In July 19, 2001, Genome Canada announced the beginning of a second national competition (Competition II) aimed at funding several large-scale genomics research projects and their related science and technology platforms. Results for Competition II were announced during the first week of April 2002 – and $155.5 million was invested in 34 innovative and exciting research projects with application in health, forestry, agriculture, bioinformatics, technology development, the environment and GE3LS. Twelve (12) of these projects were funded through Ontario Genomic.
Stem cell genomics project
Overview
Stem cells have extraordinary potential to help in the treatment of some of our most intractable diseases—for example, diabetes, arthritis, stroke and neurological conditions such as Parkinson’s and Alzheimer’s. We are not yet able to apply stem cells to the treatment of these diseases because first we need to know a lot more about them. The full exploitation of the potential of stem cells requires us to understand the genetic factors that make stem-cells what they are, and how different kinds of cells and tissues in the body are specified.
We determine which genes are active in stem cells using new methods of detection and analysis called DNA micro-arraying, Serial Analysis of Gene Expression and protein studies (proteomics). We studied stem cells from the embryos of human and mouse, and from muscle, brain and bone-marrow tissues in adults. The cells were taken from laboratory mice and from human biopsy samples and maintained in the form of laboratory cell-cultures for use in our experiments. We carried out 1,400 DNA micro-array and 11 Serial Analysis of Gene Expression experiments; we did protein analysis of almost 140 protein samples. We set up a data bank called StemBase, complete with new methods of graphical display and analysis. This is available publicly to stem-cell researchers all over the world. Altogether, twenty-five investigators from across Canada participated in our research project.
Outcomes
- StemBase, the largest stem-cell gene-expression database in the world.
- Number of research personnel employed by the project: 45 Number of peer reviewed publications published: 11, plus two book chapters and 33 invited presentations.
- Number of patents in process or obtained: 3, plus 2 commercial licenses and 1 company Resources generated: StemBase database (six libraries of gene-expression products, 62 DNA micro-array experiments composed of 188 samples and 997 files deposited)
- Number of public outreach events held: 8 technical seminars, 4 public lectures, 7 newspaper, magazine and TV articles, and 24 public laboratory tours.
- Co-funders: Stem-cell network.
The Biomolecular Interaction Network Database (BIND)
Overview
Human Genome Project researchers worldwide produce a huge amount of raw information about genes and proteins. This information must be turned into knowledge if it is to be useful for further studies and for practical applications. It must be organized into databases, analyzed in a great many ways and above all made available to researchers everywhere.
In our project, we set up specialized databases used by genomic researchers around the world. The first database, called BIND, contains information for over 200,000 protein and DNA interactions, which are the biological processes that drive living cells and are central to biological and medical research. The second database, called SMID, details over 13 million chemical binding sites on protein molecules; these can be used to identify medical and industrial applications for chemicals that are known to alter proteins involved in biological processes.
A third database, called SeqHound, contains the raw information from the Human Genome Project upon which we built BIND and SMID. We screened the information in these databases meticulously to be sure that it has the very high quality necessary for research. We also created a large set of software tools that enable many different kinds of analysis of the information contained in our databases. Thousands of biomedical researchers all over the world use our databases to discover new connections among genes and proteins that otherwise may have been missed. This reduces the cost and time of research, and leads to a better understanding of how cells work. Using BIND and SMID gives scientists the possibility of designing new drugs for the treatment of many diseases.
Outcomes
- Creation of databases that contain crucial molecular-interaction data that are used by the worldwide biomedical research community.
- Number of research personnel employed by the project: more than 100.
- Number of peer reviewed publications published: 20 plus 48 invited presentations; plus hundreds of publications that used the databases.
- Number of patents in process or obtained: 1
- Resources generated: SeqHound, BIND, SMID databases for public use plus a large set of analytical software.
