DNAprint Genomics (DNAG)

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Toronto Star story re: cancer research

http://65.54.170.250/cgi-bin/linkrd?_lang=EN&lah=261e9975ffd9d9546d58a44225177b51&lat=107982...


Mar. 20, 2004. 01:00 AM

Canada's high-tech cancer fight
A pioneering Vancouver research centre probes ways to treat and, possibly, prevent cancer Scientists are building on the discove


PETER CALAMAI

VANCOUVER—Every morning as they arrive at work, Canada's crack team of genome cancer researchers gets a new jolt of motivation.

That's because to reach their cramped quarters at the Michael Smith Genome Sciences Centre on the third floor of the B.C. Cancer Agency here, the researchers must walk past dozens of clinic out-patients, whose drawn faces hint at the toll of the disease.

Yet, it's quickly obvious from interviews that the genome centre's staff are already highly motivated to find better ways to detect and treat cancers, and eventually prevent them, even without this daily personal reminder of the human stakes.

The patients represent far more than extra motivation anyway. Tracking the detailed genetics of the clinical condition of cancer sufferers is vital to the most exciting work in a facility that is one of Canada's newest powerhouses of scientific discovery.

Ontario residents probably first heard of the centre last April when, after a six-day, around-the-clock blitz, researchers here produced the first genetic blueprint of the SARS coronavirus, posting it on their Web site for scientists everywhere to use.

That's unlikely to be the last time the centre snares headlines. Pioneering research currently underway includes investigation of the potential for preventative vaccines against cancer, the deliberate triggering of the body's own "angels of death" to destroy tumours and a large-scale study of how genetic and environmental factors interact in non-Hodgkin lymphoma.

Named after the late Canadian Nobel chemistry laureate, the Michael Smith centre is tackling cancer with two weapons that promise to revolutionize treatment — the profound findings and powerful techniques from the human genome project.

It's less than a year since this international effort published the final human genome "sequence," the order in which three billion linked chemical pairs are arranged in our genetic blueprint, the shop manual to build and operate every cell in the body.

Already, the techniques derived from the human genome project are being used at the centre to decipher the genetic blueprints of everything from spruce trees, to salmon, cows, lab mice and rats, bacteria and even wine grapes.

"We're just beginning to see all the different programs that can make use of the expertise at the genome centre," says Alan Winter, president and chief executive of Genome B.C., regional partner of the federally funded Genome Canada.

Over the last three years, Genome B.C. has directed $33 million to the Genome Sciences Centre, representing a quarter of the provincial agency's total grants. Winter sees the centre as a catalyst for life sciences in the province with a potentially large economic pay-off.

At the facility itself, however, cancer work is the priority and it's what truly gets the researchers talking.

"The patients help give us a sense of what we're capable of," says centre director Marco Marra.

Marra radiates enthusiasm and energy as he describes the centre's world-ranked expertise and unique research mission in Canada. Outside his modest office, the lab wall is adorned with four-by-six prints of the centre's 134 staff members. Even the senior researchers appear incredibly young.

"The average age is probably well below 40, a lot like you'd find at a university," says Marra, 37.

In research capability, the Genome Sciences Centre resembles university institutes as much as Tiger Woods resembles other professional golfers. The formidable scientific arsenal here includes:

The largest genomics centre in North America dedicated to cancer research.

The highest-capacity genome sequencing lab in Canada, with enough power to sequence the gene portion of human DNA 10 times over in a year.

The world's leading laboratory for the crucial sequencing step known as genome fingerprint mapping. This has been compared with determining the order of the pages and volumes before starting to read an encyclopaedia.

Canada's leading academic group in terms of computing power and resources, with more than 200 individual computing devices, a "cluster" that does supercomputing tasks at electronics superstore prices and seven terabytes of online storage. (A terabyte equals 1,024 gigabytes.)

The country's largest academic concentration in bioinformatics, the discipline of managing, analyzing and digging into Everest-sized mountains of biological data.

"There is no traditional way you could handle the data sets that are being produced here. The files are so large that you couldn't even print them out," says Steven Jones, 35, who is in charge of the bioinformatics operation. "People are now doing biology in a way that was never possible before."

This new approach isn't simply a matter of raw computing power, although Jones shows off an air-conditioned room where indicator lights blink spastically from racks holding 80 twinned CPUs, the brains of a computer.

"That computer can do one gene, while that computer does another," he says. Equally important are the instructions for the CPUs, called algorithms, custom-written by the bioinformatics staff of 60 who also devise special graphics software. And these aren't geek computer programmers. Twenty-eight hold graduate degrees, many from the biological sciences plus mathematics and astronomy, disciplines where the data arrives in continuous tsunamis.

One of their visualisation programs, called Sockeye, gives the researchers a 3-D image of where the same gene is probably found in different organisms. The coloured lines enveloping Jones in the photograph, above, pinpoint the likely locations of a common cancer-related gene, called p53, within human, mouse, rat and zebra fish DNA.

"You can buy sequencing machines, you can buy computer equipment. The various doodads aren't rate-limiting," says Marra, using an analogy to the key factor that controls a chemical reaction. "What is hard is finding talented people."

It's exactly in this area — which Marra calls intellectual bandwidth — that the Genome Sciences Centre really shines.

Take the centre's director himself. Born and educated here, Marra was attracted 10 years ago to Washington University in St. Louis, where he played a leading role in the human genome project. His name is second among the more than 100 authors of the landmark 2001 scientific paper that announced the successful preliminary mapping of the human genome.

