Brain

Convocation 2024

Temerty Faculty of Medicine

U of T Scarborough

Subheadline

“The only thing I wanted when I was a little girl was for my mom to be OK. And I want that for other people, too”

Olivia Hawco was eight years old when she heard a scream from the bathroom – it was her mom, who had just felt something pop in her brain.

Hours later, Hawco learned her mom had suffered a massive stroke, the kind that kills most people before they can even get to the hospital. She was given a 50 per cent chance of surviving.

Doctors couldn’t operate or intervene, so they transferred her to another hospital for more tests. Miraculously, they found the bleeding in her brain had spontaneously healed itself.

“I remember the neurologist saying, ‘Your mom won the lottery,’” says Hawco, who is graduating from the �ؿ�ζSM Scarborough with an honours bachelor of science degree and plans to become a clinician-scientist. “The only thing I wanted when I was a little girl was for my mom to be OK. And I want that for other people, too.”

Her mother’s recovery was difficult. She was hospitalized for a week and had to relearn how to walk. Doctors never figured out how she healed herself so suddenly, or why her only lasting symptom was minor difficulties with short-term memories.

The harrowing experience ignited Hawco’s lifelong passion to understand and treat brain diseases – and ultimately prevent them from happening in the first place.

At age 16, Hawco began volunteering at the Markham Stouffville Hospital, where her mom was initially treated. She started in the gift shop as a cashier and worked her way through the wings, assisting with CT scans, cardiology and oncology, and eventually helping in the same ICU where her mother almost died.

It was difficult to be back in that space, Hawco says, but that only made her more certain she was on the right path.

She later enrolled at U of T Scarborough to pursue a specialist in human biology and, in her third year, took a course taught by Assistant Professor Kathlyn Gan in the department of biological sciences. Hawco grew fascinated with Gan’s neuroscience research and eventually landed a position in Gan’s lab, where she has remained ever since.

“Although she joined my lab with no prior research experience, Olivia quickly grasped a wide variety of sophisticated experimental techniques that can elude experienced trainees,” Gan says. “Notably, she designed and executed her own undergraduate research project from scratch, systematically troubleshooting and optimizing her own experiments.”

Hawco is investigating neurons, the cells responsible for transmitting information around the brain. More specifically, she’s studying how neurons communicate by linking to one another through connections called synapses. Synapses degrade over time, leading to many of the aspects of aging that people dread, including memory loss, cognitive decline and dementia.

For her undergraduate thesis, Hawco focused on a protein called SLIT1, which guides neurons to their proper place during early brain development. Hawco suspected SLIT1 could also be impacting the way neurons connect to one another. By working backwards, Hawco is examining how the brain first forms to hopefully create a drug or treatment that can help a damaged brain reform.

“If you're able to form synaptic connections and prevent neuronal death sooner after a stroke, you wouldn't have the same detrimental side effects,” she says. “Maybe that can prevent some of the cognitive decline we see.”

Her work earned her the prestigious NSERC Undergraduate Student Research Award last year and she will be supported by the NSERC Canada Graduate Scholarship – Master’s Program as she prepares to build on her data and embark on more experiments during her master’s degree this fall. She also won the U of T Excellence Award to support her research this summer.

Along with her family, Hawco credits the support she received from her mentors in the department of biological sciences, including Gan and faculty members Aarthi Ashok and Emily Bell. When she wasn’t in the lab, Hawco was involved in several campus clubs, including the Biology Students Association and MedLife, a non-profit that partners with low-income communities in Latin America and Africa to improve access to medicine, education and community development projects.

Hawco also played soccer for most of her life and became a referee when she was just 16 – a role that she credits for having an influence well beyond the pitch.

“Being a referee was hard as a young girl. You have parents – grown men – yelling at you and it can be daunting. I’ve heard my fair share of sexist comments. But I wouldn't trade it for anything, because it's made me realize the importance of confidence, having a thick skin, being a leader and advocating for yourself.”

Liver can generate palmitic acid to maintain brain health, study suggests

Christopher.Sorensen — Mon, 22 Jan 2024 21:58:42 +0000

Liver can generate palmitic acid to maintain brain health, study suggests

Christopher.Sorensen Mon, 01/22/2024 - 16:58

Cutline

Researchers Richard Bazinet, left, and Mackenzie Smith, right, found that the liver will generate palmitic acid when the brain isn't getting enough through food sources, suggesting the acid's importance to brain health (photo by Temerty Faculty of Medicine)

Jim Oldfield

Topic

Breaking Research

Joannah & Brian Lawson Centre for Child Nutrition

Nutritional Sciences

Faculty of Arts & Science

Subheadline

“The results were surprising because when you lower a lipid in the diet, it usually becomes lower in the brain"

Researchers at the �ؿ�ζSM have found that palmitic acid, one of the most common fats in meats and dairy products, as well as human breast milk, is made by the liver and sent to the developing brain when it’s low in the diet.

The preclinical findings underscore the importance of palmitic acid for brain health and point to a need for more research on lowering its levels in infant formula – a step some manufacturers have taken recently to reduce costs and limit the harvest of palm trees, a major source of palmitic acid.

