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Big science depends on small mammals to understand what ails us

Story by Andrew Vowles
Photos by Dean Palmer and TCP

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Two floors below street level in downtown Toronto, Heather Goodman leads the way along a wide deserted corridor lit by fluorescent ceiling panels. Her baby-blue slip-on booties muffle her tread against the spotless floor. In matching scrubs, she looks like a hospital staffer, but her actual title is supervisor of technical services for the Toronto Centre for Phenogenomics (TCP).
Goodman stops outside a door whose red-tinted window keeps out the corridor light at night when the room’s occupants enjoy total darkness during their active period. As it’s now early afternoon, the interior lights are on.
Swiping her ID badge through a reader, she pushes open the door just enough to poke a head inside. The room is filled with stainless-steel shelving racks packed with plastic cages, row on row. Lights or no lights, it’s difficult from the partly opened doorway to make out what’s inside them. But that busy rustling is an unmistakable sound. Sure enough, behind the plastic lid of an upper-shelf cage nearest the door, a telltale form appears — one of the thousands of occupants housed in this new research facility.
Listen hard enough, and that scrabbling of mice in their cages might begin to sound like something else: a hoped-for groundswell of genetic information coming from the TCP that will help us learn more about ourselves and how to treat and perhaps cure cancer, heart disease, asthma, arthritis, neurodegenerative disorders, diabetes and numerous other diseases.

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A robot washes the cages

Opened in fall 2007, this $69-million facility is among the largest genetic centres in the world dedicated to the development and study of mouse models for human health and disease research. The three-storey, 120,000-square-foot centre stands within walking distance of its four supporting research hospitals: Mount Sinai, St. Michael’s, the Hospital for Sick Children and the University Health Network.
You can’t see the University of Guelph from here, but you can follow numerous research and teaching connections between the TCP and the Ontario Veterinary College, beginning with the two-time Guelph grad who heads the Toronto centre.
CEO Colin McKerlie, DVM ’91 and D.V.Sc. ’97, says the TCP is much more than a breeding nest for laboratory mice. “It’s a research centre that’s all about enabling human health research,” he says.

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Colin McKerlie

The University of Toronto professor and SickKids researcher holds an adjunct appointment in U of G’s Department of Pathobiology, where he earned his D.V.Sc. with now retired professor Dean Percy. (That came after McKerlie spent two years as a country vet in England, a stint that landed him in the middle of that country’s BSE crisis of the early 1990s.) A co-applicant for the grant that funded the TCP, McKerlie assumed the centre’s head post last spring after serving as interim CEO during its design and construction.
Referring to researchers’ use of its facilities — and varied mice, tissues, gametes, stem cell lines and DNA housed here — for learning more about human health, he says: “The genetic and molecular mechanisms that cause disease are very similar between humans and animals.”
Put together an organism’s genetic material ― its genome ― with physical traits we can see or measure ― its phenotype ― and you get “phenogenomics.” Here at the TCP and elsewhere in Canada and abroad, researchers are taking the next steps beyond mapping genomes for humans, fruit flies, dogs, mice and other creatures. In painstaking fashion, they’re now learning how DNA’s biochemical code works by selectively manipulating the function of each of the mouse’s roughly 22,000 genes and observing the results in tissue or in live animals. From there, they hope to learn more about how those genes work in us.

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Center for Phenogenomics

“The mouse is going to prove to be the most powerful mammalian model system for us to use and functionally annotate the human genome,” says McKerlie, who gave OVC’s 2007 Chappel Memorial Lecture. “One of the greatest scientific challenges of the 21st century is to understand the function of all 22,000 genes in the human genome. And for any human gene, there’s a 95-per-cent chance that there’s a mouse gene that has a very similar function. It’s the gene in the mouse, not the human, that we can manipulate. We can establish a mouse model of that gene’s function and, when it doesn’t function, get on with the biology and creation of new drugs.”
Observe a mouse with a precisely mutated gene and you can make some inferences about causes and treatment of disease involving the comparable bit of DNA in humans. For example, a spontaneous mutation means the “SCID mouse” has no working T or B cells, making it ideal for learning more about how the human immune system works and perhaps learning how to cure the same disease in humans — severe combined immunodeficiency syndrome. Scientists can use the “non-obese diabetic mouse” to understand what triggers diabetes, which affects about two million Canadians. Roughly the same number of Canadians suffer from asthma, says McKerlie, whose own lab team looks for genes and proteins involved in allergic responses to airborne irritants. “We’re looking for mice that wheeze,” he says. Whether it involves asthma, diabetes or cancer, manipulating the mouse genome gives us clues about disease mechanisms in ourselves. “We can humanize the mouse and then use it as a model system to inform us about the genes and the biology that contribute to human health.”

