

“My brother was an in-patient for over three years,” Omar says. “During that time, I spent 18 hours a day at his bedside making sure he had a voice and that people treated him like a human being who had a life to look forward to after he left the hospital.

“I was disappointed with the quality of care he was receiving, which I was convinced was based on our appearance and other people’s perceptions and assumptions about our background.”

While Omar had been planning to become an occupational therapist, she says she shifted her focus once she saw the potential to make rehabilitation care more equitable for people who identify as Black.

She says she soon realized there was very little academic literature addressing either racism in rehabilitation care or quality of life for Black people who live with a TBI.

In one of her first studies, a scoping review to map existing literature, Omar recalls discovering that Black people were often omitted from research, or included but with an emphasis on their underperformance. She says few people interpret those findings as racist, pointing only to the components of systemic racism and failing to name the causes that perpetuate the problem.

Today, Omar studies institutional racism and its manifestations in TBI rehabilitation research and practice. In a recent project, Omar looked at the qualitative experiences of Black people with TBIs and their family caregivers – and how their care could be improved.

“Throughout my dissertation, I’ve had multiple opportunities to work with students, faculty and people within the TBI community to break the ice on ideas of race, racism and intersectionality, and on the importance of these structural factors in peoples’ rehabilitation experiences and trajectories,” Omar says.

In addition to her research, Omar has advocated for changes to reflect greater equity, diversity and inclusion within rehabilitation curricula. She has also contributed to Temerty Faculty of Medicine’s Summer Mentorship Program, which offers high school students of African or Indigenous ancestry an opportunity to explore the health sciences at U of T.

And she continues to provide full-time support to her brother.

Omar has been recognized with several awards over the course of her studies, including the Change-Maker Award from Neurological Health Charities Canada in 2021. The award recognizes people or organizations that make meaningful differences to improve the quality of life for Canadians with brain conditions.

“I do not know of any other person with lived experience of neurological disability who has addressed anti-Black racism in such a profound way both through advocacy and science,” says Angela Colantonio, director of the Rehabilitation Sciences Institute and a professor of occupational science and occupational therapy at Temerty Medicine. “Samira has been incredibly generous with her time to illuminate others with her insights that are so badly needed right now.”

Omar has been recognized with the Brain Injury Society of Toronto’s Vetter Volunteer of the Year Award and honorary membership in the Canadian Association of Occupational Therapists, and is a recipient of U of T’s Gordon Cressy Student Leadership Award and the inaugural Temerty Faculty of Medicine Excellence in Professional Values Award.

Upon completion of her PhD, Omar plans to train at U of T to become an occupational therapist and to inspire future generations to consider the rehabilitation needs of all populations.

“We all have a responsibility to understand the role we play and how big a difference we can make to one person, whether as a practitioner or through the questions we ask in research,” Omar says. “We need to ask, ‘Who are we missing?’ And we need to consider those who might not be served by a one-size-fits-all approach.”

Researcher develops kidney stone ‘vacuum’

Christopher.Sorensen — Mon, 27 Mar 2023 14:56:03 +0000

Researcher develops kidney stone ‘vacuum’

Christopher.Sorensen Mon, 03/27/2023 - 10:56

Cutline

Monica Farcas, a surgeon-investigator at St. Michael’s Hospital and a U of T assistant professor of urology, led the development of a device that can vacuum up remaining bits of kidney stones (photo courtesy of St. Michael's Foundation)

Erin Howe

Topic

Our Community

Temerty Faculty of Medicine

Unity Health

Research & Innovation

St. Michael's Hospital

A Toronto researcher has developed a new tool to remove kidney stone fragments left over after laser surgery and is working to bring the invention to market with support from a new entrepreneurship program.

“Kidney stones can be life-altering – some people place their lives on hold [and] they worry about a potential kidney stone attack, which can be unexpected,” says Monica Farcas, a surgeon-investigator at St. Michael’s Hospital, Unity Health Toronto, and an assistant professor of urology in the University of Toronto’s Temerty Faculty of Medicine. “It’s common for people who experience kidney stones to visit the emergency room dozens of times over the course of their lives with a kidney stone attack.”

One in 10 people in Canada experiences kidney stones. The symptoms are sudden and debilitating, and laser surgery is a common treatment. Surgeons break the stones up and remove most of the pieces after laser surgery, but when remaining bits fail to pass through a person’s urine, they can develop into larger stones or harbor bacteria that lead to repeated urinary tract infections.

A researcher at Unity Health’s Li Ka Shing Knowledge Institute who holds the Agnico Eagle Chair in Endourology and Minimally Invasive Urology, Farcas led the creation and development of a device that can be inserted into a patient’s kidney to vacuum out any remaining bits of stone. In the long term, patients are less likely to need follow-up care or to visit the emergency room.

Farcas says there were significant challenges in designing the device since instruments used in these types of procedures need to be tiny and can’t disrupt the kidney in any way. She and her team built a prototype and are testing and improving the device.

