Physiology

Sinai Health

Myhal Centre for Engineering Innovation & Entrepreneurship

Toronto General Hospital

One hundred years ago this month, scientists at the University of Toronto and its partner hospitals carried out the first studies that demonstrated the ability of insulin to lower blood sugar levels in animals and prevent their death from diabetes.

Three months later, insulin was successfully administered to a person with type 1 diabetes at Toronto General Hospital. His life would become the first of millions around the world to be saved by insulin – one of the landmark medical discoveries of the 20^th century.

On Friday, the historical significance of the discovery was marked by the unveiling of a commemorative bronze plaque at a ceremony hosted by Parks Canada and the Historic Sites and Monuments Board of Canada (HSMBC) at the Myhal Centre for Engineering Innovation & Entrepreneurship on ��ֱ��’s St. George campus.

The event was attended by government dignitaries including Sonia Sidhu, member of parliament for Brampton South. The final location of the plaque, which is inscribed by bilingual text, will be determined at a later date.

“The story of insulin is a brilliant example of the power of collaboration – in this case, how a university, its hospital partners and a pharmaceutical company could work together and change the world,” said Christine Allen, ��ֱ��’s associate vice-president and vice-provost, strategic initiatives.

“On this illustrious foundation, ��ֱ�� and its hospital and industry partners built a culture of discovery, innovation and collaboration that has transformed health care and continues to have a ripple effect worldwide.

From left: Patricia Brubaker, Richard Alway, Sonia Sidhu, Christine Allen, Christine Loth-Brown and Lynn Wilson (photo by Johnny Guatto)

The ceremony marked the culmination of Insulin 100, a year-long campaign to mark the centenary of insulin’s discovery and celebrate a legacy of health innovation that continues to be advanced by ��ֱ�� and its partner hospitals, research institutes and industry partners.

“The Parks Canada plaque not only serves as a fitting reminder of the critical research discoveries made here at ��ֱ�� – it will also inspire future trainees and researchers whose work will be pivotal in the health research discoveries made over the next hundred years,” Allen said.

Patricia Brubaker, a professor in the departments of physiology and medicine at the Temerty Faculty of Medicine and member of the faculty’s Banting & Best Diabetes Centre, described the key areas of diabetes research being investigated by ��ֱ�� faculty and students today.

“Our interests cover the spectrum of diabetes research, including not only type 1 diabetes, but also type 2 diabetes, which is now reaching epidemic levels, affecting one in six Canadians, as well as gestational diabetes or diabetes during pregnancy,” said Brubaker, who has been conducting diabetes research for four decades.

“We are studying the causes of diabetes through research into obesity, a major risk factor for type 2 diabetes; we are interrogating new approaches to the treatment of diabetes, including stem cell replacement therapy and new pharmacologic treatments; and our researchers are exploring the fundamental mechanisms that underlie the normal regulation of glucose and fat metabolism and how this is disrupted in diabetes, leading to long-term complications such as kidney and cardiovascular disease.”

Brubaker also reflected on the impact of insulin and diabetes research on her own life. As a person living with type 1 diabetes, she noted she is “one of legions who would not be alive today without the discovery of insulin.”

In addition to saving countless lives, the discovery of insulin helped establish ��ֱ��, its partner hospitals and Toronto more generally as a vanguard of diabetes research and treatment.

In April, some of the latest developments in the field were discussed at the Insulin100 conference, a two-day virtual symposium that drew over 6,000 attendees from around the world.

Also in April, ��ֱ��’s Banting & Best Diabetes Centre and Diabetes Action Canada hosted “100 Years of Insulin – Celebrating its Impact on our Lives,” a public celebration and forum featuring an array of topics of interest to people living with diabetes.

It was at this public celebration that Canada Post unveiled a special stamp to commemorate the discovery of insulin. The stamp, which depicts a vial of insulin resting on an excerpt from Banting’s unpublished memoirs, was unveiled from the Banting House National Historic Site of Canada in London, Ont. – in the very room where Banting first got the idea that eventually led to the discovery of insulin. Brubaker and Scott Heximer, chair of the department of physiology at the Temerty Faculty of Medicine and a principal investigator at the Ted Rogers Centre for Heart Research, worked with Canada Post and Banting House to ensure the stamp’s historical accuracy and help source archival material.

The stamp would be the first of several commemorations to mark the place of insulin in the cultural tapestry of Canada’s heritage.

In May, Historica Canada released a Heritage Minutes segment paying tribute to the discovery. The segment depicts the plight of 13-year-old diabetes patient Leonard Thompson, and the efforts of Banting and Best to formulate and refine the insulin treatment that ultimately saves Thompson’s life. Again, experts from ��ֱ�� – including science and medicine librarian Alexandra Carter, archivist Natalya Rattan and medical historian Christopher Rutty – were consulted on the project to ensure historical accuracy.

In July, the Royal Canadian Mint issued its own commemoration in the form of a two-dollar coin depicting a monomer (a building block of the insulin molecule), insulin cells, blood cells, glucose and the scientific instruments used in early formulations of insulin.

The importance of insulin was recognized almost immediately after its initial discovery. In 1923, the Nobel Prize in Physiology or Medicine was awarded to Frederick Banting and James McLeod, who isolated insulin in ��ֱ��’s department of physiology. The prize was shared with physiology and biochemistry student Charles Best and biochemist James Collip.

��ֱ�� researchers continue to be recognized for their stellar work in advancing diabetes research.

Brubaker was honoured last year with a Lifetime Achievement Award from Diabetes Canada, a recognition of her longstanding contribution to diabetes research and the Canadian diabetes community. And, earlier this year, Daniel Drucker, professor of medicine in the Temerty Faculty of Medicine and a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health, was awarded a Canada Gairdner International Award for research on glucagon-like peptides that has helped revolutionize treatments for type 2 diabetes – an honour he shared with collaborators at Harvard University and the University of Copenhagen.

Heritage Minute showcases life-saving impact of ��ֱ��’s insulin discovery

lanthierj — Mon, 17 May 2021 19:35:42 +0000

Heritage Minute showcases life-saving impact of ��ֱ��’s insulin discovery lanthierj Mon, 05/17/2021 - 15:35

Yanan Wang

Topic

Toronto General Hospital

Thomas Fisher Rare Book Library

��ֱ�� Libraries

Christopher Rutty
(photo by Alie Rutty)

After decades studying the 100-yea

r-old discovery of insulin and its later development, Christopher Rutty faced a daunting task: select the most compelling details to be showcased in just 60 seconds.

A medical historian, he was one of three historical consultants on the team that created a new Heritage Minutes segment that pays tribute to the discovery of insulin at the University of Toronto’s department of physiology in 1921.

The segment follows the patient journey of a young and emaciated-looking Leonard Thompson, who would become the first diabetes patient to be successfully treated with the life-saving extract. Working away in their laboratory, scientists Frederick Banting and Charles Best offer an extract that they believe may save the child, who receives the treatment at Toronto General Hospital. In the evening, however, they receive a knock on the door from collaborators J.J.R. Macleod and James Collip, who says the extract is not pure enough.

“So, we try again,” Banting responds with defiance. “And again. And again.”

The decision to highlight the story of a single patient stemmed from a desire to emphasize the human element of the Nobel Prize-winning scientific discovery, according to Rutty, an adjunct professor at ��ֱ��’s Dalla Lana School of Public Health.

“If you’re going to reduce it down to a 60-second story, that’s a key moment,” Rutty says. “It shows the drama of the impact of insulin, which was that it practically resurrected the dead.”

A self-described stickler for details, Rutty says he felt a sense of responsibility to portray the story accurately because of the memory of his late PhD thesis adviser, ��ֱ�� University Professor Emeritus Michael Bliss, who wrote the acclaimed book The Discovery of Insulin.

Rutty is also the lead historian for Defining Moments Canada’s Insulin 100 website, which features a series of articles authored by Rutty that recount the historical events leading up to and following insulin’s discovery – including the story of Thompson’s treatment.

He says he drew on Bliss’s work, original documents and newspaper reports from the period to help the Heritage Minutes team develop a full historical reconstruction of what took place. The short films are released by Historica Canada, a Toronto-based non-profit that seeks to generate awareness of Canadian history.

In a nod to Bliss’s conclusion that all four scientists in the team were critical to the discovery, Rutty felt it was important that Banting, Best, Macleod and Collip all be depicted and named.

“It was critical to make sure what the Heritage Minute was saying was true,” says Rutty. “Heritage Minutes are a record. They have a reputation of being well-done and historically responsible, and they are often an entry into the story for students and the general public.”

Alexandra Carter

Alexandra Carter, science and medicine librarian at ��ֱ��’s Thomas Fisher Rare Book Library, says she was struck by the historical accuracy of the visual details in the Heritage Minutes segment.

“We have photos of the lab; it’s this shoddy-looking, cluttered space where this amazing discovery took place,” Carter says. “I love that they put that in. I was also impressed by the attention to detail with Banting’s round glasses and their outfits – I could tell right away who was who.

“Banting was known to be a bit dramatic, so they got that right as well with the voiceover.”

Natalya Rattan

Carter and Natalya Rattan, an archivist at the rare book library, have curated an online exhibition in celebration of the 100th anniversary of the breakthrough. Drawing from ��ֱ��’s extensive archives, as well as a 1996 article by Bliss, the exhibition chronicles the team’s tribulations and eventual triumph. The story is told through original handwritten notes and notebooks from the scientists themselves, patient charts, newspaper articles, letters and other historical documents.

The Thomas Fisher Rare Book Library also recently contributed to the creation of a new commemorative Canada Post stamp, which features the image of an excerpt from Banting’s unpublished memoir and an original insulin bottle with a red cap.

As for Thompson, there are few archival materials despite his reputation as the first patient to be treated with the extract, Rattan says.

Patient records from Toronto General Hospital indicate that he was 13 years old and weighed just 65 pounds. He received an injection of the first extract on Jan. 11, 1922, followed by the second version of the extract on Jan. 23. The latter shot proved dramatically successful, as Thompson’s blood sugar dropped to normal in one day.

The Heritage Minute ends with a close-up shot of Thompson, whose previously listless face blossoms into a smile as the insulin takes effect.

“When people come to see the records – they are sometimes diabetics themselves, or doctors with direct connections to patients – they are always really drawn to the patient stories,” Rattan says.

“The patient narratives within the archives are at the heart of the discovery.”

Commemorative stamp marks 100th anniversary of ��ֱ��’s discovery of insulin

Christopher.Sorensen — Thu, 15 Apr 2021 14:25:09 +0000

Commemorative stamp marks 100th anniversary of ��ֱ��’s discovery of insulin

Christopher.Sorensen Thu, 04/15/2021 - 10:25

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Canada Post unveiled the new stamp at an online symposium sponsored by Diabetes Action Canada, ��ֱ��’s Banting & Best Diabetes Centre and the department of medicine in the Temerty Faculty of Medicine

Geoffrey Vendeville

Topic

Among the treasures in the University of Toronto’s archives are letters from grateful diabetic patients and their families addressed to Frederick Banting, who, along with Charles Best, J. J. R. Macleod and James Collip, discovered the role of insulin in the disease.

So, it’s fitting that this year’s celebrations marking the 100th anniversary of the medical breakthrough at ��ֱ�� include a new Canada Post stamp.

The stamp, unveiled this week at a virtual celebration held by Diabetes Action Canada, ��ֱ��’s Banting & Best Diabetes Centre and the department of medicine, features an excerpt from Banting's unpublished memoir and an original insulin bottle with a red cap.

��ֱ�� researchers Scott Heximer and Patricia Brubaker worked with Canada Post and Banting House to ensure the stamp’s historical accuracy and help source archival material.

“When we got into this, we didn’t realize everything that went into making a stamp,” says Heximer, an associate professor and chair of the department of physiology in the Temerty Faculty of Medicine.

In addition to the stamp itself, the unveiling includes an official first day cover that also required fact-checking.

“It was fun,” says Heximer. “Our local committee was sitting around looking at pictures of Banting and letters addressed to the doctors in Toronto, and these were all things that went into building this official first day cover.”

One hundred years ago, Banting – a surgeon with a struggling practice in London, Ont. and little research experience – approached Macleod in ��ֱ��’s department of physiology in search of the support and equipment necessary to carry out his experiments. Macleod offered Best, who had recently graduated with a degree in physiology and biochemistry, the opportunity to work with Banting. Together with Collip, a biochemist on sabbatical from the University of Alberta, the researchers succeeded in producing a pancreatic extract from cattle that prevented death from diabetes.

Brubaker, a professor in the departments of physiology and medicine, notes that the influence of Banting, Best, Collip and Macleod can still be felt in the department of physiology. For example, she says, Best was chair of the department when Professor Emeritus Mladen Vranic was hired.

Vranic, in turn, hired Brubaker, who won a lifetime achievement award from Diabetes Canada last year and whose research has contributed to the development of drug treatments for patients with type-2 diabetes. The drugs work by stimulating the secretion of insulin, helping to lower blood sugar levels and reduce appetite, among other effects.

In 1923, Banting and Macleod were awarded the Nobel Prize in Physiology or Medicine. Banting was the first Canadian to win a Nobel and remains the youngest winner of the prize in physiology or medicine (he was 32). Banting and Macleod shared the prize with Best and Collip.

The discovery of insulin was such a monumental achievement that a stadium full of people listened to Banting discuss the research, according to Brubaker.

