Laboratory Medicine and Pathobiology

Institute of Biomedical Engineering

Leah Cowen

Sinai Health

Sunnybrook Health Sciences Centre

Centre for Addiction and Mental Health

Unity Health

Cell and Systems Biology

Anthropology

Astronomy & Astrophysics

Biochemistry

Chemistry

Computer Science

Dalla Lana School of Public Health

Ecology and Evolutionary Biology

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Mathematics

Physics

Psychology

University Health Network

UTIAS

Subheadline

From better batteries to preventing memory loss, nearly four dozen projects at U of T and its partner hospitals are being supported by the Ontario Research Fund

Researchers in the �ؿ�ζSM’s Thermal Management Systems (TMS) Laboratory are working to improve the way battery systems handle heat and develop structural battery pack components. 

“Whether they are being used for electric vehicles or for stationary energy storage systems that reduce strain on the grid, lithium-ion batteries are transforming the way we use electricity,” said Carlos Da Silva, senior research associate at the TMS Lab in the Faculty of Applied Science & Engineering and executive director of U of T’s Electrification Hub.

“Unfortunately, today’s batteries are still sensitive to temperature: if they get too cold or too hot, it can degrade their performance and even present safety risks. We are working on new technologies that make batteries more resilient to thermal fluctuations.”

The battery-related research is among nearly four dozen projects at U of T and its partner hospitals that are receiving almost $35 million in support through the Ontario Research Fund – Research Excellence (ORF-RE) and the Ontario Research Fund – Small Infrastructure (ORF-SIF). (See the full list of projects and their principal researchers below).

"Research at the �ؿ�ζSM and at all universities and colleges across Ontario is the foundation of the province’s competitiveness now and in the future,” said Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives.

“This investment protects and advances cutting-edge, made-in-Ontario research in important economic sectors and helps ensure universities can continue to train, attract and retain the world’s top talent."

At U of T Engineering’s TMS Lab, researchers led by Cristina Amon, a University Professor in the department of mechanical and industrial engineering, are working on two funded projects. They are developing advanced computational modelling and digital twin methodologies that predict and optimize how heat flows through battery packs. The methodologies are carefully calibrated and validated through industry-relevant experiments in the lab.

Senior Research Associate Carlos Da Silva, left, and University Professor Cristina Amon, right, chat in the Faculty of Applied Science & Engineering's Thermal Management Systems Laboratory (photo by Aaron Demeter)

These methodologies will help battery designers anticipate and prevent thermal management challenges before they arise. It can also enable them to optimize the design and deployment of fire mitigation measures, such as ultra-thin heat barriers, within their battery systems.

The team is also collaborating with Ford Canada and several other companies in the energy storage space. For example, they have worked with Jule (powered by eCAMION) on the development of direct current electric vehicle fast chargers with integrated battery energy storage systems, one of which was recently unveiled on the U of T campus.

“We are grateful for this ORF-RE funding, which will accelerate our research and help us further expand our partnerships, ensuring that battery thermal innovations have a seamless transition from the lab to the marketplace,” Amon said.

“As a result of this work, the next generation of batteries will be safer and more resilient than ever before, which is especially important in colder climates like ours here in Ontario.” 

Ontario Research Fund – Research Excellence:

Cristina Amon in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – Powering Ontario’s grid transformation and electric vehicle fast charging with thermally resilient battery energy storage & Next-gen electric vehicle battery systems: Lightweight, thermally performant and fire safe for all climates
Morgan Barense in the department of psychology in the Faculty of Arts & Science – HippoCamera: Digital memory rehabilitation to combat memory loss
Aimy Bazylak in the department of mechanical & industrial engineering in the Faculty of Applied Science and Engineering – RECYCLEAN: Critical minerals recycling & re-manufacturing for the energy transition
Ian Connell at University Health Network and the department of medical biophysics in the Temerty Faculty of Medicine – MRI-compatible innovations for neuromodulation
Simon Graham at Sunnybrook Health Sciences Centre and the department of medical biophysics in the Temerty Faculty of Medicine – Technological innovations for clinical MRI of the brain at 7 tesla
Clinton Groth in the Institute for Aerospace Studies in the Faculty of Applied Science & Engineering – Hydrogen as a sustainable aviation fuel – combustion research to remove impediments to adoption in gas turbine engines
James Kennedy at Centre for Addiction and Mental Health and the department of psychiatry in the Temerty Faculty of Medicine – Clinical utility and enhancements of a pharmacogenomic decision support tool for mental health patients
Shaf Keshavjee at University Health Network and the department of surgery in the Temerty Faculty of Medicine – Advanced solutions to human lung preservation and assessment using artificial intelligence
Aviad Levis in the department of computer science in the Faculty of Arts & Science – AI and quantum enhanced astronomy
JoAnne McLaurin at Sunnybrook Health Sciences Centre and the department of laboratory medicine & pathobiology in the Temerty Faculty of Medicine – Conversion of astrocytes to neurons to treat neurodegenerative diseases of the brain and the eye
R. J. Dwayne Miller in the department of chemistry in the Faculty of Arts & Science – PicoSecond InfraRed Laser (PIRL) “cancer knife” with complete biodiagnostics via spatial imaging mass spectrometry
Javad Mostaghimi in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – A new generation of compact, transportable mass spectrometers for rapid, in-field sample analysi
Xiao Yu (Shirley) Wu in the Leslie Dan Faculty of Pharmacy – Molecular dynamics modeling and screening of excipients for designing amorphous solid dispersion formulations of poorly–soluble drugs

