Gonna Fly Now

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

Back in the mid-1980s, three decades after James Watson and Francis Crick discovered DNA's structure, scientists still despaired of advancing genetic research beyond a technological Bronze Age.

They were saddled with cumbersome tools -- often involving radioactive dyes -- and were restricted to analyzing but a few genes at a time. Yet all the research told them that genetic disorders most often involve layer upon layer of genes. They truly couldn't see the forest for the trees.

That all changed in 1984 with the introduction of new, faster sequencing machines. Suddenly, a few scientists at a memorable genetics conference in Utah that December realized, the 100,000 pieces of the human genome were within reach. All they needed was money, and a plan.

But the remainder of the decade was spent in an intense turf war over who would oversee the research -- the Department of Energy or the National Institutes of Health. Scientists and government officials also squabbled over whether the project should all be conducted in one big lab, or parceled out to numerous research centers.

Compromises were forged, and by the time the Human Genome Project finally began in 1990, it was a co-production of DOE and NIH, with hundreds of millions of dollars designated for scientists at universities and research facilities across the land.

And mapping the human genome was not the only goal. The project was expanded to include money for finishing blueprints of the model-organism trinity -- brewer's yeast, the roundworm, and fruit flies -- since they also hold great promise for plumbing the depths of human genetics.

Scientists interested in mapping the yeast and worms were easily found. But only one researcher in the country showed any interest in mapping out the fruit fly

-- Gerald Rubin of UC Berkeley.

As the Human Genome Project was gearing up, Gerald Rubin was virtually alone among "fly people," as Drosophila researchers call themselves, in arguing the importance of completing the fruit fly genome. It nettled him that an organism that has been used to divine so much of modern genetics should not have a complete blueprint.

Beyond its similarity to human beings, there are practical reasons that Drosophila melanogaster is a popular research tool. Fruit flies have a 10-day reproductive cycle, making it easy for researchers to observe genetic mutations over several generations within a span of months. Owing to their size, millions of flies can fit in a relatively compact lab.

So in 1991, when NIH sought researchers to bid on the contract to map Drosophila, Rubin jumped at the chance.

"Rubin was the only one to step forward" when the fruit fly community couldn't see the value of a Drosophila genome, says Charles Langley, a UC Davis geneticist.

The thousands of other scientists around the globe who work with Drosophila, the fly people, didn't share Rubin's enthusiasm.

Why? Fly people tend to be conservative, especially when they're afraid someone else is going to bleed away some of their research funding. That's exactly what many other fly researchers thought would happen, a fear Rubin calls misplaced.

The traditionalists preferred the old way of doing business, identifying one gene at a time rather than filling in the entire canvas. So, many fly people were openly hostile to the genome idea. "You just had a bunch of people playing with their flies," Langley says, "seeing who could come up with the neatest trick that year," instead of looking at the big picture.

Rubin wound up with the NIH contract all to himself.
He opened the Berkeley Drosophila Genome Project in 1992 with $1.5 million a year from NIH. Now, that budget has grown to $7 million a year, and other researchers are seeing the value of the project.

Although Rubin's lab has completed only about 10 percent of the fruit fly genome, the other fly people have stopped grumbling about his work. Older researchers who initially opposed the project now try to change the subject when younger colleagues ask why the Drosophila genome fell so far behind the yeast and worm blueprints.

"Gerry's a goddamned hero" for getting the Drosophila genome off the ground in the face of significant opposition, says David Botstein, chairman of Stanford's genetics department and himself the mapper of the yeast genome.

Gerald Rubin's project is housed in a two-story corrugated metal building on the hills above the campus of Lawrence Berkeley Laboratories, where the air is fragrant with eucalyptus and oak.

For seven years, a team that has grown to include 40 researchers, lab assistants, technicians, statisticians, and computer experts has toiled in the lab to identify every genetic snippet of the fruit fly.

Decoding -- or sequencing -- genes is devilishly complex work, repetitive and sometimes boring. A British scientist once joked that a prison would be the appropriate site for a sequencing laboratory.

At Lawrence Berkeley Labs, Building No. 64's overhead fluorescent lights are bright, the floor is spotless, and there is $3 million worth of lab equipment -- sequencers the size of ovens, polymerase chain reaction machines, and Power Macs -- in various shades of industrial beige.

The point of it all, the fruit fly DNA, is kept in 7-foot-tall stainless-steel freezers, cooled to a constant minus 80 degrees. The samples come from flies that have been ground into dust and put through a chemical process that strips away any impurities. The result is "pure DNA."

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