The four investigators who are leading ambitious Grand Questions projects. Left to right: Michael Garton, Assistant Professor, Institute of Biomedical Engineering, University of Toronto; Sevan Hopyan, Orthopaedic Surgeon and Senior Scientist, The Hospital for Sick Children; Alison McGuigan, Professor, Department of Chemical Engineering and Applied Chemistry and Institute of Biomedical Engineering, University of Toronto; and Keith Pardee, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto.
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 some of the transformative advances Medicine by Design 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 the University of Toronto (U of T) and its affiliated hospitals that will undertake this ambitious research were announced on Friday at a launch event celebrating a new era in the field.
“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 at the Department of Chemical Engineering & Applied Chemistry 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.”
This week’s announcement is the culmination of more than a year of groundwork 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 Grand Questions.
“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 Grand 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,” says Sefton, whose lab is located at the Donnelly Centre for Cellular and Biomolecular Research. “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 Grand Questions 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 and the Institute of Biomedical Engineering at U of T. “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 is something like a “contact tracing app” for cells, she says, that can measure very specific inputs and outputs from cells. Through this 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 the 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 adds. “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 at U of T. “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, essentially creating portable cell manufacturing systems. This means that the process of making cell therapies could be done outside of major centres and would not require specialized skills, allowing on-demand manufacturing for cell therapies virtually anywhere.
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?
A feature of the Grand Questions Program is that international experts act as key advisers to the funded teams. Michael Garton, another of the project leads, says the Grand Questions proposal gave him an opportunity to expand his collaborations.
“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 at the Institute of Biomedical Engineering at U of T. “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?
Ambitious ideas are the hallmark of the Grand Questions program. Sevan Hopyan, an orthopaedic surgeon and senior scientist at The Hospital for Sick Children and associate professor at the Departments of Surgery and Molecular Genetics at U of T, 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, and then uses those observations to empower computational simulations of development, and then performs experiments to confirm the models.
Hopyan sees the long-term impact of this project will be 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.”
About Medicine by Design and Regenerative Medicine
Funded by a $114-million grant from the Canada First Research Excellence Fund, Medicine by Design brings together more than 150 principal investigators at the University of Toronto and its affiliated hospitals to advance regenerative medicine discoveries and accelerate them toward impact. 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 James Till and Dr. Ernest McCulloch.
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.