“It was considered not a cure for diabetes, but a cure for death due to diabetes,” says Brubaker, who lives with type 1 diabetes herself and has devoted much of her career to understanding the disease. “Type 1 diabetes was a death sentence – a slow, prolonged, painful death – and it affected mostly children.”

The announcement of a lifesaving treatment was especially welcome news after the end of the First World War and a global pandemic that, like today’s, killed millions.

“This was an exciting ray of sunshine,” Brubaker says.

In March 1922, a Toronto Star bold-face headline proclaimed: “Toronto Doctors on Track of Diabetes Cure.”

Soon, fan mail poured in for Banting and his colleagues.

Teddy Ryder, a five-year-old diabetic admitted to hospital weighing just 26 pounds, received his first insulin shots in January 1922. The next year, he wrote a letter to Banting in sprawling capital letters that filled the page. It said: “I wish you could come to see me. I am a fat boy now and I feel fine. I can climb a tree.”

Canada has issued stamps since 1851, though most early examples featured English royalty, according to Jim Phillips, director of stamp services at Canada Post. Since then, Leonard Cohen, Alexander Graham Bell and Viola Desmond are among those whose images have graced the tiny squares.

As for Banting, he was last featured on a Canada Post stamp in 2000.

“We see ourselves among the oldest Canadian storytellers,” Phillips said, adding that the discovery of insulin is a “fantastic story” for a stamp.

“These are real heroes, these four guys, and the University of Toronto for backing them and giving them space for their research ... This is a very, very positive story – and I think we need positive stories more than ever right now.”

Insulin 100: How the road to a diabetes cure is yielding better treatments

Christopher.Sorensen — Thu, 01 Apr 2021 15:09:30 +0000

Insulin 100: How the road to a diabetes cure is yielding better treatments

Christopher.Sorensen Thu, 04/01/2021 - 11:09

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(Photo by Getty Images/iStockphoto)

Jim Oldfield

Topic

Institute of Biomedical Engineering

Faculty of Applied Science & Engineering

Banting & Best

Diabetes

Insulin

Nutritional Sciences

“The pancreas,” says Gary Lewis, an endocrinologist at Toronto General Hospital and director of the Banting & Best Diabetes Centre at the University of Toronto’s Temerty Faculty of Medicine, “is like an exquisitely sensitive and perfectly networked computer.”

Second by second, he notes, the pancreas secretes just the right amount of insulin or glucagon to lower or raise blood sugar into the portal vein that leads directly to the liver, the site of key metabolic processes. Insulin is then distributed to every tissue in the body via general circulation.

“Insulin injections are life-saving, but administered under the skin and nowhere near as precise,” says Lewis, who is also a scientist and professor in the department of physiology and department of medicine at ��ֱ��. “It’s extraordinarily difficult to mimic the function of a healthy pancreas.”

That’s one reason a cure for diabetes has proven elusive 100 years after the discovery of insulin.

Another big reason is the complexity of how the disease arises. In type 1 diabetes, the immune system destroys the insulin-producing beta cells of the pancreas, creating a life-threatening spike in blood sugar. Type 2 diabetes usually comes on more slowly, as the body becomes resistant to insulin or the pancreas can’t produce enough of it.

Genetics play a role in both types. Exposure to viruses and other environmental effects may be a factor in type 1. Lifestyle factors, including weight gain and physical inactivity, are strongly linked to type 2.

The bottom line, says Lewis, is that diabetes is a multifactoral disease, and we’re not close to a cure.

Ask about treatments, though, and Lewis gets excited.

The last two decades have brought a plethora of clinical and research advances, from new drugs to boost and sensitize the body to insulin and promote weight loss, to lifestyle interventions that improve diet, continuous monitoring of blood sugar, long- and short-lasting insulin, better insulin pumps, pancreatic transplants and pre-clinical stem cell and immunosuppressive therapies.

“Progress on treatments has been fantastic, especially for type 2,” Lewis says. “I’m very, very hopeful.”

The distinction between treatment and cure in medicine is often unclear. And for the 3.6 million Canadians living with diabetes, the distinction matters less and less if the goal is a full and healthy life.

Type 2 diabetes accounts for about 90 per cent of diabetes cases in Canada. Prevalence is rising, but Canadians with type 2 diabetes are living longer and have fewer diabetes-related complications.

“The clinic doesn’t look like it did 30 years ago,” says Lewis, who mainly treats patients with type 2. “We see fewer amputees, less blindness. Patients are generally healthier, and their prognosis is often excellent if they maintain their blood sugar target and other key parameters.”

Weight loss is a cornerstone of treatments to lower blood sugar, and recent research has strengthened the link between weight reduction and type 2 diabetes management. Some people with type 2 can lose weight and control blood sugar through dietary changes and exercise alone.

Bariatric surgery is very effective for weight loss and often results in diabetes remission, although it comes with surgical risks and is expensive.

“If we could prevent obesity, we could greatly reduce the incidence of type 2,” Lewis says. “And experiments have shown we can get a remission with lifestyle changes, so we know what works.”

The problem is broad implementation.

“I’ve tried to lose weight and I know how difficult it can be, especially in an environment of convenient and inexpensive calories,” Lewis says. Moreover, factors such as income, education, ethnicity, access to healthy food and living conditions can make lifestyle changes that curb obesity nearly impossible.

“Social determinants of health are overwhelmingly the most important influence on who gets type 2 diabetes, and how well or poorly they do with it,” Lewis says.

Fortunately, dozens of new drugs for diabetes have hit the market in the last two decades.

Medications for weight loss round out the armamentarium, and some also protect against kidney damage and lower cardiac risk. Current therapies can reduce body weight up to 10 per cent, although a loss of 20 per cent or more would have a greater effect on outcomes for patients with type 2 diabetes, says Jacqueline Beaudry, an assistant professor of nutritional sciences at ��ֱ�� who studies links between obesity, hormones and diet.

Beaudry is probing the biology that underpins these medications, including the gut hormones GLP-1 and GIP. They control blood glucose and reduce appetite, but scientists are unsure how.

“If we could understand their mechanisms of action, we could design better drugs,” Beaudry says.

For people with type 1 diabetes, continuous glucose monitors, insulin pumps and even automated “closed-loop” systems that run on mobile apps to deliver insulin as-needed have radically changed the patient experience.

Sara Vasconcelos left), an assistant professor at ��ֱ��’s Institute of Biomedical Engineering, has worked with Cristina Nostro (right), an associate professor in the department of physiology, and her team in the McEwen Stem Cell Institute at UHN to extend the survival and functionality of pancreatic precursor cells generated from human stem cells.

Cell therapy could prove more liberating still.

University labs and biotechs are working on implantable devices that house insulin-producing cells derived from stem cells.