“When we changed the levels of palmitic acid in the diets of developing mice, it didn’t do a thing to the brain,” said Richard Bazinet, principal investigator on the study and a professor and acting chair of the department of nutritional sciences in U of T’s Temerty Faculty of Medicine.

“The results were surprising because when you lower a lipid in the diet, it usually becomes lower in the brain. But here the liver was able to up-regulate production to ensure the brain gets enough of it, despite extreme differences in dietary intake.”

The findings were published in the journal Nature Communications.

Mackenzie Smith, left, and Richard Bazinet, right (photo by Temerty Faculty of Medicine)

Palmitic acid is a saturated fat that supports brain health in several ways, across the lifespan. It contributes to the structure and function of myelin sheathing, which insulates neural connections and acts as precursor to molecules that regulate inflammation and promote cell signalling.

Scientists have long known that humans and other mammals can get palmitic acid from food or generate it in a process called de novo lipogenesis, which mainly requires glucose for its synthesis. Much less is known about which source the body relies on relative to diet and at different stages of growth and maturity.

Bazinet said the study findings highlight the importance of palmitic acid for brain health at all stages, but especially during development, when need for the fat appears to be highest.

“It’s interesting that although the brain can make palmitic acid, the liver up-regulated it so much. These systemic redundancies are built in, so the body won’t take a chance on not getting enough,” said Bazinet, who is also a researcher at U of T’s Joannah & Brian Lawson Centre for Child Nutrition.

The results should give pause to manufacturers looking to reduce the amount of palmitic acid in infant formula, said Mackenzie Smith, first author on the study and a doctoral student in the Bazinet lab.

“It’s possible that we can lower levels in formula, which could have a positive ecological impact, but we don’t yet know the potential health effects,” Smith said. “Are there implications for behaviour or development when the liver produces so much? Might there be negative effects for the liver?”

Smith also noted that even in mice that received the lowest amount of palmitic acid through diet, levels of the fat were still higher than those sought by some manufacturers of formula. That discrepancy adds to the rationale for further preclinical studies, as well as research in humans, Smith said.

To uncover the source of palmitic acid in the brains of developing mice, the researchers applied a new carbon isotope technique. Isotopes are different versions of the same chemical element that vary slightly in mass; for their study, the researchers drew on natural differences in carbon isotope ratios in the environment, based on how plants absorb carbon in photosynthesis.

“Most plants use the same path to fix carbon from the atmosphere and have the same carbon ratio, but sugars such as corn and sugar cane – which the liver uses to generate palmitic acid – have a different ratio,” said Smith.

In the brains of mice, a depleted carbon ratio signature indicated a dietary source of palmitic acid, Smith said, whereas an enriched signature suggested de novo lipogenesis.

The researchers were able to track those signatures at many stages throughout mouse development, to determine the liver was the main source of palmitic acid in the developing brain – a finding they corroborated by looking at changes in genetics.

The approach opens new research opportunities. “As opposed to traditional radioactive tracers, which are very expensive, this new technique allows for a cost-effective and long-term study design,” said Smith.

Building on the current study’s findings, researchers in the Bazinet lab are now applying the same technique in tissue from adult human brains. The method could also provide a new way to measure and track the dietary sources of other fats and nutrients, Bazinet said.

“Nutrition researchers often rely on people reporting their food intakes, which can lead to unreliable data,” he added. “Those problems could potentially be flagged with this kind of technology to track the source and amount of added sugars, for example. It could be very fruitful for nutritional science.”

The research was supported by funding from the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research and the Canada Research Chairs Program.

Children are learning even if they don't pay attention: Study

Christopher.Sorensen — Wed, 21 Jun 2023 18:57:25 +0000

Children are learning even if they don't pay attention: Study

Christopher.Sorensen Wed, 06/21/2023 - 14:57

Cutline

(photo by Marko Geber/Getty Images)

Psychology

Subheadline

'Children's brains can hold information in a way that adults' brains do not'

A team of researchers has shown that children’s apparent inability to pay attention allows them to outperform adults when it comes to retaining information they were instructed to disregard.

The researchers’ study shows that, as expected, adults do a great job of focusing their attention on an assigned task and do not pay attention to information they are told to ignore.

Children, on the other hand, take in the secondary information they are instructed to ignore when given the same task. The information is then encoded in their brains.

“What we found is that children's brains can hold information in a way that adults' brains do not,” says Yaelan Jung, who worked on the study as a graduate student at the �ؿ�ζSM and in her current position as a postdoctoral researcher at Emory University.

Researchers used a series of four simple icons to test how well adults and children paid attention (image courtesy of Jung, Finn, et al.)

“Although it’s not a foreign idea that children have poorer attention abilities than adults, we did not know how this poor attention would impact the way their brains receive and hold other information,” she says. “Our study fills this knowledge gap and shows that children's poor attention leads them to hold more information from the world than adults.”

The team described their study in a paper published in the Journal of Neuroscience.

In addition to Jung, the authors include: Tess Forest, who also contributed to the study as a graduate student at U of T and in her current position as a postdoctoral research scientist at Columbia University; and Dirk Bernhardt-Walther and Amy Finn – both associate professors in the Faculty of Arts & Science’s department of psychology.

