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August 19, 2002
Volume 80, Number 33
CENEAR 80 33 pp. 45-50
ISSN 0009-2347


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TRIUMPH OVER NATURE
Entrepreneurial scientist J. Craig Venter is on to new ventures, but he continues to tweak some genome researchers from the sidelines

STU BORMAN, C&EN WASHINGTON

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PHOTO BY PETER CUTTS

In Vietnam, the history of science once hung in the balance for a few frightening moments. It was the late 1960s, and J. Craig Venter was in Da Nang as a Navy medical corpsman.

Every day I tried to go over to the beach and go swimming," Venter tells C&EN. One day, "I was way offshore body surfing. Something hit me in the leg"--a sea snake--"and I reached down and grabbed it."

Fortunately, he grabbed the head rather than the tail of the snake, "or I wouldn't be here right now," Venter says. " The venom from those sea snakes is lethal in about 15 seconds. They're nonaggressive unless you mess with them, but they would probably consider grabbing their tail to be messing with them. Once

I realized I grabbed the head, I couldn't let go, and I had to swim all the way into this huge surf hanging onto this strong, rapidly squirming sea snake. It was my triumph over nature."

That sea snake is framed and mounted today in Venter's new office in Rockville, Md., where he recently established three new nonprofit scientific organizations. The organizations are the latest ventures for a researcher who has triumphed over nature in many other ways since his struggle with the sea snake.

Scientific accomplishments by Venter and his colleagues over the past dozen or so years include the large-scale use of a technique for rapidly identifying protein-coding sequences in long stretches of human DNA, the first complete genome sequence of a nonviral organism (a bacterium), the first total sequence of an archaean (a microorganism that lives in extreme environments), the sequencing of a series of other microbial organisms, and the sequencing of the human genome using private funding--at the same time it was being sequenced by the publicly supported Human Genome Project (HGP).

Some scientists have criticized Venter's contribution to the human genome sequencing effort. So when asked about his origins, Venter jokes that he was indeed born--not genetically engineered, as some of his scientific critics might think. "My parents met in the Marine Corps during World War II," he says, "and I was born [in 1946] in Salt Lake City, where my father was a student at the University of Utah. He claimed that he considered going into biology, but he chose accounting instead." The family moved to Millbrae, Calif., when Venter was two.


"Fundamentally, the public genome program was so vested in its own methodology, in its own funding bureaucracy, that it didn't want to entertain new ideas."


VENTER INVARIABLY describes his youth as directionless, unmotivated, and academically undistinguished. "I did not do well in school and really battled the entire process," he says. In high school, for example, "I got a D-minus in a government class, and if I'd gotten an F, I wouldn't have graduated. I think I got a C in biology. I hated the education system. Some people thrive in it, but I think our education system was designed for people who were good at rote memorization. I was neither good at it nor accepting of it."

For a time, Venter's preoccupation was board surfing and body surfing. "I was a surfer in high school, I was a surfer in Vietnam, and I'm still a surfer," he says. "In fact, I'm getting a very nice surfing award at the end of August."

He served in the Navy during the Vietnam War, in 1967–68. "I volunteered to go to Vietnam as a medical corpsman," he says. In Vietnam, he worked in a medical receiving unit, where all the worst casualties came in, and ran an intensive care ward. During the Tet offensive, "I would deal with maybe 100 casualties a day," he says.

His Vietnam experiences changed his attitude about the value of education. "When I started learning and practicing medicine in Vietnam, I couldn't learn things fast enough. The more you knew, the more people you could help."

After his military service was completed, he entered the University of California, San Diego, where he earned a bachelor's degree in biochemistry in three years and a Ph.D. in physiology and pharmacology in another three. After graduating, he taught at the State University of New York and Roswell Park Cancer Institute, both in Buffalo.

In 1984, he moved to the National Institute of Neurological Disorders & Stroke at the National Institutes of Health campus in Bethesda, Md., where he served as a lab chief and section chief. In 1987, Venter notes, he published in Proceedings of the National Academy of Sciences USA on "the very first genes sequenced by automated DNA sequencing."

He and his coworkers also made extensive use of partial gene sequences they called expressed sequence tags (ESTs) to identify human genes easily and quickly in long stretches of human genomic DNA [Science, 252, 1651 (1991)]. Credit for origination of the EST method is a matter of dispute. Some people believe a group led by molecular biology professor Paul R. Schimmel, now at Scripps Research Institute, described the essence of the technique in 1983, whereas others contend that Venter and coworkers conceived and first reported on the EST methodology in their 1991 paper. In any case, Venter's group used the EST shortcut to discover 3,500 new human genes--approximately doubling the number of human genes known at the time.

