New Canada Research Chairs Boost Research into Molecular Underpinnings of Disease

Two Donnelly Centre investigators have been awarded new Canada Research Chairs.

University Professor Brenda Andrews now holds CRC in Systems Genetics & Cell Biology while Professor Grant Brown is the new CRC in Genome Integrity.

Established in 2000, the federal program invests in recruiting and retaining top researchers and scholars in Canada. Today’s announcement brings the number of CRCs in the Donnelly Centre to 12, with more than a third of the faculty holding the prestigious appointment. The two new CRCs will support research exploring the biology of cells and how various genetic and environmental perturbations of cell biology can lead to disease.

Work is underway in Andrews’ lab to understand why cells that have the same mutations, or alterations in their genetic codes, don’t always develop the same defects. This phenomenon is known as incomplete penetrance and it is common in human diseases, since people with the same disease-causing gene variant can experience different disease symptoms and severity.

“We are beginning to appreciate that any kind of genetic perturbation can have a highly variable penetrance and there’s a large cell-to-cell variability,” says Andrews, University Professor of molecular genetics and inaugural Director of the Centre. “And that has implications for understanding the mechanisms of disease, and for thinking about potential treatments.”

A pioneer of functional genomics, Andrews has worked closely with Charles Boone, also professor of molecular genetics and current Interim Director of the Donnelly Centre, to study cells as systems of a multitude of molecular components whose roles need to be coordinated to sustain cellular fitness, as measured by growth rate in a laboratory dish. That work revealed how thousands of genes cooperate to underpin basic cellular function, but it lacked the power to reveal what happens inside individual cells.

Over the last decade, Andrews’ team built a fully automated high-throughput platform to collect measurements from millions of individual cells in a mixed population using automated microscopy. Coupled with computer vision tools and artificial intelligence, the platform is all set to begin to shed light on the bioprocesses behind cell-to-cell variability and will be supported by CRC funding.

“We can look at all kinds of different mutant scenarios and measure how that affects cellular traits at the single cell level,” says Andrews. “It gives us a lot more information so that we can begin to unpick the mechanisms behind disease penetrance.”

Brown is a professor of biochemistry in the Centre where he studies how cells maintain their genomes intact. Genome integrity, he says, is a “double-edged sword.”

“On one hand, when genome integrity fails it can cause disease, but on the other hand, instability of the genome is the source of variation that fuels evolution.”

Whenever a cell copies its DNA, copying errors inevitably appear but in most cases repair enzymes swiftly correct them. External insults such as UV light from the sun or tobacco smoke, as well as internal factors, such as mutations in cancer genes, further increase the number of mutations tilting the balance to where the cell is no longer able repair its DNA. When repair is overwhelmed, cancer and other diseases can result.

CRC funding will support two kinds of projects in Brown’s lab. “The first are foundational projects where we try to understand the cellular processes that preserve the genome, that prevent mutations from arising, and that repair them when they do arise, using a yeast model to understand the underlying biology,” he says.

The second are projects that aim to reveal how cancer develops and find new ways to treat it. To this end, the team will identify the genes that cause loss of genome integrity in human cancer cells, and in cancer cells that have been treated with therapeutic drugs.

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