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Biomedicine

Botstein's Caveat

Scientists have declared the human genome completely decoded. But a look back at the beginnings of their quest reveals how far we still have to go.

We’ve come a long way from the Babbling Brook Inn. That’s the hostelry in Santa Cruz, Calif., where a handful of dreamers-and a few skeptics-gathered in May of 1985 and hatched what ultimately evolved into the Human Genome Project. You’d never guess by the hosannas of press coverage in June, when the first rough draft of the human sequence was announced, that the idea initially had struck everyone as ridiculous.

To those of us who have watched this effort unfold over the past 15 years, it’s been surprising, and a little demoralizing, to see the early history of the project subsumed in the entrepreneurial brinksmanship, historical amnesia and Orwellian newspeak of contemporary science.

Biologists celebrated the “completion” of the sequence, yet it is incomplete-perhaps significantly incomplete. We were told a great race had taken place, but we allowed the participants to concoct a self-interested finish line, with no referees to certify the degree of completion or quality. We were frequently reminded of the lone-wolf virtuosity of J. Craig Venter, whose company, Celera Genomics, took on the Whole Government and won; we were too infrequently reminded that the race took place only after the public consortium had spent years clearing the brush and grooming the track.

It’s worth revisiting the Santa Cruz meeting and its cast of characters, therefore, to see how much-and how little-things have changed. The meeting was organized by biologist Robert Sinsheimer, then at the University of California at Santa Cruz, who was the first person to popularize the endeavor as “biology’s moonshot.” Leroy Hood, then of Caltech, became excited by the prospect of developing automated machines for such a project. Wally Gilbert, who helped develop some of the original sequencing techniques in his Harvard lab, riled the multitudes when he spoke of copyrighting-copyrighting!-the human genome and then selling the information to drug companies. The nerve of the guy!

And then there was David Botstein. This curmudgeonly geneticist, then at MIT, raised the most prophetic objection of all. Having the entire human sequence, he argued, was like having a complete set of Egyptian hieroglyphics and no Rosetta stone. Without the sequence of other organisms for comparison, especially the mouse (which we are still waiting for), the human sequence remains largely unreadable. And that is where we stand today, several months after the greatest achievement in the history of biology. We have 3.1 billion letters of human DNA in hand, and we’re still functional illiterates when it comes to reading the text.

Now about that famous race. Despite the negotiated “draw,” the general spin seems to be that Celera Genomics won. But Arnold Levine, president of Rockefeller University, shrewdly observed recently that Celera had a great advantage by entering the race when it was nearly over. Part of that advantage was technological, the other cultural.

Back in the days of Santa Cruz, sequencing was universally perceived as factory-style “big science,” utterly devoid of creativity. It seemed so dull that only when the Department of Energy looked poised to take over the project (and, many feared, turn it into a political boondoggle) did the National Institutes of Health reluctantly become involved. Once the government committed $3 billion to the 15-year project, a huge economic infrastructure grew up around the endeavor.

Lee Hood, meanwhile, left the Santa Cruz meeting more convinced than ever that DNA sequencing machines had a future; Michael Hunkapiller, a postdoc in Hood’s lab, went on to become the unheralded da Vinci of DNA in this whole story, designing wondrous machines at Applied Biosystems, which later became P.E. Biosystems. And it was Hunkapiller who called Venter in 1998 and convinced Celera that with the latest generation of machines, it would be possible to sequence the human genome much sooner than originally thought.

If I were a biologist, I’d be a little nervous right now about having raised public expectations unrealistically. The genome project will indeed revolutionize medicine. The question is: When? We’ve been reading advance excerpts from the “book of life” for years and haven’t been able to make much sense of it. Ask the people with sickle-cell anemia: The exact molecular nature of that genetic disorder has been known for 25 years, and still no cure.

Therefore the most interesting question now is the time frame in which this future unfolds, and whether the public has the patience to await the fruits so extravagantly promised in June. On the day the sequence was announced, I called up David Botstein and asked if “biology’s moonshot” warranted all the fuss. “We’ve flown around the moon,” he said with a laugh, “but we haven’t actually landed on it, and we haven’t collected anything yet.”

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