Backroom Boys

by Francis Spufford

  Endeavour after endeavour in human society had called on the multiplying magic Adam Smith described, but until the 1990s, biology had never needed it. There had been Big Science for decades, but it had always been Big Physics or Big Astronomy, concerned with nuclear weapons or underground supercolliders or gigantic radio telescopes. Big Biology hadn’t existed till now. Sequencing the human genome was the very first biological project that couldn’t be achieved the traditional way, by a small group in a lab. It was the very first task in biology to be so big, with such an overhead of material to be processed, that it demanded the industrial acceleration. This was important. The race that was about to begin against the Ventapiller was thus happening at the point in biology when (figuratively) the smokestacks had just begun to belch. The initial explosion of productivity was so dramatic that it wasn’t yet decisive whether an organisation was optimally streamlined or had superlative control over its costs. The cost of sequencing was being transformed anyway. By 1998 – the NIH calculated the figures, so they were denominated in dollars – the cost of deciphering the human sequence had fallen from around $10 per base to under $1. Craig Venter liked to claim, later, that he had pioneered the mass production of the genome. He told Richard Preston of The New Yorker, as they stood among ABI 3700s in Maryland, that he was ‘seeing Henry Ford’s first assembly plant’. ‘There are three people working in this room,’ he said. ‘A year ago, this work would have taken one thousand to two thousand scientists. With this technology, we are literally coming out of the dark ages of biology.’ But it wasn’t so. It was true that he leapfrogged over the public labs technologically, with his enormous suite of next-gen equipment, and that the Sanger Centre and the others were forced to retool just to keep up, to the inexpressible joy of ABI’s sales department. But the breakthrough had already happened. The pins were already coming off the production line in thousands rather than hundreds. Genome data was already a commodity, not a craft item.

  And something else unexpected had happened at the Sanger. It could not be organised along the lines of the gift economy, but John Sulston was determined to get as much of the spirit of the gift into the place as he could; and the scientific culture and the industrial culture formed a strangely stable hybrid. ‘People don’t want to work where every single thing they do is measured by money,’ Sulston told me firmly. The money was good at the Sanger, Sulston insisted on that – ‘every time I was thwarted I said, “I’m sorry, I’m doing it this way or not at all”’ – but the idea was for the money to be good enough for people to forget about it. It was a firm principle that there was always as much training available at the Sanger as you wanted to accept. ‘John was adamant’, Jane Rogers said, ‘that people came in at the bottom and they worked their way up, and the level you got to was dependent on your own ability.’ ‘In no time at all, we had people asking if they could take day release or do evening classes,’ he remembered. ‘They were chatting to me about points they didn’t understand … Maybe they’d dropped out of school, and now they realised they did like science, and they really did want to be part of the larger picture, because now they were doing something practical. I basically am that way at heart. I got very bored at university because I didn’t have enough to do with my hands.’ It was quite possible to answer an advert in the Cambridge Evening News, arrive at the Sanger to push a trolley and to emerge a few years later with a biology degree. If the Industrial Revolution was just breaking out at the Sanger Centre, then John Sulston was a kind of Quaker industrialist, presiding over not a dark satanic mill, but one of those experimental factories like New Lanark or Bournville where they tried to mobilise the division of labour to produce something humane. An atmosphere of expectation filled the Sanger Centre. It could be as persuasive as any conventional regime of incentives. ‘Nobody serious worked under their hours. They all worked a bit over them,’ said Sulston to me happily. ‘I don’t think I’m a slave-driver,’ he added, ‘though Jane says I am.’

  In one fundamental respect, of course, the Sanger Centre adhered absolutely to the rules of the gift economy. The gel trolleys rolled, the robot pickers picked, the shakers shook, the reagents poured, the assembly algorithms ran, the finishers scrutinised the fragments of sequence and ordered new clones to be dispatched through the line. Across a little digital announcement board at main reception, the results of the whole process marched prestissimo in real time, AGGTCCACGAGTT scooting by. And at the end of every day, they took the day’s production, and they gave it away. John Sulston always had the same answer when an entrepreneur approached him, even in ambiguous cases where there might have been room for discussion. Sorry, no deal. ‘There is nothing for sale at the Sanger Centre.’

