Immunology

machine learning

Medical Research

Subheadline

Even while undertaking complex research, the human biology and immunology student took the time to help her peers

While studying for her honours bachelor of science degree, new University of Toronto graduate Irene Fang capitalized on opportunities both inside and outside the classroom.

Majoring in human biology and immunology in the Faculty of Arts & Science, Fang researched innovative methods in ultrasound detection driven by artificial intelligence (AI) and machine learning. She’s also working on research into cells and proteins in humans that could lead to new treatments and therapies for immunocompromised patients.

Even amid that busy schedule, Fang was determined to help others succeed. As a senior academic peer advisor with Trinity College, she was admired for her dedication to learning and the U of T community.

“I want to keep giving back because I am so appreciative of the upper-year mentors I connected with, starting in first year,” Fang says. “They continue to serve as an inspiration, motivating me to further develop personal and professional skills.”

Fang spoke with Faculty of Arts & Science writer David Goldberg about what she learned during her undergraduate studies, the importance of peer support and her post-graduation plans.

Why was U of T the right place for you to earn your undergraduate degree?

U of T provided a plethora of academic, research and experiential learning opportunities alongside a world-class faculty to help cultivate my curiosity and consolidate my knowledge. In conjunction with an unparalleled classroom experience, I gained a real-world perspective with international considerations through the Research Opportunities Program.

I would be remiss if I didn’t also mention how extracurricular activities enhanced and enriched my university experience. The many clubs at U of T helped me focus on my passions and make meaningful connections with like-minded peers who became my support network, enabling me to reach my full potential.

How is your area of study going to improve the life of the average person?

It is absolutely fascinating that AI has already revolutionized the medical field. Specifically, AI possesses the potential to aid in the classification of ultrasound images, enhancing early detection and diagnosis of internal bleeding because of injuries or hemophilia. Overall, AI may lead to more efficient care for patients, thereby improving health outcomes.

In terms of my immunology research, since the memory B cells expressing the specific receptor are dysregulated in people suffering from some autoimmune disorders and infectious diseases, a better understanding of how memory B cells are regulated could provide valuable insight into the underlying mechanisms of such diseases so we can enable scientists to develop new therapies that alleviate patients’ symptoms.

What are you hoping to do after graduation?

I aspire to pursue a career in the medical field, conduct more research and nurture my profound enthusiasm for science while interacting with a diverse group of people. I hope to devote my career to improving human health outcomes while engaging in knowledge translation to make science more accessible to everyone.

Why was working as a peer advisor at U of T important to you?

I remember feeling overwhelmed as a first-year student until I reached out to my academic peer advisors. Had I not chatted with them, I would not have known about – let alone applied for – my first research program. Looking back, it opened the door to many more new, incredible possibilities and opportunities.

This experience made me realize the significance and power of mentorship, inspiring me to become an academic peer advisor. Seeing my mentees thrive and achieve their goals has made this role so rewarding – so much so that I am determined to engage in mentorship throughout my career after graduation.

What advice do you have for current and incoming students to get the most out of their U of T experience?

Ask all questions – because there are no silly questions. Get involved, whether it be volunteering, partaking in work-study programs, sports or joining a club. Meeting new people and talking to strangers can be daunting, but the undergraduate career is a journey of exploration, learning and growth.

Be open-minded and don’t be afraid to try something new. Immersing yourself in distinct fields enables you to discover your interests and passions, which can lead you to an unexpected but meaningful path.

Also, be kind to yourself because failures are a normal part of the learning process – what’s important is that you take it as an opportunity to learn, grow and bolster your resilience.

And finally, although academia and work can keep you busy, remember to allocate time for self-care. Exercise, sleep and pursue hobbies because mental health is integral for success in life.

Research shows how boosting immune memory could help develop improved flu vaccine

siddiq22 — Thu, 11 May 2023 20:33:55 +0000

Research shows how boosting immune memory could help develop improved flu vaccine

siddiq22 Thu, 05/11/2023 - 16:33

Cutline

PhD student Karen Yeung is one of the recipients of the inaugural EPIC Doctoral Awards for her work on boosting immune memory to enhance protection against influenza (supplied photo)

Betty Zou

Topic

Emerging and Pandemic Infections Consortium

EPIC

Leslie Dan Faculty of Pharmacy

Karen Yeung is no stranger to outbreaks of respiratory infections. As a child growing up in Hong Kong, she lived through the first SARS outbreak in 2003 and witnessed the city dealing with repeated threats of bird flu in the years that followed.