To that end, Cristina Nostro, an associate professor in the department of physiology in the Temerty Faculty of Medicine, and her team in the McEwen Stem Cell Institute at University Health Network recently discovered a more efficient way to generate and purify pancreatic precursor cells from human stem cells in the lab.

They have also found a way to vascularize those cells by working with Sara Vasconcelos, an assistant professor at ��ֱ��’s Institute of Biomedical Engineering. Together, they have extended the survival and functionality of the cells in animal models of diabetes.

The biggest problem with these therapies is that the immune system rejects them. The same challenge currently hinders pancreas and islet transplants.

“The immune system is an amazing machine, we’re lucky it’s so good,” says Nostro. “But it’s very difficult to control when it goes awry, as in autoimmune conditions.”

Nostro is working with immunologists at the university on a method to protect insulin-producing beta cells from immune rejection, and she says many researchers in the field are now focused on immune-protective approaches.

Another strategy for type 1 diabetes is to tamp down the autoimmune response before the disease progresses. The idea is to prevent immune cells that damage the pancreas while the body still produces beta cells.

“Groups around the world are bringing different ideas and creative approaches to treat type 1 diabetes, that’s the beauty of science,” says Nostro. “I am very hopeful about what the future holds. Who knows? Maybe we will see hybrid technologies combining a pump and cells. We have to keep an open mind.”

This story was originally published in ��ֱ�� Med Magazine’s Insulin Issue.

From astrophysics to literature: 29 researchers at ��ֱ�� awarded Canada Research Chairs

Christopher.Sorensen — Wed, 16 Dec 2020 17:15:54 +0000

From astrophysics to literature: 29 researchers at ��ֱ�� awarded Canada Research Chairs

Christopher.Sorensen Wed, 12/16/2020 - 12:15

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Twenty-nine ��ֱ�� researchers are among 259 in Canada to receive new or renewed Canada Research Chairs, which support exceptional work across a wide variety of fields (��ֱ�� file photo)

Alison Kenzie

Topic

Institute of Biomedical Engineering

Donnelly Centre for Cellular & Biomolecular Research

Pediatrics

Lunenfeld-Tanenbaum Research Institute

Astronomy & Astrophysics

Canada Research Chairs

Chemical Engineering

Electrical & Computer Engineering

English

Faculty of Applied Science & Engineering

St. Michael's Hospital

Sunnybrook Hospital

Ted Sargent

��ֱ�� Mississauga

Vasanti Malik’s research into the dietary and lifestyle risk factors for chronic diseases has far-reaching implications – for both individuals and the world.

By considering risk factors for type 2 diabetes across the lifespan – including in utero exposures, maternal health and childhood obesity – the assistant professor of nutritional sciences in the University of Toronto’s Temerty Faculty of Medicine intends to develop a “dietary environmental index.”

The index would allow health practitioners and the public to understand how food and lifestyle choices can affect their own health as well as the health of the planet.

“What we eat has an impact on greenhouse gas emissions, land use, water use and so on,” says Malik, adding that she can envision a smartphone app that helps underscore such connections for Canadians.

Soon, she will also be working with pregnant women in Chennai, India to study how reducing refined carbohydrate intake (for instance, substituting brown rice for white rice) can prevent gestational diabetes. This data could not only improve maternal health, but also potentially reduce childhood obesity, a risk factor for developing type 2 diabetes later in life.

Malik is one of 29 researchers at ��ֱ�� – and among 259 nationwide – to receive new or renewed Canada Research Chairs, which support exceptional work across a wide variety of fields. (See the full list below.)

“I would like to congratulate all the University of Toronto researchers who received a new chair or had their chair renewed in this round,” says University Professor Ted Sargent, ��ֱ��’s vice-president, research and innovation, and strategic initiatives.

“This important federal support and recognition will enable our leading researchers to pursue critical research across a number of fields, helping generate new knowledge and innovative ideas that could ultimately change the way we live here in Canada and around the world.”

This year marks the 20th anniversary of the Canada Research Chairs program, established by the federal government to attract and retain top Canadian researchers working in a variety of disciplines – from engineering, the natural sciences and health sciences to the humanities and social sciences. The investment is significant: up to $295 million each year.

With 315 chairs total, ��ֱ�� receives more than $46 million annually in funding from the Canada Research Chairs program.

At the same time, the Canada Foundation for Innovation (CFI) – in collaboration with the CRC program – announced support for two ��ֱ�� researchers through its John R. Evans Leaders Fund (JELF), which helps universities pay for cutting edge laboratories and equipment. The two ��ֱ�� researchers are Kieran Campbell and Hartland Jackson, both of the Temerty Faculty of Medicine and the Lunenfeld-Tanenbaum Research Institute in the Sinai Health System.

As for Malik, her tier two Chair in Nutrition and Chronic Disease Prevention brings with it five years of funding (renewable once) and the chance to pursue an ambitious three-part research project that will span Canada and India and involve collaboration with experts from nutritional science, environmental science and economics.

She says the award seemed “unattainable” during her many years of graduate and post-doctoral training, which she began at ��ֱ�� and completed at the Harvard T. H. Chan School of Public Health.

Malik adds that being situated within the Temerty Faculty of Medicine is an asset, allowing her to collaborate with clinicians working in partner hospitals and giving her a front row seat to how her research might impact clinical care guidelines.

“My ultimate goal is to create evidence for policy – evidence that links diet and lifestyle choices to chronic disease prevention,” Malik says.

Malik says she is looking forward to the opportunity to collaborate with economists and other researchers at ��ֱ�� and beyond. She has many questions: Would a plant-based diet be feasible for low-income Canadian households? Would brown rice be easily accessible to Indian families living in poverty? Can governments here and abroad afford not to invest in chronic disease prevention, given the high costs of an unhealthy population?

While COVID-19 has put her travel plans on pause, Malik is excited to prepare for teaching her first class at ��ֱ��, a fourth-year international and community nutrition course that aligns with her research interests. As she strategizes how to make the course as interactive as possible, Malik looks forward to the energy generated by her students as they learn and discuss new ideas.

“We’re all figuring this out together,” she says.

