Julie Crljen

Medicine by Design, CCRM launch alliance to bolster Canada’s leading position in regenerative medicine

Christopher.Sorensen — Mon, 11 Dec 2023 16:35:12 +0000

Medicine by Design, CCRM launch alliance to bolster Canada’s leading position in regenerative medicine

Christopher.Sorensen Mon, 12/11/2023 - 11:35

Cutline

The alliance between Medicine by Design and CCRM aims to create end-to-end capacity from discovery to clinical translation and commercialization (photo by sommersby/Getty Images)

Julie Crljen

Topic

Our Community

Institutional Strategic Initiatives

CCRM

Medicine by Design

Subheadline

The partnership will help build a strong pipeline of regenerative medicine technologies and therapies

The University of Toronto’s Medicine by Design initiative and CCRM, a non-profit that supports the development and commercialization of regenerative medicines, are launching a new strategic alliance that aims to unlock Toronto’s potential as a world-leading ecosystem for regenerative medicine.

The partnership, which was announced at Medicine by Design’s 8th Annual Symposium on Dec. 6, will see the organizations build on their existing strengths in bridging high-risk, high-reward research to industry expertise, biomanufacturing infrastructure and the clinic.

The goal of the alliance, whose key members also include the University Health Network (UHN) and U of T, is to create co-ordinated, end-to-end capacity that spans discovery through to clinical translation and commercialization.

“Medicine by Design has its deep academic network and track record of supporting world-class research across the Toronto Academic Health Science Network (TAHSN). CCRM has 12 years of success in launching and scaling cell and gene therapy companies at the interface of academia and industry,” said Allison Brown, executive director of Medicine by Design.

“With this alliance, CCRM is making an investment to sustain Medicine by Design’s discovery programs well into the future. It will enable us to build upon a strong regenerative medicine pipeline of breakthrough technologies and therapies that will ultimately provide health and economic benefits to Canada and the world.”

Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives, said the alliance is in keeping with U of T’s strategic plan, and will bring an array of benefits to academic-led innovation.

“In addition to the investment into Medicine by Design, for U of T, this partnership unlocks a global network of biomanufacturing expertise, infrastructure and a network of industry partners that expand beyond regenerative medicine – a strategic benefit to the research and clinical communities in Toronto,” said Cowen.

Launched in 2015 with the support of a $114-million investment from the Canada First Research Excellence Fund (CFREF), Medicine by Design has made large-scale, strategic investments in high-risk, high-reward research, advancing more than 190 projects. A U of T institutional strategic initiative, it has recruited world-class faculty and provided training programs to thousands of graduate students, post-doctoral fellows and other personnel at U of T and its affiliated hospitals.

CCRM, which is funded by the Government of Canada, Province of Ontario and academic and industry partners, has accelerated translation of scientific discovery into new companies and products, with a specific focus on cell and gene therapies.

Michael May, president and CEO of CCRM, said the collaboration will contribute to ensuring that the life-saving potential of regenerative medicine is realized and that a talent pool is developed that will position Canada as a leader in the global cell and gene therapy industry. “Medicine by Design and CCRM, put together, represent an end-to-end perspective of the bench-to-bedside process – research and discovery to company development to manufacturing to bringing the therapy to market,” said May.

He noted the alliance will leverage both U of T’s and UHN’s reputations for world-class research and medicine and tap into a network of regenerative medicine-focused faculty and clinicians, as well as experts from the social sciences and other non-STEM fields.

Brad Wouters, executive vice-president, science and research at UHN and a member of Medicine by Design’s executive committee, said the alliance will facilitate access to funding and infrastructure for the clinical translation of new cell and gene therapies being developed by Toronto investigators.

“Toronto is known globally for the strength of our stem cell and regenerative medicine accomplishments,” said Wouters, a senior scientist at the Princess Margaret Cancer Centre and professor in the department of medical biophysics in U of T’s Temerty Faculty of Medicine. “UHN is excited to build on our existing partnerships with CCRM through the Centre for Cell and Vector Production and Medicine by Design to support this strategic alliance and its goals to create end-to-end capacity in our ecosystem to create new medicines that will have global patient impact.

“From discovery through to clinical validation and manufacturing, we look forward to advancing the next generation of living therapies for our patients.”

Experts explore strategies for strengthening Canada’s bioinnovation ecosystem at Medicine by Design event

Christopher.Sorensen — Wed, 05 Jan 2022 17:06:42 +0000

Experts explore strategies for strengthening Canada’s bioinnovation ecosystem at Medicine by Design event

Christopher.Sorensen Wed, 01/05/2022 - 12:06

Cutline

Toronto’s MaRS Discovery District, which shares close connections to U of T and its hospital partners, is a major Canadian hub for biotechnology innovation in Canada (photo by Makeda Marc-Ali)

Julie Crljen

Topic

Our Community

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Institute of Health Policy Management and Evaluation

Munk School of Global Affairs & Public Policy

CCRM

Dalla Lana School of Public Health

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Medicine by Design

University Health Network

What can the unprecedented speed of vaccine development during the COVID-19 pandemic teach us about strengthening our bioinnovation ecosystem?

For David Walt, a professor at the Wyss Institute for Biologically Inspired Engineering at Harvard University, many of the pandemic’s innovations promise to have a lasting effect since, as a society, we “now have some of the tools in place to help catalyze continued innovation and collaboration” in the field.

“Everyone who was working on [COVID-19] had the potential to be affected by it. It was a global imperative that we all co-operate,” he said during a recent symposium hosted by the University of Toronto’s Medicine by Design program.

Walt, who co-leads the Mass General Brigham Center for COVID Innovation, made the remarks during a panel discussion titled “Strengthening Our Bioinnovation Ecosystem” that followed his plenary talk.

