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Development of advanced genetic toolbox for Sinorhizobium meliloti to enable genome scale engineering

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Overview

Genetic engineering seeks to improve agricultural outcomes by enhancing traits such as disease resistance, drought tolerance or superior levels of production. Conducting this engineering, however, requires a host where genes can be implanted and researchers perform genetic manipulations – a process known as synthetic biology. Drs. Turlough Finan, Bogumil Karas and Trevor Charles are developing a bacterial surrogate host system (Sinorhizobium meliloti) that allows replication and engineering of large DNA fragments before reintroducing them back to the original organism. In addition to its general application for genome engineering, the S. meliloti surrogate host-system technology can be used in short-term technology developments, including the generation of large DNA libraries for bioprospecting.

RapidAIM: A high-throughput assay of individual microbiome

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Overview

The more than 1,000 different species of bacteria that colonize our gastrointestinal tract are collectively known as our microbiome. Dr. Daniel Figeys and Dr. Alain Stintzi of the University of Ottawa are developing RapidAIM to gain information on how drugs affect the microbiome and vice versa. The team will also develop a computational program that will combine and analyze these results, to better predict drug efficacy and clinical outcomes. RapidAIM could allow rapid screening of candidate or current drugs for potential adverse microbiome effects. The economic benefits will come in the form of a commercializable assay and computational platform for the screening of human microbiomes.

Massively parallel single molecule protein sequencing in-situ

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Overview

Proteins in cells are responsible for virtually every biological process. When they don’t work properly, the result can be human diseases such as cancer, Alzheimer’s, diabetes and heart disease. Dr. Andrew Emili of the University of Toronto will develop a revolutionary new sub-microscopic imaging technology that will allow researchers to identify and quantify each and every one of the many millions of different protein molecules present in human cells and tissues at an unprecedented level of detail. The proprietary chemical probes and tool “kits” he and his team develop will be applicable to a wide diversity of biomedical specimens, displacing existing technologies and ultimately changing the study of human cell biology and medicine.

RNA-seq in patient derived ex-vivo models: Genetic diagnostics beyond whole exomes

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Overview

There are more than 6,000 rare diseases caused by mutations in a single gene; together they affect more than 500,000 Canadian children. Exactly what gene is causing a disease is unknown in more than half the cases. RNAseq may provide a strategy for discovering novel genetic mutations that cause rare diseases – but can’t be used without obtaining the specific tissues in which the disease is present. Drs. James Dowling and Michael Brudno, of The Hospital for Sick Children will use ex vivo disease models created at Sick Kids in place of tissue biopsies to perform RNAseq for gene mutation discovery. By combining recent advances in cell biology, genomics and bioinformatics, the lab will develop a new diagnostic methodology, fundamentally transforming the clinical diagnostics process.

AbSyn Technology for identification of synergistic cancer therapeutics

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Overview

Genome sequencing has revolutionized our understanding of the genetic changes that lead to cancer. Unfortunately, treatment still remains in the relative Dark Ages, with decades-old treatments that can be highly toxic and that don’t consider the subtle genetic differences among each patient’s disease. Dr. Charles Boone and his team at the University of Toronto are developing AbSyn, a new technology that will identify combination therapies tailored to individual cancers. AbSyn stands for the development of antibodies (Ab), whose promise for treating cancer has been hugely under-realized, and synergistic (Syn) therapies for cancer based on these antibodies. AbSyn will change the way we prioritize and discover new cancer drugs, building a new bridge between the gap of biological understanding and the commercial drug discovery process.

