The following projects received 2019 New Ideas and Seed Fund awards:

New Ideas Awards

DNA nanofabrication as a tool to manipulate spatial organization of immune-receptor signalling

Lead Investigator:
Leo Chou
Institute of Biomaterials & Biomedical Engineering, University of Toronto

Bebhinn Treanor
Department of Biological Sciences, University of Toronto Scarborough

Project Description: Autoimmune diseases including lupus, arthritis, and multiple sclerosis affect approximately 2 million Canadians. The current standard treatment for these diseases relies on the use of drugs that nonspecifically dampen the immune system, leaving patients susceptible to life-threatening opportunistic infections and long-term risk of malignancy. B cells of the immune system are implicated in many autoimmune diseases through the production of inflammatory cytokines and self-reactive antibodies. During the natural course of immune defense against pathogens, B cells produce antibodies following a process of activation, which is triggered by the binding of pathogen components (referred to as antigen) to the B cell receptor (BCR). This process becomes mis-regulated in autoimmune disorders when BCRs develop reactivity towards self-antigens. Despite the importance of BCR triggering by antigen in the process of B cell activation, we still do not understand how the spatial presentation and density of antigen impacts B cell activation. To address this knowledge gap, this project will use the precise nanofabrication afforded by DNA nanotechnology to test how 2D structural features of antigen presentation, such as density and spatial array, affect B cell activation. In addition, this project will test whether spatial features of antigen presentation can be manipulated to induce antigen-specific B cell inhibition. The outcomes from this project will provide an innovative synthetic biology tool to investigate immune receptor signaling, and generate guidelines for engineering more targeted therapeutics against B-cell mediated diseases.

Precision immunotherapy for arrhythmogenic right ventricular cardiomyopathy

Lead Investigator:
Dr. Robert Hamilton
The Hospital for Sick Children

Sachdev Sidhu
Donnelly Centre for Cellular & Biomolecular Research

Dr. Donna Wall
The Hospital for Sick Children

Project Description: A heritable heart muscle disorder with associated life-threatening arrhythmias, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), is a major contributor to sudden cardiac death (and the resultant years of potential life lost) and has no treatment. The Hamilton lab recently identified that ARVC is an autoimmune disorder in which patients generate antibodies against proteins that connect heart muscle cells. Precision therapies originally developed for cancer therapy (such as monoclonal antibodies (MAbs), synthetic antibodies or genetically modified white blood cells) are now being modified to target autoimmune diseases. Examples include Adalimumab (HumiraTM Abbott) for Rheumatoid Arthritis or Psoriasis, and anti-DSG3 Chimeric Autoantibody Receptor (CAAR) T-cells for Pemphigus (preclinical, Cabaletta Bio).

Although classical MAbs bind only one target, a new class of synthetic antibodies has been developed which can bind two or more targets. When one of the targets is a special white cell called a killer T-cell, these cells can be engaged by one side of the antibody to attack a cell targeted by the other side of the antibody. These synthetic antibodies are called Bispecific T-Cell Engager, or BiTE antibodies. For our proposed therapy, we will create a BiTE antibody that  engages patient T-cells to target the specific B-cell clone that is producing the autoantibodies contributing to autoimmunity in ARVC. We (R Hamilton) identified these antibodies (anti-DSG2), so the B-cells that produce them can be targeted by synthetic BiTE antibodies produced by Dr. Dev Sidhu, an expert in BiTE technology. (CAAR T-cells will be an alternate technology that can also be applied.)

Empirical and computational evaluation of rigidity transition and durotaxis as interrelated mechanisms that shape organ primordia

Lead Investigator:
Dr. Sevan Hopyan
The Hospital for Sick Children

Huaxiong Huang
Department of Mathematics, University of Toronto

Yu Sun
Department of Mechanical & Industrial Engineering, University of Toronto

Project Description: The proper function of human organs depends upon specialised cell types that are organised in an optimal way.  Morphogenesis, or the organisation and shaping of embryonic tissues, has long been recognised as an inherently physical process that is poorly understood.  Critically, the tools required to unravel how physical rules shape biological structures have not previously been available.