David R. Walt

The symposium – “A Systems Approach to Regenerative Medicine” – was held over two days and attracted more than 500 registrants. It included talks from invited speakers Ruslan Medzhitov, a professor in the Yale School of Medicine at Yale University, on the topic of inflammation systems biology; and Linda G. Griffith, a professor in the department of biological and medicalengineering at the Massachusetts Institute of Technology (MIT), who spoke about organ-on-chip technologies, including their application to endometriosis.

The panel discussion on strengthening the bioinnovation ecosystem looked at the symposium’s broad theme in a more “holistic fashion,” said Medicine by Design Executive Director Michael Sefton, who is also a University Professor in the department of chemical engineering and applied chemistry and the Institute of Biomedical Engineering.

“[We’re] looking at health-care systems and innovation systems with a focus on health policy and social science lessons learned from COVID-19.”

The panel discussion was timely as Medicine by Design seeks to ensure the bioinnovation system in Canada is well-prepared to advance the regenerative discoveries coming out of the labs of researchers at U of T and its partner hospitals.

“We are looking forward to continuing to excel and to prepare the future of human health – to continue to transform but also translate,” said Sefton, whose lab is located at the Donnelly Centre for Cellular & Bimolecular Research, in his opening remarks. “Our goal is to not just write great papers but to also show that these papers can be translated into impact –maybe not immediately, but certainly over the next five or ten years, if not beyond.”

The impact of COVID-19 on the bioinnovation pipeline was just one of themes panelists touched on during a wide-ranging discussion. The panel was moderated by Shiri Breznitz, who is an associate professor at the Munk School of Global Affairs & Public Policy and the director of the master of global affairs program at U of T.

A clinical pull rather than technology push

Often innovations begin with an engineer or scientist inventing a technology and filing a patent before determining the clinical need for their product. But using “design thinking” to innovate can accelerate the timeline of implementation by years, Walt said during his talk.

“If you start with the clinical need first rather than the technology – a clinical pull rather than a technology push – then you come up with a [design-thinking] model.”

In the design-thinking model, clinicians identify unmet needs and then scientists and engineers develop solutions to solve those problems. Design thinking “starts with the problem. It has a human-centred core,” said Walt.

Collaboration and trust are important elements of an ecosystem

Catherine Beaudry

The strength of an ecosystem can be measured by its level of collaboration and trust, said panelist Catherine Beaudry, who leads the Partnership for the Organization of Innovation and New Technologies (4POINTO) and is a professor at Polytechnique Montréal.

“At the heart of all these models, you have to remember that it’s individuals who are collaborating with other individuals. The glue that maintains the ecosystem is trust.”

Beaudry pointed to the importance of having strong intellectual property policies and making sure innovators are collaborating with regulators early in the therapeutics or technology development process as important elements of building trust. She added that using more thoughtful metrics – key performance indicators, or KPIs – is also a key part of measuring the health of an ecosystem.

“Bean counting is not the way to go. We need to measure how organizations collaborate, whether these relationships last over time, and what comes out of them.”

Aligning towards a common goal

Beate Sander

Beate Sander, a scientist and the director of population health economics research for the Toronto Health Economics and Technology Assessment Collaborative (THETA), pointed to how the speed of vaccine development during the pandemic showed us how the seemingly impossible could be possible.

“The pandemic has shown that we cannot separate health and the economy,” said Sander, who is also an associate professor at the Institute of Health Policy, Management and Evaluation at the Dalla Lana School of Public Health.

“[In the pandemic] everyone is rallying around similar goals. So everything aligned in a time of very high pressure, very high uncertainty. How do we move what we have now to post-pandemic times when all that pressure is gone, and everyone will be inclined to go back to what we’ve done previously?”

Sander is an expert in health technology assessment, a multi-disciplinary process that looks at the value of a technology from a wide range of perspectives – not just technical properties, but also many other factors including economic considerations, social and legal impacts and patient perspectives.

Where normally innovations would move through a linear process of approvals, Sander said things were very different during the pandemic, when many of the phases moved in tandem with each other instead of sequentially. Introducing health technology assessment earlier into the process of innovation would also help speed up the adoption of new technologies, Sander said.

At the pre-clinical stage, Sander said, provinces and territories were already planning vaccine rollouts. Health Canada accepted vaccine data on a rolling basis and data was shared with relevant parties much earlier than it normally would be.

“I hope that some of those characteristics will be maintained – [for instance] parallel review and not having to wait until each step is finished.”

Beaudry said COVID-19 demonstrated the importance of the government playing an active role in the innovation ecosystem.

“We need to de-silo the economy because innovation very often is a combination of knowledge from multiple disciplines and multiple sectors. With COVID the government has been forced to do that really quickly. We need to draw the lessons in terms of cross-sector cross agency collaboration.”

Support for new companies and access to risk capital play a large role

Michael May

For smaller companies to thrive in the bioinnovation ecosystem, collaboration is an important element, said Michael May, president and chief executive officer at CCRM (formerly the Centre for Commercialization of Regenerative Medicine).

“It’s about alignment of interests. Bringing groups together and understanding the common goal and focusing on that common goal. And it’s a recognition that multiple partners are required for success,” said May. “It’s amazing how much translation and commercialization get stopped by innovators feeling like they have to do it all on their own.”

Aside from collaborations, May said, financial resources play a large role. May contrasted the Canadian ecosystem with the ecosystem in Boston, which is well known for its biotechnology sector and has more access to capital.

“We get bogged down without the financial resources to bring people together … and we’re trying to fill gaps without those resources. [The CCRM model] was built on the premise that we needed to leverage small successes and infrastructure and investments over time to enable access to capital.”

Walt, who has founded or co-founded several life sciences start-ups including multi-billion dollar biotech ventures Illumina, Inc. and Quanterix Corp., agreed that support for small companies is crucial.

“The small companies are at the core of innovation,” he said. “That’s where invention happens; that’s where all the creativity starts.”

Walt added that Boston and Canadian hubs like Toronto have many similarities. The biotech ecosystem in Boston started because there was a recognition that there was invention and innovation at the universities.

