Writing on the Fly

© Richard Corbett Born and raised in the English countryside, where he collected birds' eggs and cared for pet hedgehogs, Michael Ashburner set out to study zoology at the University of Cambridge. It was 1963, and the policy at Cambridge was that undergraduates would specialize in their third year, taking a single focused course called a Part II. "I applied to do Part II zoology," says Ashburner, "but they turned me down." Such rejection "was a bit of a disaster," he says. "You can do something called Part II General, but it's considered a sign of failure." Then he stumbled onto genetics. Newly married, Ashburner had arranged to spend the summer, his honeymoon, at the Stazione Zoologica in Naples studying octopuses. There, he and his wife Francesca took up residence in a geneticist's home. "The apartment was full of genetics books, so I read them." He successfully completed his undergraduate degree in genetics - "So I became a geneticist because the zoologists wouldn't have me." Drosophila biologists have reaped the rewards. Among other accomplishments, Ashburner has elucidated a model for a key hormone-induced gene regulatory cascade (before scientists had even identified transcription factors), and he has exhaustively characterized a 3-megabase stretch of Drosophila DNA that former colleague Rachel Drysdale calls "one of the best-mapped regions of any eukaryotic genome" - a performance that served, she says, "as a practice run for annotating the whole genome." Ashburner has also labored tirelessly to generate resources that benefit the entire Drosophila community, including open-access sequence data, comprehensive databases, and tomes that are essential references for anyone who is serious about flies. "There's no one who's been in this business long enough to be out of diapers who doesn't know this man," says Scott Hawley of the Stowers Institute in Kansas City, Mo. "He is the senior statesman of the Drosophila genetics community." PUFF THE MAGIC GENOME After completing his undergraduate studies, Ashburner stayed at the University of Cambridge to earn his PhD. He's never left. "I've always had a job in Cambridge," says Ashburner, who worked his way up from an "assistant in research," a rank that no longer exists but that doubled his salary from £300 to £600 a year in the late 1960s, to his current position as professor of biology in the Department of Genetics. As a graduate student, Ashburner became interested in the puffing patterns of polytene chromosomes. During the life cycle of the fruit fly, certain parts of the oversized salivary chromosomes assume a puffy appearance. Scientists had postulated that this puffing might correlate with the active transcription of genes, including those that encode the proteinaceous glue that helps to anchor larvae as they pupate. Ashburner has labored tirelessly to generate resources that benefit the entire Drosophila community, including open-access sequence data, comprehensive databases, and tomes that are essential references for anyone who is serious about flies. Exploring this system to his satisfaction took Ashburner through his doctoral years, from 1964 to 1968, and into his early career. The work was grueling: setting up cultures, fixing cells at specific times, and examining the chromosomes before the patterns deteriorated. "To do an experiment, for me it meant an entire day, starting at 8 [a.m.] and finishing at 8 [p.m.], with no serious interruptions," he says. "I mean, I could go have a pee, I could go have a coffee, or later in the day I could go have a beer," but there were no meetings, seminars, or other major distractions. These painstaking cytologic examinations led Ashburner to propose a model for a gene regulatory cascade in which early-forming puffs encode protein products (the as-yet undiscovered transcription factors) that give rise to later puffs, which contain the genes that encode glue and other pupal necessities. "Michael provided strong biological evidence for the sort of hierarchy where you turn on gene 1 and the product of gene 1 turns on genes 2, 3, and 4, and so on," says Hawley. "That set the pattern for the way we now think about gene regulation. It was a huge accomplishment." Fear, in some sense, drove that accomplishment. In 1974, Ashburner was invited to present his data at Cold Spring Harbor. "In those days, if you went to the symposium to give a paper, you had to turn up with a manuscript," he says. "The woman who ran publishing was a dragon and she scared me..., and I knew if I turned up without a manuscript, she would make my life miserable." The resulting pressure encouraged Ashburner and his lab to step up their efforts to formulate a coherent story. "Every night I'd write a new version with a different model," says Ashburner. "The next day we'd come in and try to make predictions from the model, and my student Geoff Richards and I would do the experiment and show it was crap." A model did emerge, however, and after working on the overall problem for more than a decade, Ashburner had published a flotilla of papers, more than a dozen of which are single-author, including two in Nature. He was ready to move on to something new. A DRIVE FOR ANNOTATING For years, the Drosophila community had been debating the relationship between polytene chromosome bands and genes. In the early 1970s, Burke Judd, who was at the University of Texas in Austin, was pushing a "one-gene, one-band" hypothesis. He and his students had analyzed a small region on the X chromosome and found that the number of genes they