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# Controversial From the Start

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Science  16 Feb 2001:
Vol. 291, Issue 5507, pp. 1182-1188
DOI: 10.1126/science.291.5507.1182a

The human genome: the crown jewel of 20th century biology, heralded at the White House, plastered on the covers of countless magazines—and at last spelled out today in intricate detail in both Science and Nature. Deciphering this string of 3 billion A's, T's, G's, and C's is being hailed as an achievement that will usher in a new era of biology and even alter our understanding of who we are.

That's a far cry from how the idea was greeted when it was first proposed 15 years ago. “Absurd,” “dangerous,” and “impossible,” scoffed numerous critics, who noted that the technology did not exist to sequence a bacterium, much less a human. And even if the project's starry-eyed proponents could by some miracle pull it off, who would want the complete sequence data anyway?

It turns out a lot of people did. This once-ludicrous proposal became one of most hotly contested—and contentious—races in recent scientific history. Although the race has been dominated in the past few years by the acrimonious feud between the public and private teams, tensions go way back. And no wonder, with a prize this great and a project that has transcended and transformed traditional ways of doing biology. “The change is so fundamental, it is hard for even scientists to grasp,” notes geneticist Maynard Olson of the University of Washington, Seattle, who ranks decoding the human genome as one of the biggest accomplishments ever in biology.

## An impossible dream

One of the first to grasp that potential was Robert Sinsheimer, a biologist who was then chancellor of the University of California (UC), Santa Cruz. UC astronomers were already angling to build the world's biggest telescope, and Sinsheimer was looking for a project of similar magnitude in biology. Unraveling the sequence of the human genome might be just the ticket—if he could rally the scientific support and, of course, money. At the time, the largest genome yet sequenced was the minuscule Epstein-Barr virus—and that feat had taken several researchers years to complete. To apply such tools to the human genome, nearly 20,000 times bigger at 3 billion bases, was audacious beyond belief.

In 1985, Sinsheimer assembled some of the best minds in the nascent field of genome analysis to hash over the proposal at his idyllic campus, nestled in the hills above the sleepy beach town of Santa Cruz. John Sulston of Cambridge University and Robert Waterston of Washington University in St. Louis, who were already trying to map the genome of the nematode Caenorhabditis elegans, were there, as was Bart Barrell, head of large-scale sequencing at the U.K. Medical Research Council (MRC). So were genetic mappers David Botstein, then at the Massachusetts Institute of Technol-ogy (MIT), Helen Donis-Keller, then at Collaborative Research Inc., and sequencing afi-cionados Walter Gilbert and George Church of Harvard University and Leroy Hood of the California Institute of Technology in Pasadena. Their collective conclusion: bold, exciting—but simply not feasible. Sinsheimer's proposal for a genome institute at Santa Cruz died, but not before it had captured Gilbert's imagination.

Gilbert soon became the proposal's biggest champion, and his support meant the idea could no longer be blithely dismissed. A decade earlier, Gilbert and Allan Maxam, also at Harvard University, had invented a brand-new technique that enabled scientists for the first time to determine the genetic sequence of an organism. (Gilbert went on to share the Nobel Prize with Fred Sanger of Cambridge University, who independently invented a similar technique.) And he soon won over another giant of molecular biology: James Watson, who shared a Nobel Prize with Francis Crick and Maurice Wilkins for their 1953 discovery of the double helical structure of DNA.

The ambitious idea had also captivated Charles DeLisi, a cancer biologist who was then head of the Office of Health and Environmental Research at the Department of Energy (DOE). To DeLisi, the genome project was a logical outgrowth of DOE's mandate to study the effects of radiation on human health. Another equally compelling rationale—but one DeLisi did not openly tout—was that a massive new endeavor could provide new focus for DOE's national labs, whose bombmaking skills were in diminishing demand.

At the urging of DeLisi and DOE colleague David Smith, the Los Alamos National Laboratory hosted a workshop in Santa Fe, New Mexico, in March 1986 where the excitement was palpable. The idea quickly gained momentum, dominating discussion at a June meeting at Watson's Cold Spring Harbor Laboratory in New York. By then, biologists were beginning to think the project just might be doable. But whether it was worth doing was another matter (Science, 27 June 1986, p. 1598).