Here are the new and renewed Canada Research Chairs at ��ֱ��:

New Canada Research Chairs

Jennifer Adese of the department of sociology at ��ֱ�� Mississauga, tier two in Métis women, politics, and identity
Gillian Booth of the department of medicine in the Temerty Faculty of Medicine and St. Michael’s Hospital, Unity Health Toronto, tier one in policy solutions for diabetes prevention and management
Kieran Campbell of the department of molecular genetics in the Temerty Faculty of Medicine and the Lunenfeld-Tanenbaum Research Institute, Sinai Health System, tier two in machine learning for translational biomedicine
Angela Colantonio of the department of occupational science and occupational therapy in the Temerty Faculty of Medicine, tier one in traumatic brain injury in underserved populations
Herbert Gaisano of the department of medicine in the Temerty Faculty of Medicine, and the Toronto General Hospital Research Institute, tier one in diseases of endocrine and exocrine pancreas
Jennifer Gommerman of the department of immunology in the Temerty Faculty of Medicine, tier one in tissue-specific immunity
Ali Hooshyar of the Edward S. Rogers Sr. department of electrical and computer engineering in the Faculty of Applied Science & Engineering, tier two in electric power systems
Timothy Hughes of the Donnelly Centre for Cellular and Biomolecular Research in the Temerty Faculty of Medicine, tier one in decoding gene regulation
Hartland Jackson of the department of molecular genetics in the Temerty Faculty of Medicine and the Lunenfeld-Tanenbaum Research Institute, Sinai Health System, tier two in systems pathology
Hae-Young Kee of the department of physics in the Faculty of Arts & Science, tier one in theory of quantum materials
David Lie of the department of electrical and computer engineering in the Faculty of Applied Science & Engineering, tier one in secure and reliable systems
Radhakrishnan Mahadevan of the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering, tier one in metabolic systems engineering
Vasanti Malik of the department of nutritional sciences in the Temerty Faculty of Medicine, tier two in nutrition and chronic disease prevention
Stephen Matthews of the department of physiology in the Temerty Faculty of Medicine, tier one in early development and health
Nick Reed of the department of occupational science and occupational therapy in the Temerty Faculty of Medicine, tier two in pediatric concussion
Lisa Robinson of the department of paediatrics in the Temerty Faculty of Medicine and the Hospital for Sick Children, tier one in vascular inflammation and kidney injury
John Rogers of the department of English in the Faculty of Arts & Science, tier one in early modern literature and culture
Shoshanna Saxe of the department of civil and mineral engineering in the Faculty of Applied Science & Engineering, tier two in sustainable infrastructure
Greg Stanisz of the department of medical biophysics in the Temerty Faculty of Medicine and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, tier one in cancer imaging
Harindra Wijeysundera of the department of medicine in the Temerty Faculty of Medicine and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, tier two in structural heart disease policy and outcomes
Hannah Wunsch of the department of anesthesiology and pain medicine in the Temerty Faculty of Medicine and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, tier two in critical care organization and outcomes
Azadeh Yadollahi of the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering and University Health Network, tier two in cardiorespiratory engineering

Renewed Canada Research Chairs

Jo Bovy of the David A. Dunlap department of astronomy and astrophysics in the Faculty of Arts & Science, tier two in galactic astrophysics
Birsen Donmez of the department of mechanical and industrial engineering in the Faculty of Applied Science & Engineering, tier two in human factors and transportation
Lisa Forman of the Dalla Lana School of Public Health, tier two in human rights and global health equity
Alan Moses of the department of cell and systems biology in the Faculty of Arts & Science, tier two in computational biology
Anthony Niblett of the Faculty of Law, tier two in law, economics and innovation
Laura Rosella of the Dalla Lana School of Public Health, tier two in population health analytics
Arjumand Siddiqi of the Dalla Lana School of Public Health, tier two in population health equity

Nine ��ֱ�� researchers receive federal grants for COVID-19 projects

rahul.kalvapalle — Tue, 31 Mar 2020 22:58:28 +0000

Nine ��ֱ�� researchers receive federal grants for COVID-19 projects

rahul.kalvapalle Tue, 03/31/2020 - 18:58

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Vijaya Kumar Murty, a professor in ��ֱ��'s department of mathematics, is setting up a COVID-19 task force to predict outbreak trajectories, measure public health interventions and provide real-time advice to policy-makers (photo by Johnny Guatto)

Rahul Kalvapalle

Topic

Institute of Health Policy Management and Evaluation

Coronavirus

Biochemistry

Sunnybrook Hospital

Donnelly Centre for Cellular & Biomolecular Research

When it comes to assessing the risk of transmission of an infectious disease like COVID-19 and evaluating the effectiveness of measures like physical distancing, mathematics and mathematical modelling are crucial.

“How does the virus spread? How quickly does it multiply? What’s the impact of interventions like social distancing? Mathematical modelling looks at these kinds of questions,” says Vijaya Kumar Murty, a professor in the department of mathematics in the University of Toronto’s Faculty of Arts & Science.

To address such questions, mathematicians like Murty take into account numerous variables involved in the spread of a disease, including the age, occupation or pre-existing health conditions of an individual.

“So what you do is try to build a mathematical quantitative model – taking these factors into account – of what’s going to happen in terms of the propagation dynamics,” says Murty, who is also the director of the Fields Institute for Research in Mathematical Sciences at ��ֱ��.

Murty is the recipient of a $666,667 grant from the Canadian Institutes of Health Research (CIHR) that will go towards setting up the COVID-19 Mathematical Modelling Rapid Response Task Force, a network of experts who will work to predict outbreak trajectories for the disease, measure public health interventions and provide real-time advice to policy-makers.

It’s one of nine COVID-19 research projects at ��ֱ�� to receive support from a recent $25.8-million funding package announced by the Government of Canada, building on an earlier investment of $27 million on March 6 – nearly $6 million of which went to researchers who are based at ��ֱ�� or one of its affiliated hospitals.

Both rounds of funding are part of the federal government’s larger $275-million investment in research on COVID-19 counter-measures.

“From developing low-cost diagnostic tools to modelling disease transmission and exploring potential drug interventions, researchers at the University of Toronto are attacking the problems posed by COVID-19 from numerous angles,” says Vivek Goel, ��ֱ��’s vice-president, research and innovation, and strategic initiatives.

“This latest round of funding from the federal government will help our experts across several disciplines to accelerate research projects that could have a crucial impact in the global fight against this potentially deadly illness.”

(See below for the full list of researchers who received support from CIHR in the latest COVID-19 funding round).

Murty’s mathematical modelling task force was inspired by a similar network set up by Mitacs – a national non-profit that designs and delivers research and training programs in partnership with universities, governments and companies – during the 2003 outbreak of Severe Acute Respiratory Syndrome (SARS). It will comprise 14 academics from across the country as well as other partners, including the Public Health Agency of Canada and research institutes in China.

In addition to addressing the pressing issue of the coronavirus epidemic, Murty says mathematical modelling can be applied to the analysis of other infectious diseases as well as the study of social pathogens like opioid abuse.

“It explores the propagation of a pathogen in society or, in general, propagation in networks,” he says. “How something moves from node to node – or person to person – and what interventions will produce what effect on that transmission.”

“This work is of course time-sensitive and critically important right now because of the health situation we find ourselves in. But thinking beyond that, I’m envisaging that this task force will grow so that we can continue to analyze and model public health and disease from a mathematics point of view.”

