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The Legacy of Ling and Smith


In 1997, Michael Smith and Victor Ling founded the Genome Sciences Centre, a high-throughput genomics center with a sharp focus on cancer. "Here you have two of Canada's most widely respected and well-known scientists, Victor Ling and Michael Smith, coming together and saying that they were devoted to the concept of a genomics presence in Canada," says Marco Marra, director of what is now the Michael Smith Genome Sciences Centre. Smith won the 1993 Nobel Prize in Chemistry for site-directed mutagenesis, sharing it with Kary Mullis, who was recognized for his PCR work.

In the late '90s, Ling was the vice president of research at the British Columbia Cancer Agency, which was instrumental in getting the new genomics center up and running. The British Columbia Cancer Foundation gave Ling and Smith $25 million to launch the center. "At the time, this was the single largest investment put into the field in Canada," says Marra. "The cancer foundation was persuaded to back the enterprise based largely on the belief that cancer and cancer genomics would be the next big thing."

The GSC cut its teeth on its first big project, generating a BAC fingerprint map of the mouse genome in conjunction with Washington University and the Sanger Institute. Since then, Marra says, the center has had a string of grants and contract funding, totaling approximately $250 million. It has expanded to 230 staff members, with 10 principal investigators who focus on a range of projects from proteomics to mapping.

"We're all collaborating at a very highly integrated level. I'm working with the cancer genomics people and the gene expression people," says Steven Jones, head of bioinformatics at the center. "When we write large applications, we are writing them together as a team. That's really how we're running the center."

The center hasn't lost its cancer genomics focus. Of the 60 or so ongoing projects, a whole host of them are looking into the genetics and genomics behind cancer, including studying the follicular lymphoma genome in deep detail as well as analyzing which genes keep people healthy by looking at octagenarians who have never developed cancer, cardiovascular disease, or pulmonary disease. "At the time [the center was founded], it seemed like a focus on cancer genomics was exactly where this field would head. And in hindsight, it looks like Victor and Michael were right," says Marra. The GSC, through Genome British Columbia, also takes on projects unrelated to cancer.

Cancer and aging

The two big projects going on right now in the cancer genetics lab at the center are population-based SNP studies of non-Hodgkin's lymphoma and of healthy aging. The GSC functions under the auspices of the BC Cancer Agency, which is responsible for all of the cancer patients in British Columbia. Angela Brooks-Wilson, who runs the cancer genetics lab, tries to keep that in mind. "What I like to do is take into account, or base our studies around, the BC Cancer Agency's mandate for cancer care and research for the whole BC population," she says. In conjunction with researchers at the cancer agency, her lab is conducting a SNP and haplotype-based case-controlled study to uncover genetic susceptibilities to non-Hodgkin's lymphoma.

Brooks-Wilson is also looking into what it takes to grow old gracefully — that is, without developing cancer, cardiovascular disease, pulmonary disease, or diabetes. This study takes a twist on a case-control study since the cases here are people 85 years or older who have never developed any of those diseases or conditions, while the controls are middle-aged people recruited randomly from the population, regardless of their health. "The study has a genetics, rather than lifestyle, focus, and we want to find genetic factors that contribute to healthy aging," says Brooks- Wilson. In particular, her team, which includes GSC investigators Marra and Jones as well as outside clinicians, is using a SNP approach to the research.

Next-gen at the fore

Naturally, technology has a critical role at the GSC, which continues to build up its instrumentation. "Right now, perhaps not surprisingly, we're quite heavily focused on developing applications for next-generation sequencing and, in particular, the Illumina sequencer," says Marra. GSC scientists have made approximately 500 Illumina sequencing libraries and are ramping up their core instrumentation.

"The big thing is we [can] now start to attack cancer genomes fairly robustly with these new devices," adds Jones.

Marra's already got one experiment in mind to try out their new next-gen sequencers. As a continuation of their BAC fingerprint mapping projects, GSC researchers are making whole-genome, deeply redundant BAC libraries of cancer genomes that they are then fingerprinting to look for cancer mutations. Working from a library of approximately 150,000 BACs and using a combination of restriction enzymes to generate a pattern, they compare the cancer genome pattern to one predicted computationally from reference genomes. Any difference between the predicted pattern and the fingerprint gets marked as a candidate mutation to be further validated.

When they made a BAC fingerprint map of the follicular lymphoma genome and analyzed it, they found that the genome has hundreds or thousands of tiny deletions with a median size of about 5 kilobases. "It turns out that many of these itty-bitty, tiny deletions are associated with repeats," says Marra. "We think this is a fantastic structural genomics project, and we're quite keen now to take that same genomic material and analyze it on our Illumina sequencers to see what the overlap and the pickup rate is. It could be that the BAC fingerprinting gives us better detection sensitivity in these regions than the Illumina because these regions are enriched in repeat sequences and, of course, sequencing repeats with short reads is tough work."

The forestry branch

Another part of the GSC's mandate is to take on projects important to British Columbia as a whole. "With funding from Genome British Columbia, we are essentially a provincial platform for certain types of genomic activity, including DNA sequencing and bioinformatics," says Marra.

With the surrounding forestry community, GSC's team is working on the genome of the mountain pine beetle and the blue stain fungus it carries. This bug and its fungus have decimated about two-thirds of British Columbia's forests. Due to warmer winters, the mountain pine beetle population has exploded, says Marra. The beetle chews on the bark of the trees, weakens them, and leaves the fungus behind — which further harms the trees by interfering with water uptake and movement. At the genome center, scientists are looking for vulnerabilities in the beetle and fungus to control their spread throughout the province. "The idea is now to figure out how can we restrict spread by perhaps using genomics to study the beetle and fungus to find targets or susceptibility to agents — perhaps even biological agents that would allow us to control the infestation," says Marra.


Fast Facts

Michael Smith Genome Sciences Centre
Vancouver, British Columbia

Host: British Columbia Cancer Agency
Director: Marco Marra
Established: 1997, by Michael Smith and Victor Ling
Size: 50,000 square feet of lab, occupying two floors of two buildings
Staff: About 230, with 10 principal investigators
Funding: About $250 million from 25 sources, including British Columbia Cancer Agency, Genome Canada, Genome British Columbia, the National Institutes of Health
Focus: Cancer research
'Omics tools: New Illumina sequencers, BAC fingerprinting, SNP analysis, as well as bioinformatics and proteomics

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