  Tuesday 12 May 1998

  Mice? Good grief, mice? Nicholas Wade’s new piece in the New York Times, reporting the Washington press conference of the day before, treated the switch to the mouse by the public labs as an established fact. He had moved on to predicting reactions. ‘It may not be immediately clear to members of Congress that having forfeited the grand prize of human genome sequence, they should now be equally happy with the glory of paying for similar research on mice.’ Nobody had forfeited anything yet, and the public labs hadn’t given up on the human sequence, let alone agreed to substitute Mus musculus for Homo sapiens. Any dismay on Capitol Hill was entirely theoretical. But Wade seemed impatient to help Craig Venter give the public project a conclusive bum’s rush into oblivion.

  *

  Venter was discovering, however, that the scientific audience was a much harder sell than the crowd of investors and journalists who had been applauding him since Saturday. One of the regular symposiums on sequencing at Jim Watson’s Cold Spring Harbor campus was just about to open, and Venter had flown up to Long Island with his associates to make a formal presentation of his plans to his academic peers. He had been assigned a slot before the sessions of the symposium proper began at a meeting in a side hall for all the ‘principal investigators’ of the genome effort. A good fraction of those in charge of American genome research looked back at him as he got up to say his piece, including Francis Collins and his team, who’d been caucusing frantically since they arrived. Venter had basked in the public adulation of the last few days, and he was now looking forward to getting some more detailed and technical approval. But the event did not go well. A coronation it was not. Sceptical questions and critical remarks sounded from all over the room. How could Venter really promise to release sequence data free, every three months? What guarantees would his captive market of scientists have? Much of the criticism focused on the danger people saw in his map-less sequencing strategy, with people predicting disarray when he tried to make sense of the huge swathes of ‘junk’ DNA in the genome, where the double helix didn’t code for functional proteins and there would be few features for even the best pattern-recognising algorithms to latch on to. How could he check the quality of his data? Sulston’s close collaborator Bob Waterston compared the sequence Venter would generate to ‘an encylopaedia ripped in shreds and scattered on the floor’. A lot of the rest of the objections referred, again and again, to the grievous breach of scientific good manners he had committed. He had – people pointed out – broken the commandment Thou Shalt Not Muscle In about as thoroughly as it could be broken. Having no culturally straightforward way to express any ideological dissent made the American scientists more angry, not less; and the more hostility Venter encountered where he had expected praise, the blunter and more contemptuous he became in reply, because that was how he was wired. ‘Craig has a certain lack of social skills,’ the head of one sequencing centre told Richard Preston of The New Yorker. ‘He goes into that meeting thinking that everyone is going to thank him for doing the genome himself. The thing blew up in a huge explosion.’ Afterwards, another lab director remembered, ‘Craig came up to me … and he said, “Ha, ha, I’m going to do the human genome. You should go do the mouse.” I said to him, “You bastard, you bastard,” and I almost slugged him.’ Jim
Watson had not been able to bring himself to attend. He hung around in the lobby afterwards, buttonholing people and comparing Craig Venter freely to Hitler. Watson challenged Francis Collins to say if he was going to be Neville Chamberlain or Winston Churchill.

  Venter had originally planned to stick around for the remaining three days of the symposium, taking in some interesting papers, maybe doing a little quiet recruiting. Instead he did a quick deal with a fly-genome specialist who was willing to work with him, packed his bags and left.

