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GE3LS – Communication of Genetic Research Results to Research Participants

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Autism Genome Project

Project Summary

Autism, a severe neurodevelopmental disorder affecting thousands of Canadians, is characterized by impairments in social communication and a preference for repetitive activities.  In an effort to more fully elucidate the genetic basis of autism, this unprecedented initiative, led by Dr. Steve Scherer, brings together 170 researchers from around the world, including leading clinicians, geneticists, and genome scientists, to screen for autism susceptibility genes in over 6000 individuals from 1600 families.

GE3LS Research Summary

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.

GE³LS Research in Ontario

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GE³LS research funded through Ontario Genomics takes two major forms:

Large-scale, stand-alone GE³LS research

Large-scale projects which allow researchers to delve deeply into critical genomics-related economic, environmental, ethical, legal, and social issues, such as the Program on Ethics and Commercialization (formerly the Canadian Program on Genomics and Global Health).

Integrated GE³LS research

Smaller-scale GE³LS research initiatives forming part of large-scale genomics-based research programs. All Large Scale Applied Research Projects (LSARP) funded through Genome Canada must include GE³LS research, in which social scientists and humanists (such as economists, ethicists, and lawyers) work with the scientists to address relevant GE³LS issues. Integrated GE³LS research for previously-funded LSARP projects include the following:

GE3LS – Genetic Information, Privacy and Biobanks

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Assessment of Risk for Colorectal Tumours in Canada (ARCTIC) – Integrated GE3LS research

Project Summary

In Canada, over 16,000 new cases of colon cancer occur on average each year; 6,000 result in deaths.  In an effort to improve early detection and clinical intervention, the ARCTIC project team, led by Drs. Brent Zanke and Thomas Hudson, endeavoured to develop a molecular test to predict peoples’ genetic susceptibility to colon cancer.

GE3LS Research Summary

Genetic information, privacy, and human genetic research biobanks are discrete as well as intersecting notions. Issues of privacy relate not only to the nature of genetic information but also to the possibility of indefinite storage in databanks. The individual and familial nature of genetic information makes it difficult to place ‘duty to warn’, ‘disclosure’ and ‘rights to know and not to know’ squarely under the heading of ‘Genetic Information’ or under the heading of ‘Privacy’. The interrelationship of these notions suggests that they may be regarded as part of an interconnected web.

The GE3LS component of the ARCTIC project studied such issues, focusing on the following:

  • Personal information, informed consent, collection, storage and internal/international transfer in long-term genetic databanks
  • Ethical/legal duty to warn and the privilege to disclose
  • Genetic research, privacy and property in an international context
  • DNA databanks and vulnerable populations, benefit sharing and the commercialization of genetic testing
  • Access to and disclosure of data by/to research subjects/patients
  • The development of a colon cancer screening test: ethical and legal issues
  • Researchers’ access to publicly and privately funded databases

Members of the GE3LS research team included Trudo Lemmens (lead), Lori Luther, Linda Hutjens, Nisha Anand, Tom Archibald, Ron Bouchard, Arkadi Bouchelev, Daniel Brinza, Elizabeth Cuellar Barroso, Lorian Hardcastle, and Margaret Ng Thow Hing.

Segmental duplications in neurodevelopmental, neurological and behavioral disorders

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Overview

Genetics is known to contribute significantly to many of the neurodevelopmental and behavioral diseases but in most cases, the causative molecular defect has not yet been determined. Therefore, there are no tests for early detection and diagnosis of these disorders and there is little information pertaining to their biological basis. An increasing number of neurological and behavioral disorders, however, are due to changes in the architecture of specific sites along the DNA of chromosomes in the human genome. The importance of such chromosome alterations has further been stressed with the information obtained with the human genome sequence, which has now been shown to harbor “molecular signatures” which facilitate rearrangements of genomic material.x
Furthermore, it has been shown that there is variability among individuals and species regarding the genomic structure and the copy number of genes located at specific regions of the genome, which, in turn, seem to play an important role in evolution. The regions, that comprise an amazing 5% (150 million chemical bases) of the content of the human genome and contain these molecular signatures, known as segmental duplications or duplicons, have not yet been accurately or completely characterized by the large-scale DNA sequencing projects.
Other principal investigators include scientific research groups from the University of Toronto, the University of British Columbia, SeeDNA Biotech, Fundacio Parc de Recera Ciomedica de Barcelona, Universidad Pompeu Fabra, MedPlant Genetics (Spain), and CAGT-Citogen (Spain).