Ontario Research Fund – Small Infrastructure Fund:

Celina Baines in the department of ecology & evolutionary biology in the Faculty of Arts & Science – Impacts of environmental change on organismal movement
Sergio de la Barrera in the department of physics in the Faculty of Arts & Science – Facility for quantum materials and device assembly from atomically thin van der Waals layers
Michelle Bendeck in the department of laboratory medicine & pathobiology in the Temerty Faculty of Medicine – 4D quantitative cardiovascular physiology centre
Laurent Bozec in the department of laboratory medicine & pathobiology in the Temerty Faculty of Medicine – 21st Century challenge for Dentistry: Breaking the cycle of irreversible dental tissue loss
Mark Chiew at Sunnybrook Health Sciences Centre and the department of medical biophysics in the Temerty Faculty of Medicine – Next generation computational MRI for rapid neuroimaging and image-guided therapy
Haissi Cui in the department of chemistry in the Faculty of Arts & Science – A molecule to mouse approach to study the intracellular localization of genetic code interpretation in mammalian cells
Andy Kin On DeVeale at the University Health Network and the Dalla Lana School of Public Health – Sarcopenia and musculoskeletal interactions (sami) collaborative hub
Ali Dolatabadi in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – Advanced cold spray facility
Spencer Freeman at the Hospital for Sick Children and the department of biochemistry in the Temerty Faculty of Medicine – Imaging biophysical determinants of the innate immune response
Liisa Galea at the Centre for Addiction and Mental Health and the Institute of Medical Science in the Temerty Faculty of Medicine – Sex and sex-specific factors influencing brain health across the lifespan
Maged Goubran at Sunnybrook Health Sciences Centre and the department of medical biophysics in the Temerty Faculty of Medicine – AI platform for mapping, tracking and predicting circuit alterations in Alzheimer’s disease
Eitan Grinspun in the departments of computer science and department of mathematics in the Faculty of Arts & Science – A computer graphics perspective on entanglement of slender structures
Levon Halabelian in the Department of Pharmacology and Toxicology in the Temerty Faculty of Medicine – Enabling a high-throughput drug discovery pipeline for targeting disease-related human proteins
Ziqing Hong in the department of physics in the Faculty of Arts & Science – Ultra-sensitive cryogenic detector development for dark matter and neutrino experiments
Eno Hysi at the Unity Health Toronto and the department of medical biophysics in the Temerty Faculty of Medicine – Structural and functional assessments of diabetic skin microvasculature using photoacoustic imaging
Lewis Kay in the department of biochemistry in the Temerty Faculty of Medicine – Helium recovery system for the biomolecular NMR facility
Xiang Li in the department of chemistry and the department of physic in the Faculty of Arts & Science – Real-time multi-faceted probes of quantum materials
Qian Lin in the department of cell & systems biology in the Faculty of Arts & Science – 2p-RAM for whole-brain single-neuron imaging of behaving zebrafish to study neural mechanisms of cognitive behaviours
Xilin Liu in the Edward S. Rogers Sr. department of electrical and computer engineering in the Faculty of Applied Science & Engineering – Integrated circuits for wireless brain implants with multi-modal neural interfaces
Stephen Lye at the Sinai Health System and the department of physiology in the Temerty Faculty of Medicine – Healthy Life Trajectories Initiative (HeLTI) analytics platform
Caitlin Maikawa in the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering – Biointerfacing materials for drug delivery lab
Emma Master in the department of chemical engineering & applied chemistry in the Faculty of Applied Science & Engineering – Accelerating biomanufacturing innovation through enhanced capacity for scale-up and downstream bioprocess engineering
Roman Melnyk at the Hospital for Sick Children and the department of biochemistry in the Temerty Faculty of Medicine – The H-SCREEN: A platform for high throughput and high content imaging-based small molecule screens for disease modulation
Juan Mena-Parra in the department of astronomy & astrophysics in the Faculty of Arts & Science – An advanced laboratory to enable novel radio telescopes for cosmology and time-domain astrophysics
Seyed Mohamad Moosavi in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering – Machine learning for nanoporous materials design
Enid Montague in the department of mechanical & industrial engineering in the Faculty of Applied Science & Engineering – Automation and equity in healthcare laboratory
Michael Norris in the department of biochemistry in the Temerty Faculty of Medicine – Infrastructure for structural and functional virology research hub
Amaya Perez-Brumer in the Dalla Lana School of Public Health – 3P lab: Centering power, privilege and positionality for health equity research
Monica Ramsey in the department of anthropology at the �ؿ�ζSM Mississauga – Ramsey Laboratory for Environmental Archaeology (RLEA): How human-environment interactions shaped plant-food
Arneet Saltzman in the department of cell & systems biology in the in the Faculty of Arts & Science – Heterochromatin regulation in development and inheritance
Mina Tadrous in the Leslie Dan Faculty of Pharmacy – Developing a centre for real-world evidence to improve the use of medications for Canadians
Shurui Zhou in the department of electrical & computer engineering in the Faculty of Applied Science & Engineering – Improving collaboration efficiency for fork-based software development
Olena Zhulyn at the Hospital for Sick Children and the department of molecular genetics in the Temerty Faculty of Medicine – Targeting translation for tissue regeneration and repair
Christoph Zrenner at the Centre for Addiction and Mental Health and the Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering – Next-generation real-time closed-loop personalized neurostimulation