Twenty years later, in the midst of a global pandemic caused by SARS-CoV-2, the fourth-year PhD student in the department of immunology at the University of Toronto's Temerty Faculty of Medicine is leading critical research to understand how our immune systems respond to influenza infection – and how we might be able to leverage that knowledge to create a long-lasting, universal flu vaccine.

Yeung is one of 31 recipients of the inaugural Emerging and Pandemic Infections Consortium (EPIC) Doctoral Awards, which supports outstanding students pursuing infectious disease research.

“Current flu vaccines work by inducing an antibody response against a specific component of the influenza virus, but this viral component mutates very quickly every year. This means that the antibodies that you make against this year’s flu vaccine likely won’t match the strain of flu that we’ll see next season,” says Yeung, who is supervised by Tania Watts, a professor of immunology at U of T who holds the Canada Research Chair in anti-viral immunity.

Immune cells called memory CD8+ T cells might hold the key to unlocking broad protection against multiple flu strains. These immune cells retain a memory of a pathogen long after the initial infection, which allows the body to quickly mount a powerful immune response the next time it encounters that pathogen. And unlike the antibodies generated from a flu vaccine, memory T cells recognize parts of the influenza virus that are more likely to remain unchanged between strains and from one year to another.

Previous work from Watts’ lab was the first to show that a protein receptor on CD8+ T cells called 4-1BB is an important player in the formation of memory T cells after a flu infection. 4-1BB is part of a communications cascade that relays cues to regulate the immune system. Yeung’s doctoral research aims to uncover how this pathway is turned on to produce memory CD8+ T cells.

“We’re really interested in how cells can communicate to each other through the language of receptors like 4-1BB and signaling,” Yeung says.

“When you have a lung infection due to flu, what kinds of signals are the CD8+ T cells receiving in the lungs that are helping them transition to memory T cells? How can we manipulate these mechanisms to form more of these memory cells?”

So far Yeung’s work points to monocytes – a type of immune cell that is recruited to the lungs early on during an infection – as providing the activating signal to allow more CD8+ T cells to become memory cells. Next, she’ll be looking at what happens during a secondary flu infection if 4-1BB signaling is disrupted and there are fewer protective memory T cells.

By deepening the understanding of how immune memory develops, Yeung’s research – which is funded by the Canadian Institutes for Health Research – is laying the groundwork for new approaches that could complement existing flu vaccine strategies to elicit a broader and longer-lasting immune response.

“It takes us closer towards a universal flu vaccine strategy, where one shot will be enough to protect against seasonal influenza and future influenza pandemics as well.”

Researcher focuses on essential, but often-ignored, organ in pregnancy

Christopher.Sorensen — Thu, 26 May 2022 18:29:23 +0000

Researcher focuses on essential, but often-ignored, organ in pregnancy

Christopher.Sorensen Thu, 05/26/2022 - 14:29

Cutline

(photo by JGI/Getty Images)

Topic

Pregnancy

The placenta is an essential organ for the developing fetus, both protecting the fetus from potentially harmful components in the blood and transferring nutrients needed for growth and development. But it remains largely a mystery.

“For a long time, the placenta was ignored because it was seen only as a temporary organ, and that’s been to our detriment,” says Eliza McColl, a PhD student in the lab of Professor Micheline Piquette-Miller in U of T’s Leslie Dan Faculty of Pharmacy. “As much as we can describe changes that occur in the placenta and hypothesize about the effects they might have, we can’t really understand what those changes could mean if we don’t have a detailed understanding of the placenta’s baseline function.”

This lack of knowledge about the placenta is one of the major gaps in studying the health of pregnant people. Piquette-Miller and her team are helping to fill this knowledge gap. They are studying how the placenta functions by examining transport proteins that regulate how nutrients, drugs and other molecules cross the placenta to the fetus. Much of her research has focused on whether infection and inflammation during pregnancy alter these transporters, which may ultimately change a fetus’s exposure to these substances.

For example, if a pregnant parent takes a drug considered safe in pregnancy but then experiences a viral infection or inflammatory condition such as preeclampsia, the expression of drug transporters in the placenta may change and alter the safety or efficacy of the drug. The research adds far more nuance to the discussion of what is safe and unsafe in pregnancy.

Piquette-Miller’s team has also contributed to a relatively new body of work suggesting that while the placenta itself is temporary, changes to it may lead to lifelong effects on offspring, including neurodevelopmental or metabolic disorders.

