Stem Cells

Researchers look to unleash the power of stem cells to repair brain injuries

Christopher.Sorensen — Tue, 31 May 2022 14:53:57 +0000

Researchers look to unleash the power of stem cells to repair brain injuries

Christopher.Sorensen Tue, 05/31/2022 - 10:53

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Andras Nagy was the principal investigator on a study by researchers at U of T and Sinai Health that identified a new way to control the fate of neural stem cells (photo courtesy of Sinai Health Foundation)

Amanda Ferguson

Topic

Our Community

Sinai Health

Temerty Faculty of Medicine

Research & Innovation

Stem Cells

Scientists at the University of Toronto and Sinai Health say they have identified a new way to control the fate of neural stem cells, bringing researchers one step closer to unlocking the mystery of how to repair the brain after injury or stroke.

The findings, published recently in the journal Nature Communications, outline a small set of molecules able to keep two major classes of neural stem cells from losing their ability to differentiate into critical components of a mammal’s cortex, a part of the brain that controls language and information processing.

“This discovery is an exciting extension of platform technologies developed by our lab in recent years, which make cell therapy safe and universal with off-the-shelf products to treat degenerative diseases,” said Andras Nagy, who is principal investigator on the study, a professor of obstetrics and gynaecology U of T’s Temerty Faculty of Medicine, and a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health.

GABAergic and glutamatergic neurons are two major neuronal subtypes in the mammalian forebrain, or cerebral cortex. Both classes develop from cells known as neuroepithelial progenitors and play an early and important role in brain development, but then quickly lose their ability to form other cortical cell types.

To overcome this limitation, scientists in the Nagy lab identified a set of small molecules capable of keeping the progenitor cells growing without losing their developmental potential.

Furthermore, when researchers withdrew that cocktail of molecules from the stem cells, the cells continued to differentiate into cells of the human forebrain in large numbers.

“The ability to obtain an unlimited number of forebrain-forming neural epithelium from stem cells is essential for disease modelling and toxicity testing needed in the development of new drugs,” said Nagy, who is also affiliated with U of T's Institute of Medical Science and holds the Canada Research Chair in Stem Cells and Regeneration. “These cells could be used in cell therapies, with the potential to treat strokes and other neurological diseases.”

Balazs Varga, first author on the paper who developed cell-based therapeutic approaches over the span of a decade for the project, said that understanding the forces orchestrating brain development will help identify underlying causes of diseases, leading to new treatments.

"Our work identified one way we can control the fate of neural stem cells,” said Varga, formerly a post-doctoral researcher in the Nagy lab who is now a research associate at Wellcome Trust Medical Research Council Cambridge Stem Cell Institute. “Better understanding the behaviour of the neuroepithelial cells will provide us with ideas about how we could control progenitor cell function and brain regeneration.”

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

Medicine by Design-funded researchers generate cells to treat bile duct disorders resulting from cystic fibrosis

Christopher.Sorensen — Mon, 22 Nov 2021 17:23:18 +0000

Medicine by Design-funded researchers generate cells to treat bile duct disorders resulting from cystic fibrosis

Christopher.Sorensen Mon, 11/22/2021 - 12:23

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An image of the bile duct cells, or cholangiocytes, derived from stem cells (Image courtesy of Mina Ogawa)

Julie Crljen

Topic

Breaking Research

Temerty Faculty of Medicine

Graduate Students

Hospital for Sick Children

Medicine by Design

Research & Innovation

Stem Cells

University Health Network

Researchers at the University of Toronto and its partner hospitals have discovered a way to generate functional cells from stem cells that could open new treatment avenues for people with cystic fibrosis who have liver disease.

Funded by Medicine by Design and completed with the collaborative efforts of multiple labs, the research was recently published in Nature Communications.

While cystic fibrosis is well known as a lung disease, the second most common cause of death in patients is actually liver disease. This is because people with cystic fibrosis can experience a decrease in the flow of bile fluid, which is secreted by the liver that helps with digestion and detoxification. The bile duct is a tube-like structure found in the liver that carries bile to the small intestine. The loss of flow leads to liver dysfunction. As a result, some patients require liver transplantation.

Shinichiro Ogawa

“Until now, we have not had a good scientific model to study the human liver’s bile duct system physiologically,” says senior study author Shinichiro Ogawa, an affiliate scientist at the McEwen Stem Cell Institute and Ajmera Transplant Centre, University Health Network (UHN), and an assistant professor in U of T’s department of laboratory medicine and pathobiology.

“In order to study a disease in a dish at the basic cellular and molecular level, we need functional cells. The fact that we can derive these functional cells from stem cells gives us a totally different way of evaluating and treating defective cells.”

The cells that the researchers generated have the properties of mature, functional cholangiocyte cells, which are the cells that make up the bile duct. Cholangiocytes play a role in several chronic and progressive liver diseases that have few medical treatment options. These diseases are responsible for about 20 per cent of adult liver transplants and most pediatric liver transplants.

Not much is known about the bile duct disorders that can lead to liver disease, but Ogawa says this research may lead to a deeper understanding of the specific mechanisms of the disease, as well as being a powerful tool for finding new treatments.

Ultimately, the researchers say it may be possible to develop therapies that involve transplanting the cells into a patient who has bile duct disease, bypassing the need for a transplant.

The work is funded through Medicine by Design’s large team projects. Ogawa and his co-investigator Christine Bear, a senior scientist in molecular medicine at The Hospital for Sick Children and a U of T professor of physiology, are part of a team focused on harnessing the liver’s power to regenerate.

Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative at U of T and its affiliated hospitals that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

Ogawa says it was the work of many different researchers and labs that brought the study together.

Beginning with pluripotent stem cells, which have the capacity to give rise to most of the cell types in the human body, Mina Ogawa, scientific associate at the McEwen Stem Cell Institute, was able to identify methods to efficiently guide the stem cells through the process of changing into cholangiocytes. Donghe Yang – a PhD candidate in the lab of Gordon Keller, who is director of UHN’s McEwen Stem Cell Institute – analyzed the stem cell-derived cholangiocytes at a single cell level to compare to human cholangiocytes in the liver.