Researchers uncover DNA repair mechanism that could yield treatments for cancer, premature aging

Christopher.Sorensen — Wed, 08 May 2024 14:03:08 +0000

Researchers uncover DNA repair mechanism that could yield treatments for cancer, premature aging

Christopher.Sorensen Wed, 05/08/2024 - 10:03

Cutline

From left to right: researchers Mia Stanić, Razqallah Hakem, Mitra Shokrollahi, Karim Mekhail and Anisha Hundal (photo by Erin Howe)

Erin Howe

Topic

Princess Margaret Cancer Centre

Resarch & Innovation

Cancer

University Health Network

Subheadline

“It’s exciting to think about where these findings will lead us next”

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

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

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

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

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

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

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

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

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

The answer is both surprising and elegant.

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

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

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

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

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

The findings have significant implications for some cancer treatments.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

COVID-19 virus disrupts protein production, study finds

Christopher.Sorensen — Tue, 23 Apr 2024 20:58:38 +0000

COVID-19 virus disrupts protein production, study finds

Christopher.Sorensen Tue, 04/23/2024 - 16:58

Cutline

This transmission electron microscope image shows SARS-CoV-2, the virus that causes COVID-19, isolated from a patient in the U.S. (photo by NIAID)

Jenni Bozec

Topic

COVID-19

University Health Network

Subheadline

Post-doctoral researcher Talya Yerlici calls SARS-CoV-2 "a clever saboteur inside our cells, making sure its own needs are met while disrupting our cells’ ability to defend themselves"

Despite huge advances in our understanding of COVID-19 over the past four years, the disease is still very much among us – and there remains a lot to learn.

One thing we do know: Following infection, it’s critical that our cells make new proteins to defend against the virus.

(photo supplied)

But Talya Yerlici, a post-doctoral researcher at the �ؿ�ζSM’s Temerty Faculty of Medicine, recently showed how SARS-CoV-2 disrupts the manufacture of proteins.

She is the first author of a paper detailing the process that was published recently in the journal Cell Reports.

Writer Jenni Bozec recently spoke with Yerlici – who is based in the lab of Professor Karim Mekhail in the department of laboratory medicine and pathobiology – about the findings.

What have you discovered about how COVID-19 uses proteins?

One way SARS-CoV-2 makes us sick is by using a strategy called “host shutoff.” This means that while the virus makes copies of itself, it also slows the production of vital components within our cells. As a result, our bodies take longer to respond to the infection.

When SARS-CoV-2 enters our cells, it disrupts the process of making proteins, which are essential for our cells to work correctly. A particular SARS-CoV-2 protein called Nsp1 has a crucial role in this process. It stops ribosomes, the machinery that makes proteins, from doing their job effectively. The virus is like a clever saboteur inside our cells, making sure its own needs are met while disrupting our cells’ ability to defend themselves.

We found that Nsp1 is good at blocking ribosomes from making new proteins, but also interferes with the production of new ribosomes. In effect, it shuts down the machinery output and the ability to make the machinery itself – a serious double hit.

It does this by blocking the maturation or processing of specialized RNA molecules needed to build ribosomes. This adds a new layer of complexity to our understanding of SARS-CoV-2's interference with the host cell.

How could this discovery impact treatment for those with COVID-19?

Building on our published research, it will be crucial to understand how Nsp1 works to stop different types of human cells, tissues and organs from making proteins when infected with different variants of SARS-CoV-2 and related coronaviruses.

Scientists have been working to find precision medicines that can counteract Nsp1 and help fight against the continually evolving SARS-CoV-2 virus. These drugs aim to help infected cells keep producing proteins and build a robust immune response when dealing with infection. Ongoing research on such drugs should now benefit from testing whether they can block Nsp1 from interfering with both the production and function of ribosomes, and this should help find more effective precision medicines.

What drew you to this line of research?

This project started because of circumstances during the COVID lockdown. We wanted to help in the fight against the pandemic. However, since I couldn't physically work in the lab, we took the opportunity to analyze next-generation sequencing datasets computationally from home.

Looking at published RNA-sequencing datasets, we realized that cells infected with SARS-CoV-2, compared to uninfected cells, may have difficulty processing the RNA molecules needed to build ribosomes. Through this analysis, together with Dr. Mekhail, we developed hypotheses and designed the project.

I had the privilege of collaborating closely with the talented members of the Mekhail lab, including Alexander Palazzo’s group from the department of biochemistry at Temerty Medicine and Brian Raught and Razqallah Hakem’s labs at the Princess Margaret Cancer Centre (University Health Network). This work wouldn't have been possible without the collective efforts of our team and collaborators, and I’m grateful for their contributions. My responsibilities included conducting numerous hands-on experiments and bioinformatics analyses, analyzing the results and preparing the paper for peer review and publication.

What were the most challenging and rewarding aspects of this project?

The most challenging part was conducting research during a global pandemic, which presented many logistical hurdles – from disrupted lab routines to limitations on collecting and using samples infected with SARS-CoV-2.

On the other hand, the opportunity to contribute to our understanding of SARS-CoV-2 viral mechanisms and shed light on potential therapeutic targets was incredibly fulfilling. Seeing our research culminate in a published paper and knowing it could inform future strategies for combating coronaviruses is deeply gratifying.

What are your longer-term goals as a scientist?