“It’s not simply that children’s ability to pay attention is bad and they’re unable to disregard distractors,” says Finn. “Our study suggests that their brains are built to be sensitive to all information, regardless of whether it's relevant or not – that kids are more sensitive to more information.

“Depending on your definition of childhood, humans are children for eight or nine years,” she says. “Compared to other species, that’s a long time and one explanation for such a lengthy childhood is that we humans have so much learning to do. Another is that it’s important for our IQ to take in as much information as we do. Still another is that we need to take in all this information as children in order to wire our brains properly, to develop the circuits and pathways for processing information.”

The study involved 24 adults with a mean age of 23 years and 26 children with a mean age of eight years. The team asked the participants to observe a series of four static illustrations: a bumble bee, a car, a chair and a tree. Each image was accompanied by a background of grey dots moving in one of four directions: up, down, left and right.

In one phase of the study, subjects were instructed to ignore the moving dots and press a button when an object – say, the bumblebee – appeared more than once. In another phase, they were asked to ignore the objects and press a button when the direction of motion of the dots was repeated.

Subjects carried out their task while in a magnetic resonance imaging (MRI) machine at the Toronto Neuroimaging Facility at the �ؿ�ζSM. As they performed the task, the MRI measured the subjects’ brain activity which revealed how attention shapes what is represented in subjects’ brains.

“What we found in this study provides a novel way to think about what brain development means,” says Jung. “Often, we assume that as the brain develops it will do more and do things better. Thus, we often think that adults are better and smarter than kids. However, our work shows this is not always the case. Rather, children's brains may just do things differently than adults – and consequently, they can sometimes do more than adults.”

Added Finn: “The study suggests that this approach of being more sensitive to the broader environment, at the cost of paying attention to specific things, is better for understanding complex systems. It may help form a higher level of understanding of our full environment.

“So, I look at kids as these little information-processing creatures better able to represent more of the world, with brains that more accurately reflect the world than ours.”

Researcher combines AI and microelectronics to create neural implants that fight brain disorders

Christopher.Sorensen — Mon, 17 Oct 2022 17:56:45 +0000

Researcher combines AI and microelectronics to create neural implants that fight brain disorders

Christopher.Sorensen Mon, 10/17/2022 - 13:56

Cutline

Xilin Liu tests signal integrity of a prototype neural implant, which can be used to activate a neuromodulation therapy that helps manage symptoms of brain disorders (photo by Matthew Tierney)

Matthew Tierney

Topic

Breaking Research

Artificial Intelligence

Faculty of Applied Science & Engineering

Deep Learning

University Health Network

Neural implants can help treat brain disorders such as Parkinson’s disease and epilepsy by directly modulating abnormal activities – and the �ؿ�ζSM’s Xilin Liu is working with microelectronics and artificial intelligence to make this emerging technology both safer and smarter.

“Neurons talk to each other in part via electrical signals, and a therapeutic neural implant produces electrical stimulation – like a pacemaker for the brain,” says Liu, an assistant professor in the Faculty of Applied Science & Engineering. “In cases of tremors or seizures, the stimulation attempts to restore the neurons to a normal condition.

“It’s as if the stimulus turns the neural networks off and on – almost like restarting a computer, though it’s definitely not that simple. Scientists don’t fully understand how it works yet.”

Liu’s team integrates neural implants into miniature silicon chips via the same process for fabricating chips used in today’s computers and smartphones. This technology, referred to as CMOS for complementary metal-oxide semiconductor, allows them to reduce the device’s physical dimensions and power consumption, thus minimizing the risks associated with the implant’s initial surgical procedure and long-term use.

“We’ve developed many new microelectronic design techniques, such as high precision electrical stimulation with charge balancing,” says Liu. “We try to come at the problem from many different angles.”

Liu is part of the neurotechnology centre CRANIA, a collaboration between the �ؿ�ζSM and the University Health Network, that brings together electrical and computer engineers alongside neuroscientists, data and material scientists and clinicians. Together, they research ways to improve brain health and chart alternative treatment paths, especially for those who don’t respond well to current medications.

In a recent project, Liu and his team sought to leverage the power of AI to maximize the implants’ clinical efficacy and minimize the adverse effects of excessive stimulation.

Xilin Liu holds a prototype of a neural implant chip, 3 millimetres by 3 millimetres, on the tip of his finger (photo by Matthew Tierney)

The team turned to a type of AI called deep learning (DL) – algorithms that, after being trained, can extract deep-level information when faced with novel data. These models proved to be especially powerful at identifying hidden biomarkers often neglected in conventional approaches and they outperformed conventional algorithms when detecting the optimal timing.

“Most existing implants produce electrical stimulation at a constant rate, regardless of the patient’s condition,” says Liu. “With DL, we can activate the neural implants at the optimal time and only when necessary.”

However, the high computational cost of deep learning models makes it a challenge to integrate, especially considering that it’s essential that all processing runs locally in the implants.

“The cloud would provide more processing power, but you can’t have an implant fail because it loses telecommunication service – when a patient goes into an elevator or airplane, for example,” says Liu.

To reduce this computational cost, Liu and his team developed techniques for training and optimizing the models for each patient’s condition. A recent case study showed that detection of epileptic seizures by deep learning in low-power neural implants was comparable to state-of-the-art algorithms that run in high-performance computers. This work was published in 2021 in the Journal of Neural Engineering.