- Number of public outreach events held: 30
Genomics of the spruce budworm and its viral pathogens
Overview
Canada is a custodian of approximately 10% of the world’s total forests. Occupying nearly 35% of our land mass, they are an enormous renewable resource of importance for recreation, the environment and the economy. Forests contribute approximately $30 billion dollars annually to Canada; about 10% of all the jobs in Canada are forestry-related. We contribute to the health of Canada’s forests by using genomics to study one of the most devastating forest-insect pests, the spruce budworm. The aim is to develop environmentally safe biological control agents – viruses and bacteria that control spruce budworm infestations but do not affect any other forest organisms or humans.
We carried out genomic studies of the spruce budworm and its viruses, and the molecular basis of their interactions. Through these studies we have developed the following: a large body of knowledge about the genomics of spruce budworm and many of its naturally occurring viruses; environmentally friendly methods that use insect viruses to control spruce budworm; a way to produce large amounts of viral proteins that can be used for further development by the pharmaceutical industry, and veterinary and agricultural agencies.
In our work on the spruce budworm we produced a large set of DNA molecules that allowed us to study budworm genes that affect molting, development and resistance to viruses. We developed an efficient way to make proteins in the test tube. For the viruses that infect spruce budworm we determined the entire gene sequence of the most important ones. This information is the basis for further genetic characterization of the viruses, the creation of virus gene-mutations and studies of viral gene expression. We modified viruses to make them more effective than normal ones against the spruce budworm.
Outcomes
- Creation of genomic tools and knowledge leading to control of the spruce budworm, one of Canada’s most devastating pests. The developed technologies can be applied to other forest and agricultural insect pests
- Number of research personnel employed by the project: 19
- Number of peer reviewed publications published: 47 + 9 book chapters.
- Number of patents in process or obtained: 1.
- Co-funders: Canadian Biotechnology Strategy, Canadian Forest Service,
- Agriculture and AgriFood Canada
Mapping and isolation of genes influencing severity of disease in Cystic Fibrosis
Overview
An important aspect of the Human Genome Project lies in its promise of better understanding and treatment of human diseases. The more we know about the genes that underlie disease, the more skillfully we can devise treatments. It is rare for a genetic disease to be caused simply by an error in one gene. While a single-gene defect may be the primary cause, the complexity of the human body almost ensures that other genes will be involved. A case in point is the gene which, when defective, causes Cystic Fibrosis (CF).
Due to the pioneering work in the 1980s of researchers at the Hospital for Sick Children we know that all Cystic Fibrosis patients are defective in a gene called CFTR, which instructs the cell to make a protein that moves ordinary chlorine ions into and out of cells. Yet, even in patients with the identical genetic change in CFTR, the severity of Cystic Fibrosis can be very different. The reason must be that other genes interact with CFTR to alter the course of the disease.
Our aim was to use the most up-to-date genomic methods to find as many of these other genes as we could. This kind of study thrives on close co-operation between medical doctors and research scientists. It requires very careful diagnosis and description of disease symptoms. Underneath this must lay a strong organization that can identify patients and their families all across Canada, obtain samples from them for genetic analysis, and record and analyse the results.
We collaborated with all 38 Canadian Cystic Fibrosis clinics to establish a study group of over 75% of the entire Canadian CF population. All together, we collected blood samples from almost 2800 CF families, including some from foreign sources. We extracted DNA from these and also established tissue-culture cell samples that can be kept for future research; this is now the world’s largest resource for CF genetic studies. Our analysis of the extracted DNA using sophisticated genetic techniques has identified almost 100 genes that potentially could affect the progression of CF.
Outcomes
- Creation of the world’s largest repository of family-based cell lines for clinical-genetic studies; the identification of genes that potentially affect the severity of Cystic Fibrosis.
- Number of research personnel employed by the project: 19
- Number of peer reviewed publications published: 1 plus 4 indirectly.
- Resources generated: World’s largest repository of family-based cell lines for clinicalgenetic studies; the Cystic Fibrosis Mutations Database; the Canadian Consortium for Cystic Fibrosis Genetic Studies.
