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BridGE-SGA: A novel computational platform to discover genetic interactions underlying human disease

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Overview

The ability to sequence the entire human genome at increasingly lower cost has led to a fundamental change in biomedical research. But there is a gap between the amount of data available and our ability to understand and interpret that data. Addressing this gap is essential to realize the promise of precision medicine.

Dr. Charles Boone and Dr. Brenda Andrews of the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto, and Dr. Chad Myers of the University of Minnesota, have worked together to discover that a significant part of our inability to interpret genomic data likely stems from the reality that disease generally arises from complex genetic interactions. While all humans essentially have the same set of genes, most have around five million unique genetic variants. The effect of any one variant depends on its interactions with other variants. So we need to understand not just the millions of genetic differences that affect gene function, but also how all those genes interact with each other. Current computational methods and technologies lack the statistical power to do so.

Drs. Boone, Andrews, Myers have developed the first complete genetic interaction map for any organism, and have built a computational method, BridGE, to discover genetic interactions. The team is now working to develop an innovative computational platform for genome sequencing data, BridGE-SGA, to enable the discovery of disease-associated genetic interactions from large-scale human genotype data. Their goal is to discover genetic interactions for a variety of diseases. Identifying and understanding these key genetic interactions will improve our ability to interpret data from whole genome sequencing and identify novel gene targets for drug discovery and development.

Stratifying and targeting pediatric medulloblastoma through genomics (2010)

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Overview

Understanding childhood brain cancer. Brain cancer is the leading cause of pediatric cancer deaths. Children who survive have a much poorer quality of life due to the aggressive treatment used to fight the disease. This results in a staggering burden of suffering for them and their families as well as economic costs of over $100 million annually to the health system. Studies indicate that children with a good prognosis are often over-­treated and could be spared complications by reducing the amount of treatment they receive. At the same time, children with a poor prognosis are often subjected to painful treatments which may, in fact, be futile. With support from Genome Canada, scientists are using genome wide approaches to study medulloblastomas, the most common form of childhood brain cancer, to develop markers that will more accurately classify the tumors for treatment. Researchers are also identifying genetic changes that may reveal the risk factors that predispose children to this type of cancer. As they unravel the genetic basis of brain cancer, the research team is also working with families to determine what additional risks they are willing to assume in reducing therapy to improve quality of life. It is anticipated that the results of this research will lead to new ways to treat childhood brain cancers more effectively and to enhance the quality of life of children struck by this devastating disease. 

Synthetic antibody program: Commercial reagents and novel therapeutics (2010)

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Overview

Cancer is now, or will shortly become, the number one cause of death in developed countries. Hence, there is an obvious and urgent need to accelerate the development and rational application of new therapies. The central premise of our program is that achieving this goal will require the identification of new therapeutic targets, the rapid development of specific and effective drugs directed against these targets, and the testing of these agents in relevant models of human cancer. Over the past decade, recombinant antibodies that target cancer-associated proteins have emerged as one of the most effective and major classes of targeted therapeutics in oncology. Moreover, while the production of small-molecule drugs remains a costly and slow process, technological advances have enabled the development of therapeutic grade antibodies in an academic setting, which now expands the cancer therapeutic domain beyond that of pharmaceutical companies. To take advantage of these new developments, the Donnelly Centre at the University of Toronto has established the Toronto Recombinant Antibody Centre (TRAC), a state-of-the-art antibody platform that can be applied to the generation of therapeutic grade antibodies against hundreds of antigens in a high-throughput pipeline. In turn, the TRAC has partnered with the Centre for Drug Research and Development (CDRD) in Vancouver to leverage additional expertise in therapeutic antibody development. Importantly, we have assembled a consortium of leading cancer biologists from the Canadian research community, and together, we have compiled a panel of cancer related proteins that are high-value targets for next-generation cancer therapeutics. Taken together, our program represents a unique and complete platform for the development of antibody therapeutics in a Canadian academic environment. In a three-year framework, we will generate and validate hundreds of antibodies against a host of cancer-associated targets. These antibodies will be powerful tools for discovery research and a significant subset will be candidates for new therapeutic entities. In summary, the program will have major impact on basic research in cancer biology, on therapeutic options for cancer treatment, and on the development of commercial biotechnology in Canada.