Liu says that his team’s technology can be used in a broad range of clinical applications beyond epilepsy, noting that up to one billion people worldwide suffer from various brain disorders.

The necessity of open-minded collaboration is something Liu aims to impress on the graduate students who take his new neuromodulation course, debuting this fall.

“There’s so much going on in the brain,” says Liu. “You need a range of experts to understand and provide solutions for these disorders, which will only become more common as human life expectancy increases.”

Future targets include chronic pain, depression and dementias. Liu is already contemplating how neuromodulation therapies may help people with Alzheimer’s disease.

“Impaired sleep has been associated with Alzheimer’s, and many people suffer from different levels of sleep disorders,” says Liu. “We are investigating closed-loop neuromodulation techniques to improve sleep quality by reinforcing or inhibiting certain brain rhythms.

“The brain is pretty amazing.”

Researcher uses ‘fuzzy’ AI algorithms to aid people with memory loss

Christopher.Sorensen — Thu, 14 Jul 2022 14:06:32 +0000

Researcher uses ‘fuzzy’ AI algorithms to aid people with memory loss

Christopher.Sorensen Thu, 07/14/2022 - 10:06

Cutline

(Image by Eugene Mymrin via Getty Images)

Matthew Tierney

Topic

Artificial Intelligence

Electrical & Computer Engineering

Faculty of Applied Science & Engineering

machine learning

Memory

A new computer algorithm developed by the �ؿ�ζSM’s Parham Aarabi can store and recall information strategically – just like our brains.

The associate professor in the Edward S. Rogers Sr. department of electrical and computer engineering, in the Faculty of Applied Science & Engineering, has also created an experimental tool that leverages the new algorithm to help people with memory loss.

“Most people think of AI as more robot than human,” says Aarabi, whose framework is explored in a paper being presented this week at the IEEE Engineering in Medicine and Biology Society Conference in Glasgow. “I think that needs to change.”

Parham Aarabi

In the past, computers have relied on their users to tell them exactly what information to store. But with the rise of artificial intelligence (AI) techniques such as deep learning and neural nets, there has been a move toward “fuzzier” approaches.

“Ten years ago, computing was all about absolutes,” says Aarabi. “CPUs processed and stored memory data in an exact way to make binary decisions. There was no ambiguity.

“Now we want our computers to make approximate conclusions and guess percentages. We want an image processor to tell us, for example, that there’s a 10 per cent chance a picture contains a car and a 40 per cent chance that it contains a pedestrian.”

Aarabi has extended this same fuzzy approach to storing and retrieving information by copying several properties that help humans determine what to remember — and, just as critically, what to forget.

Studies have shown that we tend to prioritize more recent events over less recent ones. We also emphasize memories that are more important to us and we compress long narratives to their essentials.

“For example, today I remember that I saw my daughter off to school, I made a promise that I’d pay someone back and I promised that I’d read a research paper,” says Aarabi. “But I don’t remember every single second of what I experienced.”

The capacity to overlook certain information could supercharge existing models of machine learning.

Today, machine learning algorithms trawl through millions of database entries, looking for patterns that will help them correctly associate a given input with a given output. Only after countless iterations does the algorithm eventually become accurate enough to deal with new problems that it hasn’t already seen.

If bio-inspired artificial memory enables these algorithms to give prominence to the most relevant data, they could potentially arrive at meaningful results much more quickly.

The approach could also support tools that process natural language to help people with memory loss keep track of key information.

Aarabi and his team have set up such a tool using a simple email-based interface. It reminds participants of important information based on algorithmic priority and a relevant index of keywords.

“Ultimately, it’s geared to people with memory loss,” Aarabi says. “It helps them remember things in a way that’s very human, very soft, without overwhelming them. Most task management aids are too complicated and not useful in these circumstances.”

The demo is free and available for anyone to play with; simply send an email to mem@roya.vc for instructions.

“I’ve been using it myself,” says Aarabi. “The goal is to put the demo in people’s hands – whether they’re dealing with significant memory degradation or just everyday pressures – and see what feedback we get. The next steps would be to build partnerships in health care to test in a more comprehensive way.”

“These days, AI applications are increasingly found in many human-centred fields,” says Professor Deepa Kundur, chair of the department of electrical and computer engineering. “Professor Aarabi, by researching ways to better integrate AI with these ‘softer’ areas, is looking to ensure that the potential of AI is fully realized in our society.”

Aarabi says that this algorithm is just the beginning.

“Biologically inspired memory may very well take AI a step closer to human-level capabilities.”

U of T researcher 'reprograms' brain cells in pursuit of new therapy for stroke patients

Christopher.Sorensen — Tue, 01 Jun 2021 18:29:22 +0000

U of T researcher 'reprograms' brain cells in pursuit of new therapy for stroke patients

Christopher.Sorensen Tue, 06/01/2021 - 14:29

Cutline

Understanding the role of reprogrammed neurons, shown here in yellow, and resident neurons, shown in red, in post-stroke recovery is at the heart of research by U of T's Maryam Faiz (image courtesy of Maryam Faiz)

Blake Eligh

Topic

Temerty Faculty of Medicine

Insulin 100

Faculty of Arts & Science

Stroke

Could “reprogramming” the brain at a cellular level help people recover from strokes faster and better? One researcher from the �ؿ�ζSM’s Temerty Faculty of Medicine aims to find out.

