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The contribution of genetic modulators of disease severity in Cystic Fibrosis to other diseases with similarities of clinical phenotype

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Overview

Canada is a world leader in research on cystic fibrosis (CF). Drs. Peter Durie, a pediatrician and senior scientist and Julian Zielenski a geneticist at the Hospital for Sick Children’s Research Institute plan to build on this research strength, by investigating the genetics of other diseases with similar phenotypes – observable physical characteristics, which may be genetically determined.

Drs. Durie and Zielenski are project leaders of The contribution of genetic modulators of disease severity in cystic fibrosis to other diseases with similarities of clinical phenotype. This project will apply knowledge about the genetic factors (so called modifier genes) that influence the severity of CF to other diseases that are clinically similar to CF. These diseases include a single­gene disorder affecting the liver (a1­antitrypsin deficiency), and multifactorial conditions such as pancreatitis due to alcohol abuse and chronic obstructive pulmonary disease due to smoking.

The project will analyse mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) as well as selected modifier genes that are found to influence the severity of disease in patients with CF as well as blood­ circulating proteins, in order to identify disease biomarkers, which can help predict disease severity and progression. Diagnostic and prognostic tests will be developed, and genetic test­ based risk identification could lead to behaviour modification and disease prevention among those at risk for the diseases. Enormous human suffering and prohibitive healthcare costs are associated with alcohol abuse and tobacco smoking.

This project is expected to yield results of worldwide importance, such as development of genetic tests of disease susceptibility that will be useful in future research projects and in development of preventative strategies to modify behaviour in high risk populations. This in turn should lead to reduced morbidity and mortality and more efficient healthcare. Important components of the project are ethical issues associated with genomics research, as well as industrial, economic and social benefits.

The dynactome: Mapping spatio-temporal dynamic systems in humans

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Overview

Proteins are large molecules responsible for the structure, function and regulation of cells. Canadian­-led research over the last two decades has demonstrated that proteins interact with one another, and assemble pathways and networks within cells, which account for sophisticated cellular behaviour.

According to Tony Pawson, director of the Samuel Lunenfeld Research Institute at Toronto’s Mount Sinai Hospital, a key to understanding diseases such as cancer lies in investigating the dynamic changes in the cell’s protein interaction network. Pawson, his colleague and fellow molecular biologist Jeff Wrana, and University of Western Ontario biochemist Shawn Li, are project leaders of the Dynactome: Mapping SpatioTemporal Dynamic Systems in Humans.

This project will map protein interactions within human cells in order to determine whether diseases such as malignant cancers result not only from specific changes to individual genes and proteins, but also from changes in the entire cellular network. The project draws on important discoveries made by the research team.

For example, Pawson was the first to show that proteins interact in a regulated way through specific domains – something, which is important for normal cell organization but is taken over by cancer causing oncoproteins. Wrana is a world leader in understanding a super family of proteins, called Transforming Growth Factor Beta (TGF­ß), which plays a major role in regulating human cell growth and function, through molecular pathways. This project, drawing on international collaboration in the United States and China, represents the first large­scale effort to map dynamic interactions. It is expected to lead to new proteomic and computational technologies as well as innovative cancer therapies.

Strengthening the role of genomics and global health

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Overview

This is a stand-alone GE3LS project.

There is a tremendous need for new approaches to deal with long-standing global health inequities. While life expectancies in industrialized countries are currently about 80 years and rising, in a number of developing countries, they are at 40 years and falling. Canada has a special opportunity to help the world use advances in genomics-based knowledge to deal with some of its most pressing problems: disease, poverty, hunger and environmental degradation.

In his February 2004 reply to the Speech from the Throne, Prime Minister Paul Martin announced that Canada would devote no less than five percent of R&D spending to challenges of developing countries in the areas of health, environmental, and learning technologies. Under the leadership of Peter Singer and Prof. Abdallah Daar, the CPGGH has become recognized around the world as a leading program on genomics and global health. Through Strengthening the Role of Genomics and Global Health, the CPGGH will continue to ensure that developing countries share the scientific, social and economic benefits of the genomics revolution, to prevent the emergence of a “genomics divide,” and to address existing disparities in global human health.

The project aims to strengthen genomics research, development and commercialization activities in the developing world by examining the role of developing world biotechnology companies in meeting local health needs and south-to-south collaboration in genomics innovation. At the same time, the project seeks to ensure that advances in pharmacogenomics are appropriately used to address global health challenges and to ensure the effective mobilization of agricultural genomics knowledge through strategies to promote enduring food security in developing countries.

Strengthening the Role of Genomics and Global Health will ensure that developing countries share in the social and economic benefits of the genomics revolution, increase public awareness of the potential for genomics to address global health and environmental challenges and help mobilize a unique vision for Canada’s role in the world.

Structural and functional annotation of the human genome for disease study

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Overview

Now that the human genome has been sequenced, the next step is to undertake the complete structural and functional annotation of genes associated with diseases, according to Robert Hegele, endocrinologist and scientific director of the London Regional Genomics Centre at the Robarts Research Institute.

Hegele is project leader of Structural and Functional Annotation of the Human Genome for Disease Study, an innovative project which aims to bridge new biological knowledge with medical applications. Any two humans are 99.9% identical at the level of their DNA sequences. But recently, new forms of genomic variation have been appreciated above and beyond single nucleotide polymorphisms. These include large scale variations, such as copy number changes, insertions, deletions, duplications and rearrangements, and they may be much more widespread than was previously appreciated. In this project, collaborator Steve Scherer of the Hospital for Sick Children will define and superimpose these large scale genomic variations over top of the existing “first draft” of the human genome sequence map. Another form of genome variation occurs through a process called “alternative splicing’, which gives rise to multiple versions of a protein encoded by a single gene. Also, some parts of the genome previously thought to be dormant are now known to code for active proteins functioning in the body.

Collaborators Ben Blencowe, Tim Hughes and Brendan Frey of the University of Toronto will define and integrate these new forms of genomic variation into the current human genome sequence map.

The project will therefore deliver a “new improved edition” of the human genome map; one that annotates and characterizes large­scale copy number variants, alternative splicing profiles of genes in selected tissues and previously unknown genes and other functional elements. Hegele and collaborators will then apply the annotated genome map with its rich trove of new biological information to unravel the genetic basis of diseases that extract a huge social and economic toll in Canada, such as diabetes, heart disease and breast cancer.

The data generated from the project will be made available, free of charge, on the Internet, in order to accelerate biomedical discovery, including the diagnosis and treatment of common diseases.

Integrative Biology

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Overview

The genomes of more than two hundred organisms have been sequenced, from microscopic earthworms to humans. The function of thousands of individual genes is attracting the attention of scientists. But integrative biology is revealing that genes work not individually but as physical or functional assemblies to perform their functions.

Brenda Andrews is Director of the Terrence Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto and she is project leader of Integrative Biology. According to Andrews, genes perform their functions not individually, but in assemblies or groups. In turn, these gene assemblies work with each other to allow the cell to function and respond to its environment. The value of integrative biology is underlined by the fact that some medications are highly specific, binding to one protein and one protein alone – but these medications can have unexpected and unpredictable effects when they impact on gene assemblies.

The project led by Andrews will develop an integrated view of Saccharomyces cerevisiae (baker’s yeast) – a leading model organism, which has conserved many of the same genes and pathways as humans, and is amenable to experimentation. By investigating cells and functional sub-components in baker’s yeast, the project is expected to yield valuable intellectual property. Examples of IP include new instrumentation, reagents (substances used in chemical analysis or synthesis), methodologies for human and veterinary therapeutics, and reagents for industrial processes and for basic and applied research.

Based at the newly opened Terrence Donnelly Centre for Cellular and Biomolecular Research, this project will help develop a world-leading platform for functional genomics and proteomics, drawing on multidisciplinary approaches and research strengths in Toronto and across Canada.

Canadian Barcode of Life Network

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Overview

DNA barcodes use a small fragment of an organism’s DNA – a portion of a single gene – to identify the species to which an organism belongs. They are powerful tools, which can be used to help catalogue biodiversity. DNA barcoding began in Canada, and Canadian scientists continue to lead international work aimed at developing a complete catalogue of the Earth’s life forms.

Paul Hebert, an evolutionary biologist and Director of the Biodiversity Institute of Ontario at the University of Guelph, is project leader of the Canadian Barcode of Life Network. It has taken 250 years to catalogue some 15% of the world’s biodiversity. But with many species now under threat, the Canadian Barcode of Life Network seeks to develop comprehensive DNA barcode libraries for all the world’s birds and fishes, and then of other animals, fungi, plants and protists (these are often single-celled organisms).

This project seeks to develop a DNA-based identification system which can be used to catalogue all species. Given that this and other barcoding projects are expected to generate a flood of new data, the Network will also create an advanced databasing system to aid the storage and analysis of barcode records.

It is hoped that the barcoding project will provoke the development of hand-held barcoders. These devices could then be used by bioprospectors in the rapid identification of thousands of species with the potential to yield lifesaving drugs, or to signal the presence of animal and plant organisms in food even after processing.

The Network will initially barcode groups of particular economic and social interest in Canada, before moving on to examine environmental samples from a wide range of other species. The project is a vital step toward the creation of a complete inventory of Canadian biodiversity – the first inventory of its kind in the world.

Stem cell genomics project

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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.

Proteomics and functional genomics: An integrated approach

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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

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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

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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

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