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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 ������Ƶ’s hopes to enable through its , 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  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 .

“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.”