The Gene Hunter
THE NEW FRONTIER BEGINS INSIDE a Gaithersburg, Md., industrial park fringed by a cluster of ersatz colonial homes. Inside a yawning laboratory, several long black tables hold computer terminals and some boxy contraptions known as gene sequencers—all tended largely by a handful of clean-cut, white-coated generation Xers. From a loudspeaker pours the reedy tenor of Grateful Dead paterfamilias Jerry Garcia: “Drivin’ that train, high on cocaine…”
The languid scene lacks the edgy rush you’d expect to find on the cusp of discovery. But suddenly a dose of adrenaline strides in—J. Craig Venter, balding, buoyant and beaming behind wire-rimmed glasses. This is his playground: the Institute for Genomic Research (TIGR), a converted ceramics factory 20 miles northwest of Washington. And he can scarcely contain his enthusiasm for it. “I’ve got 30 graduate students here,” exults the biochemist, who started TIGR three years ago, after nine years at the National Institutes of Health. “And they’re doing daily what people thought it would take armies of scientists years to do.”
Venter, 48, and his young charges are pioneering a landscape at once cosmic in significance and microscopic in scale. Using advanced supercomputers, they are identifying and cataloging the 75,000 or so human genes—snippets of DNA that serve as the blueprints for proteins, the chemicals that determine every organism’s physical characteristics. Such studies probe the core of what it means to be human. They may also lead to cures for profound genetic disorders: Alzheimer’s disease, some cancers, mental illnesses, heart disease and myriad others.
Venter is also training his computers on microbial genes, including disease-causing bacteria. Late last month he told colleagues at a medical conference that he and Nobel laureate molecular biologist Hamilton O. Smith of Johns Hopkins University Medical School had deciphered the entire genetic repertoire of a bacterium called Hemophilus influenzae. Historically the feat is monumental: this is the first time the complete DNA profile of a free-living organism has ever been decoded.
The big prize, of course, remains the complete catalog of human genes. “We’ve identified 35,000 genes in the human body—four years ago, science had found only 2,000,” says Venter, who runs TIGR jointly with his wife, Claire Fraser, 39, a molecular biologist and onetime NIH colleague.
Their lab was spawned by a different sort of marriage. A nonprofit institute, TIGR received $85 million in funding from Human Genome Sciences, Inc. (HGS), a decidedly for-profit company founded in 1992 by venture capitalist Wallace H. Steinberg. HGS aims to patent the genes Venter finds and then develop drugs and therapies from them. Venter, who is not an HGS officer, was given company stock, now valued somewhere around $6 to $7 million. “But I didn’t ask for it—and I didn’t set out to get rich,” he insists. “I just wanted the money and freedom to do science.”
Still, the arrangement has heated up the debate over whether genes should be the intellectual property of private industry, patentable and offered to world science at a price. More practical questions have been raised as well. Some gene hunters have criticized Venter’s methodology, which quickly identifies fragments of genes—from which the whole-gene structure can be inferred—but doesn’t specify where they are located on the chromosomes or what their functions are.
One loud and early critic on both scores was no less than James D. Watson, the Nobel laureate biologist who in 1953 codiscovered (with Francis Crick) the double-helix structure of DNA. At a 1991 congressional hearing, Watson carped that Venter’s automated gene-hunting technique “could be run by monkeys” and deemed the patenting of genes “sheer lunacy” Says Venter, trying to fathom Watson’s attack: “I was a young guy, I was relatively unknown, and I was not a geneticist.”
In retrospect it’s amazing that he became a scientist of any kind. Born in Salt Lake City, Venter moved as a toddler to the San Francisco area with his parents, John, a CPA, and Elizabeth, a painter and two brothers and a sister. An indifferent student, he became a champion swimmer at Mills High School, from which he barely escaped with diploma and dignity intact. “If I hadn’t gotten a D-minus instead of an F in my government class,” Venter says, “I wouldn’t have graduated.”