During McColl’s PhD research, she focused on transporters that allow amino acids essential for the fetus’s developing brain to cross the placenta – specifically whether infection or inflammation change the expression of these amino acid transporters and whether these changes are related to neurodevelopmental disorders in the offspring.

Using animal models, she found that amino acid transporters decreased after infection and that the offspring had altered levels of amino acids in the brain, and she identified that the cell signaling pathways that regulate these transporters are altered by infection. The results, which McColl is presenting at the American Society for Reproductive Immunology conference this week in Nashville, are the first step in understanding whether these changes could be targeted by therapeutics to reverse the nutrient deficits in the offspring.

“It's an interesting field of research that goes beyond describing the bare minimum of understanding the placenta, which is all that we’ve had for so long,” says McColl. “This is particularly important knowing that changes that occur in the placenta can actually impact the fetus after birth and throughout life.”

The COVID-19 pandemic has highlighted another key gap in pharmaceutical research: women and pregnant people have often been excluded from clinical trials and medical research. If conditions present differently between the sexes, diagnoses or differences in drug side effects or efficacy in understudied groups could be missed. And many drugs have not been tested for use during pregnancy at all.

“We can’t effectively treat or properly care for people if we don’t have the data about how they respond to medications or how they present with different conditions or diseases,” says McColl. “It’s definitely a risk to include pregnant people in clinical trials, but we also have to give people the tools they need to make decisions about their own health.”

In the case of the COVID-19 vaccine, pregnant people were excluded from many clinical trials, but they were allowed to decide for themselves whether to get the vaccine after it was approved. Many did choose to receive the vaccine, which provided the data to show that the vaccine is safe and effective in pregnancy – as reflected in current vaccine guidelines.

“I hope that the COVID-19 vaccine has been a turning point in showing the value of letting pregnant people exert agency and volunteering to receive drugs or vaccines in trials because that is currently a huge gap in the research,” says McColl.

Blood biomarker predicts complicated Crohn’s disease years before diagnosis: Study

Christopher.Sorensen — Wed, 25 May 2022 15:04:33 +0000

Blood biomarker predicts complicated Crohn’s disease years before diagnosis: Study

Christopher.Sorensen Wed, 05/25/2022 - 11:04

Cutline

Arthur Mortha, an assistant professor of immunology in the Temerty Faculty of Medicine, co-ordinated a study with international researchers that found an antibody in the gut to be a biomarker for severe Crohn’s disease (photo by University of Toronto)

Jim Oldfield

Topic

Global

An international team led by a University of Toronto researcher has found that an antibody in the blood predicts severe Crohn’s disease and is detectable up to seven years prior to disease diagnosis.

Crohn’s disease is a chronic inflammatory condition of the intestine for which simple and effective biomarkers prior to diagnosis are lacking. A blood test could provide a quick, cost-effective and non-invasive way to assess risk for complicated Crohn’s, which may enable preventive strategies before subclinical inflammation leads to chronic symptoms.

The research team’s findings were published this week in the journal Gastroenterology.

“Our team identified a serological biomarker for Crohn’s disease that also participates in its pathogenesis and occurs years before the disease shows its full clinical spectrum,” said Arthur Mortha, an assistant professor of immunology in U of T’s Temerty Faculty of Medicine who co-ordinated the study with Professors Jean-Frederic Colombel and Sacha Gnjatic at the Icahn School of Medicine at Mount Sinai in New York and an international team of researchers from France and Portugal.

“The current arsenal of therapeutics that causes relieving remission in Crohn’s patients is good but suffers limitations. A biomarker or predictive indicators to guide interventions are a clinical need,” added Mortha, who holds the Tier 2 Canadian Research Chair in Mucosal Immunology. “In addition, our characterization of this biomarker suggests it is a suitable therapeutic target for intervention and maybe even prevention.”

The biomarker for complicated Crohn’s disease is an antibody produced by antibody-secreting cells in the gut. These antibodies prevent communication among intestinal immune cells by binding and blocking the function of a protein called a cytokine. This cytokine – Granulocyte Macrophage-Colony Stimulating Factor – sustains immune balance in the intestine by promoting protective and anti-microbial immunity.

Mortha and his colleagues showed that in a large subset of Crohn’s patients, these antibodies neutralized the protective effects of the cytokine and disrupted intestinal homeostasis. The changes were detectable in the blood of patients years before diagnosis and led to a weakening of the immune system that, over time, resulted in damage to the lower part of the small intestine – a condition known as complicated ileal Crohn’s disease.

