Neuron to Neighbourhood

by James Martin

How neuroscientist Rémi Quirion is expanding the scope of mental illness research

Rémi Quirion’s business card introduces him as the Scientific Director of the Institute of Neurosciences, Mental Health and Addiction. There’s French on one side, English on the other. There’s the requisite soup of phone numbers, URLs and e-mail addresses. No surprises here, except for something you can’t see: the info is repeated in Braille.

“The name of the institute may be Neurosciences, Mental Health and Addiction,” Quirion explains, “but we take care of all the senses.” He draws a thumb across the card’s raised surface. “It’s a little detail, but it’s an important one.”

Quirion wears many hats—Scientific Director of the Douglas Mental Health University Institute Research Centre, professor in McGill’s Department of Psychiatry, Officer of the Order of Canada—and he applies that same inclusive philosophy to all his work. “Instead of bench to bedside,” he explains, “we call it neighbourhood to neuron. Treatment is by team. At the Douglas, we’re recruiting the best people in their fields, and not duplicating expertise too much, so we can go from A to Z in relation to any given mental illness. We have the full spectrum of researchers, from people focused on health services research to people doing genomic research. We have people who are experts on genes related to circadian rhythm—that’s the basic science—then we have clinicians doing sleep research, and health services researchers looking at the quality of services that we give patients with sleep problems related to their depression or schizophrenia. That’s unique.”

The Institute of Neurosciences, Mental Health and Addiction shares this wide scope. The INMHA is the largest of the 13 “virtual institutes” in the Canadian Institutes of Health Research (CIHR), the major federal agency responsible for funding, and shaping the direction of, health research in Canada. “Everything about brain research is under the one INMHA umbrella,” Quirion says. “That gives us an edge globally. Other funding agencies worldwide are focused on biology without health services, or health services without biology, and there’s very little crosstalk between disciplines. In the American system, they have six or seven institutes that cover the same mandate.

“A researcher might be interested in one brain transmitter, like dopamine, for example. Now, reduced levels of dopamine play a role in Parkinson’s disease, too much dopamine plays a role in schizophrenia, and when dopamine is not properly activated it leads to addiction. So we’re trying to get all the people working on dopamine to collaborate instead of working in silos.”

Quirion practises what he preaches, embracing interdisciplinary collaboration in his own research. For the past 20 years, Quirion has explored how brain neurochemistry relates to cognitive deficits (such as dementia related to Alzheimer’s disease), investigating how the classical transmitters (e.g., acetylcholine, neural peptides) facilitate learning and memory in animal models. But these transmitters account for less than one per cent of all the proteins in the brain, so Quirion recently expanded his inquiry using genomics and proteomics technology at the McGill University and Génome Québec Innovation Centre. His team is now using DNA microarray technology to compare the 28,000 genes of a rat with learning and memory deficits with those of a non-impaired rat. “We decided to take a more shotgun approach,” he explains.

“That way, you can find families of genes that seem to be altered. Of course, we’ve found genes that are already known, but what’s exciting is that we’ve also found new genes that were not expected to be associated with learning and memory.”

Quirion’s lab is now testing how the absence or overexpression of two of these genes, transthyretin and Homer 1a, alter learning and memory deficit in rats—and they’ve already discovered how to fully reverse these deficits. “Of course, this is the animal model,” he clarifies, “so it’s easier than the human condition. The acid test will be to see if, as human beings age, we see a similar deficit in these proteins—and is it even worse with Alzheimer’s than normal aging? Then can we devise new treatments for it?

“The shotgun approach changed our strategy,” he adds, “and will lead us to explore new avenues that could lead to a breakthrough.”

Quirion is also using proteomic technology to develop novel animal models of schizophrenia and other mental illnesses. It’s not an easy task. “These diseases are related to language and cognition,” he says, “but it’s impossible to ask a mouse, ‘Do you suffer from psychosis?’ So basically, we look for animal behaviour that relates to the behaviour of a schizophrenic or depressive person.” It’s fairly easy to induce cognitive deficits in mice, but the challenge is to determine the neuropathological mechanisms at work. To this end, Quirion is exploring a new hypothesis about how neurons develop. The theory supposes that schizophrenia might be triggered if certain genes are exposed to stress while the brain is developing in the first 12 to 15 years of life—a most complicated balancing act of factors. Deciphering this mysterious interplay may point the way to revolutionary drug therapies.

“There’s a great deal of interest in this worldwide,” says Quirion, who received the Schizophrenia Society of Canada’s 2007 Pacesetter Award. “You invest time in exploring a drug that has some effect in the animal model, but then you move to human trial and the whole thing crashes. We’re treating depression, anxiety and schizophrenia with more or less the same drugs as we did in the early sixties, we’ve just improved on the side-effect profile.”

He’s also hoping to make similar headway in the areas of chronic pain management. Acute pain can usually be quelled by over-the-counter medication (“You get a headache, you take an Aspirin”), but chronic pain is tougher to treat. Opiates are effective, but often lead to dependence and tolerance—not to mention the risk of side effects like respiratory failure—making them a less than ideal solution to the arthritis and back pain plaguing an aging population.

Quirion is studying proteins and substances expressed in the spinal cord. He’s particularly interested in a calcitonin-gene related peptide (CGRP) receptor called adrenomedullin. Most CGRPs stop transmitting pain very quickly, but adrenomedullin is “100 times more potent,” with pain lasting up to 24 hours—raising suspicions that adrenomedullin may play a key role in chronic pain such as migraine headaches. There is currently no effective adrenomedullin blocker, but Quirion and his researchers are getting closer to understanding how it works—and how it can be dampened. “We’re excited by that,” he says, “and are working with industry to develop an adrenomedullin blocker, a much more powerful painkiller that can be used instead of opiates.”

Quirion wants to change the future of medicine, and not just by finding better drug therapies. He recently published an article titled “Psychiatry as a Clinical Neuroscience Discipline,” written with Dr. Thomas R. Insel (Director of the U.S. National Institute of Mental Health), in JAMA, the Journal of the American Medical Association. “The separation of psychiatry from other medical specialties has contributed to the stigma of those who treat mental disorders as well as those who have them,” they wrote. “Even beyond stigma, this separation has led to inadequate care…. If mental disorders are brain disorders, then the basic sciences of psychiatry must include neuroscience and genomics and the training of psychiatrists in the future needs to be profoundly different from what it has been in the past.” For Quirion, education—like the INMHA, like the Braille on his business card—is about integrating the whole.

Since joining the Douglas in 1983, Quirion has trained over 70 students and fellows, and he wants the next generation of Canadian brain experts to be even more interdisciplinary. “We want to expose our students not just to the basic research questions, but also clinical research questions and applied research questions,” he explains. “If we want to be truly effective, psychiatrists of the future should be able to understand microarray data just as well as they understand community care. At the same time, students doing their PhDs also need to be exposed to the global picture. So if they work with me on a gene related to learning and memory, they don’t only think about a mouse: At the end of the day, they think of an Alzheimer’s patient.

“Neuroscience is not just about a gene with a funny name any more—it’s about the human being.”

Rémi Quirion’s research is funded by the Canadian Institutes of Health Research and the Fonds de la recherche en santé du Québec.