The DNA behind DNA

Sitting around a table piled with seafood and wine, a group of scientists came up with an idea. It was the Fall of 2005, and the diners were from the DNA sequencing company 454 Life Sciences, celebrating the launch of the company's sequencing technology, the Genome Sequencer 20.

454 was established with the goal of making human genome sequencing an everyday technology, and that night the ambition seemed within reach. At the Stone House restaurant on the marina at Guildford, Connecticut, the company's founder Jonathan Rothberg, vice president of research and development Michael Egholm, and Richard Gibbs from the Baylor College of Medicine, who is on the 454 advisory board, paused to consider who to sequence first.

"One option we thought about was to sequence an everyday person, but then Richard Gibbs blurted out 'What about Jim Watson?' and we considered it for about two nanoseconds before agreeing," remembers Egholm. "It was just the logical thing to do."

Soon after, Rothberg made the two-hour drive from his Connecticut office to see the co-discoverer of the structure of DNA in his office at Cold Spring Harbor, hoping to convince him to take part in the project. "Jon knew this was going to be the most important conversation he was ever going to have in his life," Egholm says, "so he'd rehearsed all the arguments."

As it turned out, Watson said yes "before Jon even said more than a few words," says Egholm. Later, Watson admitted he'd said yes so quickly in part because he doubted the company would ever pull it off.

By the end of 2005, a tube containing 10 mL of Watson's blood was in the hands of Maithreyan Srinivasan, 454's lead scientist in charge of the development of the company's next-generation sequencer, the Genome Sequencer FLX. "I was very excited," says Srinivasan, called Srini by his colleagues. "I mean it's Jim Watson's genome I was going to be sequencing, right? It was a huge, huge moment for me."

In early 2006, Watson told a journalist about the project, and 454 began to feel public pressure to get the sequencing project done. But the developing GS FLX technology wasn't yet up to the job. And 'Project Jim' soon became known as the 'Project From Hell.' "There was so much pressure, and we couldn't do it," says Egholm.

By late 2006, the sequence still wasn't coming together. The reads they were achieving were too short, and the accuracy too low. "It wasn't very good," remembers Srini. With a little more fine-tuning, Srini and his small group of colleagues managed to extend the read lengths they could achieve to around 250 base pairs, and boosted accuracy to 99% and above. "Now, suddenly, you could really do something. You could make sense of the reads," he says. By February 2007, the sequencing part of the project was done.

This spring, after Baylor College performed some analysis of the data, Watson was handed a DVD containing the 20 gigabytes of data that helped him become the scientist he was. In essence, that disc contained the DNA that helped make it possible to read DNA in the first place. "It was big moment in my life," says Srini.

It was pretty big for Watson, too. "I'm thrilled to see my genome," he said at a press conference on May 31. He explained part of his motivation was to help uncover why his eldest son developed schizophrenia. "This is a disease... we still know almost nothing of at the genetic level," he said. (Watson's spokesperson said he was traveling and unavailable to comment.)

However, not everyone has expressed such enthusiasm for the project. Some scientists are concerned that sequencing celebrities (J. Craig Venter also recently unveiled his genome) gives the impression that it is only for the wealthy or well-known. "It's great that companies and academic units are making sequencing faster and cheaper," says Kathy Hudson from the Johns Hopkins Berman Bioethics Institute. But sequencing only scientific celebrities "gives a misimpression about what genomics is all about--improving people's health."

Egholm dismisses that idea. "That criticism is silly, and I don't know what to do about it but shrug my shoulders," he says. "We chose Watson because he has this incredible personal story with the human genome. Anyway, it's the next 100 genomes that count."