“[In Canada], there are great hubs where there’s concentrations of universities. That’s where most of these ecosystems start. They start with the intellectual capital, then they attract the venture capital, and then they attract more, and it just becomes a self-fulfilling enterprise.”

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen — Fri, 17 Dec 2021 20:40:18 +0000

Researchers working on injection-free cell therapy for diabetes

Christopher.Sorensen Fri, 12/17/2021 - 15:40

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Juan Carlos Zúñiga-Pflücker and Sarah Crome are among the researchers working on generating pancreatic cells that can be transplanted to diabetes patients without being destroyed by their immune systems (photos courtesy of Medicine by Design)

Julie Crljen

Topic

Our Community

Institute of Biomedical Engineering

Insulin 100

Princess Margaret Cancer Centre

Sunnybrook Health Sciences

Temerty Faculty of Medicine

Toronto General Hospital

Resarch & Innovation

Medicine by Design

Stem Cell

University Health Network

In a person with type 1 diabetes, the body mistakenly attacks pancreatic cells that produce insulin, a hormone responsible for regulating blood sugar.

Without insulin, serious and eventually fatal symptoms will occur. Yet, imagine if, instead of needing daily insulin injections, people with diabetes could have insulin-producing cells placed back into the body, fixing the problem at its source. This is the vision of a Medicine by Design-funded research team.

The approach is not without its challenges.

“Scientists are able to generate pancreatic cells from stem cells in the lab, and they can be transplanted to someone who has lost pancreatic function, but they’ll be reattacked by the immune system,” says Juan-Carlos Zúñiga-Pflücker, senior scientist at Sunnybrook Research Institute and professor of immunology in the Temerty Faculty of Medicine. “What our work is meant to do is enable those transplants to be broadly acceptable so anyone can benefit from transplanted therapies. But the barrier of the immune system is a difficult thing to overcome, and even more so in the context of autoimmunity.”

The cells are attacked because the immune system recognizes them as harmful invaders instead of helpful therapies. It is a complex problem that demands a complex strategy – and that strategy is an emerging area of research called immunoengineering, which uses bioengineering techniques to manipulate the immune system.

The only way to currently suppress the immune system is through drug treatments, but they’re not selective; they suppress the whole immune system and leave people vulnerable to infection and illness.

The team’s strategy aims to be more precise. They want to finely tune the immune system to maintain a healthy system while not rejecting a therapeutic transplant.

Zúñiga-Pflücker says a collaborative effort is important in solving this major challenge to regenerative medicine. “We can optimize cell types and engineer effective tissues in our separate labs. But if we don’t come together to create better tools to engineer the immune system, these therapies will not be usable. It’s something very fundamental.”

The 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 a strategic research initiative that is working at the convergence of engineering, medicine and science to catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

Though the research could be applied broadly across regenerative medicine therapies, type 1 diabetes makes an ideal test case, says Zúñiga-Pflücker, who is also chair of the department of immunology.

“Not only is diabetes an autoimmune disease, where the diabetic’s own immune system attacks and kills insulin producing cells, but attempts to replace the lost cells with transplanted cells are also challenged by other impacts of the disease, as well as the presence of auto-reactive immune cells,” he says. “This makes it a powerful test case for our research since we can test the transplants under multiple immune stresses.”

Zúñiga-Pflücker leads the project, which brings the work of six different labs together.

Two labs, led by the Temerty Faculty of Medicine’s Maria Cristina Nostro, a senior scientist at the University Health Network’s (UHN) McEwen Stem Cell Institute; and Sara Nunes Vasconcelos, a scientist at UHN’s Toronto General Hospital Research Institute, are using stem cells to generate tissues containing insulin-secreting cells for transplants.

Zúñiga-Pflücker says that this arm of the project is well ahead of schedule. “The Nostro and Vasconcelos labs are defining the right conditions that are necessary for generating insulin-producing cells, which are called islet cells. They’re creating newer and more effective ways to make these tissues.”

Nostro and Vasconcelos are also associate professors at U of T in the department of physiology and Institute of Biomedical Engineering, respectively.

The tissues created in their labs will be used to test the work of the other four labs involved in the project, which are concerned with engineering the immune reaction. And here, each of these labs is bringing a piece of the puzzle.

Read about research into therapeutic cell “cloaking”

Zúñiga-Pflücker and Naoto Hirano, a senior scientist at Princess Margaret Cancer Centre and a professor of immunology at U of T, work on producing regulatory T cells (Tregs). These cells can supress immune response and play a role in preventing autoimmune diseases like diabetes.

In earlier Medicine by Design-funded research, Zúñiga-Pflücker and Hirano came up with a method for producing T cells in a defined way. Some of the key breakthroughs developed as part of this research helped lay the foundation for Notch Therapeutics, a company co-founded by Zúñiga-Pflücker, which closed an $85-million (U.S.) Series A financing earlier this year.

Now, in the current research project, the two labs are crafting methods for producing Tregs and investigating how harnessing the power of other types of immune cells to work alongside the Tregs can induce the immune system to tolerate transplanted therapies.

The third investigator is Tracy McGaha, whose lab is looking at the role of macrophages, a type of white blood cell that that typically helps to attack foreign substances but can also play a role in repairing damaged tissues. McGaha is a senior scientist at Princess Margaret Cancer Centre, UHN, and a professor in the department of immunology in the Temerty Faculty of Medicine.

A fourth lab, led by Sarah Crome, is investigating a family of immune cells called innate lymphoid cells (ILCs), which act within tissues to help induce and modulate immune responses.

“We know several immune cell populations we individually study can protect from harmful immune responses and promote immune tolerance,” says Crome, who is a scientist at the Toronto General Hospital Research Institute, UHN, and an assistant professor of immunology at U of T. “The trouble is when you get into a situation that combines an autoimmune disease with rejection that can occur following islet transplantation, it’s a real challenge shutting down multiple harmful and sustained immune responses.”

Crome says that there are many different types of ILCs, so her work focuses on narrowing down which types of ILCs are best to use along with the Tregs.