The researchers used blood samples from the U.S. Department of Defense Serum Repository to identify and characterize the biomarker. They studied samples collected annually over a decade from 220 military personnel who developed Crohn’s and compared them to patients with ulcerative colitis and hundreds of healthy controls.

The biomarker strongly predicted risk for complicated ileal Crohn’s, although not all patients with the antibody showed the exact same form and severity of the disease, which Mortha said highlights the multi-factorial nature of the condition. The biomarker was present in about a quarter of patients who developed Crohn’s.

Importantly, the team also found they could preserve the protective effects of the cytokine by manipulating its biochemical features. Engineered versions of the cytokine with improved biochemical features can be made practically invisible to the antibodies, Mortha said.

“Our system allows us to see how the antibodies in each patient specifically neutralize the cytokine. We are now engineering cytokines that can escape neutralization by these antibodies within individual patients.”

He added that the approach could enable highly personalized therapies that reverse the paralyzing effects of the antibodies and restore immune balance in the intestine.

Crohn’s disease affects about 0.3 per cent of the world’s population and its incidence is increasing. In Canada, which has one of the highest rates of Crohn’s, more than 135,000 people live with the condition, which can cause abdominal pain, diarrhea, weight loss and anemia, among other symptoms.

“Maintaining a strong gut immune system is essential to control the commensal microbes living in our intestine,” said Mortha, who completed doctoral studies in Germany and post-doctoral training in New York before setting up his lab at U of T in 2016.

“It’s mind-blowing that our mucosal immune system is capable of sustaining a defense against the enormous numbers of microbes in the gut, and that we’re not in complete agony,” Mortha said. “The past decade has taught us a lot about the modes of communication used by our gut immune cells to establish a healthy balance at this interface. It is now time to bring what we have learned to use.”

The research was supported by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Canada Research Chairs Program, Helmsley Charitable Trust, Portuguese Foundation for Science and Technology, Crohn's and Colitis Foundation of America and the U.S. Department of Defence, among others.

Gut bacteria linked to immune suppression in pancreatic cancer: Study

Christopher.Sorensen — Wed, 09 Feb 2022 17:20:25 +0000

Gut bacteria linked to immune suppression in pancreatic cancer: Study

Christopher.Sorensen Wed, 02/09/2022 - 12:20

Cutline

Tracy McGaha, a senior scientist at Princess Margaret Cancer Centre and a U of T professor of immunology, says that "in some conditions, the constituency of the microbiome may have a negative impact" on cancer outcomes (photo courtesy of Tracy McGaha)

Jim Oldfield

Topic

Princess Margaret Cancer Centre

Cancer

Research and Innovation

Researchers at the University Health Network (UHN) and University of Toronto have shown how probiotic bacteria in the gut could undermine immunity in pancreatic cancer, pointing toward more personalized cancer treatments.

Lactobacillus – a type of bacteria thought to promote gut health – can alter the function of immune cells called macrophages in the pancreatic tumour environment and spur cancer growth, the researchers found.

“Most studies focus on positive correlations between the microbiome and cancer outcomes,” said Tracy McGaha, a senior scientist at Princess Margaret Cancer Centre, UHN, and a professor of immunology in U of T’s Temerty Faculty of Medicine. “This work focused on negative correlations of the microbiome with cancer, and suggests that in some conditions, the constituency of the microbiome may have a negative impact.”

The research was published this week in the journal Immunity.

Macrophages are tissue-resident immune cells thought to play an important role in tumour growth and metastasis. The researchers showed that Lactobacillus affects macrophage function by metabolizing dietary tryptophan, an essential amino acid found in protein from plant- and animal-based foods.

Indoles, a class of metabolites resulting from microbial tryptophan metabolization, activate the aryl hydrocarbon receptor, or AHR – a protein that regulates gene expression, and which can enable both beneficial inflammation and immune suppression in other areas of the body.

Deletion or inhibition of AHR in macrophages led to reduced growth of pancreatic cancer, better sensitivity to treatments and increased numbers of inflammatory T cells, the researchers found. The activation of AHR thwarted these beneficial effects.

McGaha said he was surprised the microbiome had such a strong impact on AHR and immune function.

“We weren’t thinking about the microbiome at first, we were just interested in AHR as a factor in the tumour microenvironment,” McGaha said. “But when we blocked the mammalian genes that can activate AHR, it had no effect.”