As an independent investigator in my future lab, I want to study how the complex processes of making ribosomes affect the body's natural defense against viruses. It's an area I find compelling and presents ample opportunities for further exploration. One approach I’m particularly interested in is integrating RNA-sequencing with genetic CRISPR and small-molecule chemical screens, targeting distinct stages of ribosome biogenesis across diverse infection or infection-mimicking conditions. Such integrated approaches hold promise for uncovering novel mechanisms underlying the regulation of antiviral responses and should help us find innovative and impactful ways to fight viral infections.

This research was supported by the Canadian Institutes of Health Research.

Breast milk may have protective effects against COVID-19: Researchers

Christopher.Sorensen — Mon, 29 Jan 2024 18:38:03 +0000

Breast milk may have protective effects against COVID-19: Researchers

Christopher.Sorensen Mon, 01/29/2024 - 13:38

Cutline

Samantha Ismail led a study by researchers at U of T and its partner hospitals that looked for SARS-CoV-2 antibodies in human breast milk (supplied image)

Betty Zou

Topic

Emerging and Pandemic Infections Consortium

COVID-19

Institutional Strategic Initiatives

Sinai Health

Sunnybrook Health Sciences

Vaccines

Subheadline

“COVID-19 vaccination and infection result in antibodies in human milk that have neutralizing capacity"

The COVID-19 pandemic was an especially harrowing time for pregnant people and new parents.

The uncertainties about how the new coronavirus could affect a pregnant person and their developing fetus – not to mention being cut off from support networks – left many expecting parents feeling isolated and anxious.

“It was a very surreal time,” says Jenny Doyle, a Toronto mom who gave birth to her first child, Elliott, in 2020 and spent hours researching how the first vaccines made available the following year might affect her and her child. “At the time, vaccines for infants were still so far away. I remember hoping that some of the protection I’d received from my vaccine would pass through to Elliott.”

Now, new findings from a study led by researchers at the �ؿ�ζSM and its partner hospitals suggest that is the case.

Published in the American Journal of Clinical Nutrition, the study looked for antibodies against SARS-CoV-2 in breast milk from three different cohorts: individuals who contracted COVID-19 while pregnant or nursing, routine milk bank donors and individuals who received two doses of the COVID-19 vaccine while pregnant or nursing.

The researchers detected antibodies in breast milk from roughly half of the people in the COVID-19 positive cohort. That’s compared to less than 5 per cent of routine milk bank donors, who did not have any known exposures to COVID-19. In the vaccinated cohort, they found that antibodies levels were higher in people who had received the Moderna vaccine compared to those who had received the Pfizer-BioNTech vaccine. Unexpectedly, people who had shorter intervals between their first and second doses had higher antibody levels than those who waited longer between their immunizations.

“That finding definitely surprised me,” says Samantha Ismail, the study’s first author who completed her master’s degree in the lab of Deborah O’Connor, the Earle W. McHenry Professor and chair of Temerty Medicine’s department of nutritional sciences. “In [blood] serum, it’s the other way around where longer intervals between doses typically result in higher antibody levels, suggesting that something different is happening in this lactating population.”

In addition to Ismail and O’Connor, the study was led by Sharon Unger, medical director of the Roger Hixon Ontario Human Milk Bank at Sinai Health and a U of T professor of medicine and nutritional sciences, and Susan Poutanen, microbiologist and infectious disease consultant and Sinai Health and U of T associate professor of laboratory medicine and pathobiology.

The team took the study one step further by showing that some breast milk samples could prevent SARS-CoV-2 from infecting cells in a lab setting. Within the COVID-19 positive cohort, milk that contained antibodies against the virus were more likely to be neutralizing and immunization with the Moderna vaccine was associated with a stronger neutralizing capacity than the Pfizer-BioNTech vaccine.

The researchers also found a small but significant number of breast milk samples that prevented SARS-CoV-2 infection despite having undetectable levels of antibodies, suggesting that there could be other components in human milk that are active against SARS-CoV-2.

While these findings provide strong evidence to support the potential protective effects of human milk, Ismail cautions that the study alone is not enough to prove that breast milk provides tangible protection against COVID-19.

“COVID-19 vaccination and infection result in antibodies in human milk that have neutralizing capacity, but we don’t know for sure how the neutralizing capacity seen in the lab translates to protection in infants,” says Ismail, who is now a second-year medical student at U of T.

She points out that previous studies have shown a clear protective effect of antibodies in human milk against other viruses like enterovirus and rotavirus. To date, such studies have not been done with COVID-19.

Even so, the findings provide reassuring news to parents like Doyle, who breastfed her son longer than she had intended to ensure that he was still getting breast milk when she received her second COVID-19 vaccine.

“Trying to figure out how to protect this tiny being in that scary and bleak time, I was grasping at every little piece of information and whatever little piece of hope we had.”

The study was supported by the Canadian Institutes for Health Research and was a collaboration between the department of microbiology at Sinai Health System/University Health Network, the Roger Hixon Ontario Human Milk Bank at Sinai Health System and the Toronto High Containment Facility, where the live SARS-CoV-2 neutralization studies were completed.

It involved contributions from several members of the Emerging and Pandemic Infections Consortium, a U of T institutional strategic initiative. In addition to O’Connor, Poutanen and Unger, they include Scott Gray-Owen, of Temerty Medicine’s department of molecular genetics, Samira Mubareka, of Sunnybrook Health Sciences Centre and Temerty Medicine’s department of laboratory medicine and pathobiology, and Jennie Johnstone and Allison McGeer – both of Sinai Health and Temerty Medicine’s department of laboratory medicine and pathobiology.