A novel technology for streamlined synthesis, screening, and sequencing of privileged cyclic peptide scaffolds (2011)

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Overview

Over the past several years there has been increasing interest in drugs that are peptides and proteins. The reason that peptides and proteins appear promising is that they are made of amino acids, which humans naturally have, and are therefore less likely to cause unwanted side effects. Peptides control a vast range of processes in human cells. The vast majority of peptides are linear: they are built of amino acid building blocks into longer molecules that are flexible akin to spaghetti. Despite the biological significance of these flexible molecules, they are not good as therapeutic agents because our bodies have found a way to rapidly degrade them back into the amino acid constituents. If one could “tie up the loose ends” and create a circular peptide molecule out of a linear one, it may still have the desired biological effect. However, the stability is expected to be drastically increased because the body does not know how to chop circular molecules as efficiently as their linear counterparts.

One may, therefore, ask a question: “why don’t we see more circular peptides as drugs on the market?” The answer lies in extreme technical difficulties in making these circular molecules out of linear ones. In 2010, Dr. Andrei Yudin and his students at the University of Toronto found that the molecules of cyclic peptides can be readily made using novel chemistry developed in the Yudin lab. Funded in part by OGI (SPARK), the Yudin lab has made an exciting discovery that not only the stability but also the ability to enter human cells is increased when circular molecules are made with their method. With this important finding in hand, the Yudin lab is extremely excited about asking the next logical question: “now that your molecules can enter human cells, can they also kill disease-associated proteins found in infected cells?”. The SPARK grant has enabled us to build a much needed momentum that has resulted in several other grants, most notably – CQDM. Additionally, the Yudin group has initiated a collaboration with Eric Marsault (Department of Pharmacology, University of Sherbrooke). The stage is now set for an exciting path towards real therapeutics. For more information, please click here.

Instrumentation for automated pronuclear microinjection (2011)

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Overview

Pronuclear microinjection is a technique for creating transgenic mice, an important tool in genetics/genomics and developmental biology research. Due to the inherent difficulties of manipulating delicate mouse embryos, pronuclear injection has been conducted by a handful of professional microinjectionists at Mouse Core Facilities that typically only large research institutions possess. To non-professionals, pronuclear injection of mouse embryos has high skill requirements, a long learning curve, and low success rates. Since regular lab technicians or graduate students are not up to the task, researchers usually turn to professional services provided by Mouse Core Facilities. Advanced Micro and Nanosystems Laboratory (AMNL)

In order to automate pronuclear microinjection, this project under Drs. Yu Sun and Zhe Lu at the University of Toronto developed several key technologies. Based on computer vision microscopy and precision motion control, the system prototype is capable of 3D orienting individual mouse embryos. Dynamic autofocusing techniques were embedded in the system for aligning the holding pipette, pronuclei, and the injection micropipette. Techniques based on motion history images were also implemented and proven effective for detecting the contact between cell and pipette tip. The proof-of-concept system also demonstrated the feasibility of performing pronuclear injection via computer mouse clicking. Building on the results from this project, the team will pursue partnership with industry to further develop the technology for translating it to industry.

