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Medicine by Design’s Grand Questions Program aims to change the future of regenerative medicine through research that addresses some of the field’s biggest unanswered questions.

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Through this program, Medicine by Design is investing in bold ideas and developing transformative and revolutionary solutions that will be of critical importance to regenerative medicine over the next 20 years. These solutions will enable new therapies that promise dramatically better health outcomes for people around the world, ensuring Toronto and Canada continue to lead this health-care transformation.

Medicine by Design is investing $3 million in the Grand Questions Program over the period of spring 2021- spring 2023.

Watch the Grand Questions announcement and panel recording

On May 7, 2021, Medicine by Design hosted an event to announce the funded projects. The event featured a panel discussion called, Ambitious and provocative — expanding the frontiers of regenerative medicine.

Grand Questions Funded Projects

Grand Question: Designing Tissues de novo — Can we make tissues that perform better than nature?

Mimicking the function of the native tissue is often the goal of regenerative medicine research and respects evolutionary pressure. But can we do better?

Can we generate cells and/or tissues that will provide function(s) that are enhanced, entirely novel or “borrowed” from nature (i.e. from non-human organisms) for therapeutic purposes?  Examples of new functional properties could include the ability to evade infection by viruses or other pathogens, enhanced vision (widened spectra), improved sense of smell or hearing, avoidance of senescence and neoplasia.

Is there a way we can design robust cells and tissues such that when they and we eventually expire, we do so painlessly and naturally, without having suffered debilitating conditions?

These outcomes could be achieved by creating chimeric cells, combining tissue functions in one novel cell type, or interfacing cells and tissues with electronics or soft robotics. The new cell/tissue could be designed for ad hoc use (i.e. something that could be removed once the outcome has been achieved), or it could be implanted for life.

Since the development of such a cell/tissue has ethical implications, competitive proposals will integrate ethical considerations and engage with bioethicists to create a consensus framework as part of the project. Competitive applications will propose goals that are well beyond the current state of the art.

Project: Establishing a ‘Centre for the Design of Novel Human Tissues’ to address graft cell death and promote ‘super-tissue’ development

Synthetic biology is providing a huge array of new biological components that can be arranged into circuits and inserted into cells to give them new functions. In parallel to this, huge advances have been made in the field of regenerative medicine,opening up the possibility of implantable cells, tissue or devices that are engineered to restore a loss of function or release a therapeutic factor. Engineering cells with genetic circuitry that allows to process inputs and outputs––in a similar manner to processing inputs and outputs in a computer––could revolutionize medicine by shifting diagnosis, manufacture and dose control into the human body. However, despite the vast potential of curative cell-based therapies that uses synthetic biology, implementation of this grand vision is still highly challenging. Getting synthetic circuitry working in specialized human cells in vivo faces major obstacles, including immune rejection, silencing of synthetic circuitry,unwanted perturbation of cell machinery, and competition for cell resources. In sum,the introduction of synthetic circuits to human cells tends to engender dysfunction or cell death.

The field of regenerative medicine is ideally positioned to meet the grand challenge of designing tissues de novo and to deliver innovative solutions to overcome these obstacles. Stem cell reprogramming and differentiation into a huge diversity of human tissue types has been achieved in recent years. An ability to reproducibly generate and culture primary human cells in large numbers means that synthetic circuit libraries can be screened in a high throughput fashion and optimised in environments that closely approximate their destined clinical setting. In turn, synthetic biology has the potential to provide solutions to the big challenges facing regenerative medicine.One example of a barrier that undermines the success of regenerative therapies in all organs and disease contexts is the phenomenon of graft ischemia. Graft ischemia arises during the initial period of cell transplantation due to the limited integration of the cells with the host vasculature resulting in poor supply of oxygen and nutrients to the graft. Up to 90% of implanted cells are lost due to ischemic cell death, and this challenge limits the therapeutic potential of cardiac, liver, pancreatic, and neuronal cell types, among many others. We are therefore proposing two goals:

1) Tackle the specific challenge of ischemic graft cell death (as a universal barrier to cell-therapy and tissue engineering)

2) Establish cores of expertise to promote Canadian leadership at the interface between synthetic biology and regenerative medicine. We will achieve these goals by establishing a synthetic biology–regenerative medicine hub. This hub will make the tools and techniques of synthetic biology readily available to regenerative medicine investigators and enable synthetic biologists to develop and screen their tools in clinically relevant contexts. Fundamentally, it will create expertise cores that are shared among investigators –enabling the initiative to be easily expanded and extended to more investigators. Solving the ischemia problem will be used to initially consolidate the hub around a challenge of universal interest in the first 2-5years. Our ten and twenty-year vision is a Canadian-driven, globally leading, Centre for the Design of Novel Human Tissues.

