In July 2004, Genome Canada launched Competition III, in an effort to support world-leading genomics and proteomics research at the highest level of scientific excellence.
Results for Competition III were announced on August 25th, 2005 and $346 million was invested in 33 innovative and exciting large-scale projects for a duration of 3 to 4 years.
Integrated GE3LS Research: Reporting genetic research results: Perspectives of study participants and researchers
Overview
Several recent commentaries argue that researchers bear an obligation to report genetic research findings to study participants. The nature and scope of this obligation remains disputed and unresolved. While the principles of respect for persons, reciprocity, and beneficence are fundamental to the research enterprise, they may neither be well served if results are disclosed nor denied if they are not disclosed. This integrated GE3LS research examines study participants’ and researchers’ perspectives on how to manage genetic research results with respect to this putative obligation.
Phase 1 of this research surveyed research participants from the Canadian Consortium for Cystic Fibrosis research regarding the meaning ascribed to a recent gene modifier finding reported in the academic literature. One key finding was that study participants expect researchers to share genetic research results with them. Phase II of this research involves a complex experimental design that aims to understand the factors influencing researchers’ judgments regarding reporting results. Using a cross sectional factorial survey design that includes vignettes presenting hypothetical scenarios involving genetic research findings to investigators engaged in cystic fibrosis and autism genetics research, this research aims to better understand the factors that influence researchers’ judgments about:
- Informing individuals about genetic research findings,
- the clinical significance of a hypothetical research finding,
- the nature of a research obligation to re-contact study participants with updated information about a particular finding, and
- the nature of a clinical obligation that may/may not ensue from reporting research findings.
Taken together, findings from this integrated research will inform the governance of this important research ethics issue.
The contribution of genetic modulators of disease severity in Cystic Fibrosis to other diseases with similarities of clinical phenotype
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.
Integrated GE3LS Research: Ethical issues and guidelines relating to the crossjurisdictional use of human tissues and genetic information
Overview
The GE3LS project team is examining ethical questions relating to the use of human tissues and genetic information, and ensuring confidentiality and protection of research subjects’ privacy. A critical review of consent documents from China, and evaluation of conformity with Canadian laws and guidelines set forth in Canada’s Tri-Council Policy Statement, Ethical Guidelines for Research involving Humans, as well as international guidelines (e.g., International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences/World Health Organization) and the Declaration of Helsinki (World Medical Association)) will be performed. Where nonconformities exist, the team will develop and implement an enhanced consent form for future donors to the biobank from which this project obtains its human tissue samples.
In addition, international research guidelines, including those mentioned above, will be assessed with respect to how they address biobanking studies, culminating in a review that details ways that genomics and proteomics researchers can deal with different international research guidelines in this area. The finished product will examine topics such as informed consent, standards for external review, recruitment of participants, and cultural challenges related to consent. The assessment will uncover where these guidelines are uniform and where they diverge, and highlight problems associated with this in relation to international research, particularly with the ‘Dynactome’ project. We will also study problems that arise when a standard is included on one or more documents but omitted on others.
The dynactome: Mapping spatio-temporal dynamic systems in humans
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
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.
Integrated GE3LS Research: The meanings and understandings of terms used in genomics research
Overview
In order to ensure optimal data collection and informed choice, the GE3LS project team’s over-arching goal is to investigate how the understandings of terms used in genomics research by scientists, when translated into the scientists’ meanings on consent forms, information letters, surveys, and demographic forms, may or may not be consistent with the understandings of research participants and their meanings when they respond to such documents. The team will:
- perform a textual analysis of research grants, information letters and consent forms that are being used in clinical studies of this Genome Canada grant and others funded in the last Genome Canada competition. With interview ‘prompts’ from the results of this research, research participants and researchers involved in the clinical Themes of this Genome Canada grant will be interviewed to provide further insight into the meanings and understandings of terms used in genomics research, particularly related to copy number variations (CNVs);
- survey other key stakeholders’ views of genomic research (particularly related to CNV), such as health professionals’ (medical geneticists and counselors, physicians) perceptions of the clinical meaning of CNV results (what kinds of results should provoke duty to warn, and child protection obligations);
- examine the views and experiences of patients and their families as research participants towards furthering informed choice to participate in CNV research;
- explore the meanings and understandings of terms used in CNV research by studying issues revolving around the interpretation, management and communication of whole genome scanning (WGS) results to patients and their families; and
- consider the legal issues that are emerging from the methodologies of the aforementioned studies that explore the meanings and understandings of terms used in CNV research, including qualitative content analysis, interviews of researchers and research participants, and electronic surveys.
Structural and functional annotation of the human genome for disease study
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.
Integrated GE3LS Research: Regulation and monitoring of convergent technologies
Overview
The team will systematically address the potential GE³LS issues stemming from the development and commercialization of the quantum dot (Qdot) diagnostic system, a high-throughput diagnostic system capable of detecting multiple global infectious disease threats at point-of-care; in 3 parts:
Public Engagement: The project team will develop and evaluate a public engagement tool for high school students and the general public that encompasses various emergent technologies and their application to infectious disease research.
Regulation of the Convergence of Genomics, Proteomics and Nanotechnology: The project team will identify regulatory issues related to convergent technologies and work with Canadian regulatory authorities to develop regimes and guidelines on implementation of any standards that may be developed. As such, they will
- survey Canadian and international regulatory regimes for each of the major technologies involved in the project;
- develop a database of cognate regulatory regimes;
- identify potential bottlenecks that are likely to slow down the development of convergent technologies;
- develop recommendations for the federal government on how to streamline the different regimes to develop “smart regulation” for convergent technologies; and
- work with Canadian regulatory authorities to develop regulatory regimes and guidelines on implementation of any future Canadian standards.
Monitoring of Risks and Benefits of Quantum Dots: The project team will monitor research on toxicity of Qdots and develop an annotated database of research publications and data on the potential risks of Qdots after exposure, and participate in policy discussions with the Canadian federal government on these issues.
Quantum dot diagnostics: Simultaneous Genomic and proteomic profiling of multiple pathogens at point-of-care
Overview
Worldwide, infectious diseases cause billions of infections and over 17 million deaths each year. With its well-traveled population and cultural diversity, Canada is at risk of global diseases such as SARS (severe acute respiratory syndrome), malaria and avian influenza (bird flu). But Canada is developing cutting-edge expertise in the rapid and accurate diagnosis of infectious diseases, based on nanotechnology.
Kevin C. Kain, Director of the McLaughlin Rotman Center for Global Health and Senior Scientist in the division of genomic medicine at the Toronto General Research Institute, and Michael Greenberg, FIO Corp, are project leaders of Quantum dot diagnostics: simultaneous genomic and proteomic profiling of multiple pathogens at point of care.
They have assembled a research team that will incorporate advances in nanotechnology with pathogen genomics and proteomics, in order to create a high throughput diagnostic system capable of detecting multiple global infectious diseases within minutes. The system is based on quantum dots tiny fluorescent probes that can be used as biomarkers to tag organic molecules and track them during biological processes. The research team plans to develop this diagnostic system specifically for use at point of care, in order to detect or exclude the presence of pathogens related to five major infectious diseases SARS, HIV/AIDS, malaria, hepatitis B and hepatitis C. The social and economic potential of this innovative system is underscored by the fact that these five diseases account for over 2 billion infections and 5 million deaths worldwide each year.
The project is organized into a continuous discovery pipeline, making it possible to accelerate discovery of diagnostic tools, commercialize them and translate them into clinical use. According to Kain, “the ability to definitively detect or exclude multiple pathogens at point of care within minutes would be a breakthrough with impact on our healthcare system, the quality of life of Canadians as well as global communities.”