A multidisciplinary approach to genetic medicine

DNA sequencing is becoming a standard analytical tool for disease diagnosis and to evaluate disease risk. Genetic medicine involves the translation of findings from sequencing studies to clinical practice. As a first step, the effects of mutations on clinical outcomes must be validated, usually through model organism or cell-based studies. Secondly, the impact on patient management and health outcomes must be assessed.  Finally, standards for sensitivity and specificity of data interpretation must be implemented with a view to improving patient outcome. However, sequence data obtained from patients raises issues in ethical management, release and use of the data. Alan Bernstein’s research interests intersect ethics and public policy, to ensure privacy and links with government policies. Cheryl Shuman leads an outstanding Genetic Counselling Graduate program, which intersects with health outcome. Dr. Peter Ray, Director of the Department of Paediatric Laboratory Medicine, is a pioneer in genomic medicine. The laboratory applies next generation sequencing to discover genes associated with complex genetic disease, develops new molecular tests for both single and multi-genic disorders, investigates the pathogenic relevance of genetic variations and translates the findings into patient management. Other MoGen laboratories span many genetic and genomic disciplines, providing a unique and collaborative environment for genetic medicine.

Disease gene identification, modelling and treatment

Many researchers in MoGen identify genetic alterations in disease and then use cutting edge genetic techniques, including CRISPR/Cas9, to generate models for human disease in a variety of organisms, including mouse, fish, flies and worms. Dr. Johanna Rommens was a key member of the team who discovered the gene mutated in cystic fibrosis (CF). She continues her work in CF by finding secondary mutations that modify the phenotypic outcome. Using mice as a model organism, she has discovered many organ systems impacted by mutation of the CF gene, including the pancreas. She is also interested in ribosomal deficiencies and how they cause diseases including Shwachman-Diamond syndrome. Dr. Lucy Osborne studies neurodevelopmental disorders caused by deletion and duplication of human chromosome 7q11.23, which offer a window into the genetics of human behaviour, cognition and language. Her laboratory uses mouse models and the genetic analysis of human subjects to probe the underlying molecular basis of these disorders. Dr. Irene Andrulis identifies mutations in breast cancer and sarcoma, and then determines their clinical significance. Dr. Christopher Pearson studies genetic mutations involving trinucleotide repeat sequences, a common mechanism of mutation in human diseases, including myotonic dystrophy, Huntington's disease, spinocerebellar ataxias, and Fragile X syndrome. Dr. Pearson’s foundational, or basic, research has led to strategies aimed to treat trinucleotide repeat diseases, which are supported by major pharmaceutical companies. Dr. Steven Scherer focuses on autism spectrum disorders (ASDs). Scherer and collaborators discovered numerous disease-associated copy number variants (CNVs) and the corresponding disease-susceptibility genes in over 10 per cent of individuals with ASD. These discoveries have led to broadly available tests facilitating early diagnostic information for thousands of families with autism worldwide. 

Drs. Ronald Cohn and James Dowling aim to cure muscle diseases. Research in Dr. Cohn’s laboratory focuses on the biology of muscle regeneration as it relates to disease with a particular interest in muscular dystrophies. Dr. Cohn’s lab uses model organisms and new genetic technologies to find ways to protect against skeletal muscular atrophy, and translates findings into clinical practice with the goal of making individualized treatment a standard of care for all children. In fact, Dr. Cohn’s lab, in a classical example of genetic medicine and RNA-guided nuclease editing, recently corrected a disease mutation in a patient’s cells using the CRISPR/Cas9 system. Dr. Dowling’s research focuses on disease pathogenesis and therapy for congenital myopathies and childhood muscular dystrophies.  His laboratory employs both zebrafish and mouse model systems, complemented by cellular analyses to study muscle development and disease. His research spans the continuum from gene discovery to disease pathogenesis studies in model organisms, focusing on both targeted and unbiased drug discovery.