First-of-a-kind web tool for exploring splicing misregulation in human disease (2011)

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Overview

The human genome can be thought of as a computer program that controls the generation of biological complexity and the activities within living cells. While the text comprising the genome was revealed 10 years ago when the genome was ‘sequenced’, deciphering the genetic code hidden within the genome has been difficult. Recently, Drs. Brendan Frey and Benjamin J. Blencowe at the University of Toronto have developed a method that enabled them to identify the instructions comprising a ‘splicing code’ within the genome (Barash et al, Nature 2010 Website for Alternative Splicing Prediction). In this pilot project, they examined the potential for using the splicing code to enable biomedical research. They re-oriented their analysis toward the causes of human disease, invented a methodology for predicting the effects of genetic mutations, and developed a prototype web tool that demonstrates how the tool can be used to enable medical research. This pilot project was successful and led to 1) the development of a $1 million proposal to scale up the approach to fully support medical research, 2) a collaboration between the University of Toronto, Cold Spring Harbor to investigate the causes and therapeutic treatment of spinal muscular atrophy, the leading cause of infant mortality, and 3) the training of graduate students and postdoctoral fellows who are now working to scale up the methodology to support medical research. The exploratory research enabled by this project has opened the door to a new major direction of research in the Canadian genomics community.

MedSavant: A platform for identifying causal variants from disease sequencing studies (2011)

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Overview

Using the Ontario Genomic’s SPARK award, Dr Budno and Mr Fiume of the University of Toronto have been developing MedSavant, a high-performance software platform for the analysis of DNA data that helps researchers pinpoint the causes of genetic diseases. The platform serves as a repository and search engine for huge volumes of genomic mutations that are being gathered through genome sequencing. It harnesses the information collected from many patients and studies, and provides a flexible interface for organizing data, performing sophisticated analyses, and generating reports. MedSavant continues to be developed with the aim of making genomic analysis powerful yet easy, and making the wealth of genome sequencing data being generated accessible to researchers without informatics backgrounds, including physicians and clinical geneticists.

During the SPARK grant, two beta version of the software have been publically released, and a full release is being developed. MedSavant is currently being deployed for use in leading genomic initiatives, both at the Hospital for Sick Children and as part of the nationwide FORGE consortium for finding the genes involved in rare diseases affecting Canadians. Going forward, MedSavant is expected to become central to the Hospital of Sick Children’s Genome Clinic, a large scale effort to develop the informatics, workflows, as well as ethical and legal frameworks necessary to bring whole-genome sequencing to the bedside.

BANGS: A tool for Bayesian analysis of next-generation sequencing data (2012)

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Overview

This SPARK project will develop robust statistical data analysis tools for next generation sequencing (NGS), which refers to a set of high throughput technologies for measuring signals across the genome.  Those signals may represent which genes in the genome are active, where certain regulatory molecules bind to the DNA, or even something about the state of the DNA itself. However, NGS technologies do not measure the genomic signals perfectly — there are omissions, uncertainty, and in some cases, bias in the measurements.  Dr. Theodore Perkins’ project through the Ottawa Hospital Research Institute proposes a novel approach to reconstructing genomic signals represented in NGS data using Bayesian statistics.  The main features of this approach are that the team is able to put forth a best estimate of the signal, and also to quantify the uncertainty in the estimate. Quantifying uncertainty is useful for visualization of genomic signals, and is critical for comparing them under different conditions.  This statistical approach will be implemented in efficient, open-source, well-documented software, for the benefit of the NGS community.

Development of highly diverse but fully defined phage display libraries (2012)

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Overview

Protein interactions are at the basis of all cellular processes. This project from Dr. Philip Kim and Dr. Sachdev Sidhu at the University of Toronto is developing a novel technology platform and associated methodology that can probe such interactions in a high-throughput manner. They are combining oligonucleotide chips with combinatorial chemistry and computational methods to create a powerful technology that directly scans biologically relevant interactions. The team will create novel software that will allow custom design of oligonucleotide sequences that encode for large numbers of different protein fragments.  Custom oligonucleotide chips will be ordered and used to generate the specifically designed protein fragments.  Finally they will establish protocols for making and assessing the binding of hundreds of protein fragments. This is the first time oligonucleotide chips have been used in this fashion. Initially, this project will test proteins involved in cancer, which could lead to new insights for cancer therapy. Furthermore, the platform is particularly well suited to test interactions between viral or bacterial proteins and their human targets. This project will result in new insights into the biology of viral infections and novel routes to treatment. Project deliverables are the completed technology platform as well as completed libraries suited for detection of interactions for both human and viral proteins.