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Toxicologist Smokes Out Stress Hormone
Biomedical scientist's study of enzymes that cause people to keep smoking aims to help them break the chains that bind them to cigarettes
BY ANDREW VOWLES
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| Prof. Gordon Kirby is OVC's inaugural associate dean (research and innovation). Photo by Martin Schwalbe |
Helping smokers quit their habit is Prof. Gordon Kirby's research goal — or one of them. Starting this month, the biomedical scientist is now responsible in a sense not just for his own wide-ranging toxicology studies but also for all the diverse research projects conducted across four departments in the Ontario Veterinary College. This spring, the two-time Guelph graduate was named OVC's inaugural associate dean (research and innovation).
The thought of assuming that responsibility might spark the kind of stress that causes some people to fumble for their cigarette package. But on a late-May morning, Kirby is keeping a steady hand — steady enough to deliver just the right amount of chemical into two glass vials for a must-do experiment in his lab.
Funded by the Canadian Institutes of Health Research (CIHR), he is studying enzymes that cause people to keep smoking and eventually become addicted to nicotine. Learn more about the body's interaction with nicotine and other chemicals in tobacco, he says, and we might find a way to help people break the chains binding them to cigarettes.
The particular enzyme he studies is — somewhat paradoxically — responsible not for maintaining blood nicotine levels but for ridding the body of the substance. Called CYP2A6, that enzyme is made by the liver, where it breaks down nicotine for elimination in the urine. Lower smokers' blood nicotine levels and they'll soon be heading out for a cigarette break to top them back up, he says.
The substance is among an arsenal of enzymes that the body makes to get rid of potentially toxic compounds, including drugs, chemicals and carcinogens. Beyond ideas for helping people quit smoking, Kirby's work may yield clues for doctors looking to prevent adverse drug reactions or design cancer-fighting regimens tailored for individual patients.
“We look at enzymes that metabolize drugs, medications, carcinogens,” says Kirby, referring to the research technicians and students in his basement lab (located, it turns out, directly beneath OVC's administrative offices, where he will now spend some 70 per cent of his time under that new appointment).
“Students” come in various shapes and sizes in that lab. This year, Kirby helped his son Matt, 14, put together a project on stress and smoking that won a silver medal and a scholarship for the King George Public School student at the Canada-Wide Science Fair.
“I was tickled pink,” says Kirby, dad of four kids between 12 and 17. He helped Matt figure out mouse liver cell culture and polymerase chain reaction, a key tool in molecular biology for rapidly copying DNA for genetic experiments.
That science fair project showed how stress causes the release of a particular hormone that raises levels of a nicotine-metabolizing enzyme similar to human CYP2A6. The resulting rapid drop in blood nicotine levels is what makes smokers crave another cigarette, he says.
Matt used mashed-up liver cells from mice to study nicotine breakdown products. He compared the number of metabolites contained in cells treated with the stress hormone cortisol versus cells left untreated. High-performance liquid chromatography then sorted out the metabolites and showed them as a series of characteristic spikes on a graph.
Pointing to the jagged sequence on a printout from earlier work, Gordon Kirby notes a huge increase in the “spike” for the metabolite cotinine, supporting his hypothesis: more stress hormone leads to more enzyme leads to faster nicotine metabolism and more smoking.
So how will this work help a smoker? He suggests the research might aid in making a better “stop smoking” gum like Nicorette. Not all smokers are alike, he says. Individuals may crave more or less nicotine, depending on their ability to metabolize the chemical. Some of that difference may be traced to genetics and racial differences, but he's interested in environmental factors, notably stress. Thinking beyond his mouse models, he's planning to enlist volunteers for human trials to study the effects of stress on stop-smoking products.
He widens the focus from nicotine to other kinds of chemicals and enzymes.
