The Race Is Over

By Frederic Golden and Michael D. Lemonick

One day last April, Aristides (Ari) Patrinos, a scientist at the Department of Energy who directs that agency's share of the Human Genome Project, got a call from Francis Collins, director of the National Institutes of Health's National Human Genome Research Institute and the project's unofficial head. "Let's try it," said Collins--and at those words Patrinos knew that a longstanding scientific feud finally had a chance of being resolved. For months, Collins had been under pressure to hammer out his differences with J. Craig Venter, the prickly CEO of Celera Genomics, which was running its own independent genome-sequencing project--differences over who should get the credit for this scientific milestone; over whose genome sequence was more complete, more accurate, more useful; over the free exchange of what may be mankind's most important data versus the exploitation of what may also be its most valuable.

The bickering had become downright nasty at times, upstaging the enormous importance of the project and threatening to slow the pace of scientific discovery. Therefore Patrinos had been lobbying his colleague to make love, not war, despite Venter's uncanny ability to get under the skin of Collins and other leaders of the U.S.-British genome project. So had Collins' counterparts at other NIH institutes. And so, most important, had President Clinton, who at one point scribbled a note to science adviser Neal Lane with the terse instruction: "Fix it...make these guys work together."

Venter was clearly ready. His tactless rhetoric had lost him respect among his colleagues, and he recognized that more controversy could overshadow a historic moment in biomedicine. Beyond that, he'd taken a beating in the marketplace. After a joint declaration by Clinton and British Prime Minister Tony Blair in March that all genomic information should be free, the value of Celera stock plummeted from $189 a share to $149.25.

So on May 7, over pizza and beer at Patrinos' Rockville, Md., town house, the two wary antagonists sat down in a deliberately casual setting to work out their differences. In an exclusive conversation with Collins, Venter and TIME correspondent Dick Thompson last Thursday night, Patrinos recalled, "I don't think I've ever seen them as tense as they were that day." Yet despite mistrust on both sides, Collins and Venter met a second time and a third.

And finally they came, if not to a meeting of the minds, at least to a workable understanding--and a framework for this week's joint announcement. After more than a decade of dreaming, planning and heroic number crunching, both groups have deciphered essentially all the 3.1 billion biochemical "letters" of human DNA, the coded instructions for building and operating a fully functional human.

It's impossible to overstate the significance of this achievement. Armed with the genetic code, scientists can now start teasing out the secrets of human health and disease at the molecular level--secrets that will lead at the very least to a revolution in diagnosing and treating everything from Alzheimer's to heart disease to cancer, and more. In a matter of decades, the world of medicine will be utterly transformed, and history books will mark this week as the ceremonial start of the genomic era.

But while the announcement has been exquisitely choreographed to make the two scientists look like equals, it's clear to insiders that Venter's project is a lot further along. HGP scientists may have decoded 97% of the genome's letters--the remaining 3% are generally considered unsequenceable and irrelevant--but they know the order of only 53% of them. It's as if they've got the pages in the so-called book of life in the proper order but with the letters on each page scrambled. "It's going to take us a couple of years to put this together," Collins told TIME.

Celera, by contrast, has not only the pages but all the words and letters as well--though neither side can yet say what most of these words and letters mean. And while the HGP boasts that it has done its sequence nearly seven times over to guarantee accuracy, Celera has gone over its own almost five times. Moreover, the company came up with a new technique that made its sequencing rate, already the fastest around, even faster. In addition, Venter claims that by the end of the year, he'll have sequenced the genome of the mouse--whose 2.3 billion letters contain enough similarities to ours to make it vitally important to scientists tracking down human gene function.

Given this remarkable record, why are so few of Venter's fellow scientists trumpeting his success? Or talking him up for a Nobel Prize? Why, in fact, is this cherubic-looking, blue-eyed ex-surfer hated by so many colleagues, who have called him everything from a greedy megalomaniac to a Hitler? Forget about easy explanations, such as his outsize ego (yes, one of the samples he is analyzing is rumored to contain his own DNA) or his penchant for doing science by press release (yes, he keeps his door open to reporters) or his tendency to do not science but, as pioneer DNA mapper James Watson sneered, tedious assembly-line labor on machines that "could be run by monkeys" (yes, most of Celera's analysis was done by robot gene sequencers and high-speed computers).

The real answer is that Venter thumbs his nose at the system and the scientific establishment. He scorns the feigned modesty that most scientists wear as comfortably as their lab coats and tweed jackets. He loves to buck authority (in the Navy in Vietnam he was tossed in the brig twice for refusing to obey orders), and he almost always speaks his mind. "He has no filter. He shoots from the hip," says Norton Zinder of Rockefeller University, leader of the effort to map the genome who overcame his initial hostility and joined Celera's advisory board.