The team used earlier Medicine by Design-funded research on the Human Liver Map to confirm that the cells they developed had the characteristics of mature cells, which are more functional and have more therapeutic applications as opposed to immature cells.

Researchers in Bear’s lab – Janet (Jia-Xin) Jiang, research project co-ordinator, and Sunny Xia, PhD student – were able to demonstrate that the cells were functional and responded to natural environmental cues like the force associated with fluid transport. Their work also showed that newly developed stem cell-derived cholangiocytes could, in the future, play a powerful role in developing organ-specific therapies.

“These studies highlight the importance of generating mature cells from stem cells that faithfully mimic the functional properties of the native tissue,” says Bear. “We can better understand the real effect of disease-causing mutations and cystic fibrosis therapies, especially in those hard-to-access organs”.

Bear adds that this work was made possible through an interdisciplinary effort. “This work is an excellent example of how collaboration among the research teams funded by Medicine by Design can help to target cutting-edge basic research in a way that will make a difference for patients.”

Ogawa says the power of stem cell technology is to be able to identify and correct the disease at a cellular level. One day, this research could lead to the development of personalized, customized treatments for other bile duct disorders. Ogawa adds that the McEwen Stem Cell Institute is a world leader in producing different cell types from these stem cells.

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj — Fri, 08 Oct 2021 10:57:51 +0000

Cloaking technology: Helping therapeutic cells evade your immune system

lanthierj Fri, 10/08/2021 - 06:57

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Andras Nagy (Photo provided by Sinai Health Foundation)

Paul Fraumeni

Topic

Breaking Research

Institute of Biomedical Engineering

Institutional Strategic Initiatives

Insulin 100

Temerty Faculty of Medicine

Toronto General Hospital

Diabetes

Medicine by Design

Mount Sinai Hospital

Research & Innovation

Stem Cells

University Health Network

Stem cell pioneer Andras Nagy has a way of describing the work of your immune system: “It’s surveillance inside our body.”

That surveillance does us good when harmful bacteria or viruses enter our body. The immune system releases fighter cells to kill the invaders.

But regenerative medicine therapies often involve transplanting tissues or cells into a person. When new heart or pancreatic cells are transplanted, for example, the immune system will see these good things as enemies and reject them. Drug treatment can be used to suppress this immune response, but it can leave the person open to serious infection.

Nagy, a professor in the department of obstetrics and gynaecology at the University of Toronto's Temerty Faculty of Medicine and a senior investigator at Sinai Health System’s Lunenfeld-Tanenbaum Research Institute, and his research team have been experimenting with a process called “cloaking,” which he believes could be used to hide therapeutic cells from the immune surveillance system and allow them to do their good work.

Though this research will one day be applicable to all cell therapies, Nagy’s team is currently testing the cloaking technology with insulin-secreting pancreatic cells that are made from stem cells and could be a powerful cell therapy for type 1 diabetes.

Stem cells are cells that can be reprogrammed and turned into an unlimited source of any type of human cell needed for treatment. Nagy notes that the first years of stem cell research were at the basic science level, as scientists worked to understand the nature of stem cells. He says about 10 years ago, there was a notable shift to what he calls “translational” research. His work is part of this wave of applied science; in fact, in 2015 he co-founded a biotech company, panCELLa Inc., to make his cell technologies widely available.

“Regenerative medicine is at a point now where we can translate our research into therapies that can help all humankind,” he says.

The Canada Research Chair in Stem Cells and Regeneration, Nagy says that researchers have long known that transplanted cells and tissues can be attacked by the immune system.

“We wondered if there was a way to hide or ‘cloak’ these good cells, so the immune response wouldn’t destroy them,” says Nagy. “But before we could move into that we had to deal with a significant hurdle – the safety of the implanted cells.”

Nagy points out that when these new cells are created, there is a chance they could mutate and become cancerous. The more cells needed for a therapy, the more cell divisions that take place, meaning a higher chance of mutation and cancer.

In earlier research, partially funded by a previous Medicine by Design team projects award, Nagy published a paper in Nature that described a “fail safe” cell technology that he and his team devised that can increase the safety of a cell graft and has a formula to quantify the risk of mutation so that people can make an informed decision on whether such a risk is acceptable to them.

The fail-safe system is a switch that eliminates potentially dangerous cells during cell therapy. The switch is introduced into stem cells, which are then turned into the therapeutic cells. The switch is turned on by a drug that can be added to the cell graft or applied directly into the body after transplant.

Nagy says the killer switch is fail safe because it is composed of two genes, one required for division and one that can trigger cell suicide, stitched together. If a mutated gene begins dividing, the drug is there to activate the kill switch and kill the cell. And if the cell loses the switch, it also loses the ability to multiply.

With the important first step of creating the fail safe switch done, Nagy turned to the cloaking, work that is supported by his team’s current Medicine by Design team projects award.

Nagy’s team is one of 12 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 an institutional strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

“Medicine by Design has been really important in supporting scientists in bringing the possibilities of regenerative medicine to patients. I’m grateful to Medicine by Design for funding the high-risk and high impact projects that many other funding agencies often say are just too ambitious.”

The cloaking technology involves turning off certain genetic switches in the cells created from stem cells to avoid detection by the immune system. This work was supported by findings from a devastating cancer found in Tasmanian devils, the marsupial native to the Australian state of Tasmania.

Between 1996 and 2015, 95 per cent of the Tasmanian devil population was wiped out as a result of contagious facial cancer cells transmitted when the devils bit each other. Nagy’s research found that the cancer had a way of cloaking itself from the devils’ immune system, which backed up his theory that cells could be hidden from the immune system.

Nagy identified eight genes that are central to immunity. He reasoned that just as the Tasmanian devils’ facial cancer could avoid detection by turning off the right genetic switches, his stem cell-derived cells could similarly become cloaked. Scientists in Nagy lab have been testing the cloaking in mice with encouraging results.

