Gonna Fly Now

Trading with the enemy helps a Berkeley geneticist divine the secrets of the fruit fly

What Venter needed was a genetic trial run, an organism simpler than humans that he could sequence in a few months with his rapid-fire methods. Drosophila was the perfect candidate. That meant, in short, that Venter needed Rubin.

Last May, J. Craig Venter approached Gerald Rubin with a sweet offer. In essence, Venter wanted to conduct a practice run of his speedy sequencing process using some of Rubin's fruit fly DNA.

Celera, Venter proposed, would decode the DNA and share the results with Rubin. Rubin, in turn, would compare Celera's results with his own, as a sort of quality check. With Celera's help, the fruit fly genome Rubin had expected to work on until 2001 could be finished late this year.

The genome, both men agreed, would ultimately be published in a major scientific journal for all to see and use.

Rubin saw the upside in Venter's offer -- the fly genome could be finished years ahead of schedule. But he saw the downside, too. Rubin had to strike a deal with a man whom most of his colleagues revile. Rubin may be one of the few scientists with enough respect among his peers to pull it off.

Last summer, Rubin shipped Celera 100 milligrams of Drosophila DNA, and agreed to help the company assemble all the sequence data into the fruit fly genome.

"To me," says Rubin, "having the sequence is the enabling infrastructure. It's a milestone along the way to getting to the kind of understanding we want to get to, but it's not the end of the road. So if you feel that way, you want to get there as soon as possible."

Getting the Drosophila genome done, he says, is his only responsibility: to pure science, to NIH, to taxpayers, and to himself. If that means trading with the enemy, so be it.

When the Rubin-Venter union was announced last spring at a scientific conference in New York, not everyone was thrilled. Still angered by Venter's cavalier dismissal of the HGP, genetic pioneer James Watson likened Venter to Hitler in Berlin.

And what about Rubin? someone asked.
Poland (presumably in 1939) was Watson's reply.
Rubin spent the summer fielding well-meant calls from colleagues warning him not to work with Venter, and that Venter would steal credit for decoding Drosophila.

Rubin says he's not worried about either prospect. Venter could, after all, have gotten fruit fly DNA from another researcher, and Rubin expects that his project will be given as much credit for sequencing Drosophila as will Celera.

What does Venter, who did not return requests for comment, expect to get out of the fruit fly research? Celera is investing at least $10 million and thousands of man-hours into the effort.

Venter's hope is that his sequencing methodology, known as "whole genome shotgunning," will prove accurate enough on the Drosophila DNA to augur success when he steps up to the far more complicated DNA of the human genome.

But even if the fruit fly experiment is a success, there is no guarantee that Venter's gamble will work on the human genome. "If it doesn't work on Drosophila, then it has no chance on the human genome," says Stanford geneticist David Botstein. "But the converse is not true."

Obviously, human beings are far more complex than fruit flies; our DNA is even more so. As much as 97 percent of human DNA is "repeating DNA," that is, junk serving no purpose that is apparent to the best minds of science right now.

Presumably, the repeating DNA conserves certain evolutionary functions, the point of which remains a riddle. But it's the remaining 3 percent of the human genome that is important to researchers.

For sequencers, repeating DNA makes life hellish. It represents thousands of locations on the genome map that are simply wasteland, but which still must be plotted in order to properly locate the interesting parts.

Without the proper context, trying to find the 3 percent of non-repeating genes is like consulting a shredded city map. There is no way to assemble the pieces into a whole.

That's why the HGP and Rubin's project have followed the strategy of proceeding slowly and methodically.

Critics argue that Venter's version of the human genome will resemble that shredded map. But, for the moment, none of that affects Rubin and the Drosophila genome.

Rubin is proceeding cautiously, keeping his own slower project on track even as he collaborates with Venter. Rubin's thinking is that he "can't put my eggs in one basket." Does he doubt Venter's research will produce a Drosophila genome of acceptable scientific quality?

"I've thought about it a lot," Rubin says, easing back in an oxblood chair at his campus office. "No one can predict how good that product will be." But Rubin, who says science is "the only competitive sport I've been good at," knows that no matter how the collaboration with Venter turns out, he is in a fine position.

In fact, as disliked as Venter may be, no one in the scientific community rises to criticize Rubin for working with him. "I'd do the same thing," says Botstein. "He's in a no-lose position."

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