Nor does Venter subscribe to the traditional belief that true scientists must take a vow of poverty. When he left the National Institutes of Health to begin his great gene chase, he turned almost overnight from a hardscrabble government scientist with $2,000 in the bank into a yacht- and sports car-owning multimillionaire who threw Gatsby-like parties (last year's income: $560,000, not counting options on Celera stock that were worth, at last week's closing price of $125.25, nearly $351 million). And by declaring his intention to sequence the entire human genome in only a fraction of the time (three years) and at a much lower cost ($200 million) than government-sponsored scientists had originally said it would take (15 years and $3 billion), he made his colleagues look like fools. (At the photo session last Thursday for TIME's cover, Venter needled Collins about not keeping pace with the Celera venture. Collins placidly declined to rise to the bait.)

Then there are the complaints about the quality of his work. Collins once said that Venter's map would read like Cliffs Notes or Mad magazine. Others call him a cheat for lifting data made public on the government's GenBank website www.ncbi.nlm.nih.gov at taxpayers' expense--and then patenting sequences culled from this data, thereby locking up information originally intended to be freely available. (Ironically, Celera suffered a setback when some of the government data turned out to be contaminated with nonhuman sequences.)

In the face of such attacks, Venter remains serenely optimistic. "Imagine the infinitesimally small odds of ending up in such a privileged position," he tells a visitor to his airy, press-clipping-decorated office at Celera's Rockville, Md., headquarters, just a Metro ride away from his NIH rivals, "of making these discoveries and trying to help guide and impact medicine." Sure, he admits, the criticism "gets painful at times," but, he adds, "I wouldn't trade what I'm doing for anything."

Despite some accounts likening his accomplishment to finding biology's Holy Grail, Venter points out that identifying the order of the letters in our genetic alphabet is just a first step. Still ahead for Celera as well as its competitors: the much more complicated task of telling what those letters mean, what they do and what can be done if the messages they spell out are in error--a prime cause of human disease and suffering (see following story).

Listening to Venter explain all this in his soft California voice, you hear a 53-year-old child of the '60s, not the ogre portrayed by his enemies. He is one of four children of an excommunicated Mormon accountant ("He broke too many rules--coffee, drinking, smoking," says the son, conscious of his father's death at 59) and grew up in the San Francisco suburb of Millbrae. In high school he swam competitively but didn't study. After graduating--barely--he moved down to Newport Beach to surf. But he had smarts. As a draft-eligible nonstudent, he says, he got the highest score of 35,000 recruits on a Navy intelligence test. Trained as a hospital corpsman, he saw North Vietnam's devastating Tet offensive in 1968. Says his wife Claire Fraser, a prominent molecular biologist: "Vietnam changed him. It impressed on him the idea that time is precious, that you have to make every single minute of every single day count."

Back in the U.S., he blazed through college and graduate school at the University of California at San Diego in six years. After a stint at the State University of New York at Buffalo, he was recruited by NIH's neurological institute, where he worked on locating and decoding a gene for an adrenaline-receptor protein in brain cells, but found progress exasperatingly slow. So when he learned in 1986 about a machine that could "read" genes by shining lasers on their dyed letters (A, T, C and G, the four nitrogenous bases--adenine, thymine, cytosine and guanine--that spell out the genome's "words"), he immediately flew west to meet its builder, Michael Hunkapiller, in Foster City, Calif. Though NIH wouldn't pay for a prototype, he got one anyway.

Within a year, Venter had decoded 100,000 letters (the human genome has some 3.1 billion, spelling out some 50,000 different genes, at the best guess). They were hieroglyphics to him, but not, he knew, to living cells, which recognize active genes and spin off single strands of RNA that mirror the DNA's coding. So Venter collected the new RNA, inserting it into bacterial cells and letting them clone junk-free complementary DNA, or cDNA, matching the original genes. His automatic sequencer could then read the letters of these genetic instructions.

By June 1991 he had increased the number of identified genes by 347, up from 2,000. His bosses at NIH were so pleased that they rushed to patent them, only to set off a firestorm. Watson, then head of NIH's part of the Human Genome Project (another part is under the Department of Energy), denounced the move as "sheer lunacy" that would cause paralyzing legal battles. When the dust settled, NIH had withdrawn its patent proposal, Watson had quit the genome project, and Venter and Fraser, a former graduate student at Buffalo whom he had married after splitting with his first wife, were off running their own center, The Institute for Genomic Research (TIGR), in nearby Gaithersburg, Md.

With $70 million in long-term funding from the late biotech entrepreneur Wallace Steinberg, TIGR (pronounced tiger) finally gave Venter freedom to do what he wanted. But there was a hitch. First crack at any genes it decoded went to the nonprofit institute's commercial partner, Human Genome Sciences, led by former AIDS researcher William Haseltine.