Sara Vasconcelos

Working with Nagy are Maria Cristina Nostro, senior scientist at the University Health Network’s (UHN) McEwen Stem Cell Institute and associate professor, department of physiology at U of T; and Sara Vasconcelos, scientist at the UHN’s Toronto General Hospital Research Institute and associate professor at U of T’s Institute of Biomedical Engineering.

The Nostro lab’s focus is to generate insulin-secreting pancreatic cells from stem cells. These cells could one day have the potential to treat patients with type 1 diabetes. Nostro works closely with Vasconcelos, whose lab focuses on helping to keep the transplanted cells alive once they enter the body. Cells need oxygen and other nutrients, which are delivered through the blood vessels.

Together, the team is testing ways to integrate Nagy’s technologies into Nostro’s functional pancreatic cells. Vasconcelos’s aim is for these therapies to survive in the body.

“When you just transplant the cells, they don’t have blood vessels, so they’ll die, independent of whether the immune system kills them or not. If they die, we’ll never know if it was the immune system or lack of oxygen,” Vasconcelos says. The Vasconcelos lab team repurposes small vessels, which exist in fat. They then use the vessels as units to increase blood flow and allow the cells to engraft and survive after they have been transplanted.

Nagy says the combination of the fail safe and cloaking technologies will make for a powerful therapy. “On the one hand, we can now introduce good cells into recipient’s body that can be hidden from the immune response and do the work they were intended to do. And that means doctors won’t have to use immunosuppression drugs. Finally, if one of the newly created cells is cancerous to the patient, our safe-cell technology can kill it or at least give us information on risk that we can communicate to the patient.”

When stem cell-derived therapies are created for individual patients, Nagy says, it is expensive, costing hundreds of thousands of dollars per patient. Nagy envisions turning his cells that combine fail safe and immune cloaking technologies into “off-the-shelf” products that can be used by anyone and are inexpensive.

Nagy has been building a notable research career in regenerative medicine since he came to Canada from Hungary in 1989, initially joining the lab of renowned researcher and University Professor Janet Rossant at the Samuel Lunenfeld Research Institute (now the Lunenfeld-Tannenbaum Research Institute) at Mount Sinai Hospital.

Medicine by Design to accelerate regenerative medicine discovery and translation with new $20-million investment

davidlee1 — Fri, 11 Oct 2019 15:52:34 +0000

Medicine by Design to accelerate regenerative medicine discovery and translation with new $20-million investment

davidlee1 Fri, 10/11/2019 - 11:52

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Freda Miller (left), a senior scientist at the Hospital for Sick Children, and University Professor Shana Kelley of the Leslie Dan Faculty of Pharmacy are leading two of the teams that Medicine by Design is funding

Ann Perry

Jovana Drinjakovic

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Faculty of Medicine

Gene Therapy

Institute of Biomaterials and Biomedical Engineering

Leslie Dan Faculty of Pharmacy

Medicine by Design

Meric Gertler

Regenerative Medicine

Research & Innovation

Stem Cells

Medicine by Design is strengthening the University of Toronto as a global leader in regenerative medicine with a new investment of as much as $20 million in research that will accelerate stem cell and gene therapy, advance understanding of how the body repairs itself and generate new technologies that will propel the field for decades.

The three-year awards will support as many as 12 multi-disciplinary research teams across U of T and its affiliated hospitals that are working at the convergence of engineering, medicine and life and physical sciences. These teams are leading the development of stem cell-based strategies to replace damaged heart and liver tissue and induce the body to self-repair damaged nerve and muscle, as well as tackling key challenges in the field such as the lack of control in producing specific tissue types from stem cells, with the goal of turning discoveries into new therapies, products and companies sooner.

“Medicine by Design has generated breakthroughs that are transforming regenerative medicine and sparking tremendous activity throughout Canada’s life sciences ecosystem,” said U of T President Meric Gertler. “This new investment will build on these advances, lay the foundation for translating these innovations into tangible benefits to patients and society, and advance Toronto’s position as the leading international centre of excellence in regenerative medicine for decades to come.”

Funded by a $114-million grant from the federal government’s Canada First Research Excellence Fund, Medicine by Design is a strategic research initiative at U of T that is catalyzing transformative discoveries in regenerative medicine and accelerating them toward the clinic. It builds on decades of made-in-Canada excellence in regenerative medicine dating back to the discovery of stem cells in the early 1960s by Toronto researchers Drs. James Till and Ernest McCulloch.

This is the second time Medicine by Design has awarded large-scale funding for collaborative team projects. Research supported by the first round of Team Project awards (2016-2019) has already driven significant advances, including the first “map” of the human liver, which attracted further funding this year from the Chan Zuckerberg Initiative. Another Medicine by Design-funded team has developed “safe cells” that are programmed to be killed if they become harmful, a key advance in improving the utility of cell therapies.

Over the past three years, Medicine by Design-funded researchers have also launched 15 startups.

The new awards will build on these discoveries and continue to spur innovations that will push the field forward, said Michael Sefton, executive director of Medicine by Design.

“By bringing together leading investigators across disciplines and institutions to confront the most challenging problems in the field, we have created new collaborations that have fundamentally changed how the regenerative medicine community in Toronto works together,” said Sefton, a University Professor at the Institute of Biomaterials & Biomedical Engineering (IBBME) and the Michael E. Charles Professor in the department of chemical engineering and applied chemistry.

“These new projects all have significant potential to achieve transformative and globally competitive outcomes and advance groundbreaking discoveries toward the clinic, transforming how we treat many devastating diseases.”

One team led by Shana Kelley, a University Professor at the Leslie Dan Faculty of Pharmacy, is developing a suite of advanced tools to enable researchers to gain new insights into how stem cells differentiate into any specialized cell type.

Freda Miller, a senior scientist at the Hospital for Sick Children (SickKids), heads a team that is developing a platform that will enable the rapid identification and testing of signals that activate stem cells in muscle and brain to repair damaged tissue, which could transform the treatment of muscular dystrophy and demyelinating disorders, such as multiple sclerosis.