To many, like Botstein and Nobel laureate David Baltimore, then at MIT, the project ran counter to the way biology had been conducted for decades. The best work, the mantra went, came from investigator-initiated studies in small labs, not from some massive, goal-driven effort. Moreover, this was technology development, not experimental biology, and it would be mind-numbingly dull. Sydney Brenner of the MRC facetiously suggested that project leaders parcel out the job to prisoners as punishment—the more heinous the crime, the bigger the chromosome they would have to decipher. What was truly horrifying was the price tag, which was quickly estimated at $3 billion—a number that stuck through countless reports ever since. If the National Institutes of Health (NIH) were to foot the bill, the megaproject would rob funds from the rest of biology, the critics asserted. “It endangers all of us, especially the young researchers,” warned Botstein. The scientific value seemed dubious as well. Although many biologists agreed that maps of the chromosomes would be useful for finding genes, what good would come from deciphering every A, T, G, and C, especially since most of them were “junk” that did not code for genes. The sequence might be handy to have, but “was it worth the cost, not in terms of dollars but in terms of its impact on the rest of biological science?” asked Paul Berg of Stanford University. As the biology community wrestled with the merits of the project, NIH staked out a position firmly on the fence. By contrast, DeLisi and Smith were decidedly gung ho. DeLisi aggressively gained support for the project, first from his superiors at DOE and then from Congress, starting a small Human Genome Initiative within DOE in 1986. The following year, a prestigious advisory panel to DOE called for an all-out effort and urged the agency to take the lead. DOE was the logical choice, DeLisi argued, because this was “big science,” DOE's stock-in-trade, whereas NIH had never attempted a project of this scope (Science, 8 August 1986, p. 620; 31 July 1987, p. 486). The fact that DOE—not NIH—was lobbying for the project only heightened some biologists' unease, because they put great store in NIH's peer-review system. “The fear is not big science so much as bad science,” said Botstein, who in 1986 denounced DOE's proposal as “a scheme for unemployed bombmakers.” ## Emerging consensus Political posturing continued until 1988, when a National Research Council (NRC) panel gave the project its official seal of approval (Science, 12 February 1988, p. 725). Chaired by Bruce Alberts, then at UC San Francisco, the panel contained some of the project's staunchest advocates, such as Gilbert and Watson, and also some skeptics, including Botstein, mouse geneticist Shirley Tilghman of Princeton University, and yeast expert Olson, then at Washington University in St. Louis. Within a year, the panel endorsed the project unanimously, calling for a rapid scale-up in “new and distinctive” funds to$200 million a year over the next 15 years.

In the process, the panel redefined the project, laying out a phased approach that mollified critics and has guided the initiative ever since. Rather than plunge into sequencing—which no one knew how to do on a massive scale anyway—the project should begin by constructing maps of the human chromosomes. These would greatly speed the search for disease genes, offering immediate medical payoffs. The panel recommended that full-scale sequencing be postponed until new technologies made it faster and cheaper.

But it was the panel's recommendation to analyze the genomes of simple organisms, such as Escherichia coli, yeast, and the roundworm C. elegans, and eventually the mouse, that proved most persuasive. Tilghman and Botstein, in particular, argued vociferously that biologists had no hope of understanding the human genome if they couldn't compare it to the genomes of experimental organisms. Luckily for biologists, evolution has been remarkably conservative, retaining the same genes over and over again in different organisms, explains Tilghman—and it is far easier to figure out a gene's function by experimenting with it in a fruit fly than in a human. Looking back, Tilghman sees this as one of the panel's smartest decisions: “Model organisms were an extraordinary investment. We learned how to sequence on these simpler organisms. And more important, we got a preview of the human genome by sequencing these organisms.”

Gilbert, however, was impatient with the panel's cautious approach and with the interagency dithering. Arguing that the technology was already good enough to sequence the human genome, he left the NRC panel to launch his own company, Genome Corp. His plan, remarkably similar to J. Craig Venter's vision a decade later, was to set up a sequencing factory to churn out the data, which he intended to copyright and sell. “[It will be] available to everyone … for a price,” he explained (Science, 24 July 1987, p. 358). The plan infuriated Watson, who rankled at the idea of selling something as fundamental as data on human DNA. But the debate subsided when Gilbert failed to raise sufficient funds.

## NIH makes its move

As the genome project gained congressional funding and scientific respectability, NIH wrested control from DOE. Urged on by a group of advisers who met outside Washington, D.C., in Reston, Virginia, in March 1988, then-NIH director James Wyngaarden announced that NIH would create a special office for genome research (Science, 13 May 1988, p. 878). In short order, he nabbed Watson to head it, and with that coup, NIH was firmly ensconced as the lead agency. It has remained so, even as the project gathered international collaborators and Britain's Wellcome Trust took on a prominent role.