NorCOMM2 – In vivo models for human disease & drug discovery (2010)

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Overview

Identification of the genes associated with human disease is essential to the development of new prognostic, diagnostic, and treatment options. However, to understand what happens when genes go wrong, we need to understand the normal function of all our genes. This can’t be done using humans, so experimental models similar to humans in their development, physiology, and disease state that are easy to study and genetically manipulate are needed. The mouse meets these criteria so it is the most widely used animal model in biomedical research today. In fact, 99% of the coding genes (genes that make a protein) present in humans are also present in the mouse. Therefore, the mouse will help us with one of the greatest scientific challenges ahead; to understand the function of each of our 20,000 genes. This is an enormous task and the International Mouse Phenotyping Consortium has been formed by scientists in North America, Europe, and Asia to take on the challenge in a coordinated global effort. The Project is made up of a team of Canadian and UK scientists who, over the next three years, will use publicly available resources to study the developmental problems and diseases that occur in 280 mouse models. Each of these models contains one mutated gene (different in each model) that no longer works or only partly works. The differences in the mutant models compared to normal mice will help us determine the function of that gene. This Project will represent a significant contribution by Canadian scientists to the international effort. We will use clinical tests like those used for humans (e.g. blood work, X-ray) to determine the effect of each mutation and whether the gene or the protein it produces could be a drug target or used in a diagnostic test. Our Canadian group brings specialized expertise to examine mutations in genes that cause embryonic death as well as world-leading experience in pathology screening for disease. Our team includes social scientists who will examine how this and other international research efforts can best be managed and share data and other resources to increase their real-world impacts. The global effort to understand the function of every gene is a huge project that will take the next 10 years to complete. Canada has a critical role to play. Like our UK partners, we have expertise and state-of-the-art facilities that have enabled us to establish a leadership position in this field. The knowledge generated and new discoveries made in this Project will enable the development of new drugs and new therapies by Canadian researchers in academia and the biopharmaceutical industry. Our Project has already partnered with drug discovery scientists at the Ontario Institute for Cancer Research and commercialization partners at MaRS Innovation in Toronto to create an opportunity to attract contract research to Canada and support Canadian companies that can capitalize on the mouse models that we generate. www.NorCOMM2.org 

Biomonitoring 2.0: A high-throughput genomics approach to comprehensive biological assessment of environmental change (2010)

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Overview

Sustainable development of the Canadian economy requires wise stewardship of our environment and natural resources; this is particularly true given the anticipated impacts of climate change. Biomonitoring seeks to describe and understand biological diversity at multiple ecological levels, both as a means to learn the typical mix of species that can be found in different habitats, and to establish “biological early-warning systems” that can tell us when environmental stresses are reaching a critical point. Canada is recognized as a world leader in biomonitoring, however, current practices have limitations.  They are personnel-intensive, which limit the frequency and intensity of sampling, particularly in remote areas. Also, present biomonitoring methodologies focus on a very limited subset of all species that can be found at a given location. Our project introduces ‘Biomonitoring 2.0’, a system based on cutting-edge DNA-sequencing technologies and state-of-the-art computational analysis, which will simultaneously reduce sample costs while dramatically increasing the knowledge gained from biological samples. Our test bed for this new system is Wood Buffalo National Park, a globally unique region spanning Alberta and the North West Territories that is under considerable threat from oil sands activities and other human impacts, in spite of its remoteness and protected status. By integrating our new genomics tools and technologies into a well-established Canadian biomonitoring framework, we will greatly increase our potential to manage our cherished national resources. The project team has been working closely with stakeholders including industry, government departments, First Nations and Métis, and environmental organizations. By developing a sophisticated, yet user-friendly Web-based portal, with client-based customized tools, we will be able to communicate much richer summaries of environmental health and impacts to society, through direct interactions with local stakeholders. www.biomonitoring2.org