The researchers then looked to Lactobacillus in part because previous studies had shown that the bacteria correlated with AHR activity and reduced inflammation – both of which can enable cancer growth.

They tested the effects of the bacteria in mice with surgical models of pancreatic cancer, working in U of T’s germ-free animal facility and in collaboration with Dana Philpott, who is also a professor of immunology in the Temerty Faculty of Medicine.

They also moved the project forward with single cell analysis – a technology that provides genome-scale data on individual cells, and which McGaha said was a big draw when he moved to Toronto from the U.S. in 2015.

“The technology was new then, but it’s been invaluable for us to see population responses in the gene expression patterns of macrophages and other immune cells, and what’s going on around them.”

The researchers later used tissue samples and data from human trials to show that high expression of AHR correlates with disease progression, immune suppression and patient survival.

Pancreatic cancer is notoriously difficult to treat. It is the third-most deadly cancer in Canada, despite being relatively rare, and patients with the disease have not seen the gains in survival common in other cancers over the last three decades.

To help address the urgent need for more effective treatments, McGaha is working with clinician scientists at UHN on a clinical trial called PASS-01. The study is a collaboration with other Canadian and U.S. cancer centres that aims to uncover personalized predictors of patient response to chemotherapy.

The team will collect stool samples before and after chemotherapy to look for enrichment of Lactobacillus, and whether the bacteria correlates to treatment response, patient survival and their observations on how it acts in the tumour environment.

“It’s exciting as a basic scientist to be involved in translational research, and it’s been nice to see the physician scientists interested in this work,” McGaha said.

Longer term, McGaha said his lab will pursue a deeper understanding of how immune cells interact with the microbiome. The hope is to improve on promising therapies such as fecal microbiota transplants, which have been hampered by the complexity and variety of gut bacteria – or to try a new approach.

“It could be possible to bypass the need to manipulate the microbiome, through precise targeting of the immune response to microbial metabolites,” said McGaha. “That’s a cool new direction we’d like to explore.”

The research was supported by the U.S. National Institutes of Health, the Terry Fox Research Institute, the Canada First Research Excellence Fund through U of T’s Medicine by Design, the John R. Evans Leaders Fund and the Canadian Institutes of Health Research.

U of T research may help explain children's immune response to COVID-19

Christopher.Sorensen — Tue, 05 Oct 2021 19:58:39 +0000

U of T research may help explain children's immune response to COVID-19

Christopher.Sorensen Tue, 10/05/2021 - 15:58

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(Photo by Steve Russell via Getty Images)

Jim Oldfield

Topic

Coronavirus

Ecology & Evolutionary Biology

Cell and Systems Biology

Biochemistry

Computer Science

Faculty of Arts & Science

Hospital for Sick Children

Molecular Genetics

Researchers at the University of Toronto have found that immune cells from the upper respiratory tracts of children, taken years before the pandemic began, react with the virus that causes COVID-19.

The findings hint at a possible reason why children with COVID-19 are often asymptomatic or have mild symptoms, while many adults experience severe disease and even death.

“We isolated B cells from tonsil tissues collected from children over five years ago, and found that some are reactive to the SARS-CoV-2 spike protein,” said Goetz Ehrhardt, principal investigator on the study and an associate professor of immunology at U of T’s Temerty Faculty of Medicine.

“We found that antibodies generated from these B cells have neutralizing potential against the virus in lab experiments, reducing the ability of the spike protein to bind to its target protein on the cell surface.”

The study, published in the Journal of Immunology, is one of just a few to examine the role of the mucosal immune system in COVID-19. Other studies have looked at immune components in the blood – often after infection has taken hold or during recovery.

Mucosal surfaces comprise one of the largest components of the immune system and include the gut, urogenital tract and respiratory system – all of which teem with microbiota including bacteria, viruses and fungi.

The researchers at first assumed the B cells reacted to SARS-CoV-2 because they had encountered similar coronaviruses in the past, perhaps through common colds and other infections.

But the antibodies did not react to those coronaviruses in further testing, although they did share genetic sequence characteristics linked to other triggers.

Taken together, Ehrhardt said, the results suggest cross-reactivity in the B-cell antibodies. “The immune system makes these antibodies toward certain agents or pathogens and as a by-product the antibodies react to SARS-CoV-2,” he said. “It will be interesting to find out what causes that reaction.”

