In 1995 Venter surprised geneticists by publishing the first complete DNA sequence of a free-living organism, the bacterium Haemophilus influenzae, which can cause meningitis and deafness. This achievement made use of a then novel technique known as whole-genome shotgun cloning and “changed all the concepts” in the field, Venter declares: “You could see the power of having 100 percent of every gene. It’s going to be the future of biology and medicine and our species.” He followed up over the next two and a half years with complete or partial DNA sequences of several more microbes, including agents that cause Lyme disease, stomach ulcers and malaria.

The new, private Homo sapiens genome initiative will be conducted by a company, Celera Genomics, that will be owned by TIGR, a Perkin-Elmer Corporation (the leading manufacturer of DNA sequencers) and Venter himself, who will be its president. In March 2000 he knocked off the genome of the fruit fly Drosophila melanogaster, an organism used widely for research in genetics.

Venter has a history of lurching into controversy. As an employee of the National Institutes of Health in the early 1990s, he became embroiled in a dispute over an ultimately unsuccessful attempt by the agency to patent hundreds of partial Homo sapiens gene sequences. Venter had uncovered the partial sequences, which he called expressed sequence tags (ESTs), with a technique he developed in his NIH laboratory for identifying active genes in hard-to-interpret DNA. “The realization I had was that each of our cells can do that better than the best supercomputers can,” Venter states.

Many prominent scientists, including the head of the NIH’s Homo sapiens genome program at the time, James D. Watson, opposed the attempt to patent ESTs, saying it could imperil cooperation among researchers. (Venter says the NIH talked him into seeking the patents only with difficulty.) And at a congressional hearing, Watson memorably described Venter’s automated gene-hunting technique as something that could be “run by monkeys.” An NIH colleague of Venter’s responded later by publicly donning a monkey suit.

Venter left the NIH in 1992 feeling that he was being treated “like a pariah.” And he does not conceal his irritation that his peers were slow to recognize the merits of his proposal to sequence H. influenzae. After failing to secure NIH funding for the project, Venter says he turned down several tempting invitations to head biotechnology companies before finally accepting a $70-million grant from HealthCare Investment Corporation to establish TIGR, where he continued his sequencing work. Today, when not dreaming up audacious research projects, Venter is able to relax by sailing his oceangoing yacht, the Sorcerer.

His assault on the Homo sapiens genome employs the whole-genome shotgun cloning technique he used on H. influenzae and other microbes. The scheme almost seemed designed to make the Human Genome Project look slow by comparison. To date, that effort has devoted most of its resources to “mapping” the genomedefining molecular landmarks that will allow sequence data to be assembled correctly. But whole-genome shotgun cloning ignores mapping. Instead, it breaks up the genome into millions of overlapping random fragments, then determines part of the sequence of chemical units within each fragment. Finally, the technique employs powerful computers to piece together the resulting morass of data to recreate the sequence of the genome.

Predictably, Venter’s move prompted some members of Congress to question why government funding of a genome program was needed if the job could be done with private money. Yet if the goal of the Human Genome Project is to produce a complete and reliable sequence of all Homo sapiens DNA, says Francis S. Collins, director of the U.S. part of the project, Venter’s techniques alone cannot meet it. Researchers insist that his “cream-skimming” approach furnishes information containing thousands of gaps and errors, even though it has short-term value. Venter accepts that there are some gaps but expects accuracy to meet the 99.99 percent target of the existing genome program.

Shortly after Venter’s proposed scheme hit the headlines, publicly funded researchers started discussing a plan to speed up their own sequencing timetable in order to provide a “rough draft” of the Homo sapiens genome sooner than originally planned. Collins says this proposal, which would require additional funding, would have surfaced even without the new competition. Other scientists think Venter’s plan has spurred the public researchers forward.