Strokes happen when blood flow to the brain is disrupted, resulting in irreversible damage to neurons, the brain cells that control behaviour and movement. For the 50,000 Canadians who will experience stroke each year, more than half will be left with lifelong impairments in the ability to move, eat or communicate.

But research by neuroscientist Maryam Faiz, a professor in the department of surgery who studies neuronal reprogramming, suggests a new kind of therapy for post-stroke recovery. She says astrocytes – a network of bushy cells Faiz likens to “a night sky” – are thought to play an important role in the brain’s circuitry. With reprogramming, she says, astrocytes can be converted into neurons to replace those cells lost to stroke damage.

Maryam Faiz

“We think of this as a new strategy for neural repair,” says Faiz, adding that, in the lab, the technique shows good results in mice with post-stroke impairments in mobility and gait.

“After reprogramming, those abilities recover to the level of an uninjured animal.”

The technique may help extend the window for the recovery process. Current stroke recovery interventions are time-sensitive, with the greatest gains taking place in the hours that follow a stroke.

In Faiz’s experiments, however, reprogrammed mice showed continued recovery, even at the nine-week mark. In these experiments, researchers administered reprogramming to the mice a week following their strokes.

“We could see functional recovery early in the reprogramming process,” Faiz says. “Animals were walking better and this extended to much later time points.”

While Faiz’s lab research focuses on tiny astrocytes and neurons, the patient outcome is never far from her mind.

Her work took a personal turn two years ago when a close family member suffered a traumatic brain injury as the result of an accident. Witnessing their ongoing recovery process highlighted the potential impact of Faiz’s research, which could be applied to stroke recovery – but also in the treatment of Parkinson’s or Alzheimer’s diseases or a traumatic brain injury.

“Knowing someone who has had a brain injury is eye-opening,” she says. “It can have a massive impact on every part of their life.”

Faiz, who joined the Temerty Faculty of Medicine in 2017, is one of three recipients of the inaugural Temerty Pathway Grant. Launched in 2020, the internal funding program supported by the Temerty family awards $100,000 each to three promising research projects that have not yet been successful in grant competitions.

The bridge funding allows researchers to keep working on a project and submit a stronger grant application in the next round.

“The Pathway Grant gave me room to breathe,” says Faiz. “When you don’t get your CIHR grant, you’re just back in the lab 24 hours a day, trying to get the next set of data.”

Faiz and fellow Pathway recipients Thierry Mallevaey and Scott Yuzwa, in the departments of immunology and laboratory medicine and pathobiology respectively, were awarded CIHR funding in the round of grants announced this spring.

"The Temerty Pathway Grant Program is designed to provide bridge funding for early career researchers like Professor Faiz to achieve CIHR funding,” says Reinhart Reithmeier, senior adviser to the vice-dean research and graduate education. “I congratulate the first three winners, Professors Faiz, Mallevaey and Yuzwa, on their success in the last CIHR Program grant competition."

While Faiz’s initial recovery results in mice are promising, little is known about how the reprogrammed neurons integrate into the circuitry of the brain.

With funding from the CIHR to Faiz and co-applicants Shreejoy Tripathy, an assistant professor of psychiatry and Melanie Woodin, dean of the Faculty of Arts & Science and a cell and systems biology professor, Faiz hopes to understand what’s happening at different periods during the stroke recovery process and how reprogramming contributes to brain recovery and repair.

“Is the cell we’re making important for recovery or does reprogramming exert an effect in the environment around the cells that could lead to change?” she asks. “Are these new cells actually responsible for recovery or might something else be happening here?

“Our study will answer these questions and help us understand if and how these newly generated neurons are responsible for the recovery in function that follows neuronal reprogramming.”

Medicine by Design researchers focus on promoting self-repair of the brain

geoff.vendeville — Thu, 28 Jan 2021 16:09:06 +0000

Medicine by Design researchers focus on promoting self-repair of the brain

geoff.vendeville Thu, 01/28/2021 - 11:09

Cutline

(illustration by Jolygon via Getty Images)

Julie Crljen

Topic

Institute of Biomedical Engineering

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Hospital for Sick Children

Medicine by Design

Donnelly Centre for Cellular & Biomolecular Research

If you asked Freda Miller 10 years ago if stem cells could be harnessed to repair brain injuries and disease, she would have said it was too early to tell.

Today, she describes the progress that she and other regenerative medicine experts have made in understanding what regulates populations of stem cells – cells with the potential to turn into many different cell types – and the rapid advances those discoveries have driven.

“Science is like a playground right now,” says Miller, an adjunct scientist in the neurosciences and mental health program at The Hospital for Sick Children (SickKids) and a professor in the department of molecular genetics in the �ؿ�ζSM's Temerty Faculty of Medicine.

“The approaches we’re using allow us to find so much information on things we could only dream of before.”