Development of a digital microfluidic platform to identify and target single cells from a heterogeneous cell population for lysis in an ultra-low volume for non-invasive prenatal diagnosis

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Overview

Currently prenatal diagnosis, by amniocentesis or chorionic villi sampling, is costly, is being done only by specialists in a small number of centers and carries a risk of miscarriage. Amniocentesis is done later in pregnancy, with results often not known until 17 weeks gestation. To reduce the cost, these prenatal diagnostic tests are usually offered only after an earlier prenatal screening test result or fetal ultrasound shows an increased risk for chromosomal abnormality. A safe, non- invasive and less expensive procedure, which can be done by a variety of health care professionals, would allow testing of all pregnant women for fetal chromosome abnormalities, rather than only those at an increased risk, as well as testing for single gene disorders of pregnancies at risk. This will relieve parental anxiety while reducing healthcare costs, substantially.

Experts at Mount Sinai Hospital have developed a method to collect fetal cells non-invasively, using a technique similar to a PAP smear. In the first phase of this project, Dr. David Chitayat and Dr. Elena Kolomietz from Mount Sinai worked with Dr. Aaron Wheeler and his team at the University of Toronto to develop a way to isolate and analyze these cells using microfluidics and genomic analysis. The team built a proof-of-principle digital microfluidic platform that it will now further develop for beta testing and validation for accuracy, precision, sensitivity and specificity in a clinical laboratory, culminating in a 550-patient clinical trial.

This new technique could transform prenatal diagnosis, providing a safe, non-invasive and inexpensive diagnostic test that can be performed as early as six weeks of pregnancy. With no other test like it available, it will compete in the multi-million dollar global market and save the healthcare system hundreds of millions of dollars. The technique will be commercialized through a start-up company that will attract investment and create job opportunities in Canada’s burgeoning high-tech/biotech sector.

Interactome mapping of disease-related proteins using split intein-mediated protein ligation (SIMPL)

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Overview

Every cell in the human body contains proteins, and these proteins are essential to the proper functioning of every part of our body. Proteins are not soloists, though – like an ensemble, they interact with other proteins, in a process called protein-protein interactions, or PPIs. When these interactions go awry, disease results. Because of their involvement in causing diseases, understanding how these interactions work is essential to finding targets for intervention and developing drugs that will do so.

In phase 1 of this competition, Dr. Igor Stagljar of the University of Toronto and his team developed a new method for studying PPI interactions, called Split Intein-Mediated Protein Ligation (SIMPL), which outperforms current methods for studying PPIs. They now propose to further develop SIMPL as a groundbreaking assay for biomedical research by combining it with mass spectrometry to extend its capabilities and facilitate a more powerful and convenient platform. The team will also use SIMPL to globally map PPIs involved in disease, particularly cancer development. Finally, they will use SIMPL as a drug-screening platform to identify chemicals that can interfere in PPIs implicated in cancer development.

SIMPL will be a transformative technology for studying functional genomics. It will displace current methods of studying PPIs, accelerate our understanding of cell physiology and disease development and identify new therapies for some diseases. SIMPL will be commercialized through a newly founded Canadian company, ProteinNetwork Tx, ensuring both economic and health benefits for Canada.

Beyond the Genome: Transcriptome Based Diagnostics for Rare Diseases and Cancer

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Overview

Rare genetic diseases affect more than 500,000 children in Canada, often causing severe disability and early death, while cancer is the leading cause of non-accidental death in childhood. Early diagnosis at the molecular level is essential so that the right treatment for each individual can begin as early as possible. The most advanced genetic tests, however, are able to diagnose fewer than half of all children with rare disease and cannot detect important genetic changes in tumours that are critical for successful treatment.

In the first phase of this competition, Drs. Adam Shlien and James Dowling of the Hospital for Sick Children, with co-leaders Drs. Michael Wilson and Michael Brudno, demonstrated that RNA sequencing (RNA-seq), an emerging technology that examines the activity and structure of genes, can find disease-causing genetic variants (Dowling) and detect mutations and fusions in cancer genes (Shlien). Importantly, many of these mutations are not found by current genetic testing. In this second phase, they are combining their strengths to further develop and optimize the technological elements of RNA-seq and definitively determine how well it performs as a clinical test. Their goal is to create a clinically viable, comprehensive RNA-seq–based diagnostic platform for rare diseases and cancer. This platform will be fully automated, using advanced robotics and algorithms, and will improve in accuracy for every sample it is run on.