Personalized medicine in the treatment of epilepsy (2012)

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Overview

Every time someone with epilepsy has a seizure there is a risk of brain damage. This is particularly true for children. Unfortunately, today’s anti-epileptic drugs simply don’t work on about one third of patients. The team led by Drs. Patrick Cossette, Berge Minassian and Jacques Michaud will identify genes that are associated with epilepsy and that are predictive of the response to various antiepileptic drugs. This will result in earlier and more effective care and potentially prevent cognitive decline in children. This project is co-led with Genome Quebec.

The microbiota at the intestinal mucosa-immune interface: A gateway for personalized health (2012)

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Overview

Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are incurable debilitating lifelong diseases that can affect children. Early detection is critical to avoiding complications and improving their quality of life. At the moment, however, there is no single test to determine the presence or type of IBD and the tests that exist are very uncomfortable for children. Drs. Alain Stintzi, David Mack and team are developing a simple, non-invasive approach to detecting IBD that will also be more cost effective. Using cutting-edge technology, the scientists will examine intestinal bacteria to develop better ways of identifying IBD and determining its severity. This work could also lead to new treatment, enhancing the quality of life for children everywhere.

Early detection of patients at high risk of esophageal adenocarcinoma (2012)

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Overview

Chronic heartburn can damage the lining of the esophagus, leading to a condition known as “Barrett’s esophagus”. Patients with Barrett’s esophagus have a much higher chance of developing cancer of the esophagus. Until recently, the only way to diagnose Barrett’s esophagus was through endoscopy—an uncomfortable and time-consuming procedure. However, a swallowable sponge under development in the United Kingdom allows for quick and painless diagnosis of Barrett’s esophagus in a doctor’s office. The team led by Drs. Lincoln Stein and Tony Godfrey aim to supplement this test with genomic technologies, allowing doctors to follow patients over time to identify and treat those progressing to cancer. Early detection, treatment and even prevention of these cancers could save the healthcare system over $300 million a year.

Autism spectrum disorders: Genomes to outcomes (2012)

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Overview

Genome Canada and CIHR-funded research has already led to some exciting breakthroughs in our understanding of autism spectrum disorder, a complex condition that affects normal brain development, social relationships, communication and behaviour. Among these breakthroughs is the identification of specific DNA anomalies associated with the illness. Now, Drs. Stephen Scherer, Peter Szatmari and team are going to the next level, aiming to identify the remaining genetic risk factors. This ground-breaking work will mark Canada’s contribution to an ambitious international initiative that aims to sequence and analyze the genomes of 10,000 people with autism spectrum disorder. With a more complete understanding of the genetic elements of autism, doctors will be able to make earlier diagnoses, provide better, more personalized care to patients and reduce the enormous cost autism imposes on our health care system.

Enhanced CARE for RARE genetic diseases in Canada (2012)

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Overview

Gene mutations cause not only well-recognized rare diseases such as muscular dystrophy and cystic fibrosis, but also thousands of other rare disorders. While individually rare, these disorders are collectively common, affecting one to three percent of the population. It is estimated that as many as half of Canadians with rare disorders are undiagnosed. Drs. Kym Boycott, Alex MacKenzie and team will use powerful new gene sequencing technologies to identify the genes implicated in many of these rare diseases. Besides providing important new understanding into human disease, this project will yield other benefits, including: avoiding invasive procedures, stopping ineffective treatments, developing earlier and better diagnoses, devising more appropriate treatment, and predicting the chances that one of these rare diseases could be passed on to offspring. Once the disease-causing genes have been identified, researchers will test drugs that are currently on the market to identify those that might be effective against these rare diseases.