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Functional genomics of Arabidopsis

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Overview

Canadians depend on agricultural plants for food, trees for housing and paper products, and, increasingly, distillation products from many plants for energy. In the current competitive world, the ability of our agricultural and forestry industries to maintain an international lead depends more and more on genetic improvements to important kinds of plants. But there are so many different kinds of important plants; how can we choose the best ones to study? A tried and true answer to this question is to work with a simple plant that can represent all others. We and other plant researchers around the world have chosen one called Arabidopsis. This small plant is one of the best-studied, genetically, of all organisms and it has many similarities to important crops such as rice, wheat, corn and canola.

We set up some of the basic tools that will allow us and others worldwide to carry out genetic research on Arabidopsis. This will lead to a deep understanding of many aspects of plant growth that will be important for genetic improvements such as salt- and drought-tolerance, pest resistance, increased productivity, and enhanced protein content.

We established three kinds of experimental tools. First, we created over 10,000 different gene mutations using advanced genetic methods. We and many others will be using these to study how plant growth reacts to adverse environmental conditions and which genes are important for plant survival. Second, we set up a state-of-the-art technology called DNA micro-arrays that allows us to measure which plant genes are active under many different growth conditions. Third, we provided high-performance computers and specific software that allows us to deposit and analyze our genetic results. We make these three experimental tools available to plant researchers all over the world, speeding up research and putting Canada on the map for plant researchers everywhere to appreciate.

Outcomes

  • Creation of a worldwide resource for plant genomic research.
  • Number of research personnel employed by the project: 10
  • Number of peer reviewed publications published: 10 plus 9 indirectly.
  • Resources generated: 10,000 gene mutations and plants with potential new characteristics, DNA micro-array facility, high-speed computer capability, gene database, and analysis software.
  • Number of public outreach events held: Several references and appearances in newspapers and television news.
  • Co-funders: CFI, ORDCF, and our private sector partner, Performance Plants Inc. of Kingston Ontario – Canada’s foremost plant biotechnology company.

Functional genomics and proteomics of model organisms

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Overview

Our project aimed to provide a comprehensive view of protein and genetic interactions in biomedically important model systems – bacteria, yeast, worm, and mouse.

For the bacterial, yeast and worm components, we used a variety of cutting-edge functional genomics approaches to define gene function in model eukaryotic organisms and characterize novel protein complexes in bacteria and yeast. We anticipate that our genetic network and other yeast functional genomics projects will lead to both a better understanding of the basis of genetic disease and also the discovery of new compounds that might be useful in the treatment of proliferative disorders such as cancer.

The Functional Annotation of the Mouse Genome project has moved Canada’s mouse genomics to the forefront of this rapidly growing and increasingly important field. Our team has generated mouse models for human conditions such as kidney disease and osteoporosis, developed new tools to help characterize Canada’s mutant mice, and established new mouse cell lines that are in high demand by academic and industrial investigators worldwide.

The Mammalian Protein-Protein Interactions project team developed high-throughput approaches to quantitatively assess protein-protein interactions in mammalian cell systems. Because most regulated cellular processes are carried out by complex protein-protein interaction networks, the underlying cause of many human diseases can often be traced to mutations that interfere with the assembly or function of these networks. With the successful completion of this program, these approaches now promise to provide major insights into human pathologies and highlight effective targets for therapeutic development.

Outcomes

  • Major insights into the molecular causes of a wide range of human diseases and new targets for drug and biomarker development.
  • Number of research personnel employed by the project: 191
  • Number of peer reviewed publications published: 98 referred papers (including Nature and Science), 17 invited reviews, 3 book chapters or contributions to a collective work, and over 385 invited presentations.
  • Patents: 1 provisional patent, 1 patent filed, 2 published patents, 1 commercial license in place, and 4 companies formed (MDSProteomics, Affinium Pharmaceuticals, Virtek Proteomics, and Mycota BioSciences)

Canadian program on genomics and global health

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Overview

This is a stand-alone GE3LS project.

In industrialized countries life expectancy is 80 years and rising, but in a number of developing countries, it is at 40 years and falling. While genomics/biotechnology can help address health challenges currently facing both the developed and developing world, there are growing knowledge gaps in the global community. The Canadian Program on Genomics and Global Health (CPGGH) was developed to help close some of those gaps.

Our world-leading program on genomics and global health has influenced federal and foreign policy decisions, increased the opportunity for Canadian genomics and biotechnology companies to internationalize in emerging and developing markets, and increased public awareness on the uses and misuses of genomics to address global health challenges.

Highlights include:

“Health Biotechnology Innovation in Developing Countries”: an in-depth look into biotechnology in seven developing countries, this special Nature Biotechnology report is helping non-industrialized countries develop a biotechnology sector.

“Top 10 Biotechnologies for Improving Health in Developing Countries”: extensively cited in journal articles and presentations by officials from the developing world, this special Nature Genetics report helped shape the Grand Challenges in Global Health program by the Bill and Melinda Gates Foundation.

Genomics and Nanotechnology Working Group – UN Millennium Project: members of our team were invited by the United Nations Science, Technology and Innovation Task Force to form a working group to address the role of genomics and nanotechnology in addressing the UN Millennium Development Goals.

Regulation of Genomics Research: the conference “New Biomedical Research: Regulation, Conflict of Interest and Liability” and resulting book exposed several of the weaknesses of the current regulatory review and provided arguments for a more systematic oversight.

Outcomes

  • Reports “Health Biotechnology Innovation in Developing Countries” and “Top Ten Biotechnologies for Improving Health in Developing Countries” have become highly influential with federal and foreign policy makers.
  • Number of research personnel employed by the project: 85
  • Number of peer reviewed publications published: 60 papers, 22 books and monographs, 17 book chapters and contributions to collective work, and 166 invited presentations.

The Mammalian Membrane Two-Hybrid (MaMTH) assay: Advanced proteomics technology for biomedical research

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Overview

Integral membrane proteins have roles in many human diseases, but are notoriously difficult to study due to their unique biochemical features. Dr. Igor Stagljar and his team at the University of Toronto recently developed a powerful new technology, the Mammalian Membrane Two-Hybrid (MaMTH) assay, which can map protein-to-protein interactions (PPIs) of integral membrane proteins directly in the natural context of the cell. They now propose to further develop MaMTH technology by converting it into a platform that can map these PPIs on an extremely large scale. This work will allow researchers to develop better-targeted therapies for human disease more rapidly. The technology will be the foundation for an Ontario-based company called Protein Network Sciences that will offer easy access to this novel disruptive MaMTH technology, advancing biomedical research and therapeutic discovery while benefiting Canadian social and economic infrastructure.

Development of a digital microfluidic platform to identify and target single cells from a heterogeneous cell population for lyses in an ultra-low volume

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Overview

Genetic abnormalities are a leading cause of death among Canadian newborns and infants. Less invasive, less expensive prenatal diagnostic techniques that are able to provide relevant information at earlier stages of pregnancy are needed. Scientists and physicians at Toronto’s Mount Sinai Hospital have developed a method to collect and isolate fetal cells non-invasively, using a technique similar to a PAP smear. Now Dr. Aaron Wheeler’s research group at the University of Toronto is developing techniques to isolate and analyze these cells for prenatal diagnosis of genetic abnormalities. If successful, these techniques could transform the way prenatal diagnosis is delivered, resulting in higher coverage of the population, reduced patient anxiety, increased medical options for at-risk pregnancies and significant reductions in healthcare costs.

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.