Sequencing, sushi and sang-froid
One man's account of the fly genome project
2 April 2006
It’s Bridget Jones for the geeky classes
Michael Ashburner's office in the Department of Genetics at Cambridge University is accessed by a maze of turns and stairwells, culminating in a room about the size of a walk-in closet. Within, an operatic aria issues forth from speakers and a cat-sized plastic fruit fly (a prop for a long-ago lecture) stares at me balefully from its perch on one of the filing cabinets.
Ashburner is bearded, compact and radiates restless energy, even though he has his feet up on his desk. Several years ago, he was involved in a slice of scientific history: the sequencing of the genome of the fly Drosophila melanogaster. We’re meeting today to talk about Ashburner’s personal take on this event as encapsulated in his new book, Won For All.
Drosophila is a model organism used since the beginning of the last century to understand how genes collaborate to produce and maintain all vertebrates. The large-scale effort to sequence its genome, in a period spanning from 1998 to 2000, would set the tone and culture for future major sequencing collaborations, including the Human Genome Project. Possibly aware of the historical nature of the venture, Ashburner says he found himself compelled to take notes as events unfolded.
"Nothing polished," he hastened to add. "I'm talking about little scraps of paper, steno pads, that sort of thing. I had no idea that any of it would ever be published."
Ashburner began playing a key role in Drosophila’s scientific history decades before the sequencing project was conceived or even technically possible. He gained fame back in the 1970s for divining patterns of fly gene expression, not using molecular techniques (which had yet to be well established) but by observing under a microscope how particular giant chromosomes seemed to ‘puff’ when they were switched on by hormone, and noticing how early puffs of gene expression seemed to control subsequent waves of puffs. But though his career began in old-fashioned descriptive biology, he eventually went on to pioneer the use of computers to model, store and annotate genetic information. So it was no surprise that he would have been in the thick of any joint attempts to sequence the entire fly genome.
The story began in 1998 when, in a pre-emptive strike, J. Craig Venter, then the director of a new company called Celera Genomics, brashly announced that he intended to sequence the fly genome in a ridiculously short period of time as a ‘warm-up’ for tackling that of the human. Small-scale sequencing attempts had been ongoing for years in the fly community, so in panicked response, these efforts were consolidated and refocused under an uneasy collaboration between Celera and non-commercial consortia in America and Europe.
Ashburner’s first-person account opens with the fly community’s initial reaction to Venter’s announcement:
Turmoil? Everyone is rushing around like headless chickens. Jim is calling foul, Francis is apoplectic, and Eric is shouting at some poor graduate student that she should stop wasting time at Cold Spring Harbor, hotfoot it back to MIT, and get some real sequencing done [that’s Watson, Collins and Lander, to you]. Michael [Morgan] and John [Sulston] are said to be arriving from Hinxton on the Concorde. [Nick] Wade is rushing around getting quotes from anyone, simply anyone. Gerry? [Rubin] Gerry’s immediate comment is too politically incorrect to quote here.
The entire book is like this: breathless, immediate, funny and uncompromisingly by and for the insider. But it is a pleasant paradox of the writing style that although you are tangibly on the outside, you are simultaneously within. You feel like you are, well, a fly on the wall. It’s Bridget Jones for the geeky classes.
The scientific story is brief and illuminating, but the footnotes are where the gossip really comes into its own. And there are a lot of footnotes, possibly more than half of the total text, offering film and literary allusions as well as tips about things as diverse as restaurants (particular those of the sushi variety – "I would go a long way for good eel"), air travel (Detroit Wayne winning Ashburner’s vote as the worst airport in America), and birdwatching (Olar columbianus is "probably conspecific with the European Bewick’s swan"). You are also provided with completely irrelevant information about the players (Francis Collins rides a red Honda Nighthawk 750; Martin Reese was onetime German national student table tennis champion). And some of these asides are so provocative that they open up more questions than they answer: Bill Haseltine "was not Jim [Watson]’s graduate student, despite what you may have heard." Or, "the best sushi place [in Huntington, Long Island] is hard to find, and I am afraid that I won’t help you with that one."
Another effect of these asides is that they shatter any misconception one might have harbored that scientists are boring boffins. Of a meeting in Greece, he writes: "I must admit to having only seen dancing with a chair between the teeth once (it was Kitsos Louis, from the Institute of Molecular Biology and Biotechnology in Heraklion). But that was the evening that every plate in the taverna was broken and two very distinguished biologists of the diaspora … drove me back to the Academy … as drunk as coots." Of the Centre National de la Recherche Scientifique in Gif, France, he notes that it has "quite a good canteen … but do not plan to do any serious work after lunch."
Hijinks aside, the tension mounts throughout the book: the collaboration with Celera always seems on the verge of breaking down, births occur at inopportune moments, family relations are threatened, health deteriorates, time is running out and everything is being improvised as the researchers go along. But in the end, culminating in a four-week long ‘jamboree’ hosted by Celera, the task is completed and published in the journal Science.
