C&EN: COVER STORY - TRIUMPH OVER NATURE (continued)

DID CELERA'S challenge to HGP stem in any sense from anger on Venter's part over NIH rejection of the Haemophilus shotgun sequencing proposal? "Not anger," he replies. "I think it stemmed from frustration that the best ideas in science weren't even being given a chance."

Venter points out that NIH funding for Eric S. Lander's group at the Whitehead Institute/MIT Center for Genome Research, in Cambridge, Mass., was "$60-something million" last year. "That's more NIH funding than most medical schools in this country have," he says, "and that's just for a single lab." The shotgun approach threatened what was being done at the major sequencing centers. "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. That isn't how science should proceed," Venter says. But participants in the public sequencing effort note that HGP officials consistently encouraged, sought, and funded new technologies for completing the project as rapidly and inexpensively as possible.

The dispute over whole-genome shotgun versus clone-by-clone sequencing is still going on today. A few months ago, Lander and two other leaders of the international HGP published a paper concluding that the Celera team had relied to such a great extent on public HGP mapping and sequencing data that whole-genome shotgun sequencing had not actually generated an independent sequence of the human genome [Proc. Natl. Acad. Sci. USA, 99, 3712 (2002)]. They claimed that Celera had essentially used the public mapping data to organize its private shotgun data and thus hadn't demonstrated that whole-genome shotgun sequencing alone can produce a finished mammalian sequence. Celera published a formal rebuttal.

HGP scientists, Venter says, are "still trying to justify, after the fact, that what they did was the right thing. They're trying to rewrite history. What they did in that paper in PNAS was basically use statistics to lie and fool the scientific community. It's disturbing how few independent voices there are in science. People are so afraid of offending their possible funding sources that misstated facts in science don't get challenged anymore."

Celera's upstart challenge to sequence the human genome much more quickly than HGP had planned made the public effort look plodding. From a personal standpoint, did it bother Venter to embarrass HGP leaders like National Human Genome Research Institute Director Francis S. Collins in this way?

"WE HAD a lot of private discussions with people in government and other places first," Venter says. "There were multiple stages where I tried to convince Francis and other people that there were better ways to do things, and they just fundamentally did not want to hear about it."

Celera's challenge "got them focused, unfortunately, in a way that rational discussions with them couldn't," he says. Maybe competition is good, "but it would have been much nicer, as we offered privately initially before a public announcement, to sequence the human genome through public-private cooperation to get it done faster."

HGP officials offered to cooperate with Celera as well, but a major sticking point was the issue of data release: HGP sequencing data have always been made freely accessible in the Genbank database, but Celera was not willing to deposit its data there. The company did make its data publicly available, as it had always promised to do, but the data had to be obtained from Celera (or accessed on the company's website), and there were preconditions for commercial users.

Venter believes Celera's efforts led to the availability of a substantially complete human genome sequence "maybe 10 years earlier" than would otherwise have been the case. "When we started Celera, only 3% of the human genome had been sequenced, and there was only a budget to get 50% of it done. So it's not clear that it ever would have been actually finished. A lot of people considered they would end their career sequencing the human genome."

HGP officials contend, however, that 15% of the human genome sequence was accessible in Genbank at that time in draft form, that budget commitments had already been made to pay for the entire sequence, and that researchers envisioned an earlier end point to the sequencing task.

Had HGP "been much further along, had it been clear that it would get done quickly, we would not have formed Celera to do it," Venter adds. "Most people don't realize how little had been accomplished, and [HGP officials] only changed what they did because of Celera. Which begs the question: Why wouldn't they have tried to go faster anyway when this was so clearly for the public good?" HGP participants say they were already trying to go as fast as possible.


	INSTITUTES Venter now heads three new non-profits in Rockville, Md. A depiction of the human genome sequence is on the wall of his office suite. PHOTO BY PETER CUTTS

HAS CELERA'S strategy to commercialize the analysis of human genome data been successful? "That business was profitable when I left Celera in January and was generating $130 million to $150 million a year in revenues. So I think it was highly successful," Venter says.