Right now, each of the four labs working with immune cells are optimizing their cell types and techniques, and then, Crome says they will bring all their “best players” together.

“We’re really looking at harnessing whole networks of cells, instead of just looking at one cell population at a time. It’s bringing all of our collective expertise together into one project that makes this a powerful approach.”

Zúñiga-Pflücker says Medicine by Design has been instrumental in uniting this team of experts.

“Thanks to Medicine by Design’s support of our immunoenigneering program, we’re able to bring together multiple research sites within the University of Toronto and affiliated research institutes; UHN’s Princess Margaret Cancer Centre, Toronto General Hospital Research Institute and McEwen Stem Cell Institute; and Sunnybrook Research Institute.”

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.

U of T's Medicine by Design helps unite international researchers working to map every human cell

Christopher.Sorensen — Wed, 11 Aug 2021 17:10:50 +0000

U of T's Medicine by Design helps unite international researchers working to map every human cell

Christopher.Sorensen Wed, 08/11/2021 - 13:10

Cutline

Professor Gary Bader (right), who is on the organizing committee for the Human Cell Atlas, helped researchers Sonya MacParland (left) and Ian McGilvray (right) create the first map of the human liver at the cellular level (photo courtesy of UHN)

Julie Crljen

Topic

Our Community

Institute of Biomedical Engineering

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Faculty of Applied Science & Engineering

Medicine by Design

Research & Innovation

University Health Network

The Human Genome Project, a large-scale international effort to determine the complete DNA sequence that defines the human body, took more than 12 years to complete and involved thousands of researchers.

Now, a similar effort is underway to map each of the trillions of cells in the human body.

The Human Cell Atlas (HCA) would be a comprehensive map of cells that has the potential to rapidly advance the understanding of human health and the diagnosis, monitoring and treatment of disease, according to Gary Bader, a computational biologist and professor at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research and the department of molecular genetics in the Temerty Faculty of Medicine.

“This project will likely be larger than the Human Genome Project, and it requires a massive international effort. No single individual or institute could do this on their own,” he says. “It’s multi-disciplinary in nature, and pulls in people from genomics and technology development, basic biology, clinical research, computational biology and ethics.

“We encourage participation from all countries and relevant scientific communities.”

Bader, who is on the organizing committee for HCA, is helping to co-ordinate a scientific meeting of the HCA from Aug. 25 to 27. The meeting will focus on human development and pediatrics, mapping the body from conception to adolescence. Medicine by Design is a lead sponsor of the meeting, along with the Chan Zuckerberg Initiative and others.

Bader says the August meeting will bring together groups of people who are working on critical questions about cell types and states during human development.

“We’re aiming to deliver a highly interactive meeting that will provide plenty of opportunities for virtual face-to-face interaction in breakout discussion sessions,” Bader says. “A silver lining of having the meeting online instead of in-person, as was originally planned, is that there are no space restrictions. It can be open to anyone who wants to attend. Also, there are no travel costs for attendees, and we are able to offer registration free of charge.”

Session topics will include: understanding cellular decision-making during development; lineage tracing; clonal evolution; tagging and its applications; and developmental origins of health outcomes over a lifespan. There will also be a session on regenerative medicine, led by Guoji Guo and Jason Rock, focusing on how developmental and pediatric single cell atlas data can shed light on tissue aging and repair processes.

Regenerative medicine uses stem cells to replace diseased tissues and organs, creating therapies in which cells are the biological product. Regenerative medicine can also mean triggering stem cells that are already present in the human body to repair damaged tissues or to modulate immune responses. Increasingly, regenerative medicine researchers are using a stem-cell lens to identify critical interactions or defects that prepare the ground for disease, paving the way for new approaches to preventing disease before it starts.

“There is strong evidence that we’ll have to really understand development to live up to regenerative medicine’s key aims,” Bader says. “There are questions we don’t know the answer to – for example, why do children heal better than adults? These answers are essential for researchers who are developing stem cell therapies or ways to encourage self-repair in the body.”

The HCA group is mapping 14 organ systems, each organized into its own bio network. For instance, the gut, heart and kidney each have their own bio network, comprising researchers that focus on that specific system. Bader is part of the liver bio network.

Bader, along with the Temerty Faculty of Medicine Associate Professor Sonya MacParland and Professor Ian McGilvray – a scientist, and surgeon and senior scientist, respectively, at University Health Network (UHN) – are part of a Medicine by Design collaborative research team that, in 2018, created the first map of human liver cells at the molecular level. They are currently part of the large, Medicine by Design-funded team project studying how to harness the liver’s power to regenerate.

The liver map represents the first time a human organ has been charted at the single-cell level. It illuminated the basic biology of the liver in ways that could eventually increase the success of transplant surgery and enable powerful regenerative medicine treatments for liver disease such as regenerating the liver with stem cells.

“This is a tool that can be used by researchers who are developing cells in the lab. For instance, a U of T and UHN team recently published work that showed they can develop functional blood vessel cells found in the liver. This drew on our liver map work, which provided a benchmark for those researchers to compare their cells with adult human liver cells,” says Bader. “HCA continues to expand this work – for example in pediatrics – and it will become a fundamental resource for regenerative medicine researchers.”

Medicine by Design is sponsoring the HCA meeting in August because it’s an opportunity to engage with the international effort on human cell mapping, which creates new scientific collaborations for the Medicine by Design community.

Moreover, the HCA informs new directions in regenerative medicine research, says Michael Sefton, executive director of Medicine by Design and a University Professor in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering and the Institute of Biomedical Engineering.

“This international event will connect fields and people that traditionally don’t work together,” says Sefton, whose lab is located at the Donnelly Centre for Cellular and Biomolecular Research. “A massive collaborative undertaking is what’s necessary to bring HCA to fruition, and Medicine by Design is proud to support this effort. We can’t overstate how much the HCA project could advance and transform regenerative medicine.”

Bader says in addition to the opportunities for scientific learning, the event could have other benefits for attendees.