Watson proved a shrewd strategist, skilled in the care and feeding of those who controlled congressional purse strings, and a tough taskmaster. “My name was good,” he says by way of explanation. Indeed, members of Congress were spellbound when the eccentric Nobel laureate swept in to testify. Watson was eloquent in touting the project's goal: “to find out what being human is.” He also had the refreshing quality of saying what he thought, no matter how politically incorrect—an unusual quality in Washington, D.C.

Even as the project began, Watson's advisory panel was still debating the proper balance for the project—how much should be devoted to building tools, like maps and faster sequencing machines, and how much to actually using these tools to find disease genes? (Science, 13 January 1989, p. 167) Watson was adamant: Even though disease genes captured the public imagination and kept the dollars flowing, this project was designed to build the equivalent of a particle accelerator: They should not be sidetracked. As Botstein explained at a January 1989 meeting, “We are looking at the production of a set of tools that will enable human geneticists to do what they want. We are the Cray, if you like. We don't write software for your particular applications.”

At the same time, Watson relentlessly pushed the first stage of the project and its most tangible goal—building maps of the human chromosomes. Knowing that Congress did not have the patience to wait 15 years for results, Watson staked his reputation on getting the maps done in five. With the maps in hand, genes would fall out in short order, including the putative Alzheimer's gene, which, Watson joked, should be a priority given the age of most members of Congress.

Progress was rapid. By 1990, Sulston and colleagues had nearly completed the physical map of the worm—changing worm biology forever—and Olson and colleagues were proceeding apace on yeast (Science, 15 June 1990, p. 1310). Faster and easier ways to clone and map DNA were coming on line, and sequencing trials were beginning. For a short time, the controversy that had dogged the project from the outset seemed to have dissipated.

## Venter, round one

That newfound harmony was shattered in June 1991, when Venter, who ran a large sequencing lab at the National Institute for Neurological Disorders and Stroke, went public with an iconoclastic plan: Why not focus on finding the genes—the “real goods” that both scientists and companies were clamoring for—and leave tedious sequencing until later? Venter and colleague Mark Adams had developed a new technique, called expressed sequence tags, that enabled them to find genes at unprecedented speed. Never one of Watson's inner circle, Venter boasted that this new approach “was a bargain in comparison to the genome project” and claimed he could find 80% to 90% of the genes within a few years, for a fraction of the cost (Science, 21 June 1991, p. 1618).

Watson dismissed Venter's “cream-skimming approach,” but their feud remained subterranean until a few weeks later, when Venter described his work at a congressional hearing. NIH was so impressed with his progress, Venter said, that it was filing patent applications on the partial genes he was identifying—at a rate of 1000 a month.

Watson erupted, denouncing the patenting scheme as “sheer lunacy” and noting that “virtually any monkey” could do what Venter's group was doing (Science, 11 October 1991, p. 184). What irked him was that Venter and NIH had no clue about the function of the genes from which these fragments came. If the patents held, that meant anybody could lay claim to most of the human genes, undercutting patent protection for biologists who labored long and hard to identify whole genes and figure out what they did. “I am horrified,” Watson told Congress.

Watson also went to war on this issue with his boss, NIH Director Bernadine Healy. The fight cost him his job. In April 1992 he returned to Cold Spring Harbor Laboratory, muttering that no one could work with that woman (Science, 17 April 1992, p. 301).