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 — Wed, 05 Jul 2023 03:12:54 +0000

Research challenges long-held view of early-stage Alzheimer's disease

siddiq22 Tue, 07/04/2023 - 23:12

Cutline

Gerold Schmitt-Ulms, a professor in the Temerty Faculty of Medicine's department of laboratory medicine and pathology, was one of the authors of the new study (supplied image)

Eileen Hoftyzer

Topic

Tanz Centre for Research in Neurodegenerative Diseases

Medical Research

Subheadline

A new study by researchers from U of T's Tanz Centre for Research in Neurodegenerative Diseases examines how a hormone called somatostatin influences the earliest stages of the disease

Recent research from the Tanz Centre for Research in Neurodegenerative Diseases in the �ؿ�ζSM's Temerty Faculty of Medicine is challenging long-held views of how a hormone called somatostatin influences the earliest stages of Alzheimer’s disease.

“Importantly, for the first time, this research indicates the extent to which somatostatin could be important in Alzheimer’s disease,” says Gerold Schmitt-Ulms, co-author of the study published in Scientific Reports.

“The answer is that somatostatin has a significant effect, but it’s not black or white. It doesn’t prevent clumping of the amyloid beta protein, but slows it down. This is important, but we don’t know what this means for treatment yet,” says Schmitt-Ulms, an investigator at the Tanz Centre and professor in U of T’s department of laboratory medicine and pathology.

The dominant hypothesis of how Alzheimer's disease begins – the amyloid cascade hypothesis – says that too much amyloid beta protein is produced, which clumps together to form oligomers (small clumps of varying numbers of amyloid beta monomeric building blocks), which then continue to accumulate to form larger plaques that damage neurons.

As early as the 1970s, researchers observed that brains of people with Alzheimer’s disease had lower levels of the hormone somatostatin than people who did not have Alzheimer’s, and that the plaques of amyloid beta that are characteristic of the disease tend to form near neurons that produce somatostatin.

These observations suggested a relationship between somatostatin and amyloid beta aggregation, but researchers did not know what it was.

Then, in the early 2000s, a team from Japan published research describing that somatostatin drives production of an enzyme called neprilysin that can degrade amyloid beta. This finding suggested that if somatostatin was decreased, the levels of neprilysin would decrease – without neprilysin to degrade amyloid beta, the plaques would continue to grow, and Alzheimer's disease would progress.

This understanding of the role of somatostatin is where the field stood for more than a decade.

An image from the study summarizing its key findings (supplied image)

Several years ago, Schmitt-Ulms and his team investigated amyloid beta in its monomer and oligomer forms, specifically looking for molecules in the brain that would bind to the toxic oligomeric forms. They found that, of all proteins in the brain, somatostatin was the smallest to bind to amyloid beta – and the most selective, as it only interacted with the oligomers.

They then observed that somatostatin blocked the formation of oligomers, with higher concentrations of somatostatin having a greater effect. This earlier study provided the first evidence that somatostatin interacts directly with the oligomeric amyloid beta that are known to be the earliest stages of Alzheimer's disease, providing an alternative perspective on the impact of somatostatin on the disease.

“We didn’t actually intend to work on somatostatin, but these results made us very curious about what would happen if somatostatin was absent in an animal model that was genetically engineered to develop amyloid beta aggregations,” Schmitt-Ulms explains.

To answer this question, the research team crossed a somatostatin-deficient mouse line with an amyloidosis mouse model.

They found that when somatostatin was absent, there were more amyloid beta aggregates, consistent with what is seen in Alzheimer’s disease in humans.

Remarkably, the result did not seem to be caused by an effect of somatostatin on neprilysin levels, as there were no differences – a contradiction to the long-held understanding of the mechanism through which somatostatin impacts Alzheimer’s disease. Instead, the data suggested that somatostatin blocks oligomer formation independent of neprilysin by interacting with amyloid beta.

“There isn’t a lot of literature that explains how the environment in the brain can promote or inhibit amyloid beta forming into oligomers, so this is a nice vignette that shows that one molecule – somatostatin – seems to influence that first small oligomeric aggregation step,” Schmitt-Ulms says.

“And if you get fewer of these oligomeric forms, then you get fewer of the small clumps, which are the next step of amyloid beta aggregation – so the process made sense, and it was a striking finding.”

While the results have challenged the conventional view of somatostatin in Alzheimer’s and prompted discussions in the scientific community, what they mean for treatment is still uncertain.

Somatostatin plays important roles in the gastrointestinal, endocrine and nervous systems, so selectively promoting its role in blocking amyloid aggregation would be challenging. Schmitt-Ulms says that it is also unclear whether augmenting somatostatin, and thereby arresting the growth of amyloid beta aggregates, is beneficial.

Still, the results have shaken up the research field.

“The evidence speaks for itself, and we stand by our conclusions, but the data can’t answer what this means for therapeutics,” Schmitt-Ulms says.

“They do, however, indicate that somatostatin – one of the first-ever molecules that were biochemically linked to Alzheimer’s disease – may play a different role in the earliest stages of the disease than expected, and that in itself is important.”

The study was supported by Alberta Innovates Bio Solutions, Ontario Centres for Excellence/MaRS Innovation and the Borden Rosiak family.

'We should be preparing': Researcher Samira Mubareka on the risks posed by bird flu

Christopher.Sorensen — Thu, 06 Apr 2023 15:27:52 +0000

'We should be preparing': Researcher Samira Mubareka on the risks posed by bird flu

Christopher.Sorensen Thu, 04/06/2023 - 11:27

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(Photo by Kevin van Paassen/Sunnybrook Health Sciences Centre)

Betty Zou

Topic

Institutional Strategic Initiatives

EPIC

Sunnybrook Health Sciences Centre

From Brampton, Ont. to sites in nearby Halton and Niagara regions, there are a growing number of reports of birds that have tested positive for highly pathogenic avian influenza (HPAI) virus, or bird flu.

While HPAI typically infects birds – more than seven million across Canada, including nearly 750,000 in Ontario, according to the Canadian Food Inspection Agency – there have also been growing reports since 2022 of mammals getting infected and dying of bird flu, which is also known as H5N1, across a large geographic area. They include small land animals like raccoons and skunks to large carnivores like bears and mountain lions, as well as marine mammals like sea lions and dolphins.

Just this week a pet dog died in Oshawa, Ont. after testing positive.

To learn more about the bird flu outbreak and what we can do to prepare, writer Betty Zou spoke to Samira Mubareka, an infectious diseases physician, medical microbiologist and scientist at Sunnybrook Research Institute. She is also an associate professor in the department of laboratory medicine and pathobiology in the �ؿ�ζSM ’s Temerty Faculty of Medicine and a member of the U of T-based Emerging and Pandemic Infections Consortium (EPIC), an institutional strategic initiative.

Her research uses a collaborative One Health approach – looking at the interconnection between people, animals and their shared environment – to conduct surveillance in wildlife and look at the biology of emerging viruses and transmission between species, including humans.

How widespread is bird flu right now?

The level of avian influenza activity we’re seeing at the moment is unprecedented. To step back a bit, the first cases in North America were reported in late 2021 in birds in Newfoundland – and from there, it spread along the eastern seaboard into the United States along Atlantic flyways. Subsequently, there were cases reported in the west of Canada and the United States, followed by cases in Central and South America. Beyond affecting wild and farmed birds, we are seeing spillover of HPAI into mammals, many of whom die of severe neurological complications.

There has also been renewed focus on HPAI because a reported outbreak among farmed mink in Spain, with mammal-to-mammal transmission, and large die-offs of marine mammals, including sea lions. The virus also appears to be reassorting, or exchanging genetic material among H5N1 lineages. All of these represent red flags that reflect an amount of viral activity that we really haven’t seen before.

We’ve also never seen this level of bird depopulation – both from die-offs and as a control measure. This has potential to impact biodiversity, wildlife health and conservation, as well as food costs and security. There have been a significant number of outbreaks, including here in Ontario, and some of them have been fairly close to densely populated areas. Having said all this, it is important to underscore that the risk remains low for humans and that we have not had any human cases in Canada. Regardless, we need to prepare for that possibility.

H5N1 made the news in 2003 and 2014, but in both those instances the outbreaks were relatively contained. What’s changed this time that is causing it to be so widespread?

There could potentially be multiple factors. There may be some characteristics that are specific to this strain of H5N1 that are enabling this level of viral activity. One thing we do know is that bird populations are highly mobile and often exchange viruses when they’re migrating and co-mingling at migration sites, which provides an ecological context for viral reassortment and selection.

Having said that, these birds migrate every year, so why is this so different? I don’t know that we’ll get to the bottom of that without more research. People have started to look at how influenza virus pathogenesis is changing in these birds and how migration affects bird immunity, but what we don’t understand are some of the intersections between the virus and other potential exposures and ecological factors that the birds are encountering during migration or at their overwintering sites. I think there’s a lot to be learned and this is where a One Health approach could be instrumental.

How does H5N1 affect humans and what clinical interventions are available?

With people, unsurprisingly, there’s a range of clinical symptoms. Some people will experience little to no symptoms, but we don’t know exactly what proportion are asymptomatic, have mild symptoms or more severe symptoms with poor outcomes. Frequently, people have quoted mortality rates of between 40 per cent and 60 per cent for this virus, which is very high, but that could be due to biases from past events where only the most severe cases were identified.

Like with other influenza viruses, this virus could manifest as an upper respiratory tract infection or severe viral pneumonia with multi-system organ involvement and/or a severe neurological syndrome. As health-care providers, we need to be prepared for a range of symptoms. The good news is that I’m not aware of any widespread antiviral resistance. In terms of prevention, there is no vaccine specific to H5N1 available for Canadians at this moment, but we still recommend the seasonal influenza virus vaccine. Seasonal influenza vaccination reduces the burden of seasonal influenza, and it may also reduce the likelihood of H5N1 mixing with seasonal influenza viruses and potentially reassorting to become more transmissible or severe in humans.

What should individuals and health-care providers be thinking about in terms of risk factors for H5N1?

There are a few different risk factors and they’re generally related to animal exposure. One, obviously, is to have been in direct contact with animals that were known to have H5N1. People working in certain occupations like veterinary medicine and farming – particularly poultry farming – as well as anyone working directly with wild birds and other wildlife are considered at higher risk of being exposed.

You recently received funding support from EPIC to conduct risk assessment research on highly pathogenic avian influenza. Can you tell us about that work?

Absolutely. We know that in Canada, the virus is reassorting which means it is exchanging genetic materials with other viruses. Do these new pieces of genetic material cause the virus to behave differently? Scientists at the National Centre for Foreign Animal Disease and the Public Health Agency of Canada are leading the work to try and understand that and the risks posed by these new variants. We are collaborating with them and with EPIC member Theo Moraes, who has been central to that work. Theo’s team has developed a way to take cells from inside someone’s nose and grow them in the lab. These cells serve as a model to understand how well viruses replicate and, in turn, how much of a risk they could pose to people. This work also feeds into a grant we just received from the Canadian Institutes of Health Research on using a collaborative One Health approach to zoonotic virus detection and risk assessment at the wildlife-human interface.

How worried are you about the bird flu situation right now? How should we be preparing?

I’m more worried now than I was a few months ago because there are so many reports of spillover from birds to mammals. Hearing about human cases, even sporadic ones, is another red flag. We’re sufficiently concerned that we’ve started preparatory activities like getting our sequencing protocols ready. I’m also worried about the impact on wildlife health. When you have wildlife populations that are dying off, that in and of itself should have us concerned, regardless of whether humans are getting sick.

I think every one of these events is a reminder that we should be preparing. It’s important to note that right now the risk to individuals is still low, but that can change anytime. Let’s not to wait for it to change before we start preparing. We should be more proactive in surveillance and looking at things like vaccine and antiviral development – both for poultry and for humans. Vaccinating poultry is not as straightforward as you might think because there are trade implications.

The fact that we’re seeing new HPAI viruses in Canada underscores the importance of ongoing surveillance. We also need to do a better job of communicating to frontline health-care providers, especially those working in areas where the potential for a spillover from animals to humans is high. Enhanced efforts towards surveillance, medical countermeasures, communications and research are all steps in the right direction.

Researchers discover what causes cell 'batteries' to run down

Christopher.Sorensen — Fri, 19 Aug 2022 17:58:05 +0000

Researchers discover what causes cell 'batteries' to run down

Christopher.Sorensen Fri, 08/19/2022 - 13:58

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A recent study of mitochondrial turnover by U of T's Stephen Girardin and Samuel Killackey promises to open new avenues for research into diseases where mitochondrial stability is lost (photos supplied)

Jenni Bozec

Topic

Researchers at the �ؿ�ζSM have discovered how mitochondrial turnover – a critical cellular function – begins.

Mitochondria are like the batteries of our bodies. They’re vital sources of energy for cells and are necessary to regulate function in almost all cell types. And, like batteries, mitochondria need to be replaced as they run down over time. If these cell batteries aren’t replaced efficiently, and don’t turn over properly, cells experience stress and can die.

Healthy mitochondria, in turn, are critical in energy-demanding organs such as the brain and muscle. When this degradation process is disrupted, vulnerable neurons can die. This type of disruption is present in many neurodegenerative diseases such as Parkinson’s.

Now, a study by Stephen Girardin, a professor of laboratory medicine and pathobiology in the Temerty Faculty of Medicine, and post-doctoral researcher Samuel Killackey shows that when certain nuclear encoded proteins aren’t brought into mitochondria, the mitochondria are removed.

“We’re proud we’ve identified the problem and made progress toward understanding and characterizing the molecular players and pathways, and how this is all integrated in a cell – in some surprising ways,” Giradin says.

Girardin studies a mitochondrial Nod-like receptor (NLR) called NLRX1. While NLRX1 has been implicated in diverse cellular processes, its underlying function remained elusive to researchers until now.

Generally, research in this area revolved around depolarization – the loss of electric potential across the inner mitochondrial membrane – as the major signal for mitochondrial removal.

Girardin and Killackey’s study also showed that depolarization is an upstream cause of restricted mitochondrial protein import.

The findings, published in Molecular Cell, open new avenues for research into diseases where mitochondrial stability is lost.

“This tells us the problem occurs when the protein import fails and the cell receives a signal from the faulty import of the mitochondrial protein, NLRX1. This is the cue to destroy the mitochondria, a process known as mitophagy,” Girardin says.

By looking at the process from a different perspective, the team demonstrated that the established science in this area didn’t show the whole picture.

“We took a step back and connected some of the dots in the literature, which helped us identify that disrupted protein import was a common denominator across many mitochondrial stressors that trigger mitophagy,” says Killackey, a Vanier Scholar who conducted the research during his PhD studies in Girardin’s lab.

The discovery paves the way for researchers to further investigate the role of mitochondrial dysfunction in disease and in metabolically active organs like the brain, heart and kidneys.

“We’ve seen a role for NLRX1-driven mitophagy in muscle function measured through endurance capacity, which could have implications for diseases that involve muscle atrophy or functional deficits. Modifying the extent and efficiency of mitochondrial protein import could also offer therapeutic benefit for neurodegenerative disease,” says Killackey.

The findings are the culmination of 15 years of research, marking a milestone for Girardin.

“I love fundamental questions,” he says. “What happens next with the knowledge is a question of physiology, translational medicine or drug development. So, now it’s time to pass the baton to others, or to partner with enthusiastic collaborators.”

