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Bridging the emerging genomics divide

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Overview

This is a stand-alone GE3LS project.

While life expectancies in industrialized countries are about 80 years and rising, in some developing countries, especially due to HIV/AIDS in sub-Saharan Africa, life expectancies are 40 years and falling. Inequalities in knowledge underlie these differences in health.

We have contributed to reducing these inequalities by examining the ethical, environmental, legal and social implications of advances in biotechnology and genomics.

We studied ethical questions faced by biotechnology companies and how they deal with them; our aim is to encourage companies to adopt suitable ethical policies. We led in writing a proposal for the Canadian government to guide its strategy for development of genomics and biotechnology; this has had an important effect on federal policy. We were a major contributor to the Genomics and Nanotechnology Working Group of the United Nations Science and Technology Task Force; this report was distributed all over the world. We led in the creation of a report which pointed out that in guarding against biological terrorism we should not undermine our ability to apply genomics for social benefit, especially in developing countries; the United Nations recommendations for a counter-terrorism strategy included reference to these conclusions.

We conducted courses in five regions of the developing world, with 232 participants from 58 countries, to help these countries shape policies in genomics and public health. We produced ethical guidelines for research, development, regulation and commercial use of nutritional-genomics and transgenic food products.

Outcomes

  • Reports and articles that address world-wide biotechnology issues.
  • Number of research personnel employed by the project: 5 graduate students, 2 post-doctoral fellows, 19 research associates and assistants, and 12 undergraduate students.
  • Number of peer reviewed publications published: 17, plus 12 books and monographs, and 5 book chapters.
  • Number of public outreach events held: 49 lectures, 1 public forum, media coverage – 118.
  • Co-funders: International Development Research Centre, National Institutes of Health, Indian Council for Medical Research, University of Guelph, Merck Frosst, Ontario Centre for Agricultural Genomics, World Health Organization (EMRO), United Nations University (BIOLAC), Pan American Health Organization and the Keck Graduate Institute.

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.

Annotation of chromosome 7

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Overview

Scientists and the medical community have long taken a keen interest in chromosome 7, which contains many genes crucial to development. It also carries the cystic fibrosis gene and is often damaged in some types of leukemia and other cancers.

The overall goal of our project was to complete a gene map and apply it to disease study, as well as to annotate all pertinent biological features contained in the DNA sequence of human chromosome 7. The strategy throughout the effort was to generate and collate all genomic data and to integrate this with every piece of clinical and functional genetic information available. Perhaps the highlight of the project was our publication of a seminal manuscript in Science in 2003, describing an accurate DNA sequence and annotation of the entire human chromosome 7.

This was the first such paper of its kind confirming our group’s worldwide lead studying this portion of the human genome. In collaboration with 90 scientists from 10 countries worldwide and Celera Genomics, 158 million nucleotides of DNA sequence were assembled, 1,917 gene structures identified, and numerous structural features were anchored to the sequence map. At that time we also formally launched the first website and database designed to facilitate community-based annotation of chromosome 7, which continues to be the most relevant site for information on chromosome 7. We also sent the unique molecular reagents from this project to over 240 scientists worldwide to assist their research.

The study of disease was also an important applied goal of this project. We collaborated with many scientists from around the world to further disease gene research and discovered two disease genes that have led to patent filing. The international standing of this project continues to attract outside funds related to spin-off work as well as new trainees from around the world to Canada.

Outcomes

  • Publication of a seminal manuscript in Science in 2003, describing an accurate DNA sequence and annotation of the entire human chromosome 7
  • Number of research personnel employed by the project: 23
  • Number of peer reviewed publications published: 38 peer-reviewed manuscripts and 9 book chapters.
  • Resources generated: products of this project have been distributed to over 350 investigators worldwide, many of which were probes sent for patient studies or diagnosis.
  • Number of patents in process or obtained: two disease gene discoveries leading to patent filing.

