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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.

Identification of genetic pathways that regulate the survival and development of cancer and cancer stem cells

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Overview

Breast cancer, leukemia and brain tumours are among the most common and lethal tumors that affect Canadians. Because these cancers frequently affect young women and children, many patients are given very aggressive treatments to improve their chances of survival. But these treatments often have serious side effects, and they are not effective in fighting the most serious forms of these cancers.

According to Cynthia Guidos, a Senior Scientist at the Hospital for Sick Children Research Institute in Toronto and a Professor of Immunology at the University of Toronto, treatment failure might occur if the therapy does not target the rare cancer stem cells which can re­initiate tumour growth and thus function as the “roots” of the tumour.

Guidos’ research focuses on the development of normal and leukemic immune cells. She is leader of a project entitled “Identification of Genetic Pathways that Regulate the Survival and Development of Cancer and Cancer Stem Cells”. Her team also includes experts in leukemia, breast cancer, brain tumors, and cancer stem cells. Their project will study human tumors and mouse cancer models in order to address two crucial issues: what genetic alterations distinguish very aggressive from more benign tumors, and what genetic and biological malfunctions lead to the development of cancer stem cells.

By dissecting the cellular signals that govern abnormal survival of tumor cells and cancer stem cells, the project is expected to develop new “biomarkers” that may help to reserve the most aggressive cancer treatments for patients with the highest risk of failing conventional therapies. Ultimately, the project may lead to development of new and more effective therapies specifically targeted to cancer stem cells. The project team hopes that their research will eventually increase survival rates and improve quality of life for survivors of breast cancer, leukemia and brain tumours.

GE3LS Summary

Although no specific GE3LS project has been outlined as part of this Cancer Stem Cell project, the long-term outcomes of the project’s scientific research may have the potential to alter diagnosis and management of cancer, with important ramifications for both pediatric and adult cancer patients and their families. Thus, it is important to have an ongoing GE3LS component to this project. As such, a GE³LS Advisory Committee (consisting of Stuart Howe, Randi Zlotnik-Shaul, and Aideen Moore) meets bi-annually to review research developments, focusing on two main areas:

Identifying new GE³LS  issues.

Identifying GE³LS research questions for the future: Possible GE³LS issues to consider when clinical testing begins:

  • Knowledge transfer
  • Dissemination of research findings
  • Language and cultural barriers for patient recruitment

Integrated GE3LS Research: Genome-environment interactions in Type 1 diabetes: Attitudes of Adults and Adolescents to Predictive Genetic Testing for Diabetes

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Overview

Recent research advances mean that Research Ethics Boards (REBs) are now reviewing protocols that involve predictive genetic testing in children. While issues surrounding predictive genetic testing are clear in adults, there remain significant problems regarding the ethics of predictive testing in children. Further information on the acceptability and impact of predictive testing in children and adolescents and their families is required so as to allow REBs to better quantify risks and benefits of such studies.

Objectives

The objectives of our research study include:

  • Examine the views of first-degree relatives of diabetics to predictive testing for type 1 diabetes as compared to the nondiabetic population.
  • Determine the views of first degree relatives of diabetics as compared to the general population, relating to studies on gene-environment interaction for Type 1 Diabetes (T1D).
  • Examine the views of children and young adolescents who are able to provide assent.
  • Determine the effect of having a child with T1D on parent’s perceived risk to other children and impact on anxiety levels and family functioning.

This information should help to guide investigators, REB members and research participants on the key elements that need to be included in consent forms for research in T1D that includes predictive testing. Many other childhood diseases, including asthma and Crohn’s disease, are now understood to involve genome-environment interactions. Information gained in the GE3LS component of our project will be generalisable to many other disorders and will be very important as other large population-based predictive studies are undertaken.

Integrated GE3LS Research: Exploring the Impacts of DNA Barcoding

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Overview

The project is collaborating with the “Taxonomy at a Crossroads” project, a major study being led by social science researchers at Lancaster University who are probing the impacts of DNA barcoding on taxonomy.

The project team is also combining educational outreach initiatives with GE3LS research by engaging high school students in research projects relevant to consumer fraud and food safety (e.g., market surveys of fish labeling).

In addition, the project team acknowledges that there are policy implications that arise from DNA barcoding, and as such, the GE3LS committee is continuously monitoring opportunities and discussing strategies for policy recommendations and implementation.

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.

