Rapidly expanding knowledge of the building blocks of life has profound medical implications
As a research scientist at Washington University in St. Louis, Mo., during the past five years, biologist Marco Marra has become adept at charting the microscopic landscape of DNA, the genetic material that carries the code for life. A native of Berwyn, Alta., Marra was part of an international team that announced in December the decoding of nearly the entire genetic endowment, known as the genome, of a tiny worm called a nematode. That project was pardy a practice run for a much larger one—the Human Genome Project, a massive undertaking, now nearing completion, to decipher the code that ultimately defines every human. Marras skills made him a natural for his latest job—associate director of Vancouver’s new Genome Sequence Centre, which aims to exploit the wealth of new genetic information flooding into data banks to wage war on cancer. “By learning more about genes that cause cancer,” says Marra, “there is tremendous potential for finding ways to treat and even prevent it.”
So far, the centre, headed by Michael Smith, the Canadian who won the 1993 Nobel Prize in chemistry for his pioneer-
ing work in molecular biology, is in start-up mode. With laboratory space at the B.C. Cancer Research Centre in Vancouf ver undergoing renovation, Smith’s researchers are not likely ¡ to be fully operational until early in the new year. That is still f in time for the anticipated completion of the Genome Project. \ Sometime next spring, its scientists expect to announce their * success in decoding more than 90 per cent of the estimated 70,000 to 100,000 genes that determine virtually every physical detail of humans. In time, that trove of new knowledge should help doctors predict, diagnose and treat disease, enable drug companies to develop thousands of new pharmaceuticals and perhaps even give physicians the ability to cure diseases by snipping out and replacing malfunctioning genes.
Launched a decade ago, the multibillion-dollar project, led by government-backed research teams at a dozen universities and scientific institutions in the United States, Britain, Germany and Japan, was originally scheduled to finish work in 2003. But competition from a rival project with heavy drug company backing forced the official Genome Project— funded mainly by the U.S. National Institutes of Health and Britain’s Wellcome Trust charity—to step up its pace. The troublesome rival is geneticist J. Craig Venter, head of Rockville, Md.-based Celera Genomics, who announced in May, 1998, that his company would decode the human genome by the end of2001. The Genome Project’s decision to accelerate its own operations reflected fears that while the publicly backed project is committed to making its data freely
available to all scientists, Venter may try to patent potentially valuable genetic information. “If Venter finds commercially important genes,” says Lap-CheeTsui, a Toronto genome scientist, “I think he’ll certainly try to protect his property.” While the two big genome projects race to finish first, Canadian scientists have been left largely on the sidelines. The reason: since 1992, Ottawa’s funding for academic genome research has averaged less than $5 million a year—far too little to finance the cosdy work of sequencing large stretches of DNA. But, says Dr. Tom Hudson, an immunologist and geneticist who heads a genome research centre at Montreal General Hospital, “it’s not too late for Canada to get involved, because we’ve only just scratched the surface of genomics.”
In fact, when the Human Genome Project winds up its major sequencing effort in the spring, the result will only be a “first draft,” a mind-numbing, three-billion-character string of the letters A, C, G and T—representing the four constituent elements of DNA—repeated in changing combinations. It is roughly equivalent to producing information on thousands of communities along a highway, but with no reference to where they appear on that road. Scientists already know where perhaps half of humanity’s genes are likely to be found in that maze of letters, but the rest are still to be located. “There is,” says Marra, “a lot of refining to do.”
Researchers at the Vancouver centre intend to play a role in that process, as do Canadian genome scientists in laboratories across the country. Among the researcher efforts:
► Scientists led by Montreal’s Hudson are seeking to identify and sequence the tiny variations—called polymorphisms —that occur in human genes. They determine such characteristics as height or hair colour—and can play an important role in disease. Hudson, who currendy spends two days a week in Cambridge, Mass., where he is assistant director at the Massachusetts Institute of Technology’s genome sequencing centre, says the goal is to zero in on disease-causing genes. As their knowledge grows, adds Hudson, researchers’ focus will shift from diseases that are influenced mainly by single genes—including cystic fibrosis and muscular dystrophy— towards more complex afflictions such as diabetes and heart disease, in which scores of genes may be involved.
► At Toronto’s Hospital for Sick Children, scientists led by molecular biologist Tsui have developed a detailed map of the seventh chromosome, a region of DNA dense with known and suspected disease-causing genes. Once the Human Genome Project has completed its Herculean sequencing task, that map and others being developed by researchers around the world will gain importance. The challenge then will be to arrange the projects slabs of decoded data into a coherent map.
The ultimate payoff will be huge, says Tsui, who in 1989 discovered the gene that causes cystic fibrosis. “The more we know about how all the genes function,” he says, “the better chance we have of coming up with effective treatments.”
► At the University of Victoria, researchers under evolutionary geneticist Ben Koop are also concentrating on the seventh chromosome, and particularly on two regions containing numerous cancer-causing genes. After successfully locating four such genes during the past two years, Koop’s team is working on comparing the two regions in humans and mice. When a suspected disease-causing gene is identified in a human, scientists can experiment with a genetically altered mouse to determine the function of the equivalent mouse gene.
As one of its first projects, Vancouver’s Genome Sequence Centre hopes to become involved in another mouse-related study that would give it a central role in locating previously unidentified genes in the data churned out by the Genome Project. The study would use technology known as DNA “fingerprinting” to rapidly identify large stretches of the
The Code of Life
• Inside the nucleus of cells, intertwining strands of the DNA (deoxyribonucleic acid) molecule form chromosomes— the repositories of genes, which carry the code for life.
• DNA is made of four constituent chemicals—adenine, cytosine, guanine and thymine (A, C, G and T for short).
• Working with purified DNA, computerized sequencing devices “read” the order in which the four chemicals are arranged in every chromosome and in each of the estimated 70,000 to 100,000 genes that make up the genome, the total human genetic endowment.
• For technical reasons, the genome is sequenced in small segments. Following sequencing, the challenge is to locate every gene within the three-billion-character genome code which is divided among 23 pairs of chromosomes.
mouse genome for sequencing. Because mouse genes generally resemble those of humans, similar telltale stretches of DNA would point to gene locations in both species.
Another enterprise, explains Steven Jones, who will supervise the centre’s data analysis, involves the development of socalled gene chips—technology that prints DNA samples onto glass slides that can be used, among other things, for quick analysis of human tissue to detect disease. But the centre’s broader goal is to contribute to the next phase of the Genome Project by locating cancer genes and determining their function. “There is bound to be a lot more cancer genes,” says Smith, “than the 100 or so that we already know about.” Ultimately, he adds, what the vast amounts of new genome knowledge may yield are ways of halting cancer and other diseases before they start. “We can’t yet give a time frame for finding cures,” says Smith, “but the building blocks for doing that are being put in place now.” [¡3
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