- Number of public outreach events held: 27 (public lectures, magazine articles, website, and communications with CF families)
- Co-funders: Canadian Foundation for Cystic Fibrosis; Hospital for Sick Children Foundation.
Proteomics and functional genomics: An integrated approach
Overview
Our Genome Canada project was a large-scale “basic science” research endeavour. Our goal was to use functional and chemical genomic approaches to establish a comprehensive description of the biology of the budding yeast Saccharomyces cerevisiae. We developed platforms to exploit this simple model organism to both discover drug targets and understand the genetic basis of complex disease. Mainly, our work was concerned with using a variety of cutting-edge functional genomics approaches to define gene function and to probe the mechanistic basis for drug action and the characterization of novel, unknown and microbial proteins. In our structural biology efforts, we identified the biochemical function of these proteins and made hypotheses about their cellular role in microbial cells. This new information has greatly extended our fundamental knowledge about microbial biology and created an experimental basis for the development of novel anti-microbial drugs and biotechnological processes by Canadian biotech industry.
Our research team has made many important contributions to Canadian and Canadian-led scientific, commercial and educational enterprises. For example, project co-leaders Aled Edwards and Cheryl Arrowsmith co-founded Affinium Pharmaceuticals, Mike Tyers co-founded MDS-Proteomics and Charles Boone is a co-founder of Mycota Biosciences, which was recently bought by Merck. Our project has produced reagents and has led to the development of technologies that have already produced patents, and have attracted investment from the industrial sector. For example, our work inspired Singer Instruments to develop a table-top arraying robot which is now being purchased by labs around the world. Our expertise in array-based genetics inspired our collaborator, Sasan Ragabazidah to found a new company, S&P Robotics, which markets a second-generation arraying robot which was prototyped in our laboratory. The team continues to identify significant market opportunities arising from the project.
Outcomes
- Genomic datasets and techniques important to human drug development, including large number of purified proteins, and technologies to make protein production and structure determination proceed more quickly and economically.
- Number of research personnel employed by the project: 50 Number of peer reviewed publications published: 61 journal articles, 25 reviews or contributions to books, and 364 invited presentations.
- Number of patents in process or obtained: 2 published, 1 filed, and 1 provisional Commertialization: 1 commercial licence in place and 4 companies formed.
Genetic determinants of human health and disease
Overview
Our research program explored gene variants causing and/or modulating a number of common multigenic disorders, including Alzheimer’s, inflammatory bowel disease, cancer (breast, endometrial, prostate, ovarian, melanoma) and osteoporosis. We also developed novel biometric and computational tools for expediting disease gene discovery. The disorders were selected on the basis of their prevalence and very significant morbidity, the availability of large patient populations, significant prior knowledge obtained by team members, and the urgent need for and potential major socioeconomic and medical impact of new diagnostics and therapeutics for any one of these conditions.
Results of our project have created new knowledge relevant to the medical care of a number of common debilitating diseases. The project findings include the discovery of several genes and proteins involved in inflammatory bowel disease and Alzheimer’s disease, as well as gene variants associated with risk for a set of common cancers and metabolic bone disease.
These data provide a platform for the development of tools for the diagnosis of certain conditions and for identifying molecular targets for therapeutic intervention. Discoveries of genetic variants associated with such common cancers as prostate and breast cancer have important clinical implications, all of this knowledge paving the way for predictive or diagnostic tests relative to these diseases.
In addition to knowledge relevant to the diagnosis and treatment of specific diseases, this program has provided new information and methods to improve technical platforms for genotyping, gene expression profiling and the computational management and statistical analyses of clinical and genetic datasets. Such tools are key to the exploitation of the human genome sequence for the purposes of disease gene discovery and, ultimately, for translation of genomic information to clinical and therapeutic applications.
Outcomes
- New knowledge relevant to the medical care of a number of common debilitating diseases, including Alzheimer’s, inflammatory bowel disease, cancer (breast, endometrial, prostate, ovarian, melanoma) and osteoporosis.