A better understanding of the antibody reaction could shed light on the mystery of COVID-19 susceptibility in children and adults and inform clinical and public health decisions as well as therapeutic approaches.

Whatever the cause of the reaction, it is likely due to a common element in the childhood environment: all samples tested had the SARS-CoV-2-reactive B cells, many of which the researchers observed among the immune systems' ‘naïve’ or newly generated B cells that had not encountered any pathogen.

“One explanation is that some of these B cells react to triggers in the microbiome,” said Yanling Liu, lead author on the paper and a senior research associate in Ehrhardt’s lab.

“Or it could still be that antibodies are reacting to endemic coronaviruses and we just didn’t see that,” Liu said. “We don’t really know, but one implication of our work is that it suggests children should respond to vaccines very well since they have those naive B cells ready to recognize vaccine in their lymphoid tissue.”

Several other researchers were key to the study, Liu and Ehrhardt said, including James Rini, a professor of biochemistry and molecular genetics at U of T who provided purified spike proteins from viral samples.

Amin Zia used computational biology to scan large databases and predict which antibodies would react to the virus. Zia was a post-doctoral researcher in the lab of Alan Moses, a professor in U of T’s departments of cell and systems biology, ecology and evolutionary biology and computer science in the Faculty of Arts & Science.

“About half the antibodies we generated were based on computer-generated predictions,” said Ehrhardt. “That was first for us, and it won’t be a last.”

Researchers at the Hospital for Sick Children, with whom Ehrhardt’s lab has collaborated for years, supplied the tonsil tissue samples.

“Mucosae are no doubt a very important interface for the immune system’s response to a great variety of pathogens, but availability of samples has been a major impediment,” said Ehrhardt. “Research in this area is gathering steam, and it will be interesting to see where that takes us.”

The research was funded by the Canadian Institutes of Health Research.

U of T researchers to help form national Coronavirus Variants Rapid Response Network

Christopher.Sorensen — Mon, 29 Mar 2021 19:13:41 +0000

U of T researchers to help form national Coronavirus Variants Rapid Response Network

Christopher.Sorensen Mon, 03/29/2021 - 15:13

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Anne-Claude Gingras, a professor in the Temerty Faculty of Medicine and senior investigator at Sinai Health, is among several Canadian researchers participating in a national network to track and test COVID-19 variants (photo by Colin Dewar/Sinai Health)

Amanda Ferguson

Topic

Our Community

Coronavirus

Donnelly Centre for Cellular & Biomolecular Research

Canadian scientists at the forefront of the fight against COVID-19 – including several at the University of Toronto – have received funding from the federal government to track and test viral variants that are now spreading rapidly across the country.

The federal government said it will establish the Coronavirus Variants Rapid Response Network through a $9 million grant from the Canadian Institutes of Health Research, part of $14.3 million in new funding for research on COVID-19 variants.

More than 30 scientists are part of the effort, which is led by Marc-André Langlois at the University of Ottawa.

“Viral variants are emerging that have multiple combinations of mutations that may have different effects on the virus’s ability to infect cells or to hide from the immune system,” said Anne-Claude Gingras, a professor of molecular genetics at U of T’s Temerty Faculty of Medicine and a senior investigator in the Lunenfeld-Tanenbaum Research Institute (LTRI) at Sinai Health who is among eight co-principal applicants on the project.

“While many of the research groups involved, including ours, were already working on characterizing variants, this new funding will enable them to do so in a more efficient manner through collaborations across the country.”

Gingras is a cancer researcher who specializes in proteomics. She pivoted her lab in the early stages of the pandemic to develop blood tests that can look for antibodies to viral proteins. She said laboratories with specialized expertise will be able to join the network and contribute to variant characterization and rapidly share the results back with the rest of the team.

The scientists hope the network will allow them to rapidly act on the emergence of new variants of concern by quickly learning the virus’s features, including the potential for re-infection.

Jennifer Gommerman, a professor of immunology at the Temerty Faculty of Medicine and co-applicant on the grant, said the goal of the network is to communicate the new information in real time to Canadian public health officials and decision-makers, as well to the broader international scientific community.

“The data generated will directly alert us to the potential threats of re-infection, increased transmissibility and pathogenicity, and vaccine resistance,” Gommerman said. “This network was designed on one critical principle: to provide scientifically-based rapid-response to the variants of concern.”