Miller, who is also a professor at the University of British Columbia, is leading a Medicine by Design-funded team with expertise in computational biology, neurobiology, bioengineering and stem cell biology that is investigating multiple strategies to recruit stem cells to promote self-repair in the brain and in muscle. If it succeeds, the research could improve treatments for diseases such as multiple sclerosis (MS) and cerebral palsy, as well as brain injury.

Miller’s team is one of 11 at U of T and its partner hospitals that are sharing nearly $21 million in funding from Medicine by Design over three years. Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

This is the second round of large-scale, collaborative team projects that Medicine by Design has funded. The support builds on the progress made in the first round of projects (2016-2019) and is spurring further innovation to push regenerative medicine forward. It also led to a 2017 publication – by many of the same researchers on Miller’s current project – in Cell Reports that essentially provided a roadmap for how brain stem cells build the brain developmentally, and then persist to function in the adult brain.

Miller, a neuroscientist, has always been fascinated by the brain and neurons, the network of billions of nerve cells in the brain. Around 15 years ago, when she started to take an interest in the potential regenerative capabilities of stem cells, she began to wonder if she could use stem cells to treat brain injury or disease. Though too little was known about stem cells at the time, she knew that it was a question worth investigating. But she also realized that making and integrating new nerve cells, which are the working parts of brain circuits, would be a daunting task.

“Even if you can convince the stem cells to make more neurons, those neurons then have to survive and they have to integrate into this really complex circuitry,” says Miller. “It just made sense to me that if we’re really going to test this idea of self-repair in the brain, we should go after something that’s more achievable biologically.”

So, Miller turned her attention to a substance called myelin, which covers nerves and allows nerve impulses to travel easily. In many nervous system diseases – MS is a well-known example – and brain injuries, damage to and loss of myelin is a main factor in debilitating symptoms. Thanks in part to the team project award from Medicine by Design, Miller leads a team that has a focus on recruiting stem cells to promote the generation of myelin.

Miller says repairing myelin, also called remyelination, will eventually help to better understand the effects of the target disease or injury, possibly even leading scientists to discover how to reverse it. Boosting myelin is a promising area of research, she adds, because it’s not an all-or-nothing situation.

“Even a little bit of remyelination could have a big impact. You don’t have to win the whole lottery; you don’t have to have 100 per cent remyelination to have a measurable outcome.”

The team’s work is not limited to generating myelin to treat nervous system diseases or brain injury. They are also looking at how they could recruit stem cells to generate more muscle. They are specifically looking at muscular dystrophy, but Miller says the applications from that work can be used in other diseases or situations where damage to muscles has occurred, such as age-related disorders.

Miller’s team includes experts from diverse fields: Gary Bader, a professor at the Donnelly Centre for Cellular and Biomolecular Research and a computational biologist; bioengineers Alison McGuigan, a professor in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering, and Penney Gilbert, an associate professor at the Institute of Biomedical Engineering; Sid Goyal, a professor at the department of physics in the Faculty of Arts & Science; Professor David Kaplan and Assistant Professor Yun Li, both in the Temerty Faculty of Medicine and a senior scientist and a scientist, respectively, at SickKids; stem cell biologist Cindi Morshead, a professor and chair of the division of anatomy in the department of surgery in the Temerty Faculty of Medicine; and Peter Zandstra, a University Professor in the Faculty of Applied Science & Engineering and director of Michael Smith Laboratories at the University of British Columbia.

Miller says Medicine by Design’s contribution in bringing teams like hers together is immeasurable.

“There are tangible results you can measure like publications and other grants and clinical trials,” Miller says. “But there are a lot of intangible things Medicine by Design brings to the table like developing a culture of people from very diverse places and allowing them to do science together at a time when the biggest breakthroughs are going to be made by combining technological and biological approaches. It’s hard to do that if you’re on your own.”

This large, interdisciplinary team effort combines data and computer modelling to look at individual stem cells in the brain and predict their behaviours. Through experimentation, they can then test if the cells behave the way they predicted, which Miller says they have had great success with. From there, the team casts a wide net, testing various ways to try to control cells’ behaviour with the end goal of convincing the stem cells to turn into cells that aid in healing and repair.

One approach they use is testing already approved pharmaceuticals to see if they have the desired effect on the stem cells’ behaviour. This approach has had success. In summer 2020, Morshead, Miller and their collaborators, led by Donald Mabbott, a SickKids senior scientist and professor in the department of psychology in the Faculty of Arts & Science, published a paper in Nature Medicine that showed that metformin, a common diabetes drug, has the potential to reverse brain injury in children who had had cranial radiation as a curative therapy for brain tumours.

Miller says that, to her knowledge, this is the first paper that demonstrates that this type of brain repair is possible in humans.

U of T and SickKids researchers use common diabetes drug to stimulate repair of brain cells

Christopher.Sorensen — Tue, 28 Jul 2020 15:19:01 +0000

U of T and SickKids researchers use common diabetes drug to stimulate repair of brain cells

Christopher.Sorensen Tue, 07/28/2020 - 11:19

Cutline

Cindi Morshead, Freda Miller and Donald Mabbott are co-authors of a study that shows the Type 2 diabetes drug metformin could change the way childhood brain injury is treated (photos supplied)

Julie Crljen

Topic

Breaking Research

Pediatrics

Hospital for Sick Children

Faculty of Medicine

Medicine by Design

Molecular Genetics

Psychology

Metformin, a common drug used to treat diabetes, may one day be used to repair brain injuries, a study by researchers and clinicians from the �ؿ�ζSM and the Hospital for Sick Children (SickKids) has found.

