Teammates Score
in Research Arena

By Mary Dickieson

Teamwork is the key to good research for, clockwise from top left, Patricia Bell, Steven Raynard, Richard McCulloch, Prof. Mark Baker, Leah Read and Erin Birmingham.
Photo by Martin Schwalbe

When you score a goal in hockey, almost everyone can share the excitement. But find something unexpected in the way mammalian cells control the homologous recombination of chromosomes, and you may be the only one cheering for miles around.

But cheer they do in the OVC pathobiology lab headed by Prof. Mark Baker, where the goals-scored average has been pretty high of late. Finding something that no one else has found before is a real high, says Baker, even if there are a limited number of people who can fully appreciate the significance.

You might say his lab has scored a hat trick recently in terms of recognition in the scientific and medical communities. The first goal came in the form of renewed funding from the Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council (NSERC) that will approach $1 million over the next five years.

The second relates to the publication this month of a paper by Baker and lab technician Erin Birmingham in the prestigious American Society for Microbiology (ASM) journal, Molecular and Cellular Biology.

The third goal was scored by Baker's team at the Canadian Society for Immunology meeting in April when their professional colleagues applauded the complex analyses being done at U of G.

Baker also scores his share of on-ice goals during pick-up hockey in the U of G arena. He's manager and captain of the Guelph Maple Leafs Red Team, who face off against the White Team every Wednesday evening.

Hockey or research, this captain stresses the importance of teamwork. He is one of seven people working in the recombination lab at OVC. These scientists share an interest in the molecular mechanisms of recombination and want to discover how it is involved in the control of gene structure and function and in the generation of human diseases, including cancer. They are one of the few research teams in the world that explore the fundamental biological process of homologous recombination.

An obscure concept to most of us, this basic process enables changes to take place within the DNA of all living cells and is vitally important in generating genetic diversity, in adaptation and in the evolution of new species. Homologous recombination is also a form of DNA repair that is important during the growth of mammalian cells to prevent an accumulation of mutations that could cause cancer and other diseases.

This is pure research, but there are obvious long-term implications for human medicine through gene therapy and for the growing biotechnology industry, says Baker. Every biotech discovery and application that excites people today had its roots at the very fundamental research level, he says.

Gene targeting is one example. During post-doctoral work at the University of Toronto in the early 1980s, Baker worked with mentor and U of T professor Marc Shulman on a research team that was among the first to successfully develop a technique for gene targeting in mammalian cells. Now it's a routine process in many labs around the world, used to introduce site-specific changes into the chromosomal genes of living cells in an effort to precisely manipulate the genome. This technology permits genes to be modified right in their normal chromosomal environment, affording more precise study of their function.

In applied terms, gene targeting has the potential to aid the development of new strains of plants and animals and may one day serve as an effective form of human gene therapy.

Baker continued his work in mammalian recombination at the National Research Council's Biotechnology Research Institute in Montreal from 1988 to 1990 and launched his recombination lab at OVC when he joined U of G in 1990. Leah Read has worked with him as a lab technician for 10 years; Birmingham, for about four years.

The recombination team also includes current PhD candidates Steven Raynard and Richard McCulloch and M.Sc. student Patricia Bell. Prof. Julang Li completed post-doctoral work in the lab before joining the faculty of the Department of Animal and Poultry Science last summer. And there are almost always two undergraduate students working in the lab on semester projects. This summer, the lab has received funding from NSERC and U of G to hire biomedical sciences student Cara Reith and molecular biology and genetics student Shauna Lee as research assistants.

Baker says it's important to offer research opportunities to undergraduate students. "You have to teach people how to do research - it's not intuitive. You have to teach students how to think about science, how to ask the kinds of questions that most people don't normally think about."

Recombination research requires good analytical skills, tenacity and self-motivation, he says. "We do excellent work, but are relatively unknown to most undergraduates. A lot of our own undergraduate students here at U of G don't appreciate the significance of the medical research being done at this University."

In the major leagues, OVC's recombination lab is well respected. CIHR and NSERC have provided operating funding and fellowship support to Baker's research activities and graduate students over the lab's 11-year lifetime.

"We've developed a unique system for studying the complex processes involved in homologous recombination," says Baker. "Ours is one of a handful of labs worldwide doing this level of investigation."

The paper being published in the ASM journal reports on one of the important new findings by the Guelph team.

"Our results suggest that mammalian cells exert a high level of control over how crossing over takes place between two DNA sequences during homologous recombination," says Baker.

The naturally occurring exchange of genetic information by crossing over was previously considered to happen randomly. But Baker's team has found evidence that animal cells can actually control how DNA exchanges occur, perhaps a deliberate manoeuvre to prevent abnormal chromosome changes and, potentially, large numbers of genetic mutations within a species.

"We are continuing our investigation of the crossing-over process, how mismatches created during recombination are repaired and how homologous recombination normally occurs when there is no crossing over," he says.

Baker's lab is also studying the chromosomal immunoglobulin locus, a region in the mammalian genome that is responsible for the production of antibodies during an immune response. Their evidence suggests that this locus resembles a recombination "hot spot" in that it is capable of supporting a high level of homologous recombination.

"Our understanding of how recombination hot spots function is very limited," he says. "By studying this particular locus, we hope to learn more about the mechanisms that control this activity. We think this knowledge may enlarge our understanding of how antibodies in the body develop the characteristics needed to fight an invading pathogen or what triggers the body's immune system to attack itself in autoimmune diseases like multiple sclerosis, rheumatoid arthritis and lupus. We're looking for a fundamental view of how these processes happen to provide the base understanding from which future applications for health care and industrial uses can grow."