With so many breakthroughs involving research on fruit flies, Drosophila was an ideal candidate for a genome project, says Rubin. Yet at first the Drosophilists saw no need to spend millions on such a grandiose scheme.
"Drosophila had been studied for so many years," says Rubin, "that people didn't appreciate the impact a genome project would make. Everyone already had very interesting mutations in flies that controlled interesting things like pattern formation, and they had enough tools that they could actually go isolate and clone those genes. We were moving along at a slow, steady pace, finding out something interesting every six months. It's hard to take people like that and say, 'Now spend five years building an infrastructure so you can find something interesting every six weeks.'"
Rubin got involved when his frequent collaborator Allan Spradling, an HHMI investigator at the Carnegie Institution of Washington in Baltimore, visited him in Berkeley in 1991. The two sat around complaining that nobody had jumped in to do a full-scale Drosophila genome project.
As Rubin tells it, "We said, 'Someone ought to do it,' and then we realized we were the ones in the best position to do it, and we shouldn't be sitting there complaining and whining why no one else is doing it if we're not doing it ourselves. At that point we thought, 'Let's try to coordinate it and get the project going.'" Spradling and Rubin applied for a grant to do the project at the Lawrence Berkeley National Laboratory, and they recruited promising young scientists to help them. "It all came together within months after Allan and I decided we needed to be more proactive," says Rubin.
There were still skeptics among the Drosophilists who didn't believe the project was necessary. Rubin says they changed their minds when they saw what happened to yeast researchers once the yeast genome was sequenced. "It made them realize how powerful a tool this would be. It's like having a periodic table of the elements. It enables a whole range of technologies. So when people saw what was going on in yeast, they realized they wanted a Drosophila genome. The same people who were complaining that we were wasting money were now complaining that it wouldn't be done in one year rather than three."
Rubin and his colleagues originally estimated that they would be able to sequence the entire Drosophila genome by 2002. But that feat was accomplished considerably faster through their collaboration with Celera Genomics Corporation, which was run by J. Craig Venter. Venter pioneered the use of a remarkable method of sequencing, known as whole-genome shotgun sequencing, which became more practical thanks to new sequencing machines produced by the PE Corporation, Celera's parent company.
In shotgun sequencing, the entire genome3 billion base pairs in the case of humansis randomly broken up into pieces of various sizes. The pieces are then sequenced simultaneously by hundreds of machines working in parallel, and computers figure out how the pieces fit together. "It's a way of getting a lot of information very quickly," says Rubin. Venter wanted to use the Drosophila genome as a test case for the human genome, which was his major goal. The fly sequence was published on March 24, 2000 (www.fruitfly.org/sequence/index.html).
"For me, the whole sequence is really just the beginning," says Rubin. "Chemistry didn't end with the periodic table of the elements; biology doesn't end when we have the sequences. We have to understand what all these sequences doand understand them well enough to devise ways of intervening when they don't work correctly. At that point, we'll be practicing medicine."
Gary A. Taubes
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In April 2000, HHMI vice president Gerald M. Rubin (center) testified about the status and impact of genome sequencing projects before the U.S. House of Representatitves Subcommittee on Energy and Environment. To Rubin's right is Craig Venter, former president and CEO of Celera Genomics Corporation, and to Rubin's left is Robert Waterston, head of the department of genetics at Washington University School of Medicine in St. Louis.
Photo: William K. Geiger