Guy Rouleau, MD, PhD, FRCPC, OQ

The thrill of discovery inspires a star in neurogenetics

An avid canoeist and sailor, Dr. Guy Rouleau loves the thrill of exploration and discovery. In the wilderness and in the laboratory, he likes to “go where there is no clear path”.

“Research is an intellectual adventure,” he says, “It turns my crank and fits well with my personality.”

Born in Ottawa, Dr. Rouleau studied medicine at the University of Ottawa and neurology at McGill University. His innate curiosity led him to explore how brain diseases develop. Early in his career, he realized that the best way to achieve that goal was to study genetics. In 1989, he obtained a PhD in this field from Harvard University.

At 54, he heads his own lab and is Director of CHU Ste-Justine Hospital’s Research Centre and the Réseau de medicine génétique appliquée du Québec. He is a full professor at l’Université de Montréal and an adjunct professor at McGill University. He holds the Canada Research Chair in Genetics of the Nervous System.

As creator and director of the Centre for Excellence in Neuroscience at l’Université de Montréal (CENUM), Dr. Rouleau has united more than 500 clinical and basic scientists and specialists and students with an interest in studying the brain. “Nobody really does anything alone,” he says. “Genetics is a field that requires a broad collaboration.”

Dr. Rouleau has trained large numbers of scientists and physicians who study the brain in universities around the world.

Simple philosophy

His philosophy is simple. “All human diseases result from the interaction between the genes that you’re born with and the sum total of exposure to your social and physical environment – suicide, car accidents, cancer, infection, everything,” he says.

“If you start from there, you either study the environment or genes. I study genes. That’s what I do. I try to understand what are the genes and variants in genes that predispose to disease.”

Dr. Rouleau has made significant contributions to the discovery and mapping of at least 20 loci – specific locations of an abnormal gene or DNA sequence on a chromosome – and identified more than 10 genes responsible for neurological diseases.

His work has focused on amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease, schizophrenia, migraine, juvenile epilepsy, autism, oculopharyngeal muscular dystrophy (OPMD), Tourette syndrome, familial aneurysms, restless leg syndrome, Parkinson’s disease, mirror movement disorder, and a host of other neurological and psychiatric diseases.

Outside the box

Dr. Rouleau is probably best known for his passion for discovery and ability to think outside the box.

"I don't like to follow trends or fashions in medicine," he admits. "I always try to look for alternatives – different ways to look at the problem. I’m always very skeptical and I always try to find alternative explanations.

“Often, it’s a dead end and I’m wrong,” he chuckles. “But sometimes, I’m right.”

A perfect example of his unconventional approach is the Synapse to Disease (S2D) project, funded by Genome Canada and Génome Québec from 2006 to 2011. The aim of S2D was to identify de novo mutations in synaptic genes that cause or predispose a person to a complex neurological disease. Caused by the interaction of several genes, complex diseases pose a major challenge to genetic analysis – akin to searching for an unknown number of same-colored needles in a haystack full of multicolored ones.

In the brain, networks of nerve cells or neurons control all functions. They communicate at specialized sites of contact called synapses. Dr. Rouleau and his S2D colleagues postulated that defects in synaptic formation and function might be responsible many brain diseases.

When S2D began, the common disease/common variant (CD/CV) model – the belief that common genetic variations exist in everyone with the same disease – was popular in the field of genetic research. Unfortunately, the real-world evidence did not support this theory in people with developmental neurological diseases, such as schizophrenia and autism.

“I decided it (CD/CV) wouldn’t work well for most of the diseases that interested me,” says Dr. Rouleau. “It got me thinking about other mechanisms and that’s how I ended up with the rare variant/de novo mutations idea, which at first in the late 1990s was considered to be totally crazy but is now turning out to be an important explanation for a number of neurological diseases.”

Dr. Rouleau postulated that rare genetic variants and de novo mutations in synaptic genes occur more often than anyone imagines. S2D tested the hypothesis that this type of genetic defect plays a causative role in neurodevelopmental diseases, such as autism and schizophrenia.

“Even my students, who did the work, thought I was crazy,” he recalls. “Then we found exactly what I had predicted in schizophrenia as part of the S2D project.

“S2D was a very large project that was to try to prove an unconventional hypothesis. There was a lot of organization to get people together, and it used a primitive methodology, which is what we had at the time,” he says.

“But it proved the story. Now, with better technology, it seems like it is completely confirmed.”

Dr. Rouleau has secured funding to continue portions of the project. “We had a paper in Nature Genetics just a few months ago that was a son of S2D,” he says.

Much of his basic research in neurological diseases has found real-world applications in the field of diagnostic testing. These tests are currently used to diagnose neurological problems in thousands of people worldwide. In future, he hopes that his discoveries will lead to new treatments for people with neurological disease.

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