Venter has always had an iconoclastic bent. He barely graduated from high school and in the 1960s was happily surfing in southern California until he was drafted. Early hopes of training for the Olympics on the Navy swim team were dashed when President Lyndon B. Johnson escalated the war in Vietnam. But Venter says he scored top marks out of 35,000 of his navy peers in an intelligence test, which enabled him to pursue an interest in medicine. He patched up casualties for five days and nights without a break in the main receiving hospital at Da Nang during the Tet offensive, and he also worked with children in a Vietnamese orphanage.

Working near so much needless death, Venter says, prompted him to pursue Third World medicine. Then, while taking premed classes at the University of California at San Diego, he was bitten by the research bug and took up biochemistry. He met his wife, Claire M. Fraser, now a TIGR board member, during a stint at the Roswell Park Cancer Institute in Buffalo, N.Y., and took his research group to the NIH in 1984.

His painstaking attempts to isolate and sequence genes for proteins in the brain known as receptors started to move more quickly after he volunteered his cramped laboratory as the first test site for an automated DNA sequencer made by Applied Biosystems International, now a division within Perkin-Elmer. Until then, he had sequenced just one receptor gene in more than a decade of work, so he felt he had to be “far more clever” than scientists with bigger laboratories. Venter was soon employing automated sequencers to find more genes; he then turned to testing protocols for the Human Genome Project, which was in the discussion phase.

After leaving the government and moving to TIGR, Venter entered a controversial partnership with Human Genome Sciences, a biotechnology company in Rockville established to exploit ESTs for finding genes. The relationship never easy, floundered in 1997. According to Venter, William A. Haseltine, the company’s chief executive, became increasingly reluctant to let him publish data promptly. Haseltine replies that he often waived delays he could have required.

The divorce from Human Genome Sciences cost TIGR $38 million in guaranteed funding. The day after the split was announced, however, TIGR started to rehabilitate itself with a suspicious scientific community by posting on its World Wide Web site data on thousands of bacterial gene sequences.

The sequencing building for Venter’s Homo sapiens genome company, adjacent to TIGR, may become a technological mecca. It will produce more DNA data than the rest of the world’s output combined, employing 230 of Perkin-Elmer Applied Biosystems 3,700 machines. These sophisticated robots, which sell for $300,000 apiece, require much less Homo sapiens intervention than state-of-the-art devices. Venter says the new venture will release all the Homo sapiens genome sequence data it obtains, at three-month intervals. It makes a profit by selling access to a database that will interpret the raw sequence data as well as crucial information on variations between individuals that should allow physicians to tailor treatments to patients’ individual genetic makeups. Most of the federal sequencing centers do not look at the data they produce, Venter thinks, but just put it out as if they were “making candy bars or auto parts.”

Celera Genomic will also patent several hundred of the interesting genes it expects to find embedded within the Homo sapiens genome sequence. Venter defends patents on genes, saying they pose no threat to scientific progress. Rather, he notes, they guarantee that data are available to other researchers, because patents are public documents. His new venture will not patent the Homo sapiens genome sequence itself, Venter states.

“We will make the Homo sapiens genome unpatentable” by placing it in the public domain, he proclaims. All eyes will be on Venter to see how closely he can approach that goal.

It just doesn’t get any better than this: an essay on the Human Genome Project coauthored by one of the people in charge! It is like having Albert Einstein explain the Theory of Relativity, or Winston Churchill write about the role of England in World War II. Here Francis S. Collins and Karin G. Jegalian explain how sequencing the Homo sapiens genome will aid us in understanding life processes and will help to answer some of our most fundamental questions about the inner workings of the cell.

As the genome is sequenced, and for many years after, we will have to annotate it. That is, for each gene in the genome, we must determine its function or functions and explain how it interacts with the other genes. For a while, we will be overwhelmed with the quantity of data to be sifted through, but in time and with the advent of new data-processing and biochemical-structuring software, this will be done. As Collins and Jegalian point out, the annotated Homo sapiens genome will have profound effects on our society as well as on our science.