A human genome story

‘I remember standing with Bob Horvitz at the window of the old lecture room a year or so after we moved to Hinxton, looking at the enormous hole in the ground that was to be our new building. “John,” he asked me, “do you really know what you are doing?”’ Thus Sulston recalls one moment in the huge shift from being a researcher on the genetics and development of the worm Caenorhabditis elegans at the MRC Laboratory of Molecular Biology in Cambridge to director of one of the biggest gene sequencing labs in the world. ‘Some of my oldest colleagues and friends could not hide their astonishment that I should have ended up in this position,’ he writes. Britain was set to be a major player in the goal of sequencing the human genome with funding from the Wellcome trust and Sulston was to be in charge. His book*, written with author Georgina Ferry, gives his account of this extraordinary project. Sulston looks to the first musing about such an audacious project. In 1984, molecular biologist Robert Sinsheimer at the University of California at Santa Cruz, began to wonder why the large sums of money involved in major telescope projects should not be raised for biology. He wondered if there were scientific opportunities that were being overlooked, simply because we were not thinking on an adequate scale. Sinsheimer thought about developing a genome sequencing institute at Santa Cruz and convened a meeting of around a dozen scientists with expertise in DNA mapping, automated sequencing or data management. Sulston was there, together with LMB colleague Bart Barrell standing in for Sydney Brenner. ‘The mood swung from extreme scepticism to confidence it could be done but should it be done? There was a lot of suspicion of the ‘big science’ approach. But overall the conclusion was positive.’ ‘I felt amazed that we were all sitting discussing making an attack on the human genome.’ But Sulston had no idea any such plans would affect his work on the worm. Sinsheimer didn’t get his institute because of internal politics at the University of California but the idea had been sown and advocates like Walter Gilbert of Harvard University were dubbing it the grail of human genetics. By June 1986 the ideas were being discussed at a Cold Spring Harbor meeting on human genetics, but Gilbert’s estimate that the project could cost $3 billion caused uproar with many listeners assuming that funds for biological research would diverted to it. But the US Congress had now seized on the idea so the momentum for a structure-based approach to the genome was unstoppable. The Human Genome Project (HGP) officially began in 1990 with a target of a complete sequence by 2005. The new Office of Genome Research became the National Center for Human Genome Research, headed by Jim Watson, with an annual budget of almost $60 million. In the UK, Brenner persuaded the MRC to launch a UK Human Genome Mapping Project, and in 1989 the MRC won an £11 million grant over three years. Jim Watson was developing a list of model organisms to drive the technology and convince people about the value of the project. Sulston returned from a meeting with Watson who had given support to Sulston and his colleague Bob Waterston at the University of Washington at St Louis, for going ahead with the worm. In a state of great excitement, he went straight from his plane to the LMB and its director, Aaron Klug. ‘We’re going to sequence the worm,’ he said. ‘Oh, no!’ Klug replied. But Klug quickly gave his support and Sulston believes his initial concerns were to make sure he knew what he was up against. For the first time in 20 years at the LMB, Sulston had to write a grant proposal for £1 million to sequence 1.5 megabases just 3 per cent of the genome. The funding agencies gave Sulston and Waterston everything they asked for. ‘I still have the notification from the MRC, a classic missive. It was a really big grant for them over £1 million – Feature