Other Temerty Faculty of Medicine scientists involved in the project include James Rini, a professor in the departments of molecular genetics and biochemistry; Jason Moffat, a professor of molecular genetics and in the Donnelly Centre for Cellular and Biomolecular Research; and Andrew Morris, a professor in the department of medicine who is also medical director of the Sinai Health-University Health Network antimicrobial stewardship program.

Jeff Wrana is also part of the new network. He is professor of molecular genetics in the Temerty Faculty of Medicine and a senior investigator at LTRI who recently used his robotics lab to create an automated, next-generation sequencing platform that can accurately screen thousands for COVID-19.

Wrana and colleagues are now using that system, called SPAR-Seq, to screen all positive samples identified in the shared clinical diagnostics lab at Sinai Health and University Health Network. The goal is to identify known and novel variants that emerge in the population and are resistant to vaccination.

The grant will allow the network to operate for one year and to create a Biobank for rapid sharing of samples and data with other biobanks across Canada in order to have a harmonized approach to fight against COVID-19.

U of T researchers reach across fields to stop a silent, killer disease

Christopher.Sorensen — Wed, 17 Feb 2021 14:19:57 +0000

U of T researchers reach across fields to stop a silent, killer disease

Christopher.Sorensen Wed, 02/17/2021 - 09:19

Cutline

Omar Khan and Clinton Robbins are part of a multi-disciplinary Medicine by Design research team at U of T that's focused on preventing deadly abdominal aortic aneurysms (photo supplied and by John Hryniuk)

Paul Fraumeni

Topic

Institute of Biomedical Engineering

Faculty of Applied Science & Engineering

Laboratory Medicine and Pathobiology

Medicine by Design

Regenerative Medicine

Institute of Biomedical Engineering

Abdominal aortic aneurysms kill people by sneak attack.

In most cases, they develop without you knowing it. There are usually no symptoms. And if they burst, only 30 per cent of victims survive. Even if they are discovered before rupturing – because of medical imaging done to investigate another condition – it usually means emergency surgery.

But what if these aneurysms could be prevented using a branch of regenerative medicine that focuses on stopping disease processes before they do their damage?

That is a question University of Toronto researchers Clinton Robbins, Myron Cybulsky and Jason Fish are investigating. Robbins is an associate professor in the department of laboratory medicine and pathobiology (LMP) and the department of immunology in the Temerty Faculty of Medicine. He is also the Peter Munk Chair in Aortic Disease Research at the University Health Network (UHN). Cybulsky and Fish are senior scientists at the Toronto General Hospital Research Institute at UHN and faculty members in LMP. Cybulsky is Canada Research Chair in Arterial Wall Biology and Fish is Canada Research Chair in Cell and Molecular Biology.

The multi-disciplinary team is one of 11 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 support transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

An aneurysm is a swelling in an artery. An abdominal aortic aneurysm, or AAA, occurs in the aorta, the largest blood vessel in the human body. It runs from the heart down through the chest and abdomen, supplying blood to the body. When there is a weakening of the walls of the aorta in the abdomen, the aorta will balloon out. That’s the aneurysm. It’s not a problem until it bursts. If that happens, it can cause life-threatening internal bleeding or blood clots that can block the flow of blood.

“The reality is that we don’t know why these aneurysms develop,” Robbins says. “We have no understanding as to why the tissue in the aorta weakens and we know less about how we might go about repairing that.”

But Robbins and his lab have made an important step forward in learning that cells called monocytes and macrophages play an important role in the progression of AAA.

Monocytes are born in the bone marrow, a spongy tissue inside some of your bones. They are white blood cells and travel throughout the body, fighting infection. They eventually turn into macrophages, which perform the same function as monocytes.

While monocytes play that positive role in the immune response, they also have a negative side – they can gather at certain sites and cause an AAA, which is a type of inflammation.

No one is quite sure why this happens, but it is known that certain risk factors promote AAAs. Men over 65 are more likely to have an AAA, for example. And cigarette smoking seems to be a common cause. In fact, Robbins has found through experiments that exposing mice to cigarette smoke drives the formation of AAA.

Robbins has also begun to wonder if the endothelium – the cells that line the blood vessels – “speak” to the monocytes and macrophages. He has observed that when the AAA develops, there is a buildup of macrophages at that inflammation site. Could this cross-talk between these cell types influence the development of the AAA?

And Robbins has another idea – shift the focus away from why monocytes gather to create an AAA and instead focus on preventing their excessive generation or stopping their entry into the bloodstream from their birthplace in bone marrow.