Restoring heart function after heart failure is the focus of another team led by Michael Laflamme, a senior scientist at the McEwen Stem Cell Institute at University Health Network (UHN).

“We’ve come a long way from deriving stem cell-derived heart muscle cells in the Petri dish to optimizing them now for eventual use in patients,” said Laflamme. “This massive effort would not have been possible without Medicine by Design, which brought us all together toward a common goal of finding a cure for heart failure.”

Medicine by Design selected projects for funding after an extensive evaluation process, which included consultation with the research community, external peer review and scientific and strategic advice from Medicine by Design’s scientific advisory board.

Other funded research includes projects aimed at:

Using stem cells to regenerate damaged livers, led by Gordon Keller, director of the McEwen Stem Cell Institute at UHN, in collaboration with Ian McGilvray, a senior scientist at the Toronto General Hospital Research Institute (TGHRI) and a transplant surgeon at UHN, Sonya MacParland, a scientist at TGHRI specializing in liver immunology, Molly Shoichet, a University Professor in the department of chemical engineering and applied chemistry, Axel Guenther, an associate professor in the department of mechanical and industrial engineering, Gary Bader, a professor in the Donnelly Centre for Cellular and Biomolecular Research, and Christine Bear, a senior scientist at SickKids.

Reprogramming brain cells to treat amyotrophic lateral sclerosis and stroke, led by Cindi Morshead, a professor and chair of the division of anatomy in the department of surgery, in collaboration with: Isabelle Aubert and Carol Schuurmans, senior scientists at the Sunnybrook Research Institute, Maryam Faiz, an assistant professor in the department of surgery, and Melanie Woodin, a professor in the department of cell and systems biology and dean of U of T’s Faculty of Arts & Science.

Understanding how immune cells function in healthy and damaged blood vessels, led by Clint Robbins, a scientist at TGHRI, in collaboration with Myron Cybulsky and Jason Fish, both senior scientists at TGHRI.

Studying how material exchange – a process whereby cellular material from transplanted cells is transferred to host cells – could play a role in improving outcomes of cell-based retinal therapy aimed at preserving and restoring sight. This project is led by Molly Shoichet in collaboration with Derek van der Kooy, a professor at the department of molecular genetics and the Donnelly Centre, Valerie Wallace, a senior scientist at the Krembil Research Institute at UHN, and Julie Lefebvre, a scientist at SickKids.

Additional projects, including those focused on the effect of aging on cardiac disease, organoids, diabetes and organ repair, are under review, with final decisions expected by December.

'Discover everything there is': U of T's Tak Mak awarded prestigious Gold Leaf Prize for pioneering research

Christopher.Sorensen — Thu, 23 May 2019 15:42:29 +0000

'Discover everything there is': U of T's Tak Mak awarded prestigious Gold Leaf Prize for pioneering research

Christopher.Sorensen Thu, 05/23/2019 - 11:42

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The Canadian Institutes of Health Research has named U of T's Tak Mak the recipient of its prestigious Gold Leaf Prize for Discovery, which recognizes groundbreaking health research (photo courtesy of University Health Network)

Topic

Princess Margaret Hospital

Stem Cells

Tak Mak still recalls his surprise upon learning that Canada’s Medical Research Council had granted him more money than he requested. It was the early 1980s, and Mak was an assistant professor competing for funds with the other scientists pushing Canada into a global revolution in cell biology.

“I applied for $50,000 and they gave me $67,000,” says Mak, a University Professor of medical biophysics and immunology at the University of Toronto and a senior scientist at the Princess Margaret Cancer Centre who is renowned for a career that has spanned biochemistry, virology, genetics, cancer metabolism and clinical therapy.

“Over the years Canada’s granting agencies have really supported my work in a very paramount way.”

That relationship has now come full circle after the Canadian Institutes of Health Research named Mak the recipient of its prestigious Gold Leaf Prize for Discovery, which recognizes groundbreaking health research and comes with $100,000.

The award will support new research, but for Mak it’s also a recognition that CIHR’s investments in his work was money well spent. “We did all we could to achieve the scientific excellence and innovation CIHR wanted, and to some extent we have fulfilled that intention,” says Mak. “That is gratifying, because when a person or agency is really generous, you don’t want to disappoint them.”

Mak has indeed given Canadians many reasons to be proud.

Mak’s lab co-discovered the T-cell receptor in 1984 – a finding that fundamentally changed how scientists understood the immune system and led to major advances in T-cell biology, autoimmune disease and immunotherapy. His lab was also one of the first to generate knockout mice – genetically modified mice – that enabled scientists worldwide to study the effects of individual genes. And Mak co-founded Agios Pharmaceuticals, whose leukemia drug IDHIFA became the first clinically approved therapy to target cancer metabolism in 2017.

Earlier this year, Mak’s group used genetics to show that the nervous system and immune system communicate through a molecule called acetylcholine. The discovery confirmed a long-suspected, but poorly understood, link between the two systems, and again opened several new avenues of research.

Mak attributes these and other achievements in part to the co-operation of the Canadian scientific community.

“One thing that makes Canada great is congenial and collaborative scientists across the land,” he says. “And looking back at the metamorphosis of our lab from field to field to field, it was in many cases through work with Canadian scientists.”

To take two examples: the development of genetically altered mice, Mak says, would not have happened without close collaboration from stem cell biologist and U of T University Professor Janet Rossant. And when his lab shifted focus from immunology to cancer, Mak says the approach and vision of the late Anthony Pawson, a professor of molecular genetics, was invaluable.

Mak has also benefitted from many talented trainees who have passed through his lab. That group now numbers over 130, and includes a university president, medical school deans and dozens of institute directors and departmental chairs. Mak often visits these former colleagues – most recently on a trip to the Technical University of Munich this week, where he received an honorary professorship – and he says that seeing this extended “family” succeed brings great gratification.

“There’s no substitute for that. I am reminded of the Indian proverb, ‘All the flowers of all the tomorrows are in the seeds of today.’”