Darrell Tan, a clinician-scientist at St. Michael’s Hospital and an associate professor in ��ֱ��’s Faculty of Medicine and the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health, will look at whether the HIV drug Kaletra could be useful against COVID-19 (photo courtesy of Darell Tan)

While Murty and his collaborators crunch the numbers, Darrell Tan is preparing to run clinical trials to explore whether a popular anti-HIV drug could help prevent the spread of COVID-19.

Tan is an associate professor at the Faculty of Medicine and the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health, and is a clinician-scientist in the infectious diseases division of St. Michael’s Hospital. He secured a $1-million CIHR grant for the trials, which will look at whether Kaletra – a drug that has been used in HIV treatment as well as for uninfected people with high risk of exposure – could be useful against COVID-19.

“In general, whenever we’re trying to actively find new therapies for any medical condition, one of the most efficient ways of doing that is to find existing available drugs that could potentially be re-purposed,” says Tan.

“Because obviously it saves all the steps in drug development and safety assessments if we already have a drug available that we understand the characteristics of very well.”

Tan says that in-vitro studies and animal experiments have suggested Kaletra may have an effect on COVID-19 and other types of coronaviruses such as SARS and MERS (Middle East Respiratory Syndrome), but that there’s a dearth of quality evidence from human studies.

His trial will deploy what’s known as a “ring design,” where “rings” of people who came into close contact with COVID-19 patients will be identified.

“Once we identify a case, one could draw a ring of close contacts surrounding that ‘index case,’ and, of course, those people would be the individuals who would be at greatest risk and therefore the ones we would most immediately want to intervene on in order to prevent transmission from happening,” says Tan.

Individuals selected for the study will be randomly assigned to a 14-day course of either Kaletra or a placebo and will be tested periodically to see if they develop COVID-19.

“If you have an intervention that does turn out to work, you can imagine effectively drawing a ring around a person and intervening on that ring of exposed contacts to create a buffer between the infection we already know about and the rest of the population,” said Tan.

The trials could begin as early as the first week of April, in what Tan said is a testament to the seriousness and speed of Canada’s regulatory authorities in supporting COVID-19 research projects.

“The process of having a clinical trial approved by Health Canada can usually take up to 30 days,” says Tan. “In this case, Health Canada received our application, reviewed it and issued approval within less than 24 hours over a weekend, which is quite remarkable.”

In a statement, federal Minister of Health Patty Hajdu emphasized the importance of research in tackling COVID-19 in Canada and around the world.

“The outbreak of COVID-19 evolves quickly, and protecting the health of Canadians is our priority. The additional teams of researchers receiving funding today will help Canada quickly generate the evidence we need to contribute to the global understanding of the COVID-19 illness,” Hajdu said.

“Their essential work will contribute to the development of effective vaccines, diagnostics, treatments, and public health responses.”

Here is the full list of ��ֱ�� researchers who received CIHR funding for their COVID-19-related projects:

Roy Gillis of the department of applied psychology and human development at the Ontario Institute for Studies in Education: Responding to the stigma, fear, discrimination and misinformation related to the COVID-19 disease outbreak – a novel analyses and intervention for a novel coronavirus
Shaf Keshavjee of the department of surgery in the Faculty of Medicine and the University Health Network: Reducing the health-care resource burden from COVID-19 (SARS-CoV-2) –Rapid diagnostics to risk-stratify for severity of illness
Robert Maunder of the department of psychiatry in the Faculty of Medicine and Sinai Health System: Peer champion support for hospital health-care workers during and after a novel coronavirus outbreak: It's a marathon, not a sprint
Vijaya Kumar Murty of the department of mathematics in the Faculty of Arts & Science and the Fields Institute for Research in Mathematical Sciences: Agent-based and multi-scale mathematical modelling of COVID-19 for assessments of sustained transmission risk and effectiveness of countermeasures
James Rini of the departments of biochemistry and molecular genetics in the Faculty of Medicine: Neutralizing antibodies as SARS-CoV-2 therapeutics
Simron Singh of the Dalla Lana School of Public Health and the department of medicine in the Faculty of Medicine and Sunnybrook Health Sciences Centre: Assessment of cancer patient and caregiver perspective on the novel coronavirus (COVID-19) and the impact on delivery of cancer care at an institution with a confirmed case of COVID-19
Darrell Tan of the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health and department of medicine in the Faculty of Medicine and St. Michael’s Hospital: COVID-19 ring-based prevention trial for undermining spread (CORPUS)
Xiaolin Wei of the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health: Developing integrated guidelines for health-care workers in hospital and primary health-care facilities in response to Covid-19 pandemic in low- and mddle-Income countries (LMICs)
Xiao-Yan Wen of the department of physiology in the Faculty of Medicine and St. Michael’s Hospital: Therapeutic development for COVID-19 coronavirus-induced sepsis and ARDS targeting vascular leakage

With new federal funding, ��ֱ�� researchers aid global effort to understand and control COVID-19

geoff.vendeville — Fri, 06 Mar 2020 16:28:01 +0000

With new federal funding, ��ֱ�� researchers aid global effort to understand and control COVID-19

geoff.vendeville Fri, 03/06/2020 - 11:28

Cutline

��ֱ�� researchers are among several of the 47 research teams pursuing projects related to COVID-19 that are receiving support through a rapid federal funding competition (photo by Nick Iwanyshyn)

Geoffrey Vendeville

Topic

Global Lens

Coronavirus

Institute of Health Policy Management and Evaluation

Faculty of Applied Science & Engineering

Faculty of Medicine

Global

Institute of Biomaterials and Biomedical Engineering

Laboratory Medicine and Pathobiology

Leslie Dan Faculty of Pharmacy

Molecular Genetics

Mount Sinai Hospital

St. Michael's Hospital

Sunnybrook Hospital

Vivek Goel

The University of Toronto and affiliated institutions will receive almost $6 million for research projects related to COVID-19, with $2.7 million to campus-based researchers, while $3.13 million will go to ��ֱ�� researchers at affiliated hospitals – part of a $27 million federal investment in research related to the global outbreak.

Patty Hajdu, Canada's Minister of Health, announced the results of a rapid research funding competition in Montreal on Friday for projects related to the novel coronavirus, which has so far infected tens of thousands of people around the world.

The focus of the research at ��ֱ�� includes the development of rapid and low-cost diagnostics, antiviral compounds and statistical models to forecast disease transmission.

Vivek Goel, ��ֱ��’s vice-president, research and innovation, and strategic initiatives, said ��ֱ�� researchers have the expertise and experience to make a major contribution to scientists' understanding of the coronavirus and how to deal with it.

“��ֱ�� and its partners are home to many leading experts in public health, medicine, biology and other fields that can collectively advance our knowledge of this new illness and help mitigate its impact,” said Goel, who was the founding head of Public Health Ontario. “Many of these research projects engage those who are also on the front-lines of our health system, helping to ensure that the research will be relevant and applied immediately and also inform the management of future infectious disease outbreaks.”