“One of the advantages to attending the HCA meeting is the opportunity to network and potentially find out about funding opportunities one might not be aware of otherwise. It’s a great opportunity for researchers to connect beyond their local collaborations.”

Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design brings together more than 150 principal investigators at U of T and its partner hospitals to advance regenerative medicine discoveries.

Can blood be used to predict age-related diseases? U of T researchers bet it can

Christopher.Sorensen — Mon, 12 Jul 2021 13:01:17 +0000

Can blood be used to predict age-related diseases? U of T researchers bet it can

Christopher.Sorensen Mon, 07/12/2021 - 09:01

Cutline

(Photo by Andrew Brookes/Cultura via Getty Images)

Julie Crljen

Topic

Our Community

Princess Margaret Cancer Centre

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Medicine by Design

Molecular Genetics

Research & Innovation

University Health Network

How much can a simple blood sample tell us about a person’s health? Can it give clues about whether a person will develop cardiovascular disease or leukemia? Can it predict how severe a person’s heart disease will be?

John Dick, senior scientist at Princess Margaret Cancer Centre, University Health Network (UHN) and a professor of molecular genetics at the University of Toronto’s Temerty Faculty of Medicine, believes it can – and, together with a multi-disciplinary team, is coming up with a method for monitoring blood for markers of disease.

He says the simplicity of the approach makes this a low-risk, but potentially high-impact, project.

“Blood is easily accessible. Taking a blood sample is not invasive like having a biopsy, for example,” Dick says. “The overall potential impact of our research would be to have a way to pre-screen patients using a detection tool we developed to identify those at risk for development of cardiovascular disease and other inflammatory diseases of aging.”

Dick’s lab has shown that aging blood stem cells acquire mutations that proliferate and begin to make up a large proportion of all blood cells – a process called “age-related clonal hematopoiesis,” or ARCH. Dick and other researchers have uncovered evidence that some of these mutated cells contribute to inflammation, which in turn leads to diseases of aging. While Dick’s team is currently focused on cardiovascular disease, he says the project could apply to any degenerative disease of aging.

The project’s multi-disciplinary team of investigators has two major aims. The first is developing ARCH genetic biomarkers that can predict cardiovascular disease risk. To do this, the team is studying large populations of blood samples. Dick is working with Temerty Faculty of Medicine co-investigators Assistant Professor Phyllis Billia, a cardiologist and director of research at the Peter Munk Cardiac Centre at UHN; Professor Philip Awadalla, director of computational biology and senior investigator at the Ontario Institute for Cancer Research, and Assistant Professor Sagi Abelson, a scientist at the Ontario Institute for Cancer Research.

Separately, Dick is collaborating with Gary Bader, computational biologist and professor at the Donnelly Centre for Cellular and Biomolecular Research, Temerty Faculty of Medicine Assistant Professor Steven Chan, scientist at the Princess Margaret Cancer Centre, Professor Mathieu Lupien, a senior scientist at the Princess Margaret Cancer Centre; and Assistant Professor Slava Epelman, a scientist at the Toronto General Hospital Research Institute and staff cardiologist at the Peter Munk Cardiac Centre. They are using techniques such as single-cell sequencing – a method of studying cells at the individual level – to determine how a blood stem cell with ARCH contributes to the progression of cardiovascular disease.

Some of the investigators working on this project – Awadalla, Bader and Lupien – have also been involved in an international partnership, led by Dick, with the University of Cambridge and the University of York. The strategic collaboration seeks to accelerate the global understanding of how normal human hematopoietic stem cells are regulated and how leukemia develops, and includes an exchange program for PhD students.

The 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 catalyze transformative discoveries in regenerative medicine and accelerate them toward clinical impact.

Dick’s team is currently in the process of analyzing blood samples taken from large population cohort studies. They are looking at samples from patients both with and without cardiovascular disease. DNA extracted from those blood samples are run on an ARCH-detection platform built in the Abelson lab, which identifies connections between the presence of ARCH and markers of cardiovascular disease.

Dick is world renowned for his research on normal and leukemic stem cells, which he has studied for 30 years. His team project builds on his important discovery that normal blood stem cells can mutate and start proliferating years before leukemia is diagnosed. The discovery was the catalyst to the finding of ARCH.

One of the sources of blood samples the team is working with is from the Peter Munk Cardiac Centre at UHN. Co-investigator Billia says she was brought onto the project when the Dick lab inquired about using Peter Munk Cardiac Centre’s specimens in the project.

“We have been collecting samples from patients for quite a few years. We have upwards of 13,000 patient samples,” Billia says, adding that the team is studying these samples to understand if there are markers in the blood that can predict severity of illness.

As a clinician, Billia says she can see this work being translated to have an impact on the way people are treated for cardiac disease.

“It could change how we would potentially think about – and treat – patients earlier on in their disease progression. We can monitor them at an earlier state and make more accurate predictions. We can go back a few steps when we see people in clinic and say, ‘We have to be extra cautious with you.’”

Billia did a PhD focused on stem cells and she says she was enthusiastic when the biobank team at UHN linked her to Dick.

“When I learned about the project, I had so many ideas. I’m really excited about this team because my gut says we are going to find something,” Billia says.

Dick credits Medicine by Design for providing the mechanism and resources to grow this team, which not only includes scientists, but clinicians like Billia and Epelman.

“Our new collaborations in the cardiac community are very exciting,” he says. “Thanks to Medicine by Design, we now have the opportunity to engage with people who bring new perspectives and innovative ideas on how we can work together to impact regenerative medicine with this knowledge.”