The collaborative team consisting of the Hopyan (developmental biology), Sun (mechanical engineering) and Huang (mathematics) labs is emerging as a world leader in the production of tools to measure physical properties and forces within mammalian embryos, and for establishing how physical laws drive morphogenesis.  Two important processes that we identified are rigidity transition, in which tissues flow like melting glass before solidifying into mature structures, and durotaxis, in which cells move toward stiffer areas in developing tissues.

We believe that rigidity transition and durotaxis together explain the physical basis by which all organs are initially organised.  Our primary goal is to combine physical data with a computational model we created to define how these processes are interrelated.  Our conceptual advance will open doors for explaining the structural basis of birth defects and for mechanically guiding efforts at organ regeneration.  Our secondary goal will be to validate our versatile and physically realistic computational model of morphogenesis that will be provided as a free open source program for researchers worldwide.  These advances will draw scientific recognition and also collaborative opportunities for scientists in Canada as international researchers continue to seek our tools and software.

Living Therapeutics that Sense IBD and Respond with the Secretion of Therapeutics

Lead Investigator:
Krishna Mahadevan
Department of Chemical Engineering & Applied Chemistry, University of Toronto

Keith Pardee
Leslie Dan Faculty of Pharmacy, University of Toronto

Tae-Hee Kim
The Hospital for Sick Children

Project Description: Inflammatory bowel disease (IBD) is characterized by chronic and relapsing inflammation of the gut and plagues over 270,000 Canadians. With our complementary expertise in synthetic biology (Mahadevan, Pardee) and gut stem cell biology (Kim), we propose to design gut microbiota that sense and respond to IBD with enhancers of stem cell activity to promote mucosal healing. We will engineer whole cell biosensors that can detect the IBD disease state through small molecule and bacterial RNA response profiling, and secrete anti-inflammatory and pro-regenerative molecules. MbD cycle I efforts show that engineered bacteria facilitate regeneration after damage to intestinal epithelial cells.  Here, we will build on this success with a program that explores additional therapeutic modalities and validate engineered bacteria in our established IBD mouse and gut on a chip models.

New therapeutic modalities will include secretion of neutralizing single domain antibodies for inflammatory cytokines (TNFa , Il1b), stem cell factors and muramyl dipeptide (MDP). Evidence suggests that mutations in the NOD2 receptor reduce its ability to detect microbial products including MDP – a component of peptidoglycan (PG), leading to an abnormal immune response and the manifestation of Crohn’s Disease – a form of IBD. We plan to engineer microbial strains for increased production of MDP and its derivatives to levels that are detectable by the mutated NOD2 receptor. By moving the production of these therapeutics modalities into the microbiota of patients for the long-term management of IBD, our goal is to ultimately overcome the challenges of timely medical intervention and the immunosuppression associated with conventional treatment.

Seed Fund Awards

Cerebral cortical organoids: The ultimate personalized medicine for epilepsy

Lead Investigator: Dr. Peter Carlen, University Health Network
Co-Investigators: Cathy Barr, University Health Network, and Roman Genov, Department of Electrical & Computer Engineering, University of Toronto

Engineering ILCs that induce tolerance and promote tissue repair

Lead Investigator: Sarah Crome, University Health Network

Regeneration of Auditory Neurons for the Treatment of Hearing Loss

Lead Investigator: Alain Dabdoub, Sunnybrook Research Institute

Role of Transposons in High-Order Chromatin Organization of hPSCs and the Generation of Cerebral Organoids

Lead Investigator: Miguel Ramalho-Santos, Lunenfeld-Tanenbaum Research Institute, Sinai Health System

Robocell: Functional emergence in tissues and drones

Lead Investigator: Angela Schoellig, University of Toronto Institute for Aerospace Studies
Co-Investigator: Peter Zandstra, Institute of Biomaterials & Biomedical Engineering