Farcas received support along the way from the Temerty Medicine’s Entrepreneur in Residence (EiR) program. It launched as a pilot last year with funding from James and Louise Temerty and the Temerty Foundation, and continues to be a resource for Temerty Medicine-affiliated faculty.

“Physicians are generous with their knowledge and want to find the best solutions for their patients, colleagues and the broader population. The Temerty EiR program fosters an entrepreneurial culture to help them improve human health through commercialization,” says Jarrod Ladouceur, the faculty’s industrial partnerships officer.

Farcas is among the first cohort of entrepreneurs in the EiR program. Participants gain access to a team of seven entrepreneur-advisers, staff support and help for crafting pitches to bring new health-care devices and technology to market.

The program also provides seed funding to help participants with expenses related to early-stage milestones such as hiring a lawyer to assist with contract reviews.

For many clinicians, it can be difficult to find time for mentorship and learning opportunities, but Farcas says she was able to tailor the experience to suit her busy schedule.

“My mentors have been instrumental in showing me how to think about a customer base, learn about intellectual property and patents and better understand which projects to focus on,” says Farcas, who studied engineering before she entered medicine and holds several patents in surgical innovation.

“I’ve got lots of clinical and research experience, but talking to someone who sees things from a business perspective has been tremendously helpful,” she says.

Farcas also credits the EiR program with helping her in the most recent Angels’ Den Pitch Competition at St. Michael’s Foundation last November – her second time before the judges and jury. Farcas’s pitch earned her one of the event’s three prizes, the Keenan Award for Medical Discovery, which includes $150,000 to support the next steps in developing the surgical tool.

Hybrid immunity provides better protection from COVID-19 than prior infection or vaccination alone: Study

Christopher.Sorensen — Fri, 20 Jan 2023 17:59:15 +0000

Hybrid immunity provides better protection from COVID-19 than prior infection or vaccination alone: Study

Christopher.Sorensen Fri, 01/20/2023 - 12:59

Cutline

(Photo by Creative Touch Imaging Ltd./NurPhoto via Getty Images)

Erin Howe

Topic

Breaking Research

COVID-19

Temerty Faculty of Medicine

Dalla Lana School of Public Health

Graduate Students

Research & Innovation

People who have recovered from COVID-19 and been vaccinated against the virus have the best and longest lasting protection against future infection, compared to people who have been only vaccinated or only previously infected, according to a new international study.

The findings are published in Lancet Infectious Diseases.

Niklas Bobrovitz

“These findings highlight the importance of vaccination, even for people who have already had a SARS-CoV-2 infection, and may also help inform planning and policies for future booster shot campaigns,” says researcher and lead author Niklas Bobrovitz, a student in the MD program at the University of Toronto’s Temerty Faculty of Medicine.

The study looked at the effect of COVID-19 infection or vaccination versus the combination of infection and vaccination (known as hybrid immunity) against future COVID-19 infection, hospitalization and severe disease. The researchers also explored how long protection lasts after the most recent infection or vaccination.

The findings show that people with hybrid immunity that includes a full primary dose regimen, which varies by manufacturer, are well protected from hospitalization or severe disease for at least nine months, with lesser but still substantial protection against reinfection.

The team found that prior infection and hybrid immunity both provided more robust and longer-lasting protection against the Omicron variant than vaccination alone. And although protection from infection quickly wore off following infection or vaccination (60 per cent reduced chance of infection at six months), the protection against hospitalization or severe disease remained high (97 per cent reduced chance of hospitalization or severe disease at 12 months).

To reach their findings, the team did a systematic review of 11 studies that examined people who’d been previously infected as well as 15 studies that featured people with hybrid immunity.

The study, which is the most comprehensive study of hybrid immunity to date, is part of SeroTracker, a group that tracks population immunity around the world using serology test results that show COVID-19 antibodies in a person’s blood from either vaccination or infection. The platform was created by Canadian graduate and professional students and launched early in the pandemic.

Bobrovitz first became involved in SeroTracker at the invitation of his classmate Tingting Yan, one of the platform’s co-creators who, at the time, was in the second year of the MD program and completing a master of science degree in the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health.

Having recently completed a PhD in clinical epidemiology at the University of Oxford, Bobrovitz wanted to use his research skills to help protect the public from the consequences of COVID-19.

SeroTracker caught the attention of the Public Health Agency of Canada and the World Health Organization (WHO), which used the platform to develop models of the spread of infection. The project set the stage for Bobrovitz to work with researchers from around the world including Maria Van Kerkhove, WHO’s top COVID-19 technical adviser, and members of the Canadian COVID-19 Task Force.

The team also included contributions from learners at universities in the United States and Canada, including Brianna Cheng and Christian Cao, who are both in their first year of Temerty Medicine’s MD program, and Xiaomeng Ma, a PhD student at the Dalla Lana’s School of Public Health.

Though the team’s findings suggest that hybrid immunity offers greater protective benefit than vaccination alone, Bobrovitz stresses the importance of avoiding infection.

“Despite how much scientists and physicians have learned about COVID-19, it’s still very difficult to predict how an infection will affect different people,” Bobrovitz says. “Deliberately getting infected could result in death, a need for mechanical ventilation in the ICU or a host of serious chronic health consequences. It’s not worth the risk.”

Bobrovitz says that in addition to providing lessons for managing COVID-19 in the future, the study’s results may also have implications for outbreaks of other infectious diseases.

Class of diabetes drugs cuts dementia risk in older adults, research shows

lanthierj — Wed, 14 Dec 2022 17:52:21 +0000

Class of diabetes drugs cuts dementia risk in older adults, research shows

lanthierj Wed, 12/14/2022 - 12:52

Cutline

(photo by Yiu Yu Hoi/Getty Images)

Erin Howe

Topic

Breaking Research

Sunnybrook Health Sciences

Temerty Faculty of Medicine

Diabetes

Graduate Students

Research & Innovation

A class of medication for Type 2 diabetes may help older people with the condition reduce their risk of dementia.

The findings are contained in a new study by Walter Swardfager, an assistant professor of pharmacology and toxicology at the Temerty Faculty of Medicine and a scientist in the Sandra Black Centre for Brain Resilience and Recovery at Sunnybrook Research Institute, and graduate student Che-Yuan (Joey) Wu.

Their research shows sodium-glucose cotransporter-2 (SGLT2) inhibitors are associated with a 20 per cent lower dementia risk when compared to another kind of medication known as dipeptidyl peptidase-4 inhibitors (DPP4).

Often, the first medication prescribed to people with Type 2 diabetes is metformin. When metformin alone doesn’t have the desired effect, additional therapies such as SGLT2 and DPP4 inhibitors, may be added or substituted. For many patients, physicians will choose between these two classes of drugs.

SGLT2 inhibitor medications, which include dapagliflozin and empagliflozin, are commonly prescribed. These drugs lower blood sugar by causing the kidneys to remove sugar from the body through urine. DPP4 inhibitor medications – which include linagliptin, saxagliptin and sitagliptin – work by blocking the action of an enzyme that destroys an insulin-producing hormone.

“The beautiful thing is that some diabetes medications, including the SGLT2 inhibitors, might manipulate the pathophysiology at an early stage before dementia develops,” says Swardfager. “We hope this strategy could prevent dementia for a group of people who are most vulnerable.”

From left: Walter Swardfager and Che-Yuan (Joey) Wu (photo by Erin Howe)

The study, published in the journal Diabetes Care, looked at more than 106,000 people aged 66 years and older. To make their observations, the researchers examined Ontario health records for people who were newly prescribed one of either kind of medication and who hadn’t previously experienced dementia. Then, they compared incidences of dementia between the two groups over a period of nearly three years.

They identified incident cases of dementia by hospitalization with a dementia-related diagnosis, three physician claims for dementia within a specified time frame, or by the prescription of a medication used to slow cognitive decline.

Though scientists don’t fully understand why, diabetes is known to increase a person’s risk of dementia, including vascular dementia and Alzheimer’s disease, by as much as two times.

The most common types of dementia involve deposits of abnormally folded proteins, as well as metabolic and vascular changes, in the brain.

Diabetes is known to damage blood vessels throughout the body, especially the small vessels, says Swardfager. The condition may also impair the brain’s smallest vessels.

“Under the current clinical guidelines, physicians have limited options to slow cognitive changes or lower the risk of dementia in people with diabetes,” says Wu. “Now, we have a potential candidate to help intervene in this process.”

The team next hopes to explore a newer class of diabetes drug called glucagon-like peptide-1 receptor agonists. Those drugs also have shown some promise for having brain benefits.

Wu and Swardfager hope to determine whether the benefits of particular drugs might be greater for certain individuals, and how this might contribute to personalized therapy or co-therapy with other medications to slow down dementia.

Swardfager is also excited by the potential for further studies that could help unlock some of dementia’s most complex mysteries.

“If we can give medications for diabetes early enough to protect the brain, it might have a real impact on an individual's trajectory,” says Swardfager. “Knowing which drugs show benefit may also offer new insights into how dementia begins and progresses in living people.”

This research was supported by funding from the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Alzheimer’s Association, Brain Canada, the Weston Brain Institute, Alzheimer’s UK, the Michael J. Fox Foundation and the Canada Research Chairs Program.

With the support of profs, Mitch De Snoo finds a way to balance PhD research and pro lacrosse

Christopher.Sorensen — Mon, 08 Aug 2022 13:56:11 +0000

With the support of profs, Mitch De Snoo finds a way to balance PhD research and pro lacrosse

Christopher.Sorensen Mon, 08/08/2022 - 09:56

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(Photo by Ryan McCullough)

Erin Howe

Topic

Our Community

Temerty Faculty of Medicine

Hospital for Sick Children

Institute of Medical Science

Laboratory Medicine and Pathobiology

Sports

Mitch De Snoo is not only completing his MD/PhD studies at the University of Toronto’s Temerty Faculty of Medicine – he has successful career as a professional lacrosse player, too.

De Snoo, who studies the basic mechanisms involved in memory formation, just completed the second year of his PhD studies at the Institute of Medical Science (IMS) in the lab of Professor Paul Frankland, who has appointments with IMS and physiology at Temerty Medicine and is a senior scientist at SickKids Research Institute.

De Snoo also plays defense for the Toronto Rock, and last month he was named Defensive Player of the Year by the National Lacrosse League (NLL), the world’s largest professional lacrosse organization.

He recently spoke with writer Erin Howe about how he balances science and sport.

What is the focus of your research?

I’m part of Professor Paul Frankland’s neurobiology lab at SickKids. Working with mouse models, we look at basic science factors that affect the saliency and longevity of memory. My project specifically uses a technique called calcium imaging to track the activity of neurons in the hippocampus, an essential structure for memory formation, while mice are engaged in learning tasks. Calcium imaging allows me to track the same neurons over extended periods of time so I can compare how their hippocampal representations of the task evolve with time. I also study how neurogenesis – the birth of new neurons during adulthood, and a process that is unique to the hippocampus – affects these memories.

What sparked your interest in this area?

I’m interested in neurodegenerative diseases and, in particular, Parkinson's disease. My father had Parkinson’s and was diagnosed when he was quite young, which influenced me to do research and pursue studies in medicine.

When I was doing my master’s degree in laboratory medicine and pathobiology in [Associate] Professor Suneil Kalia’s lab, I explored the cell biology involved in some of the pathways known to cause genetic forms of Parkinson’s disease.

Difficulties related to memory and cognition are among the most concerning symptoms in Parkinson’s and other neurological diseases. My goal is to better understand the fundamental science underlying memory so that I can eventually apply the concepts and techniques that I am learning in my PhD to study the pathophysiology and treatment of disease in my own research program in the future.

What drew you to lacrosse?

I'm very lucky things have worked out as they have.

I played lacrosse and hockey while I was growing up in Oshawa and never imagined that playing sports would become more than a pastime – it just sort of happened.

I was older than many players are when I began to play competitively. Some of the other people I played with were recruited for scholarship opportunities at universities in the United States. When I realized that could be a possibility for me, it was exciting. I was recruited to study at and play for Drexel University in Philadelphia. Each summer, I returned home to Canada to play in the competitive leagues here.

At some point, I was ranked on an NLL draft board and people were talking to me about prospects and playing professionally – I was surprised! Then, when I finished my undergraduate degree in 2015, I was drafted to the Calgary Roughnecks. While I initially made the team out of training camp, I was traded to play for the Buffalo Bandits in New York State before the season began. I played my first five seasons in Buffalo.

When did you join the Toronto Rock?

I was traded to the Toronto Rock early in 2020, a few weeks after our league announced a shutdown due the COVID-19 pandemic. With public health precautions remaining in place, this past 2021-22 season was the first time I got to play with the team. It was a tremendous experience to be able to play for the hometown team that I watched when I was a kid. Once it was safe for friends and family to begin coming to see our games toward the end of the year, it was great.

What was your reaction to learning you’d been named Defensive Player of the Year?

It was pretty shocking. Even though it all worked out in the end, I never thought it would be possible to have a career in the NLL. I was just focused on doing my best and becoming a better player each year.

How do you balance the demands of academic life with the rigours of professional sport?

I’ve been fortunate to work with supportive faculty members like Professors Frankland and Kalia and to do the kind of research that allows me to manage my own time. And although the NLL is a professional league, we only play games during weekends. Our team practices are also capped to once a week and I do other workouts during the week around my research schedule. When I’m on the road, I also find time to work at my computer, whether I’m on a plane or fitting in time during the afternoon between our morning shootaround and gametime in the evening.

Mohammad Asadi Lari named valedictorian posthumously by grads in U of T's Temerty Faculty of Medicine

Christopher.Sorensen — Thu, 02 Jun 2022 13:27:25 +0000

Mohammad Asadi Lari named valedictorian posthumously by grads in U of T's Temerty Faculty of Medicine

Christopher.Sorensen Thu, 06/02/2022 - 09:27

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Mohammad Asadi Lari, an MD/PhD student, was among the eight U of T community members who died in the Ukraine International Airlines Flight PS752 disaster in 2020 (photo supplied)

Topic

Temerty Faculty of Medicine

U of T Mississauga

Mohammad Asadi Lari’s memory loomed large at an event this week for the University of Toronto’s Temerty Faculty of Medicine graduates, who named the MD/PhD student their valedictorian  posthumously.