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Lisa Phaneuf, left, and Susan Newbigging

Not that the mouse is all things to all researchers. Guelph pathobiology professor Geoff Wood, DVM ’93 and D.V.Sc. ’07, split his own graduate time between U of G and McKerlie’s labs at SickKids and Mount Sinai. Wood still studies mice, but he has broadened his focus to dog phenogenomics, using canine cancer patients arriving at the OVC Teaching Hospital. For all the value of inducing pinpoint mutations in experimental rodents, he expects dogs sharing our homes and even our food will tell us other things about environmental factors involved in real-life spontaneous cancer. Studying both species, Wood says, “gives us an opportunity to mine these two data sets of what changes go on in the dog and the mouse, what’s similar and different.”
Susan Newbigging, DVM ’03 and D.V.Sc. ’07, who also worked in McKerlie’s TCP labs, now directs pathology studies at the Toronto centre and is a team investigator at SickKids. She agrees it’s important to look at all kinds of influences on various diseases. “Maybe the mouse model helps determine which genes are causing asthma, but you need a larger animal model, too.”
Still, Mus musculus remains the workhorse of the genetics lab. Up to 200,000 mice will be housed in the secure, climate-controlled Toronto facility designed to keep its occupants free from potential contamination. Staff and visitors from scientists to dignitaries must doff their street clothes, don scrubs and take an air shower before entering the below-ground holding area. Cage rooms are independently ventilated with a set number of air changes each hour. Animal attendants and a robot add sterilized bedding and food to the cages, up to 36,000 of them eventually, each identified by a computer code. A second robot empties and cleans used cages. Lise Phaneuf, DVM ’98 and D.V.Sc. ’06, is associate director of TCP research and facility operations, overseeing day-to-day care and research use by staff and scientists.
Last spring, the TCP won a 2008 North American facility-of-the-year award for its design. The modern building blends into the city backdrop of Toronto’s Discovery District. It was designed to be cost-effective and secure with areas for interaction, collaboration and training and flexible space to address future needs. A tightly constrained urban site, underground utilities, rigid zoning restrictions and plans for future vertical expansion all drove the requirement for an innovative design. Sixty per cent of the floor plan is underground. The future master plan includes a 300,000-square-foot, 15-storey tower to be built above the TCP.
Research here occurs in three main facilities connected to various researchers at member hospitals. At the Centre for Modeling Human Disease, researchers make and analyze mutant mice as well as tissue, cell lines and genetic material alone. The Canadian Mouse Mutant Repository preserves and distributes mutant mouse lines and tissue, working with researchers and clinicians in those nearby hospitals and with scientists in Canada and abroad through the Federation of International Mouse Resources. The Mouse Imaging Centre uses optical and digital technology to study the animals at all life stages.

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“It’s a one-stop shop” for studies of mouse genetics, pathobiology and human disease, says Wood. But not a stand-alone shop. The Toronto facility works with larger groups, including the Canadian Mouse Consortium, the International Knockout Mice Consortium, and North American and European organizations all developing genetically engineered models of human disease.
That spirit of collaboration drove the development of the facility, which was funded by the federal and provincial governments, the four member hospitals and industry. No one scientist or institution alone could have put together the TCP, says McKerlie. Likening the centre’s programs to the scope of the Human Genome Project, he says: “This is big science, so it required big facilities. But more important, it requires a big community of science based on sharing to make it work.”

At the same time, Newbigging says the TCP mandate hits near home. Whether cancer or heart disease, “everybody is touched by disease in their family. I’ve had family members with different illnesses. I want to do something about it.” Overseeing pathology in her unit is several steps removed from the bedside, but “I’m getting to help people even though not directly. I can say we’re finding out why it’s happening, how disease works. These are the first steps to treatments and cures.”

 

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