When the collaboration disbanded, Ashburner told me he grew very depressed; the last few months had involved incessant traveling and he'd suffered from pneumonia as well. The writing, he says, was a form of 'therapy’. The bulk of Won For All was produced in a few weekends during frantic, often middle-of-the-night bursts. This is somewhat of a feat considering that, according to Ashburner, the footnotes were not added later but rather flowed out as part of the stream-of-consciousness sessions. He says he wrote this initial account for his wife and kids, to help them understand exactly why he'd been away so much during the project. (Or as he phrases it in the Preface: "To those nearest me who have suffered, here is why.")
Ashburner printed out the manuscript and showed it to his family and a few others, such as his friend Nobel laureate John Sulston, and that seemed to be the end of it. In fact the whole thing might have come to nothing had Ashburner not been stranded in a Boston hotel one rainy afternoon with time on his hands.
"I opened up my laptop and read it in one sitting," he says. "And I thought: hey, this is good."
So Ashburner decided to send the manuscript to John Inglis, the executive director of Cold Spring Harbor Laboratory (CSHL) Press in Long Island, New York.
"John was intrigued," Ashburner recalls. "But the thing is, Cold Spring Harbor is a serious scientific press: they don't publish novels, okay?" Something as chatty, gossipy and irreverent as Ashburner’s fly diary was a bit outside of their normal remit, and Ashburner was on tenterhooks until CSHL Press gave him the green light.
But CSHL Press still had a second fundamental decision to make about Ashburner's manuscript. Should it be edited and made more accessible to a wider audience, or should the raw style, with its jargon and in-jokes and name-dropping, be preserved as is? Verisimilitude and charm versus broadening the potential readership by dumbing it down – CSHL Press deliberated, but in the end, hardly anything was altered, added or deleted – a photocopy of history, still warm from the rollers. Or as Ashburner puts it, "from the gut". A few more footnotes were added for clarity, and other players in the fly project were consulted to confirm veracity and chronology. Another extra touch was the inclusion of portrait sketches of the various dramatic personae executed by the Australian Lewis Miller, who was artist-in-residence at CSHL in 1998 and 2000. Miller, whose work adorns the walls of CSHL as well as a number of public and private exhibition spaces worldwide, drew most of portraits at a Human Genome Symposium at CSHL in 2003, but no proper home had been found for them until Ashburner realized what an asset they would be for his book.
John Inglis told me that the book is not intended to be appreciated by all, but is an important record of a significant time in history. CSHL Press has a reputation for producing prestigious books about science, for scientists, and Inglis imagines that the book would be most enjoyed by students – particularly undergraduates – and would help capture the excitement of the time and serve as an enticement.
Casting a long shadow over all books of this sort – that is, novelistic first-person accounts of a scientific event – is of course The Double Helix, written by the current Chancellor of CSHL, Jim Watson, one of the co-discoverers of the structure of DNA. Both Ashburner and Inglis agree that the impact and significance of The Double Helix has never been duplicated (not even by Watson's own second attempt at the genre).
The afternoon I spoke with Ashburner, he was on edge: the book had come out only a few days before, his large Fed-ex shipment of volumes was overdue, and he had no idea how it would be received. He thought that certainly scientists would be keen, but he wasn’t sure about the general public. I tell him that while reading a particular passage in the book I was suddenly consumed with nostalgia for my past late-night sessions in the lab, slaving away as a team in pursuit of a common goal. Ashburner, when speaking of the jamboree, had written, "It’s just like being a postdoc again". And I actually felt a pang at that description.
"But to your average person in the street," Ashburner points out, "that line would be meaningless."
After lunch, he has an hour to kill before a meeting, so he leads me through brilliant sunshine to the Fitzwilliam Museum. "Hideous, isn’t it?" he says of the vast Henry Moore in the lawn, an elongated female body crouched like a spider. Inside, we inspect an exhibition of illuminated manuscripts by William Blake. Nose almost touching the glass of one of the pages, he recites:
If thou dost go away from me, I shall consume upon these Rocks.
These fibres of thine eyes, that used to beam in distant heavens
Away from me, I have bound down with a hot iron:
These nostrils, that expanded with delight in morning skies,
I have bent downward with lead, melted in my roaring furnaces
Of affliction, of love, of sweet despair, of torment unendurable.
This wisdom dispensed, we wander through the permanent collection, and Ashburner is distressed that the gallery containing his favorite piece, a sculpture of the head of the Neo-romantic artist and muse Isabel Rawsthorne, is temporarily roped off.
"I like to visit her," he says wistfully. "She was this sexy, beautiful women, involved with all sorts of artists and composers – Bacon, Picasso, Giacometti, Derain, Lambert." The sculpture was donated to the Fitzwilliam by Ashburner’s sister-in-law.
We head back towards his office, cutting through the fine turf of Pembroke College ("It’s not permitted, but who cares?"). A large group of solemn Japanese schoolgirl tourists parts like the Red Sea as we pass. My final few moments with him are filled up by a spate of urgent gossip that he tells me I am not allowed to print.
As we say goodbye, I ask him whether he would do anything different about his writing now that it is too late to recall the book.
"No," he says. "But I do have one big regret: that I didn’t keep a diary as a Ph.D. student."
Michael Ashburner would love you to read his book, Won For All, which LabLit.com highly recommends. Click here to order now.