Enter Omar Khan, whose expertise in nanotechnology is becoming an important part of the solution Robbins and his collaborators are exploring.

“My collaborators and I have been able to model this disease in mice,” Robbins says. “But to accomplish this notion of blocking monocyte production and release, we need someone with experience in nanotechnology. That’s why I was glad when Omar joined Medicine by Design and approached me.”

Khan is an assistant professor in the department of immunology in the Temerty Faculty of Medicine and U of T’s Institute of Biomedical Engineering in the Faculty of Applied Science & Engineering. He obtained his doctorate in chemical engineering and applied chemistry at U of T in 2010 (under the supervision of Medicine by Design executive director University Professor Michael Sefton) and then moved to the Massachusetts Institute of Technology (MIT) for post-doctoral work. His research was spun out into two start-up companies, one of which he founded.

Khan returned to U of T in early 2020, becoming one of 14 new faculty members Medicine by Design has helped recruit. He’s working with nanomaterials – small chemical materials that co-ordinate the delivery of nucleic acids, which are information-carrying molecules in cells that silence, regulate, express or help edit genes. Khan’s lab is applying nanotechnologies to the treatment of chronic inflammation, autoimmune diseases, cancer immunotherapy and the clearance of viruses in incurable infections. In one of his research areas, he controls chronic inflammation by simultaneously preventing excessive monocyte generation in the bone marrow and their exit into the blood. That focus on inflammation is the connection to Robbins’ work.

Since the scientists know that the monocytes exit from the blood vessels in the bone marrow and enter into general blood circulation, eventually reaching the sites of inflammation – the AAA – Khan proposes “closing the door” to stop the out-of-control influx of these monocytes.

“Our plan is to target the bone marrow blood vessels and close the path through which these monocytes would exit the bone marrow. By closing this door, we hope to reduce inflammation and the symptoms, and other pathologies that are caused by chronic inflammation like AAA.”

But it’s not about stopping the flow of monocytes permanently. After all, the monocytes do perform that essential role of fighting infection in the body. So Khan’s technology is programmed to be a temporary therapy.

“I call it ‘on-demand.’ Our angle is to use this smart nanotechnology to send in multiple instruction sets to the bone marrow blood vessels and close the doors so the monocytes won’t come out. Once we have controlled the monocytes creating the inflammation, the nanotechnology stops the therapy to allow the monocytes to exit through the normal process and do their work in maintaining health by fighting infection.”

Khan’s smart technology also performs another important function. While he believes it will stop the release of monocytes to create inflammation, his nanotechnology is also designed to target a gene called “colony stimulating factor 1” (CSF1).

CSF1 is essential in generating monocytes. While the smart nanotechnology will be able to stop the release of monocytes to the bloodstream, the monocytes will continue to build up in the bone marrow, thus creating an eventual surge of them once the therapy is stopped. “So we will be working on slowing down the function of CSF1 to create monocytes in the bone marrow. That’s why we call our nanotechnology a multigene control. It can co-ordinate many different actions.”

For Robbins, the partnership with Khan is the reason he values Medicine by Design’s focus on collaboration.

“My role as a basic researcher is to investigate what is happening in this area of cardiovascular disease. So, we conducted various experiments and have modelled the condition in mice. But with Omar, we can take the next steps and figure out not just what is happening, but why, and, even more importantly, what we can do about it. Through Medicine by Design, my days of just wanting to do the science are over. I have a real interest in what this all means and the more applied clinical side.”

And for Khan, the collaboration is equally beneficial.

“My specialty is nanotechnology. Clint, Myron and Jason are the ones who know about monocytes and biology. So coming back to Toronto and connecting with them because of Medicine by Design is enabling me to hit the ground running and keep moving. With their animal models, we can begin to prove that our technology can work to improve people’s health.”

From astrophysics to literature: 29 researchers at U of T awarded Canada Research Chairs

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

From astrophysics to literature: 29 researchers at U of T awarded Canada Research Chairs

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

Cutline

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

Alison Kenzie

Topic

Our Community

Donnelly Centre for Cellular & Biomolecular Research

Pediatrics

Cell and Systems Biology

Lunenfeld-Tanenbaum Research Institute

Astronomy & Astrophysics

Canada Research Chairs

Chemical Engineering

Dalla Lana School of Public Health

Electrical & Computer Engineering

English

Faculty of Applied Science & Engineering

Faculty of Arts & Science

St. Michael's Hospital

Sunnybrook Hospital

Ted Sargent

U of T Mississauga