Venter, too, left NIH in 1991 when he was offered $70 million from a venture capital company to try out his gene identification strategy at a new nonprofit, The Institute for Genomic Research (TIGR). ## From tools to medicine After Watson's sudden departure, NIH picked gene hunter Francis Collins of the University of Michigan, Ann Arbor, to take the helm. Fresh from the heady success of finding several elusive genes—including those involved in cystic fibrosis, neurofibromatosis, and Huntington's disease—Collins was then in a highly competitive race to find the gene involved in a form of inherited breast cancer. A physician by training, Collins brought a different perspective to the genome project, placing its medical applications front and center. Collins charmed Congress and the media by riding to work on his motorcycle and playing guitar in a pickup rock band. Whereas Watson and his advisers had spoken of creating a tool, Collins talked about saving children's lives. “The reason the public pays and is excited—well, disease genes are at the top of the list,” he explained. It was a heyday for gene hunters. The early investments in the genome project paid off as increasingly sophisticated maps of the human and mouse genomes were compiled (Science, 1 October 1993, p. 20). With these maps in hand, the time it took to track down most disease genes dropped from a decade to perhaps 2 years. Every week, it seemed, another deadly disease gene was discovered. Lost in the hoopla, however, was the fact that finding a gene was a far cry from having a treatment, much less a cure. The consortium was growing as well, fueled by an infusion of funds from the Wellcome Trust, which in 1993 set up a major new sequencing lab, the Sanger Centre near Cambridge, with Sulston as its head. But sequencing overall was lagging behind. At the existing rate and cost, Collins lamented when he took on the job, there was no chance they could finish the sequencing by 2005. None of the “blue sky” sequencing technologies that had been imagined at the outset materialized, and with U.S. funding tight and much of the money concentrated on mapping, Collins was worried that “we have mortgaged part of our future.” Steady, incremental advances were enabling scientists to spew out longer “sequence reads,” and the cost was slowly dropping. Even so, reassembling the DNA fragments in correct order was tricky. To do so, the sequencers looked for similar patterns in the fragments—much like assembling a jigsaw puzzle—but one with lots of missing pieces. Some pieces just wouldn't fit, some “fit” in the wrong place—others “got lost” in the cloning process. Still others refused to be sequenced. Sequencing clearly needed a shot in the arm—and soon got one, but from an unlikely source. In 1995, Venter surprised the community by announcing that along with Hamilton Smith, then at Johns Hopkins, and TIGRcolleagues Rob Fleischmann and Claire Fraser, they had sequenced the first entire genome of a free-living organism, Haemophilus influenzae, at 1.8 megabases (Science, 28 July 1995, p. 496). What's more, they had done it in just a year using a bold new approach, whole-genome shotgun sequencing, that NIH had insisted wouldn't work and wouldn't fund. Sequencers in the publicly funded project had adopted a conservative, methodical approach—starting with relatively small chunks of DNA whose positions on the chromosome were known, breaking them into pieces, then randomly selecting and sequencing those pieces and finally reassembling them. Eventually, larger pieces called contigs would be hooked together. By contrast, Venter simply shredded the entire genome into small fragments and used a computer to reassemble the sequenced pieces by looking for overlapping ends. NIH's deliberate approach won its spurs a year later, when an international consortium knocked off the yeast genome. Although still tiny, relative to humans, it was a major step up in size and complexity. By April 1996, Waterston and Sulston, who were well into sequencing C. elegans, were champing at the bit, urging Collins to let them plunge into all-out sequencing. In the right hands, they argued, the technology was good enough; the only stumbling block was money. “Just do it,” Sulston urged at the time. The two also broached the heretical topic of dropping the accuracy goal to speed the process, from 99.99% to 99.9% (Science, 12 April 1996, p. 188). But Collins would not be rushed. The goal was to assemble the definitive “book of life,” and he insisted it be done to the highest possible quality. He decided to test the water with six pilot projects—a cautious style that earned him praise in some corners and criticism in others. The charge to the labs was to complete a major chunk of sequence while also demonstrating big improvements in cost and speed. After that, he said, the project would home in on its final strategy. Collins soon abandoned his measured approach—not because of the persuasiveness of Waterston and Sulston's arguments, but because Venter threw down the gauntlet. ## Venter redux Showing a knack for impeccable timing, Venter dropped his bombshell on 9 May 1998, just days before the annual gathering of genome scientists at Cold Spring Harbor Laboratory. Venter announced that he had teamed up with Perkin-Elmer Corp., which was about to unveil an advanced, automated sequencing machine, to create a new company that would single-handedly sequence the entire human genome in just 3 years—and for a mere$300 million (Science, 15 May 1998, p. 994). What's more, said Venter, when he was done he would give the data away free to the community by posting it on his company's Web site. The company, soon to be named Celera Genomics and located in Rockville, Maryland, would make money not from the raw data, he explained, but from the analysis it would perform and sell to subscribers. Venter proposed to sequence the genome with the brute-force shotgun technique that had worked so well in Haemophilus—but this time, he would be shredding the entire 3-billion-base genome into zillions of fragments.