At 17, he moved to Newport Beach in Southern California, where he worked as a night clerk for Sears and surfed and soaked up the Beach Boy Zeitgeist by-day. A non-student, Venter was ripe for the Vietnam draft, so in 1965 he enlisted for a three-year hitch in the Navy, which seemed at first like dream duty: He was recruited to perform on the swim team. “I was assured that I wouldn’t have to wear a uniform—just a swimsuit,” Venter says. “But when Lyndon Johnson escalated the war, it had a slight impact on my plans.”
Belying his checkered academic résumé, Venter scored highest, he says, among 35,000 Navy servicepeople on an intelligence test. Allowed his choice of career training, he opted for the hospital corps, and within two years he found himself pressed into performing surgery in Da Nang. “It was very M*A*S*H-like,” he recalls. “Except there were no pretty nurses and the casualties were far higher.”
Afterward he went to San Mateo Junior College and then to the University of California at San Diego, where his interest shifted from medicine to biochemistry. By 1975, he had earned a Ph.D. and was being offered numerous faculty positions. Lured by research opportunities, he settled on the State University of New York at Buffalo. There he met Fraser, who was one. of his graduate students. Was it love at first sight? “For him—not for me,” says Fraser, who grew up near Boston. Married in 1981, they moved to NIH three years later.
In the late 1980s, Venter got caught up in the excitement of the U.S. government’s Human Genome Project. The genome—all of an organism’s genetic material—is harbored in almost every one of the body’s 75 trillion or so cells, but each cell draws only on the genes it requires to perform its specific function. (“It’s as if every room of the World Trade Center contained the plans for the whole building, but uses only what that particular room needs,” explains Venter.) Unfortunately for gene sleuths, the human genome is largely mysterious stuff, disrespectfully referred to as “junk DNA.” Only 3 percent of it is genes, arrayed in tens of thousands of sequences along the 46 chromosomes of each cell.
Tracking down a gene is like isolating a grain of sand on a sizable stretch of beach. Traditionally biologists seeking the gene for an inherited disorder would search through the DNA of related people with an affliction until they isolated similarities, called DNA markers, on their chromosome. Then they would biochemically sift through all the junk DNA in that area of the chromosome—the entire parcel of beach—until they found the mutated, or defective, gene, a process that can take 10 years.
But in 1990, Venter devised a dramatic shortcut: he used the cell itself to do most of the sifting. “Every living cell can read through its chromosomes, edit out the 97 percent junk and isolate its own important genes,” Venter explains. His insight was to mimic that natural process artificially with help from supercomputers and automated gene sequencers—the boxy gadgets on the TIGR lab tables. It may still take months for geneticists to identify the precise gene they’re looking for. But Venter has saved the time-consuming middle step of separating the genes from the junk. He has also created an immense “library” of human genes, so that scientists who find genes on their own—or think they have—can cross-reference and verify their results with a 30-second computer search.
After Venter had identified some 2,000 genes with this new approach, NIH in 1991 applied to patent his technique and discoveries. The NIH plan was to license the patents at little cost to commercial firms to encourage drug development. “Patent protection is the only way to give companies the incentive to invest in new drugs and therapies,” Venter says. But Watson and many others went ballistic, reasoning that Venter’s genes were far removed from commercial application and should have remained in the public domain. In any event, publicity surrounding the patent controversy, far from actually harming Venter, attracted the financial backing that now stokes his science.
At last, Venter is gaining acceptance among colleagues, and his work is being imitated in labs around the world. It didn’t hurt, certainly, that his technique helped molecular biologist Bert Vogel-stein’s research team isolate the gene for a type of colon cancer in 1993.
By the end of the century, Venter hopes to use his sequencers to describe most human genes and the entire genomes of a dozen or more disease-causing microbes far more significant than Hemophilus influenzae. “That will revolutionize the understanding of infectious illnesses, such as tuberculosis,” he says. “Really, this is a new era—the next five years will be well remembered in scientific history.”