From happiness to health care, undergraduate summer program inspires future data scientists

Christopher.Sorensen — Thu, 18 Aug 2022 13:13:32 +0000

From happiness to health care, undergraduate summer program inspires future data scientists

Christopher.Sorensen Thu, 08/18/2022 - 09:13

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Victoria College's Anthony McCanny is exploring whether gross domestic product (GDP) is a good measure of economic and societal success as part of a Data Sciences Institute summer research program (photo courtesy of the Data Sciences Institute)

Chris Sasaki

Topic

Institutional Strategic Initiatives

Data Sciences Institute

Dalla Lana School of Public Health

Artificial Intelligence

Computer Science

Earth Sciences

Faculty of Arts & Science

Innis College

Psychology

St. Michael's College

Victoria College

What causes glacial periods to end? Can machine learning help make medical decisions? Can money buy happiness?

These were among the questions studied during the 2022 Summer Undergraduate Data Science (SUDS) Research Program run by the �ؿ�ζSM’s hub for data science research: the Data Sciences Institute (DSI), based in the Faculty of Arts & Science.

The program pairs faculty members with undergraduate students from universities across Canada who are interested in data science careers.

“The DSI SUDS program is about inspiring the next generation of data scientists and giving undergraduate students an opportunity to explore data science as a career opportunity,” says Laura Rosella, the institute’s associate director of education and training and an associate professor at the Dalla Lana School of Public Health and in the Faculty of Medicine’s department of laboratory medicine and pathobiology.

“In addition to their research projects, these students are provided with a full set of data science networking, academic and professional development opportunities. And we couldn’t be more thrilled to have the chance to inspire them and hopefully kickstart their careers in this exciting field. They are truly an exceptional bunch.”

The variety of projects tackled in the program reflects the growing number of disciplines that are increasingly reliant on data skills and expertise. Three projects involving Faculty of Arts & Science faculty members and students addressed questions in psychology, Earth sciences and the intersection of machine learning and health care.

Students presented their research during the SUDS Research Day in August (photo courtesy of the Data Sciences Institute)

What causes ice ages to end?

Innis College student Tina Tsan is working with Ulrich Wortmann, an associate professor in the department of Earth sciences on an analysis of why the last ice age came to a sudden end.

During glacial periods, ocean levels dropped as water was taken up in glaciers. This exposed the continental shelf, triggering a chemical reaction that released large amounts of carbon dioxide into the atmosphere. Tsan and Ulrich’s analysis supports the idea that this CO2 may have warmed the atmosphere enough to end the last ice age.

“The work I'm doing in SUDS is an extension of my previous undergraduate research into changes in ocean chemistry,” says Tsan. “By exploring the data science side of this work, I now have a better understanding of my research and this gives me a solid foundation for the fall when I start my master’s degree in Earth sciences.

“For me, the biggest reward from the SUDS program has been how it’s broadened my perspective and understanding of what data science is and how it's used in different fields.”

Wortmann praised the program.

“The SUDS program is fantastic – especially for students who are not embedded in a large research group or who are working in a field where few of their peers have an interest in data science,” he said.

Can machine learning help make medical decisions?

A member of St. Michael’s College, Yingke Wang is working with Rahul Krishnan, an assistant professor in the department of computer science and the department of laboratory medicine and pathobiology in the Temerty Faculty of Medicine.

Krishnan’s research exists at the intersection of machine learning and health care. Among his lab’s projects: redesigning patient risk scores, which are metrics used in hospitals to predict aspects of a patient’s care and inform clinical decisions such as who should receive an organ transplant.

One of the ways such scores are evaluated is with a population simulator called LivSim, which simulates how a group of people might be affected by a specific choice of risk score.

“Yingke will be working to help optimize LivSim,” says Krishnan. “His work will get it operational and running efficiently, so we can evaluate the efficacy of some of the novel risk scores designed in the lab.

“It's been wonderful to see the support that SUDS provides to young scholars like Yingke. Introducing students to research early is an important step for them to see the opportunities that graduate study can provide."

Wang, similarily, says he has reaped significant rewards from the program.

“Thanks to SUDS, I’m learning how to combine machine learning algorithms in the health-care industry as well as explore survival analysis,” says Wang. “Plus, the self-learning skills I gain will be essential to me for approaching graduate study.”

Can money buy happiness?

Anthony McCanny, a member of Victoria College where he was a Northrop Frye Centre Undergraduate Fellow, is interested in whether gross domestic product (GDP) is a good measure of economic and societal success –and what type of government spending improves the lives of citizens.

He is working with Felix Cheung, an assistant professor in the department of psychology who studies the determinants and consequences of subjective well-being across diverse populations – including the question of whether economic growth translates into personal happiness.

“During SUDS, Anthony and I will study an age-old question: whether money buys happiness,” says Cheung. “We examine this question at a policy level by testing how governments can allocate their expenditures to best benefit citizens' well-being.

“Anthony is using a cutting-edge method to test this long-standing research question with the largest dataset on global happiness. The results hold promise to inform governmental expenditure, an extremely timely topic as many countries around the world are reprioritizing their spending given recent events such as the invasion of Ukraine.”

McCanny, for his part, says the program brought “learning, fun, joy and community” to his summer.

“I’ve been very lucky in Professor Cheung’s lab to have the freedom to conduct my own research, paired with great guidance,” he says. “It’s hard not to feel like this summer has redefined my path in life, filling me with enthusiasm for a career in research, and connecting me with people that I hope I get to keep working with.”

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

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

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

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

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(Photo by Ryan McCullough)

Erin Howe

Topic

Hospital for Sick Children

Institute of Medical Science