Leaders of the public project were angry and incredulous. After they had spent years laying the groundwork, could Venter really beat them to the finish and steal the glory? They were also deeply worried that if Congress fell for Venter's bravado, it might pull the plug on the public project. Venter's plan would never work, they countered—the sequence would be riddled with holes and impossible to reassemble.

Yet as they disparaged Venter's claim, they could not dismiss it. Venter had surprised them before. And this time, he had a hefty bankroll and 300 of Perkin-Elmer's sequencing machines, just then rolling off the assembly line at \$300,000 a pop. And to reassemble his sequenced fragments, Venter would use one of the world's fastest supercomputers.

The leaders of the public program wasted no time in increasing the pace and reorienting the game plan in an attempt to beat him to the finish line. Collins announced new goals for the public project in September 1998, just 6 months after Venter's surprise announcement (Science, 18 September 1998, p. 1774). First, the consortium would complete the entire genome by 2003—2 years ahead of schedule, but also 2 years behind Venter. And, in a dramatic departure from previous philosophy, the project would produce a “rough draft,” covering 90% of the genome, by the spring of 2001. Scientists were clamoring for the data even in rough form, Collins said by way of explanation. Yet he also admitted that producing a rough draft and making it public was a strategic move to undercut any patent position Celera or other businesses might claim.

In a crucial test of the shotgun strategy, Celera first tackled the 180-megabase genome of the fruit fly Drosophila melanogaster. Venter teamed up with a publicly funded team headed by Gerald Rubin of UC Berkeley, and by March 2000, they had pulled it off. This proved that the shotgun methods could work on a big, complex genome, said Venter (Science, 25 February 2000, p. 1374).

The race was on, punctuated by dueling press releases. First Venter announced in October 1999 that his crew had sequenced 1 billion bases of the human genome—a feat pooh-poohed by NIH, which noted that Celera hadn't released the data for other researchers to check. Then NIH jumped into the game, announcing in November that it had completed 1 billion bases, holding a “birthday” party at the National Academy of Sciences, complete with balloons and T-shirts emblazoned with the double helix. Venter countered in January 2000 that his crew had compiled DNA sequence covering 90% of the human genome, the public consortium asserted in March that it had completed 2 billion bases, and so on. Issues of data access heated up too, with the public consortium denouncing Venter for his plan to release his data on the Celera Web site rather than in GenBank, the public database. The feud became increasingly ugly, with each side disparaging the other's work and credibility in the press. Leaders in the scientific community urged them to stop squabbling and work together.

The two had, in fact, begun talking about a possible collaboration in December 1999. Eric Lander, who runs the Whitehead/MIT Genome Center, was the main go-between. The two approaches are complementary, he said, and collaborating would speed the process.

But in March, the discussions foundered amid considerable acrimony when the Wellcome Trust leaked to the press a letter from Collins to Venter, citing irreconcilable differences (Science, 10 March 2000, p. 1723). The sniping, seemingly at its peak, escalated further, until many considered it an embarrassment. “If they were my children, I would give them both a time out,” said one leading scientist at the time.

Behind the scenes, Ari Patrinos of DOE played intermediary, finally brokering a truce under which both groups would announce their drafts at the same time, thereby sharing the glory. Venter still would not deposit his data in GenBank, as the consortium wanted, but he did concede that the public data has been useful in his own work. Defusing the issue of priority and credit, the two agreed to publish simultaneously, perhaps even in the same journal. Collins and Venter granted an exclusive interview to Time, which heralded, “The race is over,” and pictured the beaming duo side by side in their lab coats. They were all smiles, too, at a White House ceremony in June where President Clinton lauded both scientists for their phenomenal achievement, and Collins and Venter lavished praise on one another (Science, 30 June 2000, p. 2294).

The façade held for 5 months—longer than many would have predicted—before all hell broke loose over plans to publish their papers (see p. 1189). At issue, again, was Venter's refusal to deposit his data in GenBank and the terms he might impose on commercial or academic users (Science, 15 December 2000, p. 2042). The two did manage to achieve simultaneous publications—but in separate journals.

In their magnanimous moments, both concede that their race has speeded the project, to everyone's benefit. “Ten, 15 years from now, nobody is going to care about all this fuss and bother,” says Collins. “They're going to care that we got the fly sequence done, and shortly after that we got the human sequence done, and shortly after that we got the mouse sequence done. And all this back and forthing over who did what and what strategy was used and which money was public and which was private is probably going to sink below the radar screen. And hallelujah.”