Michael Garton

Lead Investigator:
Michael Garton, Assistant Professor, Institute of Biomedical Engineering, University of Toronto

Michael Laflamme, University Health Network
Yun Li, The Hospital for Sick Children
Maria Cristina Nostro, University Health Network
Shinichiro Ogawa, University Health Network
Stephanie Protze, University Health Network

Bruce Conklin, University of California San Francisco
Martin Fussenegger, ETH Zürich
Ron Weiss, Massachusetts Institute of Technology

Grand Question: Physics of Regeneration — What are the core physio-chemical principles governing organ formation, and can they facilitate organ regeneration?

Tissue engineering currently relies in large part on mimicking normal developmental processes in an in vitro setting. Often, small and rapidly developing systems the size of early embryos (e.g. cell aggregates, embryoid bodies and organoids) are used as paradigms for tissue or organ construction. However, to rationally advance the generation of functional post-natal tissues, completely different size and time scales need to be mastered by employing insights and technologies that do not currently exist. During organogenesis, cell differentiation and tissue morphogenesis are spatiotemporally coupled and regulated by biochemical and physical cues.

In contrast to current approaches such as trial-and-error experimentation, it may be more efficient to define conserved physical rules that drive key morphogenetic processes as systems transit to larger sizes and progressively acquire different mechanical features.

Can the physical and chemical principles of embryonic morphogenesis be distilled into core principles and applied to bridge the spatiotemporal gap from organogenesis to the generation of functional organs? Defining these core physical rules and applying them in vitro and in vivo will require close collaboration between developmental and cell biologists with physicists, mathematicians, and engineers.

Project: Defining biophysical mechanisms of organogenesis to facilitate regeneration 

The promise of regenerative medicine is to be able to grow structurally and functionally appropriate tissues to replace poorly functioning, deficient or damaged organs. The scientific community’s efforts to generate specialised organ cells for replacement have been highly successful because they are apply biochemical cues that normally generate those cells in the embryo. Although we can make many cell types now, we still cannot generate functional organs because we don’t yet know how the embryo creates 3D organ structures. Our team of collaborators are determined to discover the basic biophysical rules by which organ tissues are constructed in the embryo. We combine developmental biologists, physicists and engineers in our endeavour to define precisely how physical properties and forces are combined and regulated in the embryo to drive cell movements that form organs. Figuring out how the embryo does it will accelerate our ability to make those special tissues for regenerative purposes.

Sevan Hopyan

Lead investigator:
Sevan Hopyan, Orthopaedic Surgeon and Senior Scientist, The Hospital for Sick Children

Sidhartha Goyal, University of Toronto
Yu Sun, University of Toronto
Rudolf Winklbauer, University of Toronto

Eric Siggia, The Rockefeller University 

Grand Question: New Technology for Cell Tracking — Can we record the signaling history of a cell?

Observing a tissue as it undergoes a dynamic transition (e.g. during development, disease progression or during the integration of regenerated tissue) is challenging, if not impossible, to do using current methods. The capacity to spatially and temporally record cellular signalling events in a multiplexed manner would transform our understanding of the cellular heterogeneity and multicellular information processing that underlies normal and pathological tissue biology.

Can we comprehensively trace the input signals (type, magnitude, duration) that drive cell decision-making in complex multicellular systems undergoing organizational and fate transitions? Can we develop a scalable, high-content and non-destructive technique to log signalling pathways at single-cell resolution in space and time?

Project: Logging cell experience to learn how to program cell function 

Over the next twenty years, medicine will increasingly use and manipulate cells as therapeutic agents to heal injuries and cure disease. Clinical trials of cell-based therapies have already exploded in the last five years and a few success stories, such as for the treatment of cancer, have provided a glimpse of the potential impact of cell-based therapies.Currently however,many cell-based therapies fail in patients because the therapeutic cells do not function properly when implanted. This problem occurs because therapeutic cell types typically have highly variable properties depending on their local environment. Our inability to precisely program and control cell properties in patients limits therapeutic performance. In this project we will apply genetic engineering, genomics and proteomics, and tissue manufacturing/disease modelling tools to record the environmental signals a cell experiences and the resulting effect on cell function. These molecular tools will write a permanent record of the detection event into a cell’s DNA, (i.e.which lig and, and when it was detected). In parallel, we will engineer a methodology for “painting” a cell with a molecular mark that identifies each other type of cell it has been in contact with (i.e.a cell contact tracing app). This information, combined with measurements of the cell’s overall properties will be inputted into a machine learning algorithm to learn rules that program cell behavior. As an example of our approach, we will focus on understanding how to program human macrophage cell properties in environments mimicking those present in cancer patients. If successful, our approach will provide a strategy to identify the critical molecular signals that program cell properties in the environments in which these cells must function when implanted into people. Ultimately this will establish a molecular basis from which to rapidly and rationally engineer therapeutic cell function, optimize therapy performance, and personalize the cell-based therapies of the future.