As of March 6, the number of confirmed cases of COVID-19 worldwide has surpassed 100,000, with cases reported on every continent except Antarctica.

One of the newly funded projects, based at the Sinai Health System, involves ��ֱ�� researchers Allison McGeer and Samira Mubareka and aims to paint a better picture of how the virus spreads.

McGeer is a professor at ��ֱ��'s Dalla Lana School of Public Health and in the departments of medicine and laboratory medicine and pathobiology in the Faculty of Medicine. She is also the director of the Infectious Disease Epidemiology Research Unit at Mount Sinai Hospital. Mubareka is an assistant professor in the department of laboratory medicine and pathobiology as well as a virologist at Sunnybrook Health Sciences Centre.

Their team plans to collect data to shed light on how long a patient with the virus is infectious, and how the virus spreads to surfaces and through the air.

“The importance is with risk management and mitigation,” Mubareka told ��ֱ�� News.

She added that removing some of the uncertainty around how the virus spreads can help hospitals make better use of their resources.

“At some point resources will be finite, and if you have a really good sense of how long people shed [the virus] for, you know how long they will need to be isolated,” Mubareka said.

The research team also plans to systematically collect samples containing the virus, serum and immune system cells to create a bio-bank that can be shared with researchers working on vaccines or treatments.

Keith Pardee, an assistant professor at ��ֱ��’s Leslie Dan Faculty of Pharmacy, is part of a research team that involves experts in four countries who are collaborating on low-cost and easy-to-use diagnostic tests to improve the triaging of patients.

During the Zika virus outbreak, the team developed diagnostics within weeks that met the U.S. Centers for Disease Control’s gold standard for use in clinical labs. With COVID-19, the researchers propose to design a suite of diagnostic tools including a “lab-in-a-box kit” that can be used to respond to a large outbreak, a package to help produce diagnostics on-site to support a sustained response and an on-the-spot test for rapid screening of patients – even in places like a cruise ship or airport.

The team’s goal is to produce tools that will not only be useful in Canada but in countries with health-care systems less capable of handling mass emergencies.

Another project led by Xiaolin Wei of ��ֱ��’s Dalla Lana School of Public Health seeks to produce guidelines to help health-care workers respond to COVID-19 and similar outbreaks in the future. Working with researchers in the Philippines and Sri Lanka, Wei will use front-line experiences in China to develop guidelines and training so health-care workers in these and other low-to-middle-income countries can manage COVID-19 patients and infection control.

David Fisman, at Dalla Lana and the Institute of Health Policy, Management and Evaluation and the department of medicine in the Faculty of Medicine, is approaching the disease from another angle.

Fisman and his colleagues – doctors, epidemiologists, public health professionals and statisticians – specialize in data analysis and modelling to help answer three basic questions about an epidemic: When will it peak? When will it end? And how big will it be?

The team, which has experience dealing with SARS, H1N1 and Ebola, will use mathematical and statistical modelling to forecast the near-term course of the disease, make sense of “messy or noisy” public data and use the information to build simulations that can help guide Canadian health agencies’ decisions.

Read a Q & A with Professor Fisman

Other ��ֱ�� experts who received federal grants for research related to the novel coronavirus are: Isaac Bogoch, of the Faculty of Medicine and the University Health Network; Prabhat Jha, of the Dalla Lana School of Public Health and St. Michael’s Hospital in the Unity Health Toronto network; Sachdev Sidhu, of the Donnelly Centre for Cellular and Biomolecular Research, the department of molecular genetics in the Faculty of Medicine and the Institute of Biomaterials and Biomedical Engineering; and Haibo Zhang, a professor in the department of physiology in the Faculty of Medicine who also works at St. Michael’s Hospital.

In total, 47 research teams across the country received funding through several agencies and non-profits: the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Social Sciences and Humanities Research Council of Canada, the Canada Research Coordinating Committee, the International Development Research Centre and Genome Canada.

In a statement, Theresa Tam, the chief public health officer of Canada, spoke of the importance of research in responding to emerging disease outbreaks.

“The research to be undertaken by the successful teams will help to answer some of our most pressing questions about COVID-19 and help to develop the tools we need to effectively respond to this global public health emergency,” she said.

From the lab to the gym: ��ֱ�� Mississauga physiology students receive hands-on experience

Christopher.Sorensen — Tue, 18 Feb 2020 17:02:01 +0000

From the lab to the gym: ��ֱ�� Mississauga physiology students receive hands-on experience

Christopher.Sorensen Tue, 02/18/2020 - 12:02

Cutline

Fourth-year student Athulya Ajith tests her respiratory volume during her physiology lab at ��ֱ�� Mississauga's Recreation, Athletics and Wellness Centre (photo by Drew Lesiuczok)

Patricia Lonergan

Topic

Biology

Donnelly Centre for Cellular & Biomolecular Research

��ֱ�� Mississauga

Undergraduate Students

A group of undergraduate physiology students at the University of Toronto Mississauga are ditching their lab coats in favour of gym clothes.

The students are hitting the gym and getting their hearts pumping for a fourth-year course created and taught by Bryan Stewart, a professor in the department of biology and cell and systems biology. The course relies on a first-time partnership with the Recreation, Athletics and Wellness Centre (RAWC).

Every second week, the students head to the RAWC for their lab, where they use a myriad of tests to measure physiological responses to activity, including blood pressure and respiratory output. Each session has a specific component; one week students might use electrocardiograms, the next they may learn about respiratory volume.

Students analyze the data they’ve collected during the weeks between labs.

Students measure respiratory volume during a fourth-year physiology lab held at the RAWC (photo by Drew Lesiuczok)

“It is the only course on campus like this,” says Stewart, noting the hands-on experience is useful not only for for students heading into the medical field, but for anyone who wants to speak intelligently with health-care providers about electrocardiograms or gas levels when they, or their relatives, receive care.

“It is important they are exposed to this,” Stewart says.

Athulya Ajith, a fourth-year biology and psychology student, signed up, in part, because she had never gone to the RAWC to work out and this was one way to stay fit and healthy while also learning new skills.

“The equipment is cool to see,” she says, adding that the lab gives her a chance to see results on an actual subject and gives her exposure to testing equipment before she goes to medical school.

Stewart, who recently completed a one-year leave after serving as the vice-principal, research at ��ֱ�� Mississauga, developed the class as a natural continuation of the third-year physiology class he previously taught.

“I have always wanted to do a lab course,” says Stewart, whose first degree was in human kinetics. The third-year class is a foundational physiology course, Stewart says, while the focus of this new course is about adaptations to a variety of environments.

Students use exercise and activity to learn about adaptation, such as examining how someone’s physiology adapts when training, or answering questions like why a resting heart rate decreases over time with exercise. The focus, Stewart says, is what happens on a physiological level.