Startup built by U of T alumnus develops ‘Nespresso machine for protein production'

Christopher.Sorensen — Thu, 08 Jul 2021 12:57:44 +0000

Startup built by U of T alumnus develops ‘Nespresso machine for protein production'

Christopher.Sorensen Thu, 07/08/2021 - 08:57

Cutline

With the support of U of T's Medicine by Design community, Liberum founders (from left to right) Chris Leichthammer, Aidan Tinafar and Alex Klenov want to make manufacturing proteins as simple as brewing a cup of coffee (photo courtesy of Liberum)

Julie Crljen

Topic

Our Community

Alumni

Creative Destruction Lab

Entrepreneneurship

Innovation & Entrepreneurship

Leslie Dan Faculty of Pharmacy

Medicine by Design

Research & Innovation

Rotman School of Management

Startups

Manufactured proteins are used as therapeutics, industrial catalysts and biomedical research tools – just to name a few applications.

But making them is a time-consuming and complex process.

Now, a new venture called Liberum formed within the University of Toronto’s Medicine by Design community wants to make manufacturing proteins nearly as simple as brewing a cup of coffee.

“Current methods of making and purifying biologically active proteins require at least a week of work in most instances,” says Aidan Tinafar, co-founder and CEO of Liberum. “Our system is a desktop protein manufacturing platform that enables users to go from synthesized DNA to purified proteins within hours.”

The technology would have many applications for regenerative medicine.

“Faster, cheaper and easier manufacturing of biomolecules could transform regenerative medicine,” says Tinafar. “Examples include developing new-media formulations and helping regenerative medicine scientists design proteins that they can use in manufacturing stem cells at scale.”

Liberum's prototype protein manufacturing unit is inspired by single-serve coffee makers.

Tinafar was trained as a graduate student in the lab of Keith Pardee, a Medicine by Design investigator and assistant professor at the Leslie Dan Faculty of Pharmacy. He is also a co-founder of the company.

“There is an increasing need for rapid prototyping of recombinant proteins in regenerative medicine research,” Pardee says. “Liberum is pioneering an automated system that can be thought of as a ‘Nespresso machine for protein production’ that is going to provide on-demand and custom synthesis with the push of a button.

“I’m extremely excited about the potential for the device to accelerate research in the field.”

The Liberum team recently went through the Creative Destruction Lab (CDL), a seed-stage program for massively scalable, science-based companies affiliated with Rotman School of Management that offers ventures the opportunity to connect with mentors, investors and venture funding opportunities. Medicine by Design is a partner of CDL.

On June 14, Liberum marked its completion of the program with a presentation at CDL’s Super Session event, which brings together entrepreneurs, investors and scientists and high-potential start-up founders.

Tinafar says that going through the CDL program was an inspiring experience.

“CDL offers a great network of investors and advisers and, from our perspective as a participant, runs like a well-oiled machine taking young companies through key early milestones,” Tinafar says. “We are time and time again astonished by the level of generosity offered by the high-caliber investors and advisers present at their sessions. We are really grateful to have been part of the program.”

Before CDL, says Tinafar, there was Medicine by Design. He says he first heard of Medicine by Design during a talk at a stem cell conference. Then, in 2019, Tinafar and the Liberum team got involved with Medicine by Design’s Pitching Science workshops, which teach trainees how to effectively communicate their scientific ideas and their research to diverse audiences including investors. They won first place in a pitch competition held at the end of the program.

Tinafar also participated in a mentorship session with Allison Brown, who is the director of strategy & translation at Medicine by Design.

“We are grateful for the mentorship Medicine by Design provided us in terms of setting the right priorities as founders,” says Tinafar. “We also really appreciate Medicine by Design’s support in showing us the best ways to communicate our mission to the world. It helped us get ready for more advanced programs like CDL and the IndieBio accelerator, another program we participated in.”

Brown says the Liberum team’s success is a result of their dedication to their venture.

“This is a team that’s serious about taking their venture far. Their technology and concept are extremely well thought-out, and we know they will continue to be successful,” says Brown. “We’re proud to be part of the early journey of science-based ventures like Liberum. It’s part of our commitment to ensuring Medicine by Design trainees have opportunities to develop the skills they need to translate their research into innovative products and companies.”

The Liberum team also includes Alex Klenov, a molecular biologist who is chief technology officer for the company, and Chris Leichthammer, who is lead molecular biologist and lab manager.

In addition to being a co-founder, Pardee advises the Liberum team on strategic matters. He is also a leading expert on cell free systems in synthetic biology, meaning systems that contain no living cells. Pardee recently received funding through Medicine by Design’s Grand Questions Program.

The Liberum platform is a cell-free technology, and Tinafar says he has become passionate about this area since working as a graduate student in the Pardee lab.

“I joined the Pardee lab after working as a corporate lawyer and have been working in the field of cell-free biology ever since. I truly believe biology has the power to feed the hungry, heal the unhealthy and save the climate.”

Grand Questions: U of T's Medicine by Design invests $3 million in the future of regenerative medicine

Christopher.Sorensen — Mon, 10 May 2021 20:03:33 +0000

Grand Questions: U of T's Medicine by Design invests $3 million in the future of regenerative medicine

Christopher.Sorensen Mon, 05/10/2021 - 16:03

Cutline

From left to right: U of T researchers Sevan Hopyan, Keith Pardee, Alison McGuigan and Michael Garton.

Julie Crljen

Topic

Our Community

Institute of Biomedical Engineering

Insulin 100

Temerty Faculty of Medicine

Faculty of Applied Science & Engineering

Hospital for Sick Children

Leslie Dan Faculty of Pharmacy

Medicine by Design

Research & Innovation

Treating heart failure without transplant surgery. Delivering powerful cell therapies to patients where they live – no matter how remote. Recording how cells talk to one another in the body to personalize future therapies.

These are just some of the transformative advances the University of Toronto’s Medicine by Design initiative hopes to enable through its Grand Questions Program, which is investing $3 million to prepare for the future of regenerative medicine.

The four multi-disciplinary teams from U of T and its partner hospitals that will undertake the research were recently announced during a launch event.

“The Grand Questions we posed are not safe or easy to address,” says Michael Sefton, executive director of Medicine by Design and a University Professor in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering and the Institute of Biomedical Engineering. “Our ambition for the Grand Questions Program is to set the agenda for regenerative medicine for years to come and improve health outcomes for people living with degenerative diseases. To achieve that, we need to go beyond the obvious and provoke new ways to think about these problems.”

