Peter Roy Marks 20th Lab Anniversary With Prestigious Appointment Renewal

Peter Roy has much to be proud of as he looks back on the two decades since launching his own lab. There’s a string of discoveries with medical potential, a vibrant team of graduate students and postdocs and a wellspring of new projects that could transform infectious disease treatments.

Throughout his career, Roy has been using Caenorhabditis elegans, a soil-dwelling nematode, to understand how drug molecules interact with their cellular targets. The research has wide-ranging implications, from having the potential to lead to new treatments for human diseases, to the development of novel pesticides to safeguard global food security.

Known among scientists as just “the worm”, C. elegans has been a key research tool since the dawn of molecular genetics that has helped reveal numerous biological insights relevant for human health.

“From one point of view, this amazing little (one-millimeter) worm has fed my family,” said Roy, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research, at the Temerty Faculty of Medicine.

“Many years ago, the scientific tractability of the worm inspired me to make a living out of understanding its biology and its potential utility. And I’ve been able to get grants to support other people who also love working on the worm—it's  a full circle,” he said.

The work has won Roy millions in research funding, including from the federal Canada Research Chair program, which aims to attract and retain world-class researchers in the country. Roy holds the tier 1 Canada Research Chair in in Chemical Genetics, which has now been renewed for another seven-year term. Earlier this year, he also won funding from Canada Foundation for Innovation’s John R. Evans Leaders Fund (JELF), which provides support for outstanding researchers.

“The big strengths of the worm are its simplicity and its transparency that let you see things with or without fluorescent reporters,” says Roy. “Over a course of three days you can pharmacologically or genetically probe every aspect of its biology throughout its entire development and do that in a 96-well format. You just can’t do that with any other model system.”

Because humans and worms share basic cellular components, understanding how drug molecules interact with those components in a simple animal can inform drug development for patients.

Take for example their recent discovery which holds hope for patients with a rare liver disorder, progressive familial intrahepatic cholestasis, or PFIC3. Caused by a mutation in a gene called ABCB4, PFIC3 starts in childhood and can lead to organ failure where liver transplant is the only treatment option.

Graduate student Muntasir Kamal discovered the worm counterpart of ABCB4 which, like the human gene, is important for lipid export out of cells. The lab found that under certain conditions, worms lacking the same gene die as larvae, prompting the team to screen for drugs that can reverse this defect, which in turn, might be developed into patient treatments. Another graduate student, Duhyun Han, screened more than 1000 compounds that are used in the clinic and identified 30 drugs that suppress lipid export defect. A third graduate student, Levon Tokmakjian then discovered that these molecules work by upregulating lipid export via other routes. The team is collaborating with Carolyn Cummins, an associate professor at the Leslie Dan Faculty of Pharmacy and her PhD student Sarah Cash, who is testing the compounds’ therapeutic effects in the mouse model of PFIC3. If they look promising, human trials could be next.

But the worm is not just a simple stand-in for humans. It also serves the Roy lab as a model for parasitic nematodes, which are some of the world’s greatest pests and cause billions of dollars in crop damage.

Through their testing of tens of thousands of chemicals on the worm, they came across compounds that hold promise as future pesticides.

“We go where the science takes us,” says Roy, ‘and it turns out that these molecules seem to do very well against soil dwelling plant parasites.” Several compounds turned out to be effective against the parasite Meloidogyne incognita, also known as the root-knot nematode and “arguably the world’s most destructive parasitic nematode and will eat on hundreds of crops,” said Roy.

It is estimated that plant parasitic nematodes are responsible for a 12 per cent loss in global food production each year. The problem is only going to get worse as the parasites’ host range expands under climate change. It’s an added toll on a rising food insecurity, which is already compounded by a global surge in food prices after Russia’s invasion of Ukraine as well as the ongoing impact of COVID-19, according to a recent report by the Oxfam charity.

“Food and food security is central to our health, and that’s going to become even more apparent with the geopolitical events that are taking place right now,” said Roy.

“The more that we can get a handle on this the more we can increase the global food security. What greater impact on human health is there aside from food security and mental health in knowing that you can provide food for your family? These are very important questions for large parts of the world,” he said.

Andrew Burns, a research associate in the lab and former graduate student, and graduate student Jessica Knox identified the mechanism of action for some of these nematicides, as anti-parasitic drugs are known. They established that these compounds work by engaging a target shared among many human parasites and pathogens. This finding inspired them to develop a new technology called PEXIL that has the potential to vastly accelerate drug discovery for infectious diseases by screening many drugs against many targets simultaneously.

“PEXIL is just getting off the ground so its all very hush-hush at this point”, said Roy. 

In a way, it took his whole career to get to this point.

 “It’s based on years and years of work in our lab and thinking about how to incorporate the technologies developed by other groups,” he said. “That’s human culture. Good ideas have their foundation on what others have built in the past.”

“You don’t show up in the lab one day and suddenly you invent this thing out of thin air.”

But it takes a knowing eye to tell if an idea has legs. Judging by Roy’s excitement, he’s on to something.

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