He adds that he "said from the beginning that we were going to sequence the genome and give it away for free, and we did."

However, Olson points out in his Journal of Molecular Biology paper that "none of Celera's data has been released to Genbank ... and even academic researchers who want single-query access to Celera's data must execute elaborate legal agreements with the company to acquire it. I will leave it to historians to judge Venter's 'sincerity' in promising free, unrestricted public access to the sequence."

A Celera spokesman tells C&EN that sequence data published in the February 2001 Science article is available at no cost to scientists from academic and nonprofit institutions. After registering, a researcher can download 1 MB of data per day. Updates to the sequence since the Science paper was published are not freely accessible.

However, Venter notes that "it was not the data, not the raw base pairs, that have value. It's the tools for interpreting the genome that are so critical. That's what we tried to build at Celera--software tools and computational tools that allowed analyses to be done that could not be done any other way. And also things like the mouse genome, which we sequenced in six months at Celera versus a five-year government program. So genome data on their own are virtually worthless. It's the analyses that you do, the interpretation, the understanding that creates the value, both intellectually and commercially."

Nevertheless, he says that since he left Celera, the company has largely abandoned that model and is trying to become a pharmaceutical company, "because that's where investors can get billions of dollars, in theory, versus hundreds of millions."

CELERA'S STOCK price has been hovering around $10 a share recently, whereas it reached over $300 a share two years ago, before a two-for-one stock split. "The company was briefly worth something like $14 billion," Venter says. "The businesspeople associated with it saw that, and, greedy is a harsh word, but they started demanding far more than was realistic for that business. Had the original business plan been followed through, I think Celera would have continued to grow as an online information business over a long period of time."

Venter was recently characterized in print as having a "headline-grabbing style" and being "explosive like a firecracker," but he disagrees with that characterization. "I think I'm very calm and cool most of the time," he says. "I think the work that I've engaged in has captured people's imagination. So whether I wanted headlines or not, the fact is that most people don't understand how such a small team could take on this massive government project and be successful. That's the sort of thing that would have grabbed headlines whether or not I ever spoke to the press. We didn't have a massive media effort, but the controversy drove a lot of the media attention."

He believes the media generally do a good job, but scientific issues can "get distorted when people try to hype things," he says. "For a lot of the hype that's out there, I blame biotech executives and I blame scientists really just trying to seek headlines. That happened recently with the synthesis of the poliovirus. That was just a straight media stunt--somebody looking for attention. There was no scientific advance, basically. People have synthesized larger pieces of DNA," and poliovirus had previously been created in a cell-free enzyme medium--two aspects of the synthesis that were combined in the report published this past month [Science, 297, 1016 (2002) and C&EN, July 29, page 28]. "If scientists are going to act irresponsibly like that, it's hard to blame the media for covering it," he says.

Does Venter want to be liked? "Wanting to be liked is too simple of a cliché," he says. "People want the respect of their colleagues, which is very different from having broad, universal acceptance. But I would like people to understand and appreciate the accomplishments that my teams have made. The reality is that, for the most part, I haven't worried whether people liked me or not. What I've done in my career and the accomplishments and risks I've taken aren't risks that anybody would take if their goal was to be liked. The science and the pursuit of truth have to come first."

Speaking of risks, Venter loves to ply the seas in sailboats in his spare time, and in 1998, just before starting Celera, he ran into some pretty rough seas. "We were sailing from England to Gibraltar," he recalls. "There were just a couple of us on the boat. We got caught in a gale off the Bay of Biscay, and there was the largest wave I'd ever seen in my life. It was so huge that our boat was like a surfboard, only covering about one-third of the face of the wave. As the wave passed, it totally engulfed the boat. There was just my head and the other guy's sticking up out of the water in the cockpit. It was a pretty scary moment." Another day, another triumph over nature.