  Wednesday 13 May 1998

  The boardroom on the Euston Road: shiny table, panelled walls, glasses of water, stacks of photocopied documents. The scientific governors of the Wellcome Trust had been booked for months to meet today and give the final verdict on the application to double the Sanger Centre’s funding. Originally, the idea of the Sanger moving up from one sixth to one third of the genome had been that it would galvanise the public effort in the US into showing a bit more speed and urgency. It wasn’t just Craig Venter who had chafed at the slow progress of Francis Collins’ coalition. John Sulston and his St Louis colleague Bob Waterston had been frustrated too. Now though, suddenly, the significance of the funding request had changed. Now the imperative was to claim a large enough slice of the human genome to prevent the public project from failing altogether. If the Trust could make a big, loud, rich, confident intervention, right then, it might be enough to restore the determination of the Americans. The Sanger team were asking, in effect, for a sack of Wellcome money to be dropped on the public end of the wavering see-saw.

  Michael Morgan knew that the governors had received nothing but positive reports on the application from the scientific referees they’d sent it out to. So that was OK. The piles of paper on the governors’ side of the table were all complimentary. What had worried him since the taxi ride on Friday was the chance of the governors taking the news of Venter’s initiative as a sign that the genome was now nicely taken care of elsewhere; that they had been liberated to spend the Trust’s money on something else. ‘My concern was that the news would actually justify the governors in refusing the increase.’ He had worked his phone assiduously. But, to his relief, the governors seemed not to be thinking along those lines. They too were peeved that the Trust’s flagship effort was being shoved aside by people who hadn’t even acknowledged the British involvement in sequencing. ‘Everyone’s dander was up.’ John Sulston stood up and made a little speech. It was crucial that there be a strong international presence in the genome project, he said, if the policy of free release were to survive. And the international presence had to be British, because everyone else had dropped out. And a sixth of the genome was not enough to ensure a significant influence. ‘Perhaps you would give us a few minutes?’ said the governors. The Sanger contingent – Sulston, Jane Rogers, Richard Durbin the database creator – filed out and sat in the hall while the governors deliberated. The ‘few minutes’ were literal. Very shortly afterwards, the governors sent out the message that the answer was yes. The Sanger Centre could have the £200 million necessary to do a third of the genome – and more besides, if more was required. John Sulston was being trusted with a very large new microscope.

  Michael Morgan popped the bottle of champagne he’d had on ice, and immediately they all sat down to write a press release. ‘The Wellcome Trust has today announced a major increase in its flagship investment in British science in the sequencing of the human genome, the book of life …’ That small group, sitting with champagne glasses and pencils above the Euston Road, were the first people in the world to know for sure that the human genome was not going to be passively relinquished to Craig Venter. But the news, they decided, had better be taken at once to where it would do most good, to the temporary hub of genome sequencing that had coalesced at Cold Spring Harbor. Michael Morgan and Sulston would wait till next day and cope with press reaction to the statement; Jane Rogers would go right now to feel out the lie of the land and announce that the cavalry were coming. She had brought a suitcase against this eventuality. A taxi was summoned, she hopped in, and a scant couple of hours later she was in the air on her way to New York, wondering about the degree of discombobulation that was going to greet her.

  Thursday 14 May 1998

  Sulston and Morgan, following her across the Atlantic the morning after, had psyched themselves up for a confrontation. ‘I suppose we were a little bit gung-ho,’ Michael Morgan told me. ‘You know, we were off to slay the dragon. We were still expecting Craig and Mike Hunkapiller to be there, addressing the meeting, and we didn’t know how the encounter would work out.’ But when they’d landed at JFK and driven their rented car up Long Island to Cold Spring Harbor in the late afternoon sun, through fields and woodland alternating with shopping malls, they learned from Jane Rogers that the dragon had flapped off in a huff. And the rest of what she had to say was equally adrenalin-dispersing. The news from London had not had the desired effect. ‘Jane was very concerned,’ Sulston remembered. ‘She felt that people were responding in a very headless-chicken kind of way, and that the house was divided against itself, which it was.’ ‘We’d got our scale-up, and I thought it would gee the other American groups into action,’ she recalled. Instead, a gloomy fatalism prevailed. The attendees at Cold Spring Harbor might be appalled, many of them, at what was happening, but they seemed to take it for granted that the most they could do about it was to give Venter himself a hard time; and meanwhile, the strain of the situation was fracturing the genome community along the lines of self-interest. Latent resentment of the big labs’ big budgets was oozing to the surface in some people, and others were trying resignedly to work out what kind of deal they could do with Venter to protect their own research topics. Deep down, all too large a proportion of those on the Cold Spring Harbor campus seemed to believe that Venter’s success was inevitable.