The Grand Questions Program is the culmination of more than a year of work that began with community consultations, a widely attended workshop in spring 2020 and engagement with Medicine by Design’s scientific advisory board to define the questions to be explored.

“The Grand Questions Program began with ‘pooling the imagination’ of the community, exploiting the wealth of disciplines of our researchers and having a conversation about how we would collectively prepare for the future,” says Sefton.

Through community consensus, six questions emerged that were deemed to be of paramount importance to regenerative medicine. An initial call for proposals resulted in eight teams being shortlisted to submit detailed proposals.

“We admire the bravery of all those who applied,” Sefton says. “All four of the funded projects are risky and we do not expect their projects to lead in a straight line to a successful outcome. But that is exactly what is required to move regenerative medicine forward.”

Can we create technologies that track cells?

Alison McGuigan, who leads one of the projects, says the program pushed her and her team to think of concepts they might not have thought about otherwise.

“Going through the Grand Questions process was disorienting – in a good way,” says McGuigan, who is a professor in the department of chemical engineering and applied chemistry in the Faculty of Applied Science & Engineering and the Institute of Biomedical Engineering. “It was such an interesting way to think of a problem: The Grand Questions Program sets goals and then asks us to think about how we could use our skill sets, in combination with those of others in the community, to address that problem.”

McGuigan adds, “Normally, research funding is for a further extension of what I’m already doing. Grand Questions allowed me to look at what I was doing and ask myself how I could apply it in a new, ambitious way.”

McGuigan’s project focuses on recording cell history. Her team is finding ways to record cells’ communications with other cells, also known as signalling. To make cell therapies work, researchers need to understand not only how cells function on their own, but also how interactions with neighbouring cells and the environment affect what they do.

The technology McGuigan and her team are proposing resembles a “contact tracing app” for cells that can measure very specific inputs and outputs from cells. Through its work, the team envisions being able to precisely program how a cell interacts with the environment where a cell therapy is taking place, dramatically increasing the effectiveness of therapy. In time, this research could also lead to therapies being personalized to individuals.

“Our project brings synthetic biology, molecular engineering, machine learning and other disciplines together,” McGuigan says. “Grand Questions gives us a chance to form collaborations that will outlast the two year-funding period and keep solidifying and growing.”

How can we make regenerative medicine accessible to everyone?

Keith Pardee and his team want to make regenerative medicine affordable and accessible to everyone.

“Regenerative medicine currently requires specialized skills and expensive labs and equipment,” says Pardee, who is an assistant professor in the Leslie Dan Faculty of Pharmacy. “To make cell therapies available in every community – not just urban and well-resourced ones – is an important ethical challenge we need to address.”

Pardee’s project will focus on laying the groundwork to one day make the cell manufacturing that normally takes place in complex manufacturing facilities available in a sealed cartridge – effectively creating portable cell manufacturing systems. This means the process of making cell therapies could be done outside of major centres and would no longer require specialized skills, allowing on-demand manufacturing for cell therapies.

The project leverages multiple technologies and approaches, including nanotechnology, synthetic biology, microfluidics and cell analytics – some of which are already running in the labs of U of T investigators – and combines them into a novel approach.

“In an ideal scenario, patients would come in for an outpatient procedure for cell collection and then either receive their custom cell therapy the same day or within a week,” Pardee says. “This is a tall order, but enabling the vision of bedside cell therapy is what is needed to solve the challenge of accessibility and affordability of these potentially life-saving cancer therapies. The Grand Questions program is an exciting opportunity to do just that: take on big needs and set a course toward solving the problem.”

Can we make tissues that perform better than nature?

Michael Garton, another of the project leads, says the Grand Questions proposal gave him an opportunity to expand his collaborations given that the program includes international experts who act as key advisers to the funded teams.

“Through Grand Questions, I connected a team of people that includes some of the pioneers of regenerative medicine and synthetic biology,” says Garton, who is an assistant professor in the Institute of Biomedical Engineering. “As a newer investigator, this ambitious project and the potential of the Medicine by Design funding gave me a vehicle to reach out to these individuals and assemble this amazing team.”

Garton’s project merges synthetic biology with stem cell biology and aims to overcome the challenges of tissue transplants by genetically “upgrading” tissue before it is used. An important part of his team’s proposal is to establish a hub called Centre for the Design of Novel Human Tissues, which will facilitate the merging of the disciplines.

Currently, when tissues are transplanted, up to 90 per cent of cells will die because of lack of blood flow, or ischemia. Garton’s project explores the idea of introducing new gene circuits into tissue that will be sophisticated enough to control the ischemic response. Gene circuits are engineered systems that mimic natural function in cells to perform customized, programmable actions.

“In the next 20 years, we aim to have a stem cell therapy that could repair damaged tissue after a heart attack within a week or two,” Garton says. “It could also lead to gene therapies that give brains or hearts the ability to survive ischemic stroke and heart attack.”

Can understanding the physics of organ development lead to regeneration?

Sevan Hopyan, an orthopaedic surgeon and senior scientist at the Hospital for Sick Children and associate professor in the departments of surgery and molecular genetics in U of T’s Temerty Faculty of Medicine, says the Grand Questions Program gives him and his team an opportunity to do work that might not be funded by conventional means.

“The Grand Questions program allows us to pursue ideas that, while still rigorous, are outside of traditional approaches,” Hopyan says. “Medicine by Design allows us to be part of a community where these approaches are not only acceptable but encouraged.”

Hopyan leads a Grand Questions project that focuses on tissue and organ regeneration, but, in his team’s case, the aim is to study the physics of regeneration. Currently, regenerative medicine researchers can make many cell types, but are still figuring out how to bring those cells together to form functional, three-dimensional organs.