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`The (cancer) patients help give us a sense of what we're capable of'

Marco Marra, cancer genetics researcher

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Lured back to Vancouver in 1999 when the centre was begun by Smith and Victor Ling, head of the B.C. Cancer Research Centre, Marra now finds himself trying to keep tabs on two dozen research projects here in contrast to the two or three huge projects tackled at Washington University.

As well, while the centre has been successful in attracting government grants for specific projects, like the bovine genome, and for costly equipment like $600,000 DNA sequencers, Marra says there is some concern that staff salaries depend largely on public fundraising by the B.C. Cancer Society.

"You can't have a vision based on a three- to five-year time frame," he says. At the same time, there appears to be no lack of vision at the Genome Sciences Centre, or of top-notch scientists pursuing research with a potential for big payoffs.

Consider 35-year-old Rob Holt, another example of "brain return" at the centre.

The B.C.-born Holt was a star at Celera Genomics, the American private sector competitor in the human genome race, where he helped pioneer a superfast "shotgun" sequencing method.

In October, 2002, Holt was the lead author of the scientific paper that laid out the genetic blueprint for the malaria mosquito. A week after that was published, he arrived here to oversee the centre's sequencing operations.

That would be a full-time job for most people, especially with regular improvements in quality control and cost reductions. But Holt is also pursuing three independent research investigations, including continuing the malaria work plus probing possible genetic factors in schizophrenia and bipolar disorders.

The potential big payoff, however, involves searching for a vaccine against colorectal cancer. "In cancer research, people are only just beginning to explore the idea of prophylactic vaccines," Holt says.

The approach is relatively straightforward: Find the common gene mutations responsible for a certain cancer, isolate them and then insert them back into the organism being tested, starting with lab animals.

"We're trying to fire up the immune system before it is too late," Holt says. In collaboration with Dr. Isabella Tai, a gastroenterologist, Holt is testing the approach by giving cancer-causing chemicals to a strain of mice already prone to colitis.

The researchers will then create genetic profiles of the tumours that develop in the mice and try to pinpoint the responsible gene mutations.

Holt acknowledges that meaningful results from the mouse studies will probably take a couple of years. "But we could have something that would actually prevent a cancer," he says.

In another cramped corner of the lab, Angela Brooks-Wilson is equally enthusiastic about the potential benefits from her research into non-Hodgkin lymphoma. As head of the centre's cancer genetics effort, the 41-year-old researcher is intrigued by the question of susceptibility to cancers.

"There are people who smoke heavily all their lives and they don't develop cancer. And then there are people exposed to second-hand smoke, and they do," she says.

Clinicians and epidemiologists at the cancer agency had a similar interest in susceptibility and also a long-standing program focusing on non-Hodgkin lymphoma, a form of cancer more prevalent in agricultural workers exposed to pesticides.

So the groups teamed up in a project just getting underway that will genetically compare 750 non-Hodgkin lymphoma patients with an equal number of matched people free of cancer.

That number is large enough, says Brooks-Wilson, that the research should be able to detect a genetic factor that increases the risk of developing the cancer by as little as 50 per cent. Because of natural variations and other uncertainties, epidemiologists usually pay attention only when factors appear to double the risk, a 100 per cent increase.

But statistically teasing out possible effects from environment influences like pesticides combined with genetic factors needs a much larger sample, only possible by adding results from other similar research.

"It's most likely going to prove to be a combination of genes that give a genetic susceptibility, plus environmental factors," Brooks-Wilson says.

In addition to gaining new insights into the biology of cancer and promoting the use of state-of-the-art technology, the centre's mission also encompasses the training of new top-drawer researchers in bioinformatics, cancer biology, genomics and molecular biology.

One of 14 current trainees is Sharon Gorski, a 39-year-old post-doctoral fellow working with Marra on a biomedical topic known as programmed cell death.

Genetically encoded signals in the body arrange for obsolete or damaged cells to self-destruct, just like a spy swallowing the traditional suicide pill.

There are two different self-destruction methods and Gorski's research focuses on the least understood — autophagy, which means the cell eats itself, dissolving from the inside out. It's this process that eliminates the residual webbing between the fingers on the hands of human fetuses in the womb.

"It's an appealing model if you wanted to get rid of a tumour in the quickest way possible," Marra says.

Yet, autophagy is complicated, acting in some cases as a protector of cells and in different circumstances as a killer. Gorski says autophagy probably plays a role in prolonging the survival of cancerous cells in the centre of solid tumours. The absence of blood vessels in the tumour interior means such cells would normally expire from a lack of nutrients.

By dissolving the damaged bits of these interior cells, autophagy provides a substitute source of nutrients to keep the cell alive. Similarly, the self-destruct mechanism may get rid of components in cancer cells that have been damaged by chemotherapy or radiation. That removal would prevent apoptosis, the better-known form of programmed cell death, from kicking in.

"We need to know the genes involved in autophagy and the molecular pathways," Gorski says.

To unravel these genetic mysteries, Gorski has turned to the fruit fly. As the fly matures from the pupae stage, autophagy destroys the salivary glands. Using the sophisticated arsenal of techniques developed in the human genome project, Gorski is slowly homing in on some of the genes responsible.

Before her work is finished, the Michael Smith Genome Sciences Centre will have moved twice — first, next month, to a building a few blocks away that has enough space to house the bioinformatics researchers currently working out of other offices in Vancouver, and then, in 2005, to a combined new home with the B.C. Cancer Research Agency.

So, cancer patients will still be around for a jolt of motivation — not that the researchers are likely to need it.