Mak offers special praise for the mentorship he received as a young researcher, including his time in the lab of Nobel laureate Howard Temin, and his early years in Toronto working with Ernest McCulloch and James Till, who discovered stem cells.

“McCulloch taught me to think differently, to have original ideas and integrate my thoughts,” Mak says. “Till was a staunch, vigorous physicist, who insisted that all results be statistically significant and re-confirmed. The two together made an almost perfect mentorship for me.”

Today, that oblique but rigorous approach to science still informs Mak’s thinking, which increasingly centres on inflammation, another frontier in medical science. Inflammation is essential to the immune system’s ability to fight germs, but it can create problems that result in autoimmune diseases. Researchers are recognizing the role of inflammation in neuro-degeneration, cardiac disease and many other conditions, and in our ability to fight cancer.

“We need to understand that important yin and yang,” says Mak. “When the thermostat of inflammation needs to be up, and when certain aspects need to come down – this is where we need to focus.”

Mak is still very engaged with these and other scientific questions. The “party,” he notes, is still going strong.

“I have tremendous gratitude for the support I’ve received from the Canadian scientific community and from CIHR,” he says.

“When you’re a kid you get to play with toys and figure things out, and you’re not supposed to do that as an adult. But science is like toys for adults, and we get to discover everything there is.”

Banting painting of lab where insulin was discovered sells for 10 times more than expected

noreen.rasbach — Thu, 22 Nov 2018 20:21:35 +0000

Banting painting of lab where insulin was discovered sells for 10 times more than expected

noreen.rasbach Thu, 11/22/2018 - 15:21

Cutline

U of T had hoped to purchase the painting sold at auction Wednesday night, but a determined buyer paid $313,250 for the artwork (photo by Geoffrey Vendeville)

Topic

Research & Innovation

Sir Frederick Banting

Stem Cells

Subheadline

Heffel Fine Art Auction House pledges its $53,250 commission to diabetes research at U of T

Sir Frederick Banting’s only known painting of the lab where he discovered insulin was sold at auction Wednesday for ten times its expected value. And fittingly, a portion of the sale price will go toward funding advances in diabetes research at the University of Toronto – just down the street from where the world-changing discovery was made almost a century ago.

Banting created the painting, called simply The Lab, in 1925. Although an accomplished painter of landscapes, he rarely chose his scientific work as a subject.

Twenty bidders competed for the historic work, including U of T, but a determined mystery buyer outbid the university in the end, paying $313,250 for the artwork over the telephone. To honour the painting’s subject and Banting’s legacy, Heffel Fine Art Auction House has pledged its commission of $53,250 to diabetes research at U of T.

“It is a privilege to be able to make this donation to the Banting & Best Diabetes Centre,” said Heffel’s Rebecca Rykiss. “At our auction previews across the country, we heard from countless enthusiasts, collectors and many affected by the disease just how meaningful this painting is. It’s not often that we have such a historically important work consigned to us and we are thrilled to honour the Nobel Prize winning scientist and his significant artistic career in this way.”

The Lab (1925) by Frederick Banting is his only known painting of the lab where he discovered insulin (image courtesy of Heffel Fine Art Auction House)

Several philanthropists had pledged to help U of T buy the painting so that it could be part of the upcoming centennial anniversary of the discovery of insulin. But the eventual winner appeared very determined to acquire the painting, said Professor Scott Mabury, U of T’s vice-president, university operations and vice-provost, academic operations.

“We were quite disappointed,” he said. “We tried. We gave it a great effort. Still, I hope in the fullness of time this painting will find its way into the 2021 celebrations of the discovery of insulin at U of T.”

The donation will further Banting’s legacy at U of T, where diabetes researchers like Maria Cristina Nostro are using techniques nobody could have envisioned in the early 20^th century to create a goal that seems futuristic even today.

Toronto is home to robust research communities in both diabetes and stem cell research. Nostro straddles both fields in her quest to regenerate the pancreas, or at least its function. She is part of a worldwide cohort of scientists engineering stem cells to cure type 1 diabetes.

A native of Italy, Nostro was completing a post-doctoral fellowship in New York, studying stem-cell biology, when her supervisor, Professor Gordon Keller, was recruited to Toronto to lead the McEwen Centre for Regenerative Medicine. She soon found herself in the city where both insulin and stem cells were discovered.

“Toronto is a great place to do research on diabetes and stem cells,” says Nostro (pictured left). “With the huge legacy from insulin, we have the Banting & Best Diabetes Centre that’s connecting all the scientists doing diabetes research in the city. And there’s so much going on with stem cell research. It’s a perfect match.”

People with type 1 diabetes lack pancreatic beta cells, which play the crucial role of detecting sugar in the blood and signalling for the release of insulin. In the early 2000s, diabetes researchers first began experimenting with embryonic stem cells, which can potentially be turned into the cells associated with any organ. So far, scientists have used stem cells to create “immature” beta cells, which aren’t fully functional – but become more functional when placed in an animal’s body. As a result of this success, the first human trials with stem-cell derived pancreatic cells are now being conducted.

With human trials, there will be a need for more, and better functioning, pancreatic cells. Nostro and her team have made a major contribution to the process of creating them.

“We were among the first labs to understand how to efficiently create pancreatic cells,” she says. “And we’re collaborating with other Toronto scientists to find the best way to transplant the cells, making sure they’re not destroyed by the immune system and that they’re properly nourished right away by the body so they survive.”

Nostro is optimistic about improving treatment for type 1 diabetes in her lifetime.

“We need to be better than insulin,” she says. “We need something very safe and long-lasting. The beauty of regenerative medicine in diabetes is that we don’t have to recreate the entire pancreas. In type 1 diabetes, the pancreas works fine. We need to replenish the beta cells. If we can do that, we can cure diabetes.”

