University Professor Shana Kelley (left) at the Leslie Dan Faculty of Pharmacy, Dr. Michael Laflamme (centre), a senior scientist at the McEwen Stem Cell Institute at University Health Network, and Freda Miller, a senior scientist at The Hospital for Sick Children, are leading three of the teams that Medicine by Design is funding through its second round of Team Project Awards.
By Ann Perry and Jovana Drinjakovic
Medicine by Design is strengthening the University of Toronto (U of T) 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 Government of Canada’s Canada First Research Excellence Fund (CFREF), 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.
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 & Applied Chemistry. “These new projects all have significant potential to achieve transformative and globally competitive outcomes and advance ground-breaking 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.”
Dr. Michael Laflamme (left) and Gordon Keller are part of a Medicine by Design-funded team that is aiming to do the first clinical trial testing stem cell-derived heart muscle cells as a novel therapy for heart failure. (Photo courtesy of UHN Research)
Capitalizing on world-leading efforts in Toronto to “remuscularize” injured hearts, Dr. Michael Laflamme is leading a team whose goal is to enable the first clinical trial testing stem cell-derived heart muscle cells as a novel therapy for heart failure. Their approach could transform the treatment of heart failure from one of disease management to one that is truly regenerative.
In partnership with the Ted Rogers Centre for Heart Research and BlueRock Therapeutics, the team is working to improve the functional integration of stem cell-derived heart tissue grafts by generating cells that are genetically engineered to prevent arrhythmia, developing strategies to monitor them non-invasively, and testing their application for other diseases such as childhood heart disease.
The team leverages diverse expertise from across U of T and its affiliated hospitals: stem cell pioneer Gordon Keller, director of the McEwen Stem Cell Institute at UHN; Dr. Slava Epelman, a scientist at the Toronto General Hospital Research Institute (UHN); Anthony Gramolini, an associate professor at U of T’s Department of Physiology; Hai-Ling Cheng, an associate professor at IBBME and Department of Electrical & Computer Engineering; Scott Heximer, an associate professor and interim chair of U of T’s Department of Physiology; Dr. Mark Friedberg, a cardiologist and senior associate scientist at SickKids; and Nilesh Ghugre, a scientist at Sunnybrook Research Institute.
Shana Kelley, a University Professor at the Leslie Dan Faculty of Pharmacy, is leading a Medicine by Design team that is developing tools to overcome bottlenecks in cell manufacturing. (Photo by Neil Ta)
One hurdle facing stem cell therapy is our limited understanding of how to control tissue-specific stem cell differentiation, hindering the cost-effective manufacturing of relevant cell types at the quantities and purities required for any given treatment. To overcome this bottleneck, Shana Kelley’s team is developing tools to reveal the processes that control stem cell differentiation during mesoderm development, a tissue formed from stem cells in the embryo. In one of the major aims of the project, Kelley is collaborating with Jason Moffat and Benjamin Blencowe, both professors at the Donnelly Centre for Cellular and Biomolecular Research, to find all human genes that play a role in this process using the gene-editing tool CRISPR.
“We can look at the cells as they are differentiating to see what’s preventing them from differentiating efficiently in the early stages of the process,” says Kelley.
Also key to the project is a new microfluidics device, developed by Kelley’s group as part of her initial Medicine by Design Team Project grant, which uses tiny magnets to sort cells according to their molecular makeup to reveal new gene candidates involved in early cell differentiation. The technology could hold the key for identifying rare but potent cells. Learn more about how magnetic beads are helping researchers find new treatments.
In the other major aim of the project, Stephane Angers, a professor and associate dean of research at the Leslie Dan Faculty of Pharmacy, and Sachdev Sidhu, a professor at the Donnelly Centre, are developing antibody molecules that could be used to activate and guide cell differentiation, while Keith Pardee, an assistant professor at Pharmacy, is developing synthetic biology approaches for the cost-effective synthesis of these antibodies into potential therapeutics. Also on the team are Alison McGuigan, a professor at the Department of Chemical Engineering & Applied Chemistry, and Aaron Wheeler, a professor at the Department of Chemistry, who are investigating molecular pathways acting on the tissue.
“By being involved with Medicine by Design over the last three years, we got to know each other’s scientific strengths and decided to combine our expertise to solve some of the biggest problems facing regenerative medicine,” said Kelley.
“The combination of chemistry, biology and engineering expertise that will be deployed in our project will be extremely powerful,” she added.
Freda Miller’s team is studying how stem cells’ environment affects their ability to drive tissue repair. Their goal is to find a way to stimulate regeneration on demand as a treatment for degenerative conditions such as multiple sclerosis and muscular dystrophy, in which nerves and muscles waste away, respectively.
Professor Gary Bader
Miller’s team is applying new single-cell technologies to map the molecular makeup of cells that governs their responses to signals in their tissue environment. They are in search of clues for how to stimulate their repair. In collaboration with computational biologist Gary Bader, a professor at the Donnelly Centre, Miller has already helped establish a robust pipeline for collecting and analyzing single-cell data, which has also enabled Bader and other Medicine by Design researchers to develop a “map” of the human liver, the first single-cell map of any healthy human organ in the body.
“Thanks to Medicine by Design, we have broad expertise on our team to draw insights from the vast molecular data we are generating and apply them in human tissue samples as a first step toward finding new treatments for these devastating conditions,” said Miller.
In addition to Bader, Miller’s team comprises experts from diverse fields: neurobiologists David Kaplan and Yun Li, a senior scientist and a scientist, respectively, at SickKids; bioengineers Penney Gilbert, an associate professor at IBBME, Alison McGuigan, a professor at the Department of Chemical Engineering & Applied Chemistry, and Peter Zandstra, a University Professor at IBBME and the director of Michael Smith Laboratories at the University of British Columbia; Sid Goyal, a professor at the Department of Physics; and stem cell biologist Cindi Morshead, a professor and chair of the Division of Anatomy in the Department of Surgery.
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.
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 Sunnybrook Research Institute, Maryam Faiz, an assistant professor in the Department of Surgery, and Melanie Woodin, a professor in the Department of Cell & 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.
University Professor Molly Shoichet
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.