Lap-Chee Tsui Publication Award (2012)

The Canadian Institutes of Health Research-Institute of Genetics (CIHR-IG) is pleased to announce the Lap-Chee Tsui Publication Award (2012) recipients and finalists, a prize for exceptional trainee-conducted research within the CIHR-IG's mandate. CIHR-IG established the award to honour one of Canada's greatest researchers, Dr. Lap-Chee Tsui, whose discovery of the gene for cystic fibrosis was a milestone in human genetic disease research.

Lap-Chee Tsui Publication Award Recipients

Biomedical research:

Clinical, health services, population health, or genetic ethical, legal and social issues research:

Lap-Chee Tsui Publication Award Finalists

A total of 24 nominations were received by CHIR-IG, 21 in biomedical research and 3 in clinical, health services, population health, and genetic ethical, legal and social issues research.

We would like to take this opportunity to thank all the nominators for their interest in this program and all the nominees for their outstanding contribution to genetic research.

For details regarding the next competition round please visit the CIHR-IG website in fall 2013.

Sincerely,

Paul Lasko, PhD
Scientific Director
CIHR Institute of Genetics

Lay Summaries

An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming

Stem cells are “primitive” cells which have the unique abilities to renew themselves almost indefinitely (a process referred to as self-renewal) while retaining the capacity to give rise to all cell types of the body (e.g., heart muscle cells or brain neurons). Stem cells therefore hold great promise for disease modelling as well as for regenerative medicine. Along this line, researchers have for years looked for ways to use stem cells to replace cells and tissues that are damaged or diseased, for example in the case of neurodegenerative pathologies such as Alzheimer's disease. In order to reach this ambitious objective, important efforts have been invested to precisely characterize the regulatory mechanisms underlying stem cell fate during development so that by manipulating these mechanisms, stem cells can be directed towards cell types of interest for therapeutic applications. Using state-of-the-art genomic technologies, this study revealed a novel layer of regulation that controls gene expression in mouse and human embryonic stem cells. More precisely, we identified a new gene acting as a switch on stem cell fate, either to promote self-renewal or the acquisition of novel cell identities. This discovery has therefore significantly changed the way genetic program controlling stem cells were conceived to date. This research is the result of a fruitful synergy between five laboratories from the University of Toronto and was made possible thanks to the strong support from the Canadian Institute for Health Research through operating grants for the Blencowe team and a postdoctoral fellowship for M. Gabut.

Evaluating genetic counseling for family members of individuals with schizophrenia in the molecular age

Schizophrenia is a serious mental illness that affects about 1 in 100 Canadians in their lifetime. The disease is often called “youth’s greatest disabler,” presenting a significant burden to those afflicted, their families, and society in general. Schizophrenia is a disorder with a major genetic component to causation that is yet to be completely understood. Genetic counselling is a communication process that deals with the concerns associated with the occurrence, or risk of occurrence, of a genetic disorder in a family. Increasing public awareness of genetic risk for disease and the advent of personalized medicine make it likely that individuals with a family history of schizophrenia will more often desire genetic counselling in the future. The purpose of our study was to assess for the first time the value of genetic counselling for schizophrenia. We found that genetic counselling was helpful in addressing concerns and misconceptions about the illness and how it may or may not run in families. Notably, there was a significant associated reduction in stigma. The results provide much needed strategies to improve the procedure, availability, and uptake of genetic counselling in mental healthcare. Our study represents a pioneering effort to actively translate genetic discoveries into valuable services for Canadians with serious mental illness and their families.

Species-dependent post-transcriptional regulation of NOS1 by FMRP in the developing cerebral cortex.

The evolution of the cerebral neocortex is thought to underlie some of our species’ most remarkable cognitive capabilities, including speech and language, theory of mind, and abstract thinking. The emergence of these higher cognitive functions, however, is associated with our increased susceptibility to disorders that affect cognition, such as autism and schizophrenia. Many cognitive disorders are developmental in origin, resulting from early disruptions in the wiring of key neocortical neural circuits. This study uncovered a regulatory mechanism that controls how proteins are translated from mRNA in neurons located in the developing Broca’s speech and language area when the neural circuits of this uniquely human neocortical region are being wired. This regulatory interaction is mediated by the mRNA-binding protein FMRP. The loss of FMRP in humans leads to fragile X syndrome, the leading inherited form of intellectual disability and autism. Interestingly, this regulatory mechanism is species-dependent, occurring in the neocortex of primate, but not rodent, species. By showing that a specific protein is disrupted in human fragile X cases, this study implicates a new candidate disease pathway that may provide novel therapeutic targets. Furthermore, the discovery that FMRP function can have species differences has critical implications for the modeling of FMRP biology and the study of this human disorder.

Subgroup specific structural variation across 1000 medulloblastoma genomes

Medulloblastoma, the most common malignant childhood brain tumour, is currently treated with non-specific therapies including surgery, whole-brain radiation, and aggressive chemotherapy, which are associated with life-long, debilitating side-effects. Rational, targeted therapies based on genetics have the potential of eliminating side-effects, but they are not currently in use for medulloblastoma. In order to facilitate development of targeted therapy, we analyzed a large cohort of in 1,087 medulloblastoma samples collected by the Medulloblastoma Advanced Genomics International Consortium (MAGIC), and we aimed to identify recurring mutations that may serve as candidate drug targets.

The genomic architecture of medulloblastoma subgroups are strikingly heterogeneous, and necessitated the division of medulloblastoma into its molecular subgroups: WNT, SHH, Group3, and Group4. In the SHH and Group3 subgroups, we identified several novel mutations that for which existing drugs are available for treatment of other cancers, which might allow rapid translation for targeted therapy in these patients. In the Group4 subgroup, we identified a recurrent aberration in the SNCAIP gene, which is probable disease-causing gene, and merits investigation as a target for therapy.

We identified a number of highly targetable, recurrent mutations that could form the basis for future clinical trials. The cooperative approach of our global consortium has allowed us to overcome the barrier of intertumoural heterogeneity in an uncommon paediatric tumour and to identify relevant drug targets for the affected children.

Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein

Cystic fibrosis (CF) is a fatal genetic disorder that affects many organs including the airways. The most predominant genetic mutation in the CF gene (deltaF508) results in lack of the functional protein CFTR that is essential for proper functions of the epithelium, (a cell layer that lines cavities of many organs). The limited availability of patient CF epithelium remains a major roadblock for the potential development of therapeutic drugs. Generated from skin, induced pluripotent stem (iPS) cells hold great promise as a renewable source of patient-specific cells. Following manipulation, these cells resemble embryonic stem cells and are capable of generating all cell types of the body. The ability to generate a renewable airway epithelial cell source will allow high-throughput drug screens for CF treatment. However, lack of a reliable method to generate functional mature airway epithelia from human pluripotent stem cells impeded the use of iPS cells for therapeutic discoveries for airway diseases. In our Nature Biotechnology report, we developed a method for generating functional CFTR-expressing airway epithelia from human embryonic stem cells (hESC) and human iPS cells. Using carefully timed treatment of select growth factors known to play an important role in lung development, hESC were converted into airway epithelial cells that also expressed functional CFTR protein. As a proof-of-concept we also showed that patient CF iPS-derived epithelial cells could be used to evaluate novel CF corrector compounds. The ability to generate a renewable source of airway cells from patient iPS cells for drug discovery, tissue engineering and cell transplantation offer great hope for alternative medicines to treat CF.