Asadi-Lari and his sister, Zeynab Asadi Lari, a fourth-year biology student at U of T Mississauga, were among eight U of T community members who died aboard Ukraine International Airlines Flight PS752 on Jan. 8, 2020. The pair had been travelling back to Toronto after visiting family in Iran when the plane was shot down by an Iranian surface-to-air missile shortly after taking off rom Tehran. In all, 176 people were killed, including 55 Canadian citizens and 30 permanent residents.

Graduating MD class co-presidents Maria Leis and Christopher End announced the honour for Asadi Lari during an annual pre-convocation event at Convocation Hall. There was also a video tribute featuring comments from many of Asadi-Lari's friends and classmates, as well as clips from Asadi Lari’s October 2018 Ted Talk about youth empowerment and other interviews.

Leis and End met Asadi Lari when he served as vice-president, global health at the U of T Medical Society (MedSoc). In the position, Asadi-Lari advocated for matters of international aid and equity related to human health.

The class co-presidents say “Moh,” as he was known to friends, was a kind, caring person who would go out of his way to help his classmates. 

“I remember Moh staying in the anatomy lab, long after class had ended. We all needed to study, but if there was anyone struggling with the material, he made time to help his classmates succeed,” says End. “By extension, while working with MedSoc, I saw how he shared opportunities with other students to ensure everyone had a chance to gain valuable experience.

“Seeing how Moh lifted others up continues to inspire me.” 

Upon learning of Leis’s interest in working with the United Nations Entity for Gender Equality and the Empowerment of Women (UN Women), Asadi Lari used the network he'd formed in his role as a youth adviser with the Canadian Commission for the United Nations Educational, Scientific and Cultural Organization (UNESCO) to help her connect with the agency. 

“For someone with such an expansive resume, Moh was down-to-earth. You wouldn’t know he’d worked internationally and that he’d achieved so much before beginning medical school. Where he could, he used those experiences to help others reach their own goals,” says Leis. 

Asadi Lari was especially passionate about youth empowerment and co-founded STEM Fellowship, a youth-led non-profit organization that uses mentorship and experiential learning to equip young people with skills in data science and scholarly writing. 

During his time at Temerty Medicine, Asadi Lari also helped establish Physician Innovator Canada, a national network for doctors transforming health care through innovation.

Professor Nicola Jones, director of the integrated physician scientist training program, came to know Asadi Lari over the two years he spent in the program.  

“In his too short time with us, Mohammad made a remarkable impact,” she says. “He was a friend to all who were fortunate enough to meet him and will be remembered for his commitment to innovation and making positive change both locally and beyond. We will always hold him in our hearts and his legacy as a change-maker will continue to live in our program.” 

In the years prior to his death, Asadi Lari was also involved in other organizations, including the Canadian Institutes of Health Research, the Canadian Red Cross, Science World British Columbia, the civic-engagement group ‘Apathy is Boring’ and the World Economic Forum.  

Asadi Lari's efforts were recognized through various awards including a 3M National Student Fellowship, a Society for Scholarly Publishing Fellowship, a bronze Governor General’s Academic Award and a British Columbia Faces of Today Leadership award. He also won numerous national and international Science Olympiad medals. 

“Mohammad was an outstanding and inspirational leader, as well as a caring and compassionate colleague and friend to many in his class and beyond. He truly would have changed the world. We must work together to honour his legacy and ensure that his vision and values live on,” says Patricia Houston, vice-dean, medical education at the Temerty Faculty of Medicine. 

An award in the siblings’ names, established by Asadi Lari’s friends and colleagues, was also presented to Tina Binesh Marvasti during the ceremony. It recognizes an MD/PhD student who has demonstrated excellence in innovation and brought about positive change.  

Researchers unravel a cellular mystery related to salmonella

geoff.vendeville — Mon, 30 May 2022 19:58:58 +0000

Researchers unravel a cellular mystery related to salmonella

geoff.vendeville Mon, 05/30/2022 - 15:58

Cutline

Glenn Walpole, an MD/PhD student in U of T's Temerty Faculty of Medicine, was part of a team that investigated how salmonella manipulates a fundamental class of cellular lipids called phosphoinositides (photo by Julia Soudat)

Erin Howe

Temerty Faculty of Medicine

Hospital for Sick Children

Research and Innovation

University Health Network

Salmonella has been at the centre of a scientific riddle that’s puzzled researchers for more than 20 years.

The pathogen is well known for causing food-borne illnesses and can infect people through contaminated food or water. But until recently, no one knew how the microbe – strains of which can also cause typhoid fever and post-infectious arthritis – manipulates a fundamental class of cellular lipids called phosphoinositides.

Glenn Walpole, an MD/PhD student in the University of Toronto’s Temerty Faculty of Medicine, is part of a team that solved the mystery. Their study was published in the journal Nature Cell Biology and featured on the cover of its May issue.

Walpole spoke with writer Erin Howe about the findings.

Tell us about your research and the question you set out to answer with this study.

During my PhD studies in the department of biochemistry, I explored how different microbes interact with human cells.

There are good microbes that help shape the development of our immune system, metabolism and several other important pathways. But my research focused on the small subset of microbes that are disease-causing, harmful to humans and which can be harmful to animals. This is the case with salmonella.

Researchers often use salmonella as a model system for intracellular pathogens, which can invade host cells and reside inside specialized compartments they create there.

These intracellular microbes secrete specialized proteins into human cells that manipulate our biology, which allows the pathogens to create a niche where they can extract nutrients, grow, replicate and even spread to other cells in our body. Several pathogens are capable of this type of behaviour, which is a challenge for our immune systems to recognize and clear.

Antibiotic-resistant forms of many pathogens that adapt to this intracellular lifestyle have recently been noted in the scientific literature; this adds to our concern, given that intracellular pathogens are a significant cause of death and disease around the world.

During my PhD, my supervisors and mentors (Sergio Grinstein, a senior scientist at The Hospital for Sick Children and professor in the department of biochemistry in the Temerty Faculty of Medicine; John Brumell co-director of the Inflammatory Bowel Disease Centre at SickKids and a professor of molecular genetics at U of T; and Greg Fairn, who is now in the department of pathology at Dalhousie University) and I wanted to study the initial stages of infection – when the pathogen invades the cells that line the gastrointestinal tract and set up residence.

We were interested in the lipids that form part of the membrane surrounding each and every cell in our bodies and how salmonella manipulates the lipids called phosphoinositides.

About 20 years ago, research showed that when salmonella infects a cell, it activates host signaling pathways that depend on phosphoinositide lipids. The host cell is ‘tricked’ into surviving despite having a harmful pathogen inside, which allows the bacteria to grow and replicate.

Similar survival pathways go awry in several types of cancer. It’s almost as though the bacteria impose a cancer-like characteristic on the cell, by manipulating phosphoinositides. This is what we wanted to understand – because how salmonella was doing this had remained a real mystery to our field.

Two human epithelial cells [that] express a fluorescent biosensor specific for the lipid (in blue) were exposed to invasive salmonella (in red). In their study, Walpole and his collaborators reveal that this lipid, which supports bacterial entry and host survival, is generated by an unconventional phosphotransferase reaction driven by the secreted salmonella protein SopB.
Human epithelial cells expressing a fluorescent biosensor specific for the lipid (blue) were exposed to invasive salmonella (red).

Human epithelial cells expressing a fluorescent biosensor specific for the lipid (blue) were exposed to invasive Salmonella (red).

So, what did you and the team discover?

We found that salmonella secretes a protein called SopB, which is like a little soldier that goes into the cell and manipulates phosphoinositides through a specialized enzymatic reaction. The reaction SopB performs on the lipid, called a phosphotransferase reaction, had never been described for any human or bacterial enzyme before this study.

This new knowledge is a breakthrough for the fields of host-pathogen interactions and cell biology. The implications are also quite interesting in terms of human biology.

What new pathways does this discovery open?

There are two new avenues we can explore from here. The first is the direct application to the infection process. By discovering a new enzymatic reaction, there's now a new target for treatment. Further research could help scientists discover or develop new antibiotics to target this specific enzymatic reaction.

And along those lines, we also discovered that a related protein secreted by a different pathogen – shigella, which also causes severe diarrhea – seems to have the ability to perform the same kind of reaction. So, we could target this reaction during salmonella infections, but potentially for other pathogens as well.

The second big possibility this study raises is whether the enzymatic reaction we discovered also takes place in human cells on an everyday basis in the absence of infection, and that we just never realized it.

Researchers who work in this field have carefully noted the primary pathways thought to be involved in forming these lipids such as PI3-kinases, another class of host enzymes. But our findings throw a curveball at our previous understanding. For example, several of these enzymes like PI3-Ks are drivers of certain forms of cancer. So, if human enzymes perform this additional phosphotransferase reaction, it could change the way that we think about this signaling pathway in cancer.

What has the response to your research been so far?

The response from the scientific community has been immensely positive. Through social media, for example, people are engaging with the paper and sending us questions and positive vibes from around the world, which is really cool. It’s neat to see comments coming in from other researchers, either in the host-pathogen field, or who study phosphoinositides in the context of cancer or diabetes.

Also, when we uploaded this story in its preprint format, we received an invitation a day later to present at a worldwide zoom seminar series. I also presented this work at the Ontario Cell Biology Symposium, and we've been accepted to present in Lisbon, Portugal this coming summer. I think the field is excited about what our findings mean not only for host-pathogen interactions, but also for the many other processes that phosphoinositides regulate.

How exciting is it to make these kinds of waves when you are still completing the MD/PhD program?