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CHILD TO MAN Venter as a child and with captured sea snake in Da Nang, Vietnam, where he served as a Navy medical corpsman. PHOTOS COURTESY OF J. CRAIG VENTER SCIENCE FOUNDATION


IN 1991, NIH filed patent applications on these EST-discovered genes. The filings sparked a controversy about whether genes that had been identified only by partial sequences and whose functions were still unknown should be patentable and whether such filings would impede the free flow of scientific information. The U.S. Patent & Trademark Office eventually denied the claims.

By then, however, Venter had obtained private support from a venture-capital firm for his gene-finding efforts--a $70 million, 10-year research grant that enabled him to leave NIH and set up the Institute for Genomic Research (TIGR) in Rockville in 1992. A condition for the funding was that development rights to TIGR discoveries would go to a newly formed commercial firm, Human Genome Sciences (HGS), also in Rockville. "When I left NIH, I had $2,000 in the bank," Venter says. He's now reportedly extremely wealthy.

Venter remains closely associated with TIGR. He was TIGR's president until 1998; he is currently its chairman; and his wife, Claire M. Fraser, is the current president and director.

In 1994, Venter and microbiologist Hamilton O. Smith (who shared the 1978 Nobel Prize in Physiology or Medicine with Daniel Nathans and Werner Arber for discovering restriction enzymes) applied for an NIH grant to support what turned out to be the first complete prokaryotic genome sequence--that of Haemophilus influenzae, a bacterium that causes ear and respiratory tract infections.

They proposed to do the sequencing by a totally untested technique--whole-genome shotgun sequencing, which "was described for the first time in our landmark publication on H. flu," Venter explains. In the whole-genome shotgun approach, random pieces of DNA generated by fragmenting an entire genome are analyzed, and software is then used to reconstruct the original sequence from the resulting data. This is distinctly different from traditional "clone-by-clone" sequencing, in which a genome is first mapped to produce an overall view of its composition and then segments of it are sequenced systematically, piece by piece.

Venter believed strongly that the whole-genome shotgun technique would prove to be a shortcut to bacterial and larger genome sequences. Indeed, most genome sequences have been obtained with this method, and today it is "the standard method for genome sequencing around the world," he says. But at some point in 1994, Venter, Smith, and coworkers realized that NIH didn't support the shotgun concept and would most likely turn down their grant application for shotgun sequencing of Haemophilus. So they began doing it solely with TIGR funding. "We dipped into the TIGR endowment when there was very little money there," Venter says.

The whole-genome strategy did work, the researchers obtained the Haemophilus sequence after about a year of effort, and they reported on it in Science [269, 496 (1995)] only about a month after they received final notice that their grant proposal had been rejected.

At that time, the publicly funded HGP was providing grants to a number of research centers to sequence the human genome using the clone-by-clone technique. In light of TIGR's success with the Haemophilus sequence, Venter says, "you have to ask, why did the government set up massive distributed projects" to sequence the human genome and the genomes of model organisms? It did so, he says, "because sequencing was considered so tedious, so complicated, that no one center could possibly do it. These projects were so big you had to break them down into multiple smaller projects, and then do them one at a time. That's the difference we've brought with whole-genome shotgun sequencing. We just said these projects weren't that complicated and could be done in a small center using just a few scientists."

Venter points out that, in his group's Haemophilus paper, "there was this very controversial paragraph that said this is the method I believe will be used for sequencing the human genome. Everyone thought I was just crazy to be writing that. But when you understand the technique, you see that there is no theoretical block to its potential. I think the major sequencing labs didn't want it to work because they had a vested interest in what they were doing."

However, HGP researchers discussed the merits of shotgun sequencing at the time, and "the consensus conclusion was that clone-by-clone sequencing was the better strategy, a position that was vindicated by the technical difficulties [Venter and coworkers] ultimately encountered" in their human genome sequence, writes Maynard V. Olson, director of the University of Washington Genome Center, in Seattle [J. Mol. Biol., 319, 931 (2002)].

Some participants in the international HGP believe that whole-genome shotgun sequencing works well for simple genomes having little repetitive DNA and can also be used to generate draft sequences of large, complex genomes with lots of repetitive DNA. However, they doubt it can be used by itself to finish a mammalian genome because it leaves many gaps that can't be closed without reference to a map of overlapping clones. Venter disagrees, saying "gap closure works even faster and better from whole-genome assemblies."

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