How the Tasmanian devil inspired Medicine by Design-funded researchers to devise a method to create ‘safe cell’ therapies

noreen.rasbach — Wed, 14 Nov 2018 17:34:42 +0000

How the Tasmanian devil inspired Medicine by Design-funded researchers to devise a method to create ‘safe cell’ therapies

noreen.rasbach Wed, 11/14/2018 - 12:34

Cutline

The Medicine by Design project found inspiration from an unlikely source – the Tasmanian devil population in southern Australia (photo by Arterra/UIG via Getty Images)

Lisa Willemse

Topic

Our Community

Faculty of Medicine

Institute of Medical Science

Medicine by Design

Research & Innovation

Stem Cells

A contagious facial cancer that has ravaged Tasmanian devils in southern Australia isn't the first place one would look to find the key to advancing cell therapies in humans.

But that’s exactly what first inspired a Medicine by Design-funded research team to improve the safety of stem cell-derived treatments by programming the cells to die if they mutate in ways that harm patients. The development of “safe cells,” an advance outlined in a paper published today in Nature, could be a critical step toward the widespread use of cell therapies, which hold the potential to treat and even cure diseases such as heart failure, eye diseases, diabetes and stroke.

“Moving a cell therapy from the lab to the clinic requires answering two important questions: Does it work? And is it safe?” says Andras Nagy, a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health System and a professor in the department of obstetrics and gynecology and the Institute of Medical Science at the University of Toronto. “We believe our ‘safe cells’ help answer the second question and will have a significant impact on the use of stem cells to treat a broad range of diseases.”

Safety in cell therapy involves preventing or mitigating the risk that the cells will develop tumours or unwanted tissues, or trigger an immune response that may jeopardize the health of the patient. It’s a tricky thing to predict, given that cells are living entities.

The development in 2007 of induced pluripotent stem (iPS) cells – adult cells that have been engineered back to a pluripotent stem cell state and have the potential to become any cell type in the body – promised to revolutionize the field by creating an endless supply of stem cells without the ethical baggage of their embryonic counterparts. However, along with embryonic stem cells, iPS cells share a proclivity toward uncontrolled and potentially cancerous growth. This, plus the risk of genetic mutations and current cost of iPS cell production, have hampered their progress to clinical application.

Nagy first became interested in the plight of the Tasmanian devils in previous research that looked at developing “cloaked” cells to enable off-the-shelf cell therapies that would be more cost-effective and timely than personalized treatments using a patient’s own cells. The transmissible cancer, which spread when the highly territorial marsupials bit each other, wiped out 95 per cent of their population between 1996 and 2015. As scientists and conservationists raced to prevent the total demise of the animals, Nagy wondered if the devils might hold the key to overcoming a key hurdle in developing off-the-shelf cell therapies: to prevent the patient’s immune system from attacking the therapeutic cells, immunosuppressive drugs are administered, raising the risk of other, potentially serious, health complications.

“What I found interesting about the Tasmanian devil’s cancer is that the tumour cells were not being recognized by the immune system of the bitten animal, so they were not rejected, and the tumour was able to grow,” explained Nagy. “The transmission between animals was essentially a cell graft and it told us that it was possible to introduce cells that would not be recognized by the host immune system.”

He set out to discover how the cancer cells could evade the immune system. It was no easy task. The immune system is very complex, involving many cell types that are adept at rooting out invaders, which is why instances of transmissible cancer are virtually non-existent. In the case of the Tasmanian devil, the common theory is that the animals are too similar, genetically speaking, and the cancer was able to use that to avoid detection. So how could this apply to more genetically diverse humans? The key was finding the right genes: Nagy and his team identified eight of them that are central to immunity.

From there, he reasoned that just as the devils’ face cancer could avoid detection by turning off the right genetic switches, his iPS cells could similarly become cloaked. Testing in mice showed that the cloaked cells worked. But it led to another problem.

“Cloaked cells could be enormously dangerous because they could develop into cancer cells which are also cloaked. The immune system has an important function to eliminate hotbeds of cells in our body that look weird and could be tumorigenic,” said Nagy (pictured left). “So, we are creating a highly tumour-prone cell type and this is a problem. We have to solve the problem of safety.”

The idea of safe cells – the subject of this week’s Nature paper – emerged from this need to ensure safety, or at the very least the ability to quantify risk. It’s perhaps the biggest barrier in getting iPS cell therapies into patients: Until now, no one could predict the exact likelihood that a batch of cells might be aberrant. In this paper, Nagy and his team have devised a method to increase the safety of a cell graft and a formula to quantify the risk of mutation “unsafeness” so that people can make an informed decision on whether such a risk is acceptable.

At its core, the safe cell calculation revolves around mutation. DNA replication is error-prone and mutation is unavoidable. In cell therapy, mutation is precisely what you don’t want, because it can negatively alter the intended result, say by producing a tumour rather than a remedy for cystic fibrosis, or diabetes, or any other target disease. And the more cells needed for the therapy, the more cell divisions take place, meaning a higher chance mutation will occur.

Knowing this, Nagy’s team found a way to predict the odds of obtaining potentially dangerous therapeutic cells and ameliorate these odds through gene-editing. The edited cells have a suicide gene spliced into the DNA, directly connected to a gene necessary for cell division and survival. In addition, if a harmful mutation is detected, the application of a small drug can prevent those cells from dividing and causing harm. They’re also cloaked, removing the need for immunosuppression.

“We have an absolute external control on a safe cell,” said Nagy. “There is the possibility that mutations could kill the suicide gene but leave the cell-division gene unharmed. But we can calculate the probability of this mutation happening, and this is how the safe cell level is generated.”

Read the research in Nature

The safe cell level measurement itself is based on the probability of getting a batch containing mutated cells. In this case the higher the number, the greater the safety. A safe cell level of 100 means the odds of getting a mutated batch of cells are one in 100; a safe cell level of 1,000,000 represents odds of one in 1,000,000.

“What’s important here,” Nagy qualified, “is that the patient can decide what level is acceptable. So, if someone has a life-threatening illness and their chance of survival is only 10 per cent, a lower safe cell level might be acceptable, versus a patient who has a non-life-threatening illness.”

“And if that risk is low, then it becomes like many other activities we do, such as riding a bike, getting in a car, taking a flight. Everything we do in life, when we step out of the house, is a risk-benefit decision. That’s what this is. What is needed in cell therapy is good knowledge of the risk we are taking which is enough to allow us to make informed decisions.”