It’s very exciting, but it's important to remember an effort like this was really like being part of a football team. In addition to my supervisors, a really important collaborator and mentor of mine was our senior author, Fairn. He brought a lot of the technical expertise and creativity that we needed to probe such a difficult question.

And sometimes there's a bit of serendipity in science that isn’t captured in publications. People have wondered about this question for 20 years since some of the initial work was published. It took perseverance to answer this question, but it also required the careful application of tools that didn’t exist two decades ago.

We collaborated with a group at the University of Pittsburgh to do optogenetics with this enzyme, so we could activate the enzyme on demand with high energy light. This allowed us to see, on a minute-to-minute basis, what happened when we turned on the enzyme. This method only became available within the last few years.

We also did a type of lipid analysis called mass spectrometry with a group in England at the Babraham Institute. This approach to analyze the subset of phosphoinositides we were interested in was developed by that group and published only about two years ago. The findings in this study are truly the result of many people’s efforts.

And what drew you to the MD/PhD program?

Pairing MD studies with doctorate research provides a really unique lens to view each field. Many fundamental insights into how people develop and experience illness and disease come from the clinic. Physician-scientists can take this forward and ask meaningful and important research questions from this lens. And here at Temerty Medicine, there are researchers in essentially every imaginable area of health research. The productivity is extraordinary.

What’s next for you?

I'm finishing my second year in the MD program at the end of the month and looking forward to the sunshine this summer, travelling to Portugal and clerkship in a few months. I’ll also be diving into a new area of research with Robert Inman and Nigil Haroon [both physicians in the University Health Network and faculty in rheumatology in the Temerty Faculty of Medicine] at the Schroeder Arthritis Institute in the coming months.

Docs got talent: Choir made up of physicians impresses in TV singing debut

geoff.vendeville — Thu, 14 Apr 2022 15:46:15 +0000

Docs got talent: Choir made up of physicians impresses in TV singing debut

geoff.vendeville Thu, 04/14/2022 - 11:46

Cutline

(Photo couretsy of Rogers Media)

Erin Howe

Topic

City & Culture

COVID-19

Temerty Faculty of Medicine

Music

As doctors, Chetana Kulkarni, Sarah Kim and Susan Thouin are used to high-pressure situations. But they nevertheless felt an adrenaline rush while auditioning for Canada's Got Talent, singing “Fight Song” by Rachel Platten in an episode that aired last week.

The three doctors, who are affiliated with the University of Toronto's Temerty Faculty of Medicine, are part of an all-female choir of physicians called Voices Rock Medicine.

“I knew 'Fight Song' before the pandemic and it had become my anthem,” says Kulkarni, an assistant professor of psychiatry at U of T and child and adolescent psychiatrist at the Hospital for Sick Children. “But leading up to Canada’s Got Talent, we only had a few gatherings to practice outside at a distance and often in the dark. It was so powerful to be together to sing it.”

Judges Howie Mandel, Lilly Singh, Trish Stratus and Kardinal Offishall all gave the choir a “yes,” which means the group will be one of the 18 acts eligible to move forward in the competition.

“We just sang our hearts out,” says Kim, a family and community medicine lecturer and artist-in-residence in the health arts and humanities program at U of T, and a staff physician at St. Joseph’s Health Centre who is focused on sports and exercise medicine and mindful psychotherapy. “We love to sing, and we want others to experience the joy, healing and growth that we have as part of this group.”

All three physicians say Voices Rock Medicine has offered them a way to express themselves and counteract burnout.

“Singing is such a vulnerable act, but it’s easier in a group because our voices blend,” says Kim. “And as we become more compassionate towards ourselves, our ability to receive others with compassion grows.”

Voices Rock Medicine was formed in 2019, after Thouin saw how much her daughter and husband enjoyed being part of other Voices Rock choirs.

Juggling work and other responsibilities made it challenging to join her husband’s choir, says Thouin, a family and community medicine lecturer at U of T and palliative care physician at Mount Sinai Hospital. But after a series of chats with her colleagues about the pressures they face, Thouin was motivated to help them all combat stress and burnout.

She pitched her idea for a singing group of female physicians to the director of Voices Rock Canada, an organization that offers choir programs for kids, adults and seniors. She invited other doctors to join, but it took time for others to develop the confidence to take part.

“So many people said to me, ‘I can’t sing,’” Thouin recalls. “But, as our director says, he can teach anyone to sing. If you can speak, you can learn to sing.”

Prospective members don’t have to audition, and many only learned to read sheet music after joining the group.

The ensemble, which began with about 30 singers, gathered in person until the onset of the pandemic and then moved their practices online. Another 40 doctors are part of a second group that meets virtually. Today, the choir counts 60 members including doctors specialized in everything from family medicine to anesthesiology to surgery.

Despite some early recognition – a video of their virtual performance of the song “Rise Again” has more than a million views since April 2020 – none of the singers expected their music to reach such a massive audience, Thouin says.