Until then, Venter had been randomly sampling and sequencing small bits of cDNA. But one of his new recruits, Hamilton Smith, a Nobelist from Johns Hopkins', proposed a bolder approach: "shotgunning" the entire genome of an organism. The idea was dramatically simple. Using an ordinary kitchen blender, they would shatter the organism's DNA into millions of small fragments, run them through the sequencers (which can read 500 letters at a time), then reassemble them into the full genome using a high-speed computer and novel software written by in-house computer whiz Granger Sutton. By contrast, the HGP divided the genome into larger, known segments, delaying the sequencing to learn more about the genes first. As an added fillip, Venter cross-checked his results by sequencing the genes in both directions, achieving a level of accuracy that so impressed his initially skeptical rivals that British sequencers, along with labs funded by NIH and DOE, later announced they too would adopt this strategy.

Within a year, TIGR had published the entire genome of Haemophilus influenzae, a bacterium with nearly 2 million letters that causes meningitis and ear and respiratory infections. It was the first free-living organism to be completely sequenced. Even Watson was impressed, calling it "a great moment in science."

Still, many researchers considered shotgunning crude and inaccurate. By this time, Venter's relationship with Human Genome Sciences had soured over quarrels about patenting and publication of data, and he and TIGR split with HGS. Other labs were now in the shotgunning game--though of the 30 or so organisms decoded to date, two-thirds were decoded by TIGR, with results that are generally acknowledged to be of high quality.

In 1998, when Hunkapiller showed Venter his new ABI Prism 3700, a sequencer five times as fast and even more highly automated, Venter formed a partnership with Hunkapiller's company, Applied Biosystems (now PE Biosystems). Venter named his new outfit Celera, from the Latin for "quick." It was. Backed with an infusion of $300 million from his new collaborator, Venter boldly announced that he would sequence and assemble the entire human genome by the year 2001.

Venter's challenge jolted the lumbering Human Genome Project into a long-overdue overhaul. It cut back to four (now five) major centers. The Brits coughed up more money, and the consortium even began buying some of Hunkapiller's hot new machines. Collins admits that Venter "stirred the pot."

Venter first targeted the genome of an old laboratory favorite, the fruit fly, Drosophila melanogaster, whose genes have many counterparts in humans. By March he had succeeded in sequencing its genome--work that ultimately helped break down the barriers between Venter and Collins. The latter had implied all along that Venter could not be trusted to release gene sequences to the public, despite promises that he would. "This was a major frustration," said Venter last week. "Fundamentally, nobody believes you're going to release the data. Your integrity is constantly being challenged."

In March, Venter eased the minds of other scientists by releasing the Drosophila data; moreover, he had done the research in collaboration with Gerald Rubin, now vice president for biomedical research at the Howard Hughes Medical Institute and highly respected at DOE and NIH. "Rubin reassured us all that this was someone to trust," Patrinos said last week.

Somewhat unconvincingly, Venter now denies he was ever racing the HGP. "To me it's really a race to impact people's lives," he says. Collins, who has been pooh-poohing the idea of a race, insists in an almost perfectly crafted sound bite that "the only race involved here is the human race."

The big question is whether, with the publicly funded project's data online, there will be a market for Celera's products. Venter says yes. He'll be offering sophisticated, contamination-free, gilt-edged data, he explains, that include the comparative genomes of other species and the genetics of specific diseases, plus special proprietary software to analyze this genetic mother lode.

Having signed up five major pharmaceutical houses as well as Vanderbilt University, Venter says Celera has jumped ahead of all its rivals, with revenue doubling every year. Celera's stock has gyrated wildly from $15 a share to more than $320 and down to $50 in the space of a year, so Wall Street obviously can't make up its mind about the company. But, says Venter, "our business model is working terrifically." He expects profitability in another couple of years.

What's next? To get a fuller racial and gender mix, Venter will go through at least six more human genomes, probably including his own ("Why not, if that's the business I'm in?" he asks, admitting nothing). After the mouse, he'll probably go on to the chimp, among our closest primate kin, and explore plant genes, including rice and corn. He is also taking Celera into the emerging field of proteomics--understanding how genes make and manage proteins, the actual building blocks of life.

Given the dramatic differences in their personalities, Venter and Collins will never be close collaborators. The agreement that led up to this week's announcement has more the character of a statesmanlike cease-fire than of a scientific merger. The two teams will try to publish their work simultaneously--but not jointly--in an upcoming issue of a major journal, probably Science. They have agreed that patents are appropriate only at the point where a gene's function is understood.

Most of all, they'll try to avoid publicly criticizing each other. "All of us in this room," Venter told TIME last Thursday, "have found a way to put the human emotions behind us. There are things we have all said that, given a rational condition, we wish we hadn't said." Said Collins simply: "I heartily agree." With any luck, their bitter dispute, which has loomed so large for so long, will be a minor footnote in the genomic revolution that has barely begun.

--Reported by Dick Thompson/Washington

With reporting by Dick Thompson/Washington