Nagy is optimistic, based on feedback thus far, that they are moving in the right direction. His next steps are to conduct more tests in animal models and he has initiated talks with Health Canada to move to human clinical trials. He has also created a new company, panCELLa, to help with these efforts. If the safe cell method can be implemented into all iPS cell manufacturing, it could well become a standard for cell therapy safety that will provide a measure of confidence and predictability and allow a rapid progression of gene-edited iPS cells into clinical trials and clinical approval.

This research is one of 19 team projects funded by Medicine by Design, a regenerative medicine research initiative at U of T that aims to accelerate discoveries and translate them into new treatments for common diseases. It is made possible thanks in part to a $114-million grant from the Canada First Research Excellence Fund, the single-largest research award in U of T’s history. The project was also funded by the Canadian Institutes of Health Research and The Foundation Fighting Blindness.

U of T researcher James Till receives international honour

noreen.rasbach — Fri, 19 Oct 2018 20:24:53 +0000

U of T researcher James Till receives international honour

noreen.rasbach Fri, 10/19/2018 - 16:24

Cutline

James Till will officially be honoured with the inaugural Edogawa-Niche Prize on Sunday. He received a medal and plaque in Toronto last month, and the award presentation will be videocast in Tokyo this weekend

Topic

Regenerative Medicine

Research & Innovation

Stem Cells

James Till, professor emeritus in the department of medical biophysics, is the inaugural recipient of the Edogawa-Niche Prize.

The international award recognizes a physician or scientist based on their contributions to interdisciplinary research leading to health-care solutions in disease prevention, diagnosis or treatment.

Till will be officially honoured in Tokyo, Japan this weekend at the 2018 Nichi-In Centre for Regenerative Medicine (NCRM) NICHE International Stem Cells and Regenerative Medicine meeting.

Till and his collaborator, Professor Emeritus Ernest McCulloch, were first to find evidence of clone cells, which at the time they referred to as ‘lumps,’ in the spleens of mice. They published their findings in Radiation Research in 1961. In 1963, the pair followed up with publications in Nature and the Journal of Cellular and Comparative Physiology, which established that the lumps were in fact multilineage stem cells capable of self-renewal and becoming specialized cells.

Born in Lloydminster, Sask., Till received a bachelor's degree at the University of Saskatchewan, where he also completed a master's degree in physics in 1954. After finishing his PhD in biophysics at Yale University in 1957, Till was recruited to the Ontario Cancer Institute at Princess Margaret Hospital as a U of T postdoctoral researcher, where he began working with McCulloch.

“Arthur Ham, who was head of the biological division at the Ontario Cancer Institute where Ernest and I were research recruits, encouraged us to get to know each other. Ernest made a great presentation to the group, which prompted me to volunteer to help him when he wanted to use our irradiation facility. That’s how the inspiration for our work began,” recalled Till, who would collaborate with McCulloch for more than 20 years.

Till and McCulloch’s work has had applications in the field of bone marrow transplantation, cancer treatment and the treatment of autoimmune disease and tolerance induction. He also helped blaze a trail for other groundbreaking scientists.

“Perhaps the greatest testimony to Dr. Till has been the training of other exceptional scientists. Including Professors Norman Iscove, Robert Phillips and Ron Worton to name a few,” said Gary Levy, a professor in the departments of medicine, immunology, laboratory medicine and pathobiology. “As well, Toronto continues to be a great world stem cell centre.”

Levy, who is also the founding director of University of Toronto Transplant Institute and the CIHR Training Program in Regenerative Medicine, presented Till with a medal and plaque in Toronto last month. The award presentation will be videocast at the NCRM NICHE event on Sunday.

Upon receiving the award, Till dedicated the honour to his collaborator, McCulloch, who passed away in 2011.

“Ernest’s contributions to our team made our work possible. Without him, it wouldn’t have happened,” said Till.

The prize is awarded by the NCRM, which is devoted to research, training and clinical applications-protocol development in regenerative medicine with a special emphasis on stem, progenitor and autologous adult cells with regenerative capability. The institute provides a platform for collaboration between scientists across various specialties.

NCRM is an Indo-Japanese joint venture institute affiliated with Tamilnadu Dr. MGR Medical University and Acharya Nagarjuna University. In 2009, the institute entered a formal agreement for training students with the CIHR Training Program in Regenerative Medicine at U of T.

Till’s plaque and medal will be displayed at the Edogawa-Niche Hall of Fame, which is set to open in Tokyo next year.

Till was also awarded one million Japanese yen (approximately $11,800), which he donated back to NCRM NICHE to establish the Joyce and James Till Travel Grant, which will support travel and other associated necessities for young scholars from developing countries to take part in future NCRM NICHE events.

Till’s Edogawa-Niche prize is the most recent in a string of honours and appointments including:

Gairdner Foundation International Award, 1969
Officer, Order of Canada in 1994
Order of Ontario in 2006
Royal Society of London in 2000
Canadian Medical Hall of Fame in 2004
Albert Lasker Award for Basic Medical Research in 2005

Dr. Hans Messner was a pioneer in stem cell transplantation

noreen.rasbach — Wed, 25 Jul 2018 16:33:57 +0000

Dr. Hans Messner was a pioneer in stem cell transplantation noreen.rasbach Wed, 07/25/2018 - 12:33

Cutline

(photo courtesy of University Health Network)

Topic

Professor Hans Messner, a physician who pioneered stem cell transplantation at Princess Margaret Cancer Centre and helped thousands of patients during his nearly 50-year career, died at the centre on Tuesday.

A professor of medical biophysics, Messner completed his PhD at the University of Toronto under the mentorship of Professor Ernest McCulloch. His early research focused on studying the "mother" cells that give rise to all other blood cells. Messner was part of McCulloch’s team that began to explore the potential benefits of bone marrow transplants for the treatment of patients with leukemia.

In 1976, Messner completed his first bone marrow transplant in which he transplanted stem cells collected from a matching donor to the patient to suppress the disease – in this case leukemia – and restore the patient's immune system. The procedure is formally known as an allogeneic transplant.

He went on to become a leader in the field of bone marrow transplantation. He developed and served as the first director of a clinical transplant program at the University Health Network’s Princess Margaret Cancer Centre (which was then called the Princess Margaret Hospital or PMH) and held the position of director of the Bone Marrow Transplant Centre until 2006. He was also a senior scientist at the Ontario Cancer Institute.

He was the founding president of the Canadian Bone Marrow Transplant Group and was a member of an expert working group that developed the Canadian Standard for Transplantation of Cells, Tissues and Organs. He also served as director of PMH’s Philip S. Orsino Cell Therapy Facility, where he developed the regulatory systems, supervised the facility construction and directed early clinical phases.

In 2007, Messner received the Canadian Blood Services Lifetime Achievement Award for being a pioneer of allogeneic bone marrow and stem cell transplantation in Canada.

Last year, he was presented with the American Society for Blood and Marrow Transplantation Lifetime Achievement Award, which recognizes people who have made continuous clinical and scientific contributions to the field.

In June, Messner reflected on his almost 50 years at the Princess Margaret as he inspired thousands of cyclists with a heartfelt message at the start of the annual Ride to Conquer Cancer, a fundraising event in which he was a rider for 10 years on his beloved "Heme Team."

Earlier this month, the stem cell transplantation program was renamed the Messner Allogeneic Transplant Program to honour his legacy.

Although Messner said he was retiring after 44 years, he never really did. In his final weeks, despite increasing frailty, he continued to come to work to consult with and advise his colleagues.

When one teased him saying, "I guess you're never going to retire," his reply was: "Might as well keep going!"

Funeral arrangements are still being finalized.

Researchers at U of T's Medicine by Design scale up stem cell production

ullahnor — Thu, 07 Jun 2018 20:41:13 +0000

Researchers at U of T's Medicine by Design scale up stem cell production

ullahnor Thu, 06/07/2018 - 16:41

Cutline

Medicine by Design researchers scaled up the production of human stem cells by growing them in large volumes of liquid, in suspension bioreactors (photo by James Poremba)

Topic

Regenerative Medicine

Stem Cells

Yonatan Lipsitz became a biomedical engineer because he wanted to “see patients cured by new stem cell therapies.”

“That’s a real motivating factor for me,” says Lipsitz, a recent University of Toronto graduate whose PhD focused on growing stem cells in the lab on a much larger scale.

Published this week in the journal Proceedings of the National Academy of Sciences, Lipsitz’s findings are part of a wave of efforts funded by U of T’s Medicine by Design initiative to accelerate regenerative medicine discoveries and translate them into new treatments.

Thanks to their ability to self-renew and turn into any cell type in the body – a characteristic known as pluripotency – stem cells hold promise as a potentially unlimited source of cells from which replacement tissue can be grown to treat disease and injury.

For more than half a century, transplants of bone marrow tissue, rich in stem cells that create blood, have been saving the lives of patients with leukemia and other blood disorders. In recent years, a new generation of experimental therapies using lab-grown pluripotent stem cells have shown promise in treating a wide range of diseases, including blindness, Parkinson’s disease and diabetes.

But growing small quantities of cells in plastic dishes as is typically done in labs around the world is one thing. Scaling this process up in a cost-effective manner to obtain the billions of cells needed to treat each patient is far more challenging.

“When you try to scale up from growing cells in plastic dishes to growing them on an industrial scale, you run into problems,” says Lipsitz, who completed his PhD in 2017 at U of T’s Institute of Biomaterials & Biomedical Engineering in the lab of University Professor Peter Zandstra, located in the Donnelly Centre for Cellular and Biomolecular Research.

Lipsitz has been working to expand human stem cells by growing them in large volumes of liquid in so-called suspension bioreactors, as opposed to attached on the surface of the laboratory dish. In the bioreactors, cell growth can be scaled up for industrialized manufacturing. But “as soon as the cells are placed into suspension they have reduced survival and proliferation,” Lipsitz says.

Studying mouse stem cells, which can be readily expanded in suspension unlike the human cells, offered clues for bolstering cell growth. Cells from the two species have very different growth rates, as well as other manufacturing properties.

“We set out to find a cocktail of molecules and growth factors that could convert human stem cells into an alternative, high-growth state,” says Lipsitz. The trick was to boost the suspension survival and growth of stem cells without affecting their pluripotency.

After testing many different molecular formulations, the researchers identified a new combination of factors that allowed them to obtain yields of human stem cells in suspension more than five-fold greater than previously possible.

“This paper represents a step forward in our ultimate goal to enable robust suspension growth of pluripotent stem cells for cellular therapeutic production,” says Zandstra, who was Medicine by Design’s inaugural executive director and is now director of the Michael Smith Laboratories and the School of Biomedical Engineering at the University of British Columbia, where he also has a research lab. Zandstra is also chief scientific officer of the U of T-affiliated Centre for Commercialization of Regenerative Medicine (CCRM), which is helping the team commercialize its technology.

Lipsitz, who now works as a scientist at a Boston biotechnology startup developing cell therapies, credits the “unique environment” in Zandstra’s lab for his research accomplishments.

“Peter’s lab combines fundamental understanding of stem cell biology with advanced technical engineering approaches, making it one of the most cutting-edge research environments in the stem cell field,” Lipsitz says, adding that his new job in Boston directly builds on the cell manufacturing skills he developed as a graduate student.

“I’m excited about bringing cell therapies to patients by solving manufacturing challenges for these complex therapies.”

Medicine by Design, made possible thanks to a $114-million grant from the federal government’s Canada First Research Excellence Fund, brings together more than 110 scientists, engineers and clinicians from across U of T and its affiliated hospitals to conceive, create and test strategies to address critical problems in regenerative medicine. Researchers from various disciplines generate and use emerging methods such as genome editing, computational modelling and synthetic biology to deepen understanding of core biological concepts and devise new therapeutic approaches.