Alison McGuigan

Lead investigator:
Alison McGuigan, Professor, Department of Chemical Engineering and Applied Chemistry and Institute of Biomedical Engineering, University of Toronto

Gary Bader, University of Toronto
Leo Chou, University of Toronto
Michael Garton, University of Toronto
Hartland Jackson, Sinai Health
Tracy McGaha, University of Toronto
Andrew Woolley, University of Toronto

Fei Chen, Massachusetts Institute of Technology
Trey Ideker, University of California San Diego
Harris Wang, Columbia University

Grand Question: Affordability and Accessibility — How can we make regenerative medicine available to everyone?

Regenerative medicine and cell-based therapies have the potential to cure otherwise intractable diseases and are among the most promising domains for the delivery of paradigm-changing health care. However, the anticipated cost of these therapies will strain even well-resourced health-care systems. Globally, these costs will pose a much greater challenge, with most people not expected to be able to access the benefits of these technologies. Furthermore, it is expected that such technologies, as currently envisioned, will be hard to implement outside major medical centres.

Reducing the cost of developing and delivering these advanced therapies is critical for patient access, but also for researchers and innovators in the field.  Society’s continued investment in research is critical to bringing their products to market. Reducing the barriers to access is a separate but equally critical task.

While some regenerative medicine therapies are based on approaches that do not involve cells, for cell-based therapies can we look to automation, robotics, machine learning or other technologies to simplify their scale-up or scale-out, perhaps making them no more complex than dialysis or chemotherapy?

The development of such technologies will require perspectives from global health practitioners among others with a health accessibility perspective. Therefore, competitive applications will integrate an array of disciplines to inform the team on how best to reach the goal of affordable, accessible regenerative medicine.

Project: On-demand cell therapies for affordable patient access in Canada

Cell therapy research has made tremendous advances in recent years and is now becoming available to patients. Cellular immunotherapy is leading the charge, with Chimeric Antigen Receptor (CAR) T-cell therapy for the treatment of multiply relapsed blood cancers now being used in the clinic. Beyond cancer, the next generation of cell therapies, such as those based on T cell regulatory cells, offer hope to cure chronic diseases like: type 1 diabetes, inflammatory bowel disease, lupus and multiple sclerosis. While on track to revolutionize the field of medicine, cell therapies face a critical challenge inpatient accessibility. With the need for expensive and sophisticated laboratories to create these treatments, availability is limited by infrastructure logistics and cost, which exceeds hundreds of thousands of dollars per patient.

Here we bring pioneering research in cell therapy together with leaders in molecular tool and hardware development to create a platform for the automated manufacture of cell therapies. Canada, with highly distributed communities, could benefit greatly from such an approach by extending the reach of cell therapy to smaller medical centers. While this is a long-term goal, here we begin with the development of new cellular, molecular and hardware technologies to establish an automated platform capable of isolating T cells for the reprogramming, expansion and quality control needed to create custom CAR T therapies. This strategy allows us to create near-term impact using a therapeutic class already on the market,while creating a platform that can extended broadly to cell therapies (e.g. iPSC-derived insulin secreting cells). To demonstrate the potential of this approach, and to build momentum for a sustained effort, we propose a series of clear, near-term milestones in each of the technical domains. These technologies will be tested by an independent cell therapy lab for iterative improvements throughout the project, and therapeutic efficacy of cell products validate in year two. Canada is poised to become a leader in cell therapy and through the Medicine by Design Grand Question program there is an opportunity for Canada to catalyze this revolution in medicine into an economically sustainable and broadly available option for patients. Pioneering first-in-class technologies that can transform cell therapy into a mainstream option for patients and will position trainees and research in Canada strategically well, with exciting opportunities for economic growth.

Keith Pardee

Lead Investigator: ​
Keith Pardee​, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto

Co-Investigators: ​
Leo Chou, University of Toronto​
Shana Kelley, University of Toronto​
Teodor Veres, University of Toronto, ​National Research Council Canada​

​Advisors: ​
Laszlo Radvanyi, Ontario Institute ​for Cancer Research​
Wilson Wong, Boston University