Their work will result in the first clinical RNA-seq diagnostic test in Canada. When fully implemented, the test will significantly increase the success rate of genetic testing in children with rare genetic diseases and cancer and improve access to clinical trials. The researchers will also create a dynamic digital library to integrate RNA-seq data with a range of health information, setting the stage for true precision medicine for all Canadians.

AbSyn Technology for Identification of Synergistic Cancer Targets

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Overview

Diagnosing disease has been revolutionized by our ability to decipher the genetic changes that lead to cancer; our treatment abilities have not kept up and most patients still receive decades-old treatments that do not target the individual genetic nuances of each individual’s tumour and are highly toxic as well. The development of antibody-based drugs, such as Herceptin for breast cancer and Humira for rheumatoid arthritis, has changed the treatment landscape and had a tremendous impact on patient survival in these areas. But the success of antibodies is limited by our lack of ability to develop and apply efficacious new antibodies to kill target cells, particularly because of the complexity of diseases such as cancer.

Drs. Jason Moffat and Charles Boone of the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research, with previous funding from Genome Canada, have invented AbSyn, a disruptive technology that combines expertise in the production of antibodies (Ab) and the deciphering of genetic networks to produce combination or synergistic (Syn) treatments for cancer. In the first phase of this competition, the researchers confirmed AbSyn’s potential to be a robust drug discovery pipeline. Now, in phase 2, their goal is to promote the development of AbSyn into a platform that is attractive to the pharmaceutical industry. With the support of Celgene, a global leader in biopharmaceuticals, they will undertake large-scale screening to further demonstrate AbSyn’s potential. The technology will ultimately be incorporated into Bridge Genomics, a Canadian start-up company, where it will enhance their mission of searching for disease-specific interactions that can be targets for drug development.

AbSyn presents an opportunity for Canada to attract the biotechnology investment needed to create a vibrant biotech sector in Ontario and attract and retain talented, highly trained researchers and have far-reaching economic benefits in terms of intellectual property and revenues. It will also highlight Canada’s growing influence in the field of precision medicine.

RapidAIM: A technology to rapidly assess the effects of compounds on individual microbiomes

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Overview

Human microbiomes – the microbial colonies that exist in our guts –play a key role in disease development, progression, and therapeutic response. While global changes in the microbiome have been correlated to a disease or response to therapies, we lack methods to rapidly assess the impact of drugs and compounds on individual microbiomes. The development of a rapid screening platform would provide a groundbreaking and effective tool to screen novel and existing drugs and compounds for their effect on individual microbiomes. This would allow the screening of compounds for drug development to induce the desired changes in the microbiome.

Dr. Daniel Figeys and his team, in the first phase of this competition, demonstrated the proof-of-principle of RapidAIM, an assay that measures functional changes in individual microbiomes following exposure to drugs or compounds. The team is currently developing commercial applications, which include a fully automated, high-throughput prototype of the RapidAIM platform, together with a bioinformatics analysis platform, MetaLab. The Companion software developed for RapidAIM, METAMCI, will rapidly assess the effects of drugs/compounds in individual microbiomes. The team will also create a drug-microbiome interaction database of FDA approved and novel compounds to test RapidAIM and METAMCI , in collaboration with their industrial partners Biotagenics and Filament BioSolutions.

The development and commercialization of RapidAIM will provide significant economic benefit. The product will enable identification of new drugs/compounds that target the microbiome, facilitate more rapid clinical development of drug candidates, prevent unwanted negative effects on the microbiome of new therapeutics, and achieve a better understanding of the impact of currently used therapeutics on the microbiome. The technology can also be used to select the most effective treatment for individuals, based on their microbiome’s differing responses to drugs, improving health and reducing healthcare costs by targeting treatments to those who will benefit most.