  ‘I didn’t know what to do,’ said Sulston. As a preliminary, they linked up with Bob Waterston, and with Francis Collins and his boys and girls. Then, for the rest of that evening and too much of the night, the increasingly jet-lagged travellers politicked with the senior staff of all the other public labs, in small groups convened all over the campus, from the cafeterias down to the waterfront, where Cold Spring Harbor announced its purpose to the world in the form of a weathercock shaped like an adenovirus on one of the trim, white-planked buildings. The news of Wellcome’s doubled support for the public project obviously had to be announced with more emphasis, in a way that penetrated the gloom and made people believe once more that the public project was still a genuine contender. That was the psychological aspect of the problem; but they also needed at least the outline of a strategy that would let them match Venter’s sequencing speed without discarding elements of the sequencing process they believed were scientifically vital. Because he was planning to dispense with the clone-mapping stage and with most hands-on human judgement at the finishing stage, Venter’s production line was going to be inherently shorter. It would therefore run faster than theirs even when the public labs were fully re-equipped with as many ABI 3700s as he was going to have. But they could not emulate him, because they were convinced that his abbreviated method would not work. Or rather, that it could only produce an approximate, unreliable draft of the genome, full of holes, rather than the permanent, archive-grade product that science deserved. ‘It was going to leave a mess,’ said Jane Rogers. ‘He was installing machines and computers, and that would bung things together in some sort of fashion,’ said John Sulston, ‘but we all knew from the mathematics and the biology that only our way would work. Somehow, simultaneously, we had to meet the challenge and say, “We are going to provide a product as fast, as good, as cheap, as everything else, as Celera” – and yet at the same time not be deflected from our long-range project. It was a real Catch-22 situation, and I think it was entirely justified that people were scurrying around squawking a bit!’

  Nonetheless, the first inklings of the public counter-plan emerged that evening, though
it wouldn’t become policy until a formal meeting at the NIH at the end of the month. If, they decided, they dropped their own immediate target from 99.99 per cent accuracy to 99.9 per cent accuracy in the sequence, they would be able to publish a ‘rough draft’ of the genome at a rate that competed visibly with Venter, while the finishers came up behind with a better version. This way, they could hope to arrive at a complete first draft sometime in 2000 or 2001, the same sort of date that Venter was naming as his goal. And the final, letter-perfect, for-the-ages edition would be done in – rapid calculation on scrap paper, factoring in the accelerating effect of the new machines – 2003, or thereabouts. Which still represented a respectable two-year gain on the 2005 finishing date they’d been working to before this nightmare week began. Thank you, Craig Venter, for that.

  While they huddled, while they squawked, they kept catching half-suppressed grins on some of the faces they passed on the pathways. Knowing looks flickered in the corridors as they scurried by. It was glee breaking out among the younger attendees at Cold Spring Harbor, who had no direct professional stake in the genome yet, on either side, and couldn’t help relishing this rare chance to see so much dignified Anglo-American talent with its knickers in a twist. ‘They thought it was hilarious,’ John Sulston told me, fondly. ‘They were running around going, “Hee-hee-hee, oh God, what fun!”’ What a floorshow! Nobel laureates ago-go! Well worth staying up for. ‘They loved to see their elders being bashed about a bit. But’, he said, ‘their hearts were in the right place. Scientists, you have to remember, are all anarchists. That’s the way science works, that’s the great strength of it …’