All three physicians say music boosted their emotional wellbeing, and that the impact reverberates through their work in medicine. One choir member found herself singing softly as she did medical rounds recently, lifting her own spirits and brightening the mood of her patients, Thouin says.

“I’ve also spoken with the medical students I mentor about the choir, and how important it is to have an outlet to relieve the stress of medicine and life,” Thouin says. “Whether that’s singing or some other activity that gives you a reprieve, it’s so beneficial for preventing burnout.”

While it remains to be seen how far Voices Rock Medicine will progress in Canada's Got Talent, fans of the choir will be able to catch them live at the Jane Mallet Theatre, on May 29.

U of T medical student Nicole Mfoafo-M’Carthy named a Rhodes Scholar

Christopher.Sorensen — Mon, 29 Nov 2021 19:41:51 +0000

U of T medical student Nicole Mfoafo-M’Carthy named a Rhodes Scholar

Christopher.Sorensen Mon, 11/29/2021 - 14:41

Cutline

(Photo courtesy of Nicole Mfoafo M'Carthy)

Erin Howe

Topic

Global Lens

Temerty Faculty of Medicine

Rhodes Scholar

Nicole Mfoafo-M’Carthy, a second-year medical student at the University of Toronto, is one of 11 Canadians selected this year to receive a prestigious Rhodes Scholarship.

The Rhodes Scholarship covers expenses for a postgraduate degree at the University of Oxford in the United Kingdom and is awarded to exceptional, public-spirited leaders from around the world. It identifies and supports young people with potential to make a positive impact on the world.

One way Mfoafo-M’Carthy is seeking to make an impact is through research. She has a keen interest in workplace policy related to gender, disability and intersectionality.

“Work is such a large part of many people’s lives, but differences between the experiences of people of different genders are often overlooked – especially how gender interacts with our other social identities and positions such as disability,” she says. “There's a tremendous opportunity to explore what can make workplaces safer and better for everyone.”

Mfoafo-M’Carthy, an MD student in U of T’s Temerty Faculty of Medicine, began to explore this area during her undergraduate studies at the University of Calgary. Her thesis focused on mental health in gendered workplaces, and how employers can create more inclusive policies that account for diversity and individual needs.

At U of T, Mfoafo-M’Carthy is working on a qualitative assessment of moral injury – the cognitive and emotional response after events that go against a person’s own moral code – in long-term care workers. As part of the project, Mfoafo-M'Carthy looks at how people working in long-term care experienced the COVID-19 pandemic, and what could have been done to better support them. At the University of Oxford, she plans to pursue her interest in the intersection of health and policy.

Mfoafo-M’Carthy, who is also a junior fellow at Massey College, says she always intended to pursue a master’s degree or doctorate, but was unsure about timing. She never dreamed that one of the world’s most highly regarded scholarships would give her the opportunity.

As she prepares to join the network of more than 4,500 Rhodes Scholars worldwide, Mfoafo-M'Carthy says her story is one of community.

“If someone had told me when I arrived at U of T last fall that I would become a Rhodes Scholar, I’d never have imagined it,” she says. “But over time, and with more exposure to the opportunities here, I could see how this opportunity aligned with what I wanted for myself. And I was fortunate to receive so much support from people here at U of T.”

Among her supporters, Mfoafo-M'Carthy lists U of T faculty Ayelet Kuper, Marcus Law, Tony Pignatiello and Jennifer Bryan, who was her mentor through the diversity mentorship program. She also credits neurology resident Victoria Reedman, who encouraged her to apply to Rhodes, and notes that many faculty members extended their support throughout the application process, helping her prepare for the two-day long interview.

Mfoafo-M'Carthy says her experiences as a mentee helped cement her own commitment to mentoring others in the community. She received mentorship through Community of Support and, after she was accepted to the MD program, became a mentor herself.

Mfoafo-M'Carthy is heavily involved with the Black Medical Students Association as a mentor and as co-director of community outreach. As well, she is a committee member for the Ontario Medical Association’s OMA Women.

In 2015, she created Gurl, a mentorship program in Calgary for girls from immigrant families between the ages of nine and 13. Gurl continues to operate and provide participants with a sense of community.

Mfoafo-M'Carthy also founded a non-profit organization called Career Match, which ensures youth are provided with the tools and resources to make informed decisions about their careers. The organization provides networking opportunities along with career fair events to match students with mentors.

Within days of learning she is headed to Oxford, Mfoafo-M'Carthy began to connect with other Rhodes Scholars, including a few at U of T. She says she is excited to embark upon her next academic adventure at Rhodes House in Oxford, but is still taking in the big news.

Mfoafo-M'Carthy will begin her studies at the University of Oxford in September of 2022 and return to study in the MD program at U of T upon completion of her graduate degree.

Erin Howe

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U of T medical student Nicole Mfoafo-M’Carthy named a Rhodes Scholar