- Number of research personnel employed by the project: 57
- Number of peer reviewed publications published: 16 journal articles, 20 book chapters or contributions to collective works, 23 abstracts or notes, and 109 invited presentations.
- Number of patents in process or obtained: two applications filed for methods for diagnosing Inflammatory Bowel Disease, and two novel patents granted related to intestinal peptides.
Functional genomic analysis of soil micro-organisms
Overview
Genome Projects include the study of many kinds of organisms that are important in our daily lives, for example bacteria. One of the most important groups of bacteria in the world is also one of the least known by many people—microbes that cause the formation of nodules on the roots of many plants. Inside these nodules specialized bacteria convert atmospheric nitrogen into a chemically useful form, which is essential for plant growth and thus ultimately for life on Earth. One of the best studied nitrogen fixing bacteria is called S. meliloti, which fixes nitrogen in the roots alfalfa and other plants.
We aim to understand more about S. meliloti by using genomic methods to study its genes—how they direct nitrogen fixation and many other important biochemical reactions.
Using complex genetic methods, we constructed light emitting versions of almost 50% of S. meliloti proteins. This gave us an easy way to measure the amount of these proteins present in S. meliloti cells, a reflection of genetic activity, under over 100 conditions of growth. We used similar genetic methods to remove many individual genes from the S. meliloti genome. This enabled us to learn how the absence of these genes affected bacterial growth under many conditions. We used a method called DNA micro arraying to measure gene expression from all S. meliloti genes (6,200). The deeper understanding of S. meliloti growth that stems from our research will lead to better and more environmentally friendly methods of nitrogen fixation for the food and agricultural industries in Canada and the world.
Outcomes
- Creation of a body of knowledge about S. meliloti, a bacterium that fixes nitrogen, which is an essential process for plant growth.
- Number of research personnel employed by the project: 28 undergraduates, 9 graduate students, 3 fellows, and 15 technicians
- Number of peer-reviewed publications: 17 research papers
- Co-funders: McMaster University, Ontario Research Development Challenge Fund, Premier’s Research Excellence Fund, Canada Foundation for Innovation, University of Waterloo
Functional genomics of Type 1 Diabetes
Overview
There is unanimous agreement that Type 1 Diabetes (T1D) is a complex, autoimmune-mediated disease caused by multiple genetic risk factors and currently unknown environmental factors. The incidence of T1D varies widely between populations. Canada has the third highest rate in the world, and approximately $13 billion is spent annually in T1D-related health care, disability, lost work, and premature deaths.
While childhood T1D was uncommon in the first half of the 20th century, its incidence has risen rapidly over the past 50 years in Finland, England, Norway, Israel, Austria and several other countries. The reasons for the increasing incidence of T1D are not known, largely because the etiology of the disease is still poorly understood.
Our aim was to identify key genes conferring T1D risk to humans, and gain insight into the biological pathways that confer early stages in disease progression. Results from our analyses of rat and mouse rodent models were used to compile a list of potential T1D related genes for family-based association studies. Leveraging the recent progress in high-through put genotyping platforms and human HapMap data, we designed a genotyping analysis to examine 176 genes from our list.
Findings generated through our program will significantly impact our understanding of T1D. Markers to identify at-risk individuals prior to overt disease promise great opportunity for use of tailored therapeutics.
Importantly, the progress made under this project was essential to formation of an expanded $15M, 4 year T1D research effort that recently began funding with support from Genome Canada/Ontario Genomics Institute, the National Institutes of Health, Celera Diagnostics, Inc., several European funding agencies, and support from our research institutions.
Outcomes
- Identification of key genes conferring Type 1 Diabetes (T1D) risk to humans and insight into the biological pathways that confer early stages in disease progression.
- Number of research personnel employed by the project: 45
- Number of peer reviewed publications published: 13 journal articles, 1 book, and 35 invited presentations.
- Number of patents in process or obtained: 1 invention disclosure for the identification of a gene potentially controlling T1D and Human Hematopoesis, and 1 provisional patent for three novel loci for T1D susceptibility.
Functional genomics of Arabidopsis
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.