“No one’s actually shown before that you can take a drug where there’s a known mechanism on endogenous stem cells and demonstrate that it’s even possible to induce brain growth and positive recovery,” says Donald Mabbott, program head and senior scientist in the neurosciences and mental kealth program at SickKids and an associate professor of psychology at U of T.

Mabbott is co-author of a study published in Nature Medicine this week. He says metformin is a potential game-changer in terms of how childhood brain injury is treated.

“We’re really moving from a model that says ‘let’s help children manage and compensate for their injury,’ to ‘let’s actually treat the injury itself in an active way by harnessing the brain’s own capacity for repair,’” says Mabbott.

The published research showed that metformin has positive sex-dependent effects on neurogenesis, which is the process of growing neurons in the brain, and cognition in animals, while also demonstrating that it is safe to continue into a Phase 3 clinical trial on humans. The human participants in this study were pediatric brain tumour survivors who had received cranial radiation.

“This study is so novel compared to most studies because it looked at both animal models and human participants. And we found these really consistent and interesting effects in terms of memory and brain recovery,” says study co-author Cindi Morshead, a professor at U of T’s Donnelly Centre for Cellular and Biomolecular Research and chair of the division of anatomy in the department of surgery in U of T’s Faculty of Medicine. “This pre-clinical work in animal models will inform the design of the new study, currently in place, to help the brain recover from injury.”

Morshead, whose work is funded by Medicine by Design, says that she is excited not only by the promising results of the study, but also by the way its novel design encouraged clinical translation.

“There’s a lot of history of pre-clinical models not working – drug therapies that go to the clinic and then don’t make it to the next phase. That can be devastating for a lot of reasons. But I think, in us combining human and animal work, it really promoted the translation of this work into human testing,” Morshead says.

Medicine by Design provided crucial support for the study. In a past multi-disciplinary project led by Gary Bader, a professor at U of T’s Donnelly Centre and the department of molecular genetics in the Facult of Medicine – and also involving Freda Miller, a senior scientist in the neurosciences and mental Health program at SickKids and a U of T professor of molecular genetics, and Morshead, both co-authors on the Nature Medicine publication – the team mapped brain development over time using single cell genomics. Insights into the circuits that control brain tissue growth led to the identification of compounds that can stimulate resident stem cells to promote brain tissue repair, including metformin.

“I am so excited by this paper since it describes a potential endogenous stem cell-based therapy for brain disorders that are currently untreatable,” says Miller. “And, just as importantly, the metformin story provides a classic example of why we need to support basic research, and why working in collaborative teams is essential. The original finding that metformin recruits endogenous brain stem cells came from fundamental studies on how stem cells build the brain developmentally, and then it was moved forward to animal models and humans by highly interdisciplinary scientists and clinicians like Dr. Morshead and Dr. Mabbott.”

Miller is continuing her work to develop endogenous repair strategies for both brain and muscle in another Medicine by Design-funded team project.

At the core of Medicine by Design’s team projects is convergence – bringing together experts from a range of disciplines including stem cell biology, computational science, biomedical engineering and clinical medicine. The Nature Medicine study exemplifies the translational impact that a multi-disciplinary team-based approach can have, particularly when pre-clinical and clinical studies are run in parallel.

This study presents important evidence that stimulating resident stem cells is a feasible approach for tissue repair in settings where regeneration does not readily occur. And, since metformin is an approved drug, the timeline for further clinical testing and regulatory approval could be accelerated.

The results from both the rodent and human trials have informed a Phase 3 clinical trial on paediatric brain tumour survivors treated with cranial radiation currently starting at 14 hospitals in Canada and Australia.

In the lab, investigators found that metformin enhanced the recovery of endogenous neural precursor cells (NPCs) in the dentate gyrus (DG), a part of the brain that plays a critical role in learning and memory. But the results were sex-dependent: Metformin was sufficient to rescue neurogenesis and behaviour in females, but not males.

In addition to the results to the lab study, a concurrent study with 24 children found that metformin is safe to use, with no significant adverse events reported, and is well tolerated by this population.

Both Mabbott and Morshead say their work is motivated not just by the novel science of activating cells that are already resident in the brain to repair injury, but also by their desire to offer hope to a vulnerable population.

“Working as a clinical psychologist with families for 20 years, it was really the families that motivated me – in fact, they challenged me,” says Mabbott. “My job was to tell parents that while their child was successfully treated for brain cancer there was a cost, as their child will have learning problems, cognitive disabilities and some will never live independently. It was a parent who said to me, ‘That’s not good enough, you have to figure out a way to help our kids recover better.’ That’s what motivated me to start to look at how to harness brain plasticity for repair.”

“Until recently, our after-care programs were offering very little to children suffering the consequences of radiation treatment to their brain,” says study invesitgator Eric Bouffet, director of the brain tumour program, haematology/oncology and senior associate scientist at SickKids, who is also a professor of pediatrics at U of T. “This study suggests that we can repair some of the damage associated with radiation to the brain, and children with brain tumours worldwide may potentially benefit from this discovery.”