Stewart says the partnership with the RAWC is new for both the gym and the academic arm of the university. The RAWC not only gives students access to exercise equipment, but provides them with a real-world environment where they have to troubleshoot or work around other users.

“I am really happy with the level of support I’ve gotten both from my department and from the dean’s office,” Stewart says, adding that he plans to continue the course in upcoming years.

Gene fragment could explain link between autism and cognitive difficulties: ��ֱ�� study

Christopher.Sorensen — Wed, 29 Jan 2020 21:37:12 +0000

Gene fragment could explain link between autism and cognitive difficulties: ��ֱ�� study

Christopher.Sorensen Wed, 01/29/2020 - 16:37

Cutline

Thomas Gonatopoulos-Pournatzis, the study's lead author, says the team's research sheds light on the mechanisms that cause autism and may lead to the development of better therapeutic strategies (photo by Jovana Drinjakovic)

Jovana Drinjakovic

Topic

Breaking Research

Lunenfeld-Tanenbaum Research Institute

Autism

Biochemistry

Hospital for Sick Children

Faculty of Medicine

Molecular Genetics

Mount Sinai Hospital

Autism is associated with brilliance as well as cognitive difficulty, but how either scenario plays out in the brain is not clear. Now a study by University of Toronto researchers has found that a tiny gene fragment impacts the brain in a way that could explain swathes of autism cases that come with cognitive challenges.

Researchers led by Benjamin Blencowe, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research and Faculty of Medicine, and Sabine Cordes, a senior investigator at Sinai Health System’s Lunenfeld-Tanenbaum Research Institute (LTRI), have identified a short gene segment that is crucial for brain development and information processing. Writing in the journal Molecular Cell, the researchers describe how an absence of this segment is sufficient to induce altered social behaviour –a hallmark of autism – in mice, as well as learning and memory deficits, which are seen in a subset of autism cases.

Best known for causing difficulties in social interaction and communication, autism is thought to arise from mishaps in brain wiring during development. It can strike in various ways. Those who experience it can have superior mental ability or need full-time care. Where on the autism spectrum a person falls depends in large part on their genetics, but most cases are idiopathic, or of unknown genetic origin.

“It’s very important to understand the mechanisms that underlie autism, especially in idiopathic forms where it is not clear what the underlying causes are,” says Thomas Gonatopoulos-Pournatzis, a research associate in Blencowe’s lab and lead author of the study. “Not only have we identified a new mechanism that contributes to this disorder, but our work may also offer a more rational development of therapeutic strategies.”

Blencowe’s team had previously uncovered a link between autism and short gene segments, known as microexons, that are predominantly expressed in the brain. Through a process known as alternative splicing, microexons are either spliced in or left out from the final gene transcript before it is translated into a protein. Although small, microexons can have dramatic effects by impacting a protein’s ability to bind its partners as required during brain development. However, how individual microexons contribute to autism is not clear.

The team focused on a specific microexon located in a gene known as eIF4G, which is critical for protein synthesis in the cell. They found that this microexon is overwhelmingly excluded from eIF4G gene transcripts in the brains of autistic individuals.

Hippocampal neurons from a normal mouse (above) and a mouse bred to lack the eIF4G microexon (below). The latter contains fewer particles that represent paused protein synthesis machineries. In these mice, higher levels of protein synthesis in neurons lead to disrupted brain waves and autistic-like behaviors as well as cognitive deficits down the line.

To test if the eIF4G microexon is important for brain function, Gonatopoulos-Pournatzis, together with Cordes’s team, bred mice that lack it. These mice showed social behaviour deficits, such as avoiding social interaction with other mice, establishing a link between the eIFG4 microexon and autistic-like behaviours.

A surprise came when the researchers found that these mice also performed poorly in a learning and memory test, which measures the animals’ ability to associate an environment with a stimulus.

“We could not have imagined that a single microexon would have such an important impact not only on social behaviour but also on learning and memory,” says Gonatopoulos-Pournatzis.

Further analysis revealed that the microexon encodes a part of eIF4G that allows it to associate with the Fragile X mental retardation protein, or FMRP, which is missing from people affected with Fragile X syndrome, a type of intellectual disability. About a third of individuals with Fragile X have features of autism but the link between the two remained unclear – until now.

FMRP and eIF4G work together to act as a brake to hold off protein synthesis until new experience comes along, as the brake is removed by neural activity, the researchers also found.

“It’s important to control brain responses to experience,” says Gonatopoulos-Pournatzis. “This brake in protein synthesis is removed upon experience and we think it allows formation of new memories.”

Without the microexon, however, this brake is weakened and what follows is increased protein production. The newly made proteins, identified in experiments performed with Anne-Claude Gingras, a senior investigator at LTRI and a professor in the department of molecular genetics, form ion channels, receptors and other signaling molecules needed to build synapses and for them to function properly.

However, making too many of these proteins is not a good thing because it leads to the disruption of the type of brain waves involved in synaptic plasticity and memory formation. This is revealed by electrode recordings of mouse brain slices in experiments performed by the teams of Graham Collingridge, a senior investigator at LTRI and a professor in the department of physiology, and Melanie Woodin, a professor of cell and systems biology at ��ֱ�� and the dean of the Faculty of Arts & Science.

Moreover, an excess of similar kinds of proteins occurs in the absence of FMRP, suggesting a common molecular mechanism for Fragile X and idiopathic autism.

Researchers believe that their findings could help explain a substantial proportion of autism cases for which no other genetic clues are known. The findings also open the door to the development of new therapeutic approaches. One possibility is to increase the splicing of the eIF4G microexon in affected individuals using small molecules as a way to improve their social and cognitive deficits, Blencowe said.

The study would not have been possible without a close collaboration among multiple teams contributing diverse expertise. Blencowe and Gonatopoulos-Pournatzis also worked closely with Julie Forman-Kay, a professor of biochemistry and program head and senior scientist in the molecular medicine program at the Hospital for Sick Children, and Nahum Sonenberg, a professor of biochemistry at McGill University.

The research was made possible by grants from the Canadian Institutes of Health Research, Simon’s Foundation and the Canada First Research Excellence Fund Medicine by Design program, among others.

��ֱ�� neurobiologists discover switch that turns muscles on and off

Christopher.Sorensen — Wed, 22 Jan 2020 17:09:00 +0000

��ֱ�� neurobiologists discover switch that turns muscles on and off

Christopher.Sorensen Wed, 01/22/2020 - 12:09

Cutline

John Peever, a neurobiologist in the department of cell and systems biology, and research associate Jimmy Fraigne hope their research could lead to treatments for a variety of muscular disorders (photo by Diana Tyszko)

Chris Sasaki

Topic

Faculty of Medicine