The team is studying animal embryos to understand how organs are formed by the embryo. The novelty of the approach, Hopyan says, is applying the principles of physics to their observations. Most of the current work that studies organ formation observes development but does not deconstruct the underlying physical forces driving the development in the body.

“Approaches to regenerating functional tissues or organs often rely on the self-organizing properties of cells in a dish or on a scaffold. Those methods advance by trial and error and commonly reach an impasse,” says Hopyan. “By seeking to define the possibly small number of physical rules by which tissue building blocks are generated in the embryo, we’re hoping to facilitate more rapid advances in tissue regeneration.”

Hopyan’s project combines physics, mechanical engineering and cell biology, among other disciplines, to make observations about development. Then it uses those observations to empower computational simulations of development and performs experiments to confirm the models.

Hopyan sees the long-term impact of this project enabling the generation of organs in the lab to replace ones that are deficient or damaged. And he says that the project takes an expansive view.

“Any disease or congenital condition that causes tissue to not be formed and functioning correctly would benefit from being able to create solid organs in the lab. This project could impact dozens of diseases, and it’s the inter-disciplinary nature of this project that raises the ceiling of what we can accomplish.”

Learn more about the full Grand Questions teams

Diabetes drug could prevent brain damage in children receiving radiation for tumours: U of T study

Christopher.Sorensen — Wed, 07 Apr 2021 19:40:48 +0000

Diabetes drug could prevent brain damage in children receiving radiation for tumours: U of T study

Christopher.Sorensen Wed, 04/07/2021 - 15:40

Cutline

(Photo Illustration by Scott Olson via Getty Images)

Julie Crljen

Topic

Breaking Research

Insulin 100

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Hospital for Sick Children

Medicine by Design

Research & Innovation

Radiation can be life-saving for a child with a brain tumour. But the therapy can also cause damage to the brain that leaves deficits in cognitive function, including learning and memory challenges.

Now, thanks to funding from Medicine by Design, a University of Toronto scientist and her team are closer to finding a way to protect the brain from damage for children who must be treated with cranial radiation by using a drug commonly used to treat diabetes.

“We found that if we gave metformin, which is an approved, safe drug used to treat diabetes, as a pre-treatment in animal models, we could actually stop the damage from happening,” says Cindi Morshead, a professor and chair of the division of anatomy in the department of surgery in the Temerty Faculty of Medicine.

The study, published in the journal Cell Reports Medicine, builds on previous work done with metformin. Last summer, Morshead and researchers from The Hospital for Sick Children (SickKids) showed that metformin administered after cranial radiation encouraged neurogenesis, or the process of making new neurons in the brain.

Morshead says that, given the safety of metformin, the research will hopefully proceed quickly to clinical trials.

“Anything we can do to stop children from having these long-term impairments would be very positive,” she says. “For children with brain tumours who need cranial radiation, to be able to do something that would ensure their brain is damaged less in the first place, rather than try to repair it after the fact, would be life-changing for these children and their families.”

Notably, the previous metformin study, which looked at administering the metformin after the cranial radiation and once the damage had already occurred, found that the benefits of metformin were seen only in juvenile females. Morshead says the more recent study showed no sex-specific effect, which indicates that pre-treating children with metformin could provide additional benefit.

Cognitive deficits from radiation can result from killing newborn neurons that underly learning and memory. Morshead says the study shows that metformin offers neuroprotection to animals who were given the drug prior to the cranial radiation.

“Radiation is an insult on the brain, and our study showed that we’re able to protect the micro environment because the metformin decreases brain inflammation. After the drug treatment, newborn neurons were not lost and could keep making new connections in the part of the brain that is important for olfactory memory.”

Morshead, whose lab is located at the Donnelly Centre for Cellular and Biomolecular Research, says that, for this project, the researchers taught animals where to find a food reward based on a particular smell. One type of scent belonged to a dish that had a hidden treat and another type of smell belonged to a dish that had no hidden treat. Only mice that had the metformin treatment before radiation could remember which scent was associated with the treat.

“It was really quite a striking effect. The ones that were not administered the metformin prior to radiation couldn’t remember the association,” Morshead says. “The ones that were given the metformin remembered the association weeks after the radiation. So we concluded that the mice that were not treated with the metformin had an impairment in long-term memory, and metformin protected against this impairment.”

The study is part of a large team project funded by Medicine by Design, led by Freda Miller, an adjunct scientist in the neurosciences and mental health program at SickKids and a professor at the department of molecular genetics. Miller’s research team, which includes eight labs at U of T and SickKids, is taking a wide-ranging approach to promoting self-repair in the brain and muscle. Miller and her colleagues at SickKids made the discovery that metformin had potential to be used for self-repair in the brain. Morshead’s metformin research builds on this original finding.

“I am excited by this paper since it describes a potential protective therapy for children who need cranial radiation,” says Miller, who is also a professor at the University of British Columbia. “And, just as importantly, the metformin story provides a classic example of why we need to support basic research, and why working in collaborative teams is essential.

“The original finding that metformin recruits endogenous brain stem cells came from fundamental studies on how stem cells build the brain developmentally, and then it was moved forward to other models by highly interdisciplinary scientists like Dr. Morshead.”

Morshead credits funders including Medicine by Design for being strong supporters of this and other promising metformin work.

“My lab – as well as the labs of Freda Miller and Don Mabbott at SickKids and others – are grateful to have the opportunity to do this research,” she says. “Being able to show these positive results using a drug that we know is safe, approved and accessible is really the best-case scenario. Our hope is that this is one day a low-risk solution for children who would otherwise be living with cognitive deficits after surviving a brain tumour.”

In addition to her work with Miller on this large team project, Morshead also leads another Medicine by Design project that’s focused on enhancing neuroplasticity in the brain, regenerating cells that are lost or damaged by a stroke.

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

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

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

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

Cutline

(illustration by Jolygon via Getty Images)

Julie Crljen

Topic

Our Community

Institute of Biomedical Engineering

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Brain

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Hospital for Sick Children

Medicine by Design

Research & Innovation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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