For Medicine by Design, accelerating the translation of new regenerative medicine therapies into patient impact is a strategic priority. The implications of this work go beyond childhood brain tumour survivors, says Morshead. Toronto researchers are also looking at metformin and cerebral palsy, and metformin as a preventative treatment for cranial radiation.

Major funders on this study include Brain Canada, Canadian Institutes of Health Research (CIHR), the Garron Family Cancer Centre, SickKids Foundation, Ontario Institute of Regenerative Medicine and Stem Cell Network.

U of T PhD student named change-maker for developing program for patients with traumatic brain injury

noreen.rasbach — Wed, 15 May 2019 04:00:00 +0000

U of T PhD student named change-maker for developing program for patients with traumatic brain injury

noreen.rasbach Wed, 05/15/2019 - 00:00

Cutline

“I know that for me, exercise after [traumatic brain injury] was the most positive and influential factor in my long-term recovery,” says Enrico Quilico, a PhD student at U of T's Rehabilitation Sciences Institute

Topic

Dalla Lana School of Public Health

Subheadline

His own experience surviving a traumatic brain injury has fuelled his passion for researching the subject. Now Enrico Quilico, a PhD student at the �ؿ�ζSM’s Rehabilitation Sciences Institute (RSI), has been named a winner of the 2018 Change-Maker Award by Neurological Health Charities Canada.

Quilico, who is based in Montreal, developed a sports participation program for individuals who have moderate to severe traumatic brain injury (TBI). Supported by a grant from Canada’s Social Science and Humanities Research Council (SSHRC) and with the participation of YMCAs of Québec and the Quebec Association for Traumatic Brain Injury, the nine-month program helps individuals with TBI to learn to work out, integrate into the YMCA community and train for sporting events that have included indoor triathlons and, this year, the Mont-Royal Marathon.

“Individuals with moderate to severe TBI often can’t return to full-time employment after their injury, so they have a lot of time on their hands,” says Quilico. The program provides participants with structure, an objective and a supportive community.

Quilico’s interest in TBI stems from his own experience with the condition. In 2006, he was thrown from the motorcycle he was riding, leaving him with a severe brain injury. He spent two weeks in a coma, three months in hospital, followed by two years of rehabilitation. Quilico credits his return to sports and recreation for his eventual recovery.

“I know that for me, exercise after TBI was the most positive and influential factor in my long-term recovery,” he says. In 2016, he completed the Lake Placid Ironman and, in the process, raised over $10,000 for Brain Injury Canada.

Quilico returned to the classroom and became a certified teacher after finishing his bachelor’s degree in education at Concordia University in 2012. However, the idea for the YMCA-based program was borne from a health promotions course that Quilico took in 2013 at McGill University while completing a master’s degree in kinesiology and physical education. He used that initial blueprint to establish the program in 2017, which now serves as the basis for his PhD, which he’s undertaking at U of T under the supervision of Professor Angela Colantonio, director of RSI, and Université de Montréal Professor Bonnie Swaine.

The program begins by establishing a baseline for participants so they can track their progress through different phases of the nine-month program. Quilico and a team of researchers collect data at various points throughout the program to evaluate its impact on participants as they become more physically active and learn to train for a sport challenge. Currently, he’s working in partnership with the participants to refine the program and establish a manual so the program can eventually be replicated.

“I foresee this community program becoming an adjunct form of treatment after the final phases of rehabilitation have ceased,” Quilico says. The program, which began with an initial cohort of 12 people, has grown to 20 and includes four mentors who previously completed the program.

The Change-Maker Award recognizes individuals who have made a meaningful difference in improving the quality of life for Canadians living with brain conditions. Quilico was nominated for the award by Brain Injury Canada.

“Enrico is so deserving of this award. He has survived near-death, disability, depression, doubt and has demonstrated such resilience. His spirit of determination and drive, like so many others living with acquired brain injury, personifies that acquired brain injury doesn’t have to be the end of the road,” said Michelle McDonald, executive director of Brain Injury Canada.

In addition to his recognition through the award, Quilico is among the Top 25 finalists for SSHRC’s 2019 Storytellers challenge. He was selected by a panel of 25 expert judges from Canada and abroad from the more than 200 entries. As a finalist, he receives a cash prize of $3,000 and the opportunity to compete in the Storytellers Showcase, which will be held at the 2019 Congress of the Humanities and Social Sciences, taking place June 1 to 7 at the University of British Columbia in Vancouver. That is when the final five winners will be selected.

“I feel very supported by U of T and the other members of the team I work with,” says Quilico. “I am so proud of what we’ve been able to establish and I am just thrilled to be conducting research about the value and impact of a community-based, peer-run physical activity program for people who live with a moderate to severe TBI like me.”

U of T researchers look back in time to help prevent future brain injuries

noreen.rasbach — Tue, 30 Apr 2019 22:29:47 +0000

U of T researchers look back in time to help prevent future brain injuries

noreen.rasbach Tue, 04/30/2019 - 18:29

Cutline

(photo by Michael Hall/Getty Images)

Topic

Faculty of Medicine