been completed, except for virus genomes, which are relatively small. Venter and Hamilton Smith (the Nobel laureate and discoverer of DNA “scissor” enzymes, who was then at the Johns Hopkins School of Medicine) proposed speeding things up by using a technique known as whole-genome shotgun sequencing. In shotgunning, the genome is broken into small, random, overlapping pieces, and each piece is sequenced, or read. Then the jumble of pieces is reassembled in a computer that compares each piece to every other piece and matches the overlaps, thus assembling the whole genome. It’s quite a lot like putting together a picture puzzle by matching the edges of the pieces to neighboring pieces, except that a genome can consist of millions of pieces and the task of matching them up to form a whole image of a genome requires superpowerful computers and really hot software.
Venter and Smith applied for a grant from the NIH to shotgun-sequence the genome of a disease-causing bacterium called
It seems quite possible that Venter’s grant was denied because of politics. The NIH, the National Institutes of Health, is funded by tax dollars. The review panel seems to have hated the idea of giving taxpayer money to TIGR to make discoveries that would be turned over to a corporation, Human Genome Sciences, which could then profit from the discoveries. It turned down the grant in spite of the fact that “all the smart people knew the method was straightforward and would work,” said Eric Lander, one of the leaders of the Human Genome Project.
Around this time, the venture capitalist Wally Steinberg died of a heart attack, and his death provided a catalyst for a split between TIGR and Human Genome Sciences, which was run by a former AIDS researcher, William Haseltine. Venter and Haseltine were widely known to despise each other. Venter had already sold his stock in Human Genome Sciences because of the rift between them, and after Steinberg died the relationship between the two organizations was formally ended.
Late in 1997, TIGR was doing some DNA sequencing for the Human Genome Project, and Venter began going to some of the project’s meetings. That was when he started calling the heads of the public project’s DNA- sequencing centers the Liars’ Club, claiming that their predictions about when they would finish a task and how much it would cost were lies. His calling them liars did not win him many friends.
Francis Collins, a distinguished medical geneticist from the University of Michigan, had become the head of the NIH genome program shortly after James Watson resigned in 1992. In early January 1998, an internal budget projection from Collins’s office somehow made its way to Watson (he seemed able to find out anything that was happening anywhere in molecular biology). This budget projection was supposed to be secret. It was an “eyes only” document intended to be seen by only about eight people, namely the top heads of the Human Genome Project. It contained a graph marked “Confidential” indicating that Francis Collins planned to spend only sixty million dollars per year on direct human-DNA sequencing through 2005. This was peanuts. It also predicted that by that year— when the human genome was supposed to be completed—actually only 1.6 billion to 1.9 billion letters of human code would be sequenced; that is, slightly more than half of the human genome would be done by then. The implication was that the whole human genome wouldn’t get done until maybe 2008 or afterward.
This upset James Watson. Watson had hoped that his successor, Francis Collins, would aggressively pursue the human genome and get the work done as fast as possible; for one thing, he, James Watson, wanted to be alive to see the human genome. Second, the millions of people around the world who suffered from genetic diseases weren’t getting any younger. He decided to discuss it with Eric Lander, the head of the Human Genome Project’s DNA-sequencing center at MIT. Lander was a voluble, articulate, brilliant man in his forties who projected a high degree of self-confidence. He spoke in a rapid voice. He had a broad face and a mustache, and he owned stock in biotech companies that he advised or had helped to found. Eric Lander had become quite wealthy.
On January 17, James Watson traveled to Rockefeller University, on the East Side of Manhattan, where Eric Lander was giving the prestigious Harvey Lecture. The two men met after the lecture at the faculty club at Rockefeller. They were dressed in tuxedos, and Eric Lander had been drinking. By long tradition among medical people, the Harvey Lecture is given and listened to under the influence. Watson himself seemed a little tipsy. The scientists continued to drink after the lecture.
The Rockefeller faculty club overlooks a lawn and sycamore trees and the traffic of York Avenue. Watson and Lander sat down with cognacs at a small table in a dim corner of the room, on the far side of a pool table, where they could talk without being overheard. Also present and drinking cognac was a biologist named Norton Zinder, who was one of Watson’s best friends. Zinder, like Watson, was a founder of the Human Genome Project. One of the older men brought up the confidential budget document with Lander, and both of them began to press him about it. They felt that it provided evidence that Francis Collins did not intend to spend more than sixty million dollars a year on human-DNA sequencing—and this was nowhere near enough money to get the job done anytime soon, they felt.
Watson evidently believed that Eric Lander had influence with Francis Collins, and he urged him to try to persuade Collins to spend more on direct sequencing of human DNA, and to twist Congress’s arm for more money.
Norton Zinder was somewhat impaired with cocktails. “This thing is potchkying along, going nowhere!” he said, hammering the little table and waving his arms as he spoke. For him, the issue was simple: he had had a quadruple coronary bypass, and he had been receiving treatments for cancer, and now he was afraid he would not live to see the deciphering of the human genome. The human genome had begun to seem like a vision of Canaan to Norton Zinder, and he thought he wouldn’t make it there.
Eric Lander did not view things the way the older biologists did. In his opinion, the problem was organizational. The Human Genome Project was “too bloody complicated, with too many groups.” He felt the real problem was a lack of focus. He wanted the project to create a small, elite group that would do the major sequencing of human DNA—shock cavalry that would lead a charge into the human genome.
The three men downed their cognacs with a gloomy sense of frustration. “I had essentially given up on seeing the human genome in my lifetime,” Zinder said.
NOT LONG BEFORE Watson and his friends began lamenting the slowness of the public project, the Perkin- Elmer Corporation, which was a manufacturer of lab instruments, had started secretly talking about an ambitious corporate reorganization. It controlled more than 90 percent of the market for DNA-sequencing equipment, and it was developing the Prism machine. The Prism was then only a prototype sitting in pieces in a laboratory in Foster City, California, but already it looked as if it was going to be at least ten times faster than any other DNA- sequencing machine. Perkin-Elmer executives began to wonder just what it could do. One day Michael Hunkapiller, who was then the head of the company’s instrument division, got out a pocket calculator and estimated that several hundred Prisms could whip through a molecule of human DNA in a few weeks, although only in a rough way. To fill in the gaps—places where the DNA code came out garbled or wasn’t read properly by the machines—it would be necessary to sequence the molecule again and again. This is known as repeat sequencing, or manyfold coverage, and he thought it might take a few years. Hunkapiller persuaded the chief executive of Perkin-Elmer, Tony White, to restructure the business and create a genomics company.
In December 1997, executives from Perkin-Elmer began telephoning Craig Venter to see if he’d be interested in running the new company. He blew them off at first, but a few months later he went to California with a colleague, Mark Adams, to check out the prototype Prism. When they saw it, they immediately understood its significance. They were looking at the equivalent of a supersonic jet in relation to a propellor aircraft. Before the end of that day, Venter, Adams, and Hunkapiller had laid out a plan for decoding the human genome