For example, similar enzymes are found in cancerous cells. Just as bacteria can become resistant to antibiotics, some cancer cells may be able to pump out more of a particular enzyme to battle anti-cancer drugs. Kirby says that mechanism may help explain why some cancers return after remission in a stronger and more aggressive form, confounding drug therapies that worked earlier.
He's studying a class of enzymes called glutathione transferases that may enable cancer cells to resist drug treatment. Paradoxically, the same substances normally help protect you against such things as carcinogens. In fact, says Kirby, health regulators are pushing for dietary recommendations to eat more foods containing substances that boost these protective enzymes, such as leafy greens.
Learning more about how these substances work — both normally and in cancer cells — is the purpose of his work. He says that might help cancer patients live longer or even help wipe out cancer in some patients. Last month, that research netted a three-year $266,000 grant from the CIHR, part of a recent announcement of more than $2.2 million in U of G funding from the federal agency.
Kirby's cancer studies might also benefit dog owners. Based on a project funded by the OVC Pet Trust, he is now investigating a patent for a screening test that would detect blood vessel cancer in dogs. Vets often uncover the problem too late. Even after treatment, the animals live an average of only six months.
Five years ago, U of G received funding from the Canada Foundation for Innovation for the Institute for Animal-Human Links in Health Science Research to develop a clinical proteomics facility. There, researchers scan tissue or body fluid samples for proteins that act as “biomarkers” for specific diseases, including cancer. By screening serum from normal and diseased dogs, Kirby's lab has found a particular protein that may serve as a marker for blood vessel cancer.
“It's quite exciting,” he says, adding that he's now trying to refine the test. He envisions an assay that a vet could use as easily as a woman conducting a home pregnancy test.
Linking human and animal health is a natural segue to his new job as associate director (research and innovation). That theme resonates in research and teaching across OVC.
Animal models are increasingly important for researchers studying human diseases from cancer to arthritis to asthma, he says. Veterinarians and associated researchers are also integral to tackling zoonotic diseases such as bird flu and SARS that cross borders between animals and humans.
Kirby says a key part of his job will lie in raising public awareness of those links and of OVC's specific role. Gesturing to a magazine on his desk, he points to a headline about plans for an E. coli cattle vaccine involving a private biotech firm and says: “Why can't that happen here?”
He also hopes to help OVC members connect with each other and with granting agencies, industry and other researchers beyond campus.
A few months ago, while preparing a presentation for his new position, he drew on a personal interest. Building, planning, visioning, working around obstacles: those administrative skills sounded a lot like the kinds of things he uses in a different context — woodworking. On one wall of his office hangs a photo of a timber framing project he completed at home — no nails, he says, just mortise and tenon joints used by generations of woodworkers to assemble structures like that garden shed.
Elsewhere hang two pen and ink drawings he did in the early 1980s, one depicting a white-tailed deer, the other an impala. More or less self-taught — although he took one fine art course at Guelph while working toward his DVM in the early 1980s — Kirby used that talent during a stint in Zambia with Crossroads International in his second year. His work, including that impala, showed up in a wildlife brochure he illustrated for a game park.
A glass-fronted cabinet holds the collection of rocks, fossils and gemstones he inherited from his father, who was a doctor in Hawkesbury, Ont. Kirby recalls tagging along on a few calls with his father and seeing some unsavory aspects of medicine that made him consider a different profession.
In the process, he was bucking family convention. Those medical implements on a shelf behind his desk — an apothecary weigh scale, a glass flask and other items — came not from his father but from his great-grandfather, who had worked in the same Hawkesbury practice. Kirby says family lore has it that there's a long line of doctors extending back on his father's side to before the American Revolution.
Travels with a vet in eastern Ontario sent Kirby in a different although not unrelated direction. After earning his DVM in 1983, he studied toxicology for a master's degree at the University of Surrey before returning to Guelph for a PhD in pathobiology in 1991. Three years later, following post-docs at the International Agency for Research on Cancer in France and at McGill University, he joined the faculty of the Department of Biomedical Sciences.