John Sulston on Mapping the Worm Genome
  John Sulston     Biography    
Recorded: 15 Jun 2005

Well, we’re talking about the early ’80s, I mean, specifically I think it will be 1982. And in 1982 I was rather bored, rather dissatisfied, or I’d succeeded at that point in observing the embryonic cell lineage of the worm, which was, it was something of a triumph because people had thought it would be really difficult. It was very difficult and people had been trying for ages to do this. I’d finally got through it, really by brute force, just by sitting at the microscope for a long time and looking. And so this was the combination of work that I and others had been doing all through the ’70s of gradually working out the cell lineage; and that just means the ancestral tree of cells starting from the single cell, the single fertilized egg, up to the approximately thousand cells of the mature nematode body. And bit by bit over the years we put all this together. Okay, so I’d sort of finished that. I actually, at that point I didn’t really see any huge value in this. I knew it was useful. I was pleased that people were using it, but I didn’t see it as scientifically very important. And it’s not, it’s a tool. The cell lineage in itself is of no great value, but it is valuable as a tool, and it turns out to be more valuable than I realized at that time. So basically, I was at a loose end, and I was writing up this embryonic paper and I was wondering what to do, and thinking well, you know I’m not sure, I’m not really a scientist, I probably shouldn’t do this stuff anymore. So I was minded to just try out something. But then I did get quite stirred, and it’s the – specifically, it was as I recall we told in the book , it was listening to a seminar by Matt Scott at a Gordon Conference I think. He was talking about the work on the antennapedia complex in the fruit fly. And they had a very similar bottleneck that I described, and he’d solved it for this particular region by an enormous amount of work. They had worked very, very hard, and they’d walked, as we say; that’s to say they cloned each little bit of that antennapedia complex, which is a whole series of very important key developmental genes in the fruit fly, and they got it out. And I looked at that work and I thought, well, it’s wonderful work, it’s heroic work, but we should just do it for the whole genome. Because we—you know, the genes aren’t neatly put together in locations where you want them; they’re all over the place, and you start out not knowing where they are. So we should do what they’ve done, but we should devise ways of parallelizing and to some degree automating it or at least, you know, doing it in a way where we can efficiently do lots of things at once, and just get out the whole genome. So I came back to LMB from that conference, I remember I talked to Sydney about it, I talked to John Cairns about it, and I got going.

For the first few months or year, really, it was just me, and then I had an assistant. Then the key thing that happened was that Alan Coulson joined me. Well, we started fully in 1983, because that’s when Alan came from Fred and we really got going. And I think it was 1986, if I remember rightly…Fred Sanger retired, Alan looked for a job, he found me, he found the project, he thought, this is great, I’d been sequencing and now I’m going to map, you know, it’s a natural sort of development. And it was Alan really who made this whole thing work. After about three years we were in a position where we got a lot of individual pieces of the genome. The second key step in the project was the joining with Bob Waterston, who came on sabbatical, again was fed up by what we were doing—

Sydney was interested in the project, and he supported us in the sense of giving us some new space, which he had. He—it was called room 6024, I shall always remember, because that was where we did this stuff. So room 6024, and that became the base for the worm genome map. Bit by bit we sort of built up, got it together. It was never a big group, though, in that mapping stage, because it just didn’t take a lot of people. It was more just a way of finding out how to handle the clones neatly, do the reactions that would allow us to identify some sort of pattern problem and put them together in a big jigsaw puzzle.

Well, Sydney was enthused, but I came and spoke to him about this and I said, Sydney, I think the right way to do—to solve this bottleneck is to map the genome. What I meant by mapping the genome was to get very large numbers of these clones, that’s the little chunks of DNA which are sized – they’re a bit bigger than the gene, they contain several genes typically. In fact at that time we were using chunks which were 40,000 bases long. So we were going to clone these at random, because that’s all we could do, just break the DNA up, clone at random, and then on each bacterial clone of worm DNA, we would do a reaction, which we called fingerprinting at that time. All it means is just going through some little tricks with restriction enzymes that you can do quickly to get results on a gel and you get a kind of bar code coming out of each clone. This is nothing like the whole sequence, it doesn’t even show any part of the DNA sequence at all, but it uses the characters of the sequence cut by restriction enzymes to give you a bar code. And the point about the bar code is that each piece of DNA has its own bar code, but if you have two pieces, or two fragments from the original genome to overlap, so one here and one here, then you will see a bit of that bar code in common. You don’t have to know anything about the bar code, all you’re looking at is a pattern. And the computer—you can set up computer programs that will recognize similarities in the pattern and so will help you put together this jigsaw puzzle of the genome. Now, Alan Coulson and I and one or two assistants who came with us, were able to do all this. But then we got stuck, because it turned out that not all of these chunks from the worm would actually grow in bacteria.

John Sulston was born in Buckinghamshire on 24 March 1942, the son of a Church of England minister and a schoolteacher. A childhood obsession with how things worked – whether animate or inanimate – led to a degree in Natural Sciences at the University of Cambridge, specialising in organic chemistry. He stayed on to do a PhD in the synthesis of oligonucleotides, short stretches of RNA. It was a postdoctoral position at the Salk Institute in California that opened Sulston's eyes to the uncharted frontiers where biology and chemistry meet. He worked with Leslie Orgel, a British theoretical chemist who had become absorbed in the problem of how life began. On Orgel's recommendation, Francis Crick then recruited Sulston for the Medical Research Council's Laboratory of Molecular Biology in Cambridge.

He arrived there in 1969, and joined the laboratory of Sydney Brenner. Brenner had set out to understand the sequence of events from gene to whole, living, behaving organism by studying the tiny nematode worm Caenorhabditis elegans.

For more than 20 years Sulston worked on the worm, charting for the first time the sequence of cell divisions that lead from a fertilised egg to an adult worm, identifying genetic mutations that interfere with normal development, and then going on to map and sequence the 100 million letters of DNA code that make up the worm genome.

The success of this last project, carried out jointly with Bob Waterston of Washington University in St Louis, led the Wellcome Trust to put Sulston at the head of the Sanger Centre, established in 1993 to make a major contribution to the international Human Genome Project. There he led a team of several hundred scientists who completed the sequencing of one third of the 3-billion-letter human genome, together with the genomes of many important pathogens such as the tuberculosis and leprosy bacilli.

As the leader of one of the four principal sequencing centres in the world, Sulston was a major influence on the Human Genome Project as a whole, particularly in establishing the principle that the information in the genome should be freely released so that all could benefit.

In 2000 Sulston resigned as director of the Sanger Centre (now the Wellcome Trust Sanger Institute), though he retained an office there for a few more years, continuing to work on the Human Genome Project publications and on outstanding problems with the worm genome.

Anxious to promote his views on free release and global inequality, he published his own account of the 'science, politics and ethics' of the Human Genome Project*, while adding his voice to influential bodies such as the Human Genetics Commission and an advisory group on intellectual property set up by the Royal Society. The same year he gave the Royