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Development of SIMPL, a novel protein-protein interaction assay based on split intein for biomedical research

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Overview

Proteins control every function of every cell in our body. Proteins, however, never act alone; rather, they interact with many other proteins in what are called protein-protein interactions (PPIs). Gain or loss of PPIs can be the driving force behind disease development. Dr. Igor Stagljar of the University of Toronto is leading a team to develop and implement a novel disruptive genomics technology that can detect and monitor PPIs in human cells. This technology can be used to identify novel proteins as components of many essential cellular processes, leading to greater understanding of the role of specific proteins in our cells. Furthermore, the technology also has the potential to identify drugs that disrupt a defined set of PPIs when the PPIs cause disease.

Economical high throughput de novo whole genome assembly

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Overview

“De novo” sequencing, or constructing an individual’s genome from his or her own data alone (as opposed to comparing it to a reference genome), is a formidable task, akin to assembling a jigsaw puzzle comprising hundreds of millions of small blank pieces. Drs. Si Lok, Stephen Scherer, and their colleagues from The Hospital for Sick Children are developing a new “mate-pair” technology that would overcome the financial and logistical barriers to de novo sequencing by linking sequences to one or more other reads in precisely known orientations and distances. Mate-pair technology would create a high-resolution backbone to enable de novo sequencing to be carried out in a single simple step. This new adaptation of mate-pair sequencing is a disruptive technology that could supersede all current methods of de novo sequencing, thereby representing a leap forward in many areas of research and, ultimately, in healthcare.

Cell biosensors for rapid screening of insect attractants

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Overview

Forestry and agriculture together contribute close to eight per cent of GDP in Canada, but insect pests pose a continual threat. Functional genomics has long promised to bring new solutions to recurrent and new pest problems. Dr. Peter J. Krell of the University of Guelph, in collaboration with Drs. Daniel Doucet and Jeremy Allison (NRCan), is creating highly sensitive surveillance and mitigation systems targeting insects, using a family of insect genes known as odorant receptors (ORs). This innovation should not only disrupt the discipline of functional genomics, but also the field of insect pest management, making surveillance and mitigation more feasible and faster, while helping preserve Canada’s position as a leading exporter of forest and agricultural products.

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.