identified equaled the number of bands in the area. Ashburner decided to investigate further. "Of course we ended up getting compulsive about it," he says. They genetically saturated a 75-band region, looking for mutations that would disable genes required for viability. "It was a beautiful genetic assault," says Hawley. "He generated hundreds of mutations and identified as many breakpoints and complementation groups as he could." Although the one-gene, one-band idea was eventually shown to be "bollocks," says Ashburner, it inspired him to characterize this one genetic region thoroughly. Along the way he discovered a few interesting genes, including vasa, which people use as a marker for germ-line cells in everything from flies to humans. "But the real prize of that work," carried out through the 1980s and 1990s, "was that it allowed people to begin to think seriously about sequencing and annotating the entire fly genome," says Ashburner. In the early days, that annotation was serious manual labor. "I probably still have this 35-foot roll of paper we used to put up on the wall and annotate by hand," says Ashburner. Those seemingly antiquated efforts formed the backbone of what later became FlyBase. "Michael has been the driving intellectual force behind this community database in which all the literature is made accessible to everyone in a very user-friendly way," says Gerry Rubin, director of Howard Hughes Medical Institute's Janelia Farm Campus. "The vision for that came from Michael." In the late 1990s, Ashburner applied the same personal touch to the Gene Ontology Project, which was an effort to come up with a structured vocabulary that would allow members of the community to search across different databases to find, say, all the protein tyrosine kinases in flies, mice, and yeast. "If you looked at all the Gene Ontology annotation for Drosophila genes, they were virtually all hand-annotated by Michael," says former postdoc Steve Russell, still at the University of Cambridge. "I think he's driven by wanting to get as much information out of the work we're all doing as can possibly be gotten," says Drysdale. In addition to championing FlyBase and the Gene Oncology Consortium, Ashburner launched a reprint collection in Cambridge. "His aim at the time was to have a paper reprint of every article published about Drosophila in every journal everywhere in the world," says former postdoc Daniel Barbash of Cornell University. Of course, Ashburner seems to carry most of that information in his head. "He's a walking encyclopedia of Drosophila biology and genetics," says Suzanna Lewis of the University of California, Berkeley. "I'm always astounded. Almost any question you put to him, he can answer." SHARING THROUGH TEACHING AND WRITING He shares that knowledge through his teaching. For 20 years, Ashburner has cotaught - first with Rubin, then with Hawley - an advanced course on Drosophila genetics. One year, Ashburner missed the start of the session because of a mysterious 105-degree fever. "He'd been in Africa, bird watching or bug collecting or tracking wildebeest," says Hawley, who then had to wing it. "For three days I proceeded to tell the students everything I knew about Drosophila, including my whole life story, because I didn't have that much to say. On the morning of the fourth day, I looked out the window, and there, trampling across the grass, was Michael. He had been in the hospital with a tropical fever. Anyone else would have seen that as sufficient excuse to blow the whole thing off, but not Michael. He asked me what I'd covered, asked why I'd wasted their time on that, then just grabbed the chalk and started talking." Ashburner is similarly indefatigable when it comes to writing. Between 1976 and 1986, he edited a massive 12-volume collection, The Genetics and Biology of Drosophila, which at the time was essentially a compendium of everything known about Drosophila. He followed up that effort with a handbook of Drosophila genetics in which, Hawley says, "Michael sat down, by himself, and wrote up a century's worth of genetic analyses in Drosophila." "He didn't edit it, he wrote it," stresses Jeff Hall of Brandeis University. "He's the only person on the planet who could do such a thing. He called it a laboratory manual, but it covered the entire history of anything and everything ever done with fruit flies. It's an incredible work of scholarship." More recently, Ashburner penned Won for All, a gossipy little memoir about his involvement with the fly genome sequence. Ashburner claims he wrote the book as "therapy," but Hawley says it "stands as a recounting of a truly critical achievement: how we got the sequence and how we made the sequence useful." For his role in that effort, Hawley says that Ashburner should be hailed as a hero, and Hawley says as much in a brief epilogue to the book. "Of course, that was one of the first things he changed. So the epilogue now reads, 'Michael is not a hero.' But if anyone's a hero, Michael is." Rubin agrees. "So many scientists are motivated by 'how will this help me, how will this get me another high-profile paper,' not by 'how is this going to advance the field or help the progress of science.' But Michael's work has helped make hundreds of people's work better. He's been a tremendous force for good in the scientific community." He will be fondly remembered for that. "There are people like Sturtevant and Bridges. These guys will never be forgotten," says Hall. "Same with Michael."

Writing on the Fly

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