Dr. Monica Justice’s research merges mouse modeling with clinical genetics to understand the basis for human diseases and to use mouse models to find avenues for disease improvement. Dr. Justice is using genetics to find new avenues for therapy. Using a mouse model for the neurological disease Rett syndrome, pharmacologically targetable pathways for disease amelioration were identified, leading to clinical trials. Dr. Peter Roy’s lab uses the worm C. elegans as a model system for a variety of diseases, including neurodegeneration, mood disorders, muscle excitability, and infection. In his research, Dr. Roy performs high-throughput screens in worms to identify novel drug leads. He subsequently tests these drugs in other complex animal model systems through collaboration, and finally dissects the mechanism of action of the bioactive small molecules in the simpler worm system. Drs. Sevan Hopyan and Bret Pearson use model organisms to understand basic developmental processes arising from stem cells. Dr. Hopyan’s lab identifies mutations that cause human skeletal anomalies.

Dr. John Dick’s lab aims to understand human hematopoiesis and leukemogenesis using unique human tissue-based models to examine critical genes, proteins, or epigenetic factors. He is a world leader in understanding cancer stem cells, ultimately aiming to target them in pre-clinical studies. By sequencing tumours, his work identifies potential biomarkers that may stratify leukemia patients and advance personalized medicine. Dr. Kathy Siminovitch’s research is directed at defining the molecular and cellular pathways that underpin normal immune responses or the altered immune responses engendering autoimmune disease. Disease risk loci are mapped in large patient cohorts and mouse models and molecular technologies are used to delineate pathways that link specific gene variants to cell dysfunction and disease. The long-term goal of Dr. Peter Dirks' research program is to understand how a normal neural stem cell or progenitor cell can be transformed into a brain tumour, and to use this knowledge to eradicate tumour stem cells. His lab also identifies tumour biomarkers and stratifies patient risk by sequencing brain tumours.

Dr. Tom Hudson, the Director of the Ontario Institute for Cancer Research (OICR), studies genome variation that affects cancer predisposition, progression and response to therapy, especially in colorectal cancer. Dr. Hudson is internationally renowned for his work in genomics and human genome variation, promoting an international framework to allow genetic and clinical data to be collected, managed and shared in an effective, responsible, interpretive manner.

Computational biology

Sequencing generates large datasets that must be correlated with clinical parameters and outcome. Many researchers the Department of Molecular Genetics are experts in analyzing large datasets and developing the tools to analyze genomic data and correlate data with phenotypic outcome. Dr. Lincoln Stein leads the OICR's Informatics and Bio-computing Program, which undertakes the management and analysis of large integrative cancer research projects. His research uses network and pathway-based analysis to identify common mechanisms in multiple cancer types and to devise prognostic and predictive signatures to aid in patient management. Dr. Philip Awadalla’s group at the Lunenfeld-Tanenbaum Institute uses empirical genomic data and computational models to address how genetics and the environment influence the frequency and severity of human conditions such as aging, cancer and infectious diseases. Dr. Frederick Roth’s group develops experimental and computational methods to build gene and proteins networks and determine how they function in living systems and are perturbed in human disease.

The labs of Drs. Tim Hughes, Michael Wilson and Adam Rosebrock employ experimental technologies and computational data analysis to understand genome regulatory and functional relationships that impact human disease. The Hughes lab carries out functional studies in organisms ranging from yeast to mouse, correlating gene expression and function with global analysis of DNA binding and RNA processing, and genome-scale characterization of proteins.  The Wilson lab analyzes evolutionary conservation of regulatory sequences computationally, and combines this knowledge with high throughput gene expression analysis to predict disease relationships and responses to therapies in blood, liver and cardiovascular disease genes. Dr. Rosebrock uses single cell genomics to correlate changes in phenotypes and genes, moving beyond population averages to understand variation in individuals.

Together with other groups within the Molecular Genetics Department, these researchers are helping to advance our knowledge of the causes of human diseases and to develop new therapies with the goal of improving health outcome.