SANGRE-seq (systematic analysis of blood gene regulation by sequencing): Bringing RNA-seq to clinical diagnostics

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Overview

Diagnostic tests based on blood samples are mainstays of the healthcare system. Adding RNA sequencing (RNA-seq) can extract more information from blood samples, including a snapshot of all the genes active in a patient’s blood cells. Such a snapshot can tell us about the current condition of the patient’s immune system, whether there are cancer cells in the blood and/or whether blood cells are fighting an infection. Drs. Michael Wilson and Adam Shlien of The Hospital for Sick Children are developing an RNA-based clinical test called SANGRE (systematic analysis of blood gene regulation in blood) that will provide unprecedented power to use RNA expression as a routine and affordable test that can better diagnose disease, disrupting clinical practice and improving the health of Canadians.

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.

Functional genomics in human cells for drivers of lethal metastatic human cancers

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Overview

Often in cancer it’s the spread of the cancer to other areas of the body, a process called metastasis, that kills. This is particularly the case with two highly lethal types of cancer, medulloblastoma (MB), the most common malignant brain tumour in children, and pancreatic adenocarcinoma, the fourth leading cause of cancer deaths in Canadians. Recent results from the lab of Dr. Michael Taylor of The Hospital for Sick Children have shown that the biology of the metastases is extremely different from the primary tumour, making it unlikely that treatments developed to treat the primary tumour will work on the metastases. Dr. Taylor has teamed with Dr. Rama Khokha (Princess Margaret Cancer Centre) to develop and deploy unique tools to discover the drivers of metastasis, helping to improve survival rates of Canadians with these deadly human cancers.

Solid-state nanopore-based quantification of low-abundance biomarkers

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Overview

Many illnesses, such as cancer or cardiovascular disease, leave physical evidence in our bodies, called biomarkers. Spotting these biomarkers early would make it possible to begin treatment with personalized, targeted therapy, or even prevent disease entirely. Solid-state nanopore-based devices can do this, but are too expensive for widespread use. Dr. Tabard-Cossa’s laboratory has pioneered a technique to fabricate nanopore devices more rapidly and at substantially lower cost than present-day technology. They are integrating the devices into a disposable cartridge within compact platforms offering comprehensive sample-in, answer-out capability. The lab is positioned to develop a point-of-care prototype that can be used in the lab and the clinic, resulting in significant economic and health benefits for Canada.

Development of SIMPL, a novel protein-protein interaction assay based on split intein for biomedical research

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Overview

Proteins control every function of every cell in our body. Proteins, however, never act alone; rather, they interact with many other proteins in what are called protein-protein interactions (PPIs). Gain or loss of PPIs can be the driving force behind disease development. Dr. Igor Stagljar of the University of Toronto is leading a team to develop and implement a novel disruptive genomics technology that can detect and monitor PPIs in human cells. This technology can be used to identify novel proteins as components of many essential cellular processes, leading to greater understanding of the role of specific proteins in our cells. Furthermore, the technology also has the potential to identify drugs that disrupt a defined set of PPIs when the PPIs cause disease.

Economical high throughput de novo whole genome assembly

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Overview

“De novo” sequencing, or constructing an individual’s genome from his or her own data alone (as opposed to comparing it to a reference genome), is a formidable task, akin to assembling a jigsaw puzzle comprising hundreds of millions of small blank pieces. Drs. Si Lok, Stephen Scherer, and their colleagues from The Hospital for Sick Children are developing a new “mate-pair” technology that would overcome the financial and logistical barriers to de novo sequencing by linking sequences to one or more other reads in precisely known orientations and distances. Mate-pair technology would create a high-resolution backbone to enable de novo sequencing to be carried out in a single simple step. This new adaptation of mate-pair sequencing is a disruptive technology that could supersede all current methods of de novo sequencing, thereby representing a leap forward in many areas of research and, ultimately, in healthcare.