Integrated GE3LS Research: The communication of genomics research results to research participants

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Overview

Genomic research on the autism spectrum disorders (ASD) raises a number of social and ethical issues. These include issues in human subjects research more generally, and in the ethics of research on a medically and social complex child-onset disorder more specifically.

Most of our research has concerned the issue of communicating genetic research results to research participants. Recent commentaries argue that researchers bear an obligation to report genetic research findings to study participants. Others contend that while the principles of respect for persons, reciprocity, and beneficence indeed apply to the research context, they may neither be well served if results are disclosed nor denied if they are not disclosed. This issue is particularly challenging in the context of autism genomics, given the intensity of the relationship between researchers and the participant community, the complexity of the scientific information generated, and the multifaceted ways in which this information may be interpreted and used by research participants and families. The communication of genetic research results also bears on issues of health and social service delivery, and the extent to which research can or should serve a compensatory function.

We have pursued research on these issues through a review of relevant sub-national, national and supra-national policy guidance, and a set of qualitative interviews with researchers and research participants. We are currently mounting a survey of ASD genomics researchers using an experimental design, to understand the myriad factors influencing professional judgments regarding the disclosure of genetic research results.

Related publications:
Miller, F.A.; Giacomini, M.; Ahern, C.; Robert, J.S.; de Laat, S. 2008. When research seems like clinical care: A qualitative study of the communication of cancer genetic research results. BMC Medical Ethics, Vol 9: 4.
Miller, F.A.; Giacomini, M.; Robert, J.S.; Christensen, R. 2008. Duty to disclose what? Querying the putative obligation to return research results to participants. Journal of Medical Ethics, Vol 34: 210-213.

Autism genome project

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Overview

Autism, a severe neurodevelopmental disorder affecting thousands of Canadians, is characterized by impairments in social- communication and by a preference for repetitive activities. Although it is generally agreed that a strong genetic basis underlies the condition, the causes of autism are still unknown.

According to Stephen Scherer, senior scientist in the Department of Genetics and Genomic Biology at SickKids Hospital, it will be extremely valuable to characterize the human genome in search of autism susceptibility genes, and the mechanisms governing their action. Scherer is project leader of the Autism Genome Project, an unprecedented initiative bringing together many of the leading geneticists, clinicians and genome scientists undertaking autism research in Canada, and linking to 170 other scientists from 10 other countries worldwide.

This project will screen the genomes from over 6000 members of 1600 families to find where susceptibility genes reside along the chromosomes. Advanced genomic methods will then be used to assess the DNA in these chromosome regions in order to identify disease-associated genes. This project will incorporate genetic information about autism into health care delivery and policy development, and eventually lead to new and more accurate diagnostic tests.

Genome-environment interactions in Type 1 Diabetes

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Type 1 Diabetes (T1D) is a complex disease often arising in childhood in which the immune system destroys the insulin producing cells of the pancreas. Insulin is a crucial hormone in sugar and fat metabolism. Despite insulin therapy, T1D greatly increases the probability of heart attack, stroke, blindness and limb amputation, as well as shortened life expectancy. T1D afflicts some 200,000 Canadians and is caused by multiple genetic risk factors and currently unknown environmental factors. Now an innovative research project is investigating the interactions of genetic risks and environmental factors underlying T1D.

Jayne Danska, Senior Scientist at Toronto’s Hospital for Sick Children and Professor in the Faculty of Medicine at the University of Toronto, and Andrew Macpherson, Canada Research Chair in mucosal immunology at McMaster University, are project leaders of Genome Environment Interactions in Type 1 Diabetes.

This project aims to understand the genetic control of T1D in humans and rodent models, and to study the role of exposure to common intestinal bacteria in regulating immune system development and how such exposures affect the probability that persons at genetic risk of T1D will develop the disease.

By identifying genetic variants and bacterial exposure associated with T1D, this project is expected to discover new genetic markers, and to identify environmental exposures to intestinal bacteria that modify inherited T1D risk.

Canada has the third highest rate of T1D in the world and the incidence is rising. T1D accounts for 10% of cases of all diabetes cases, and costs the Canadian healthcare system $1.32 billion in 2002 and is projected to rise to $1.6 billion by 2010. This project aims to decrease the disease burden and increase the quality of life and life expectancy of persons with T1D and their families.

Moreover, discoveries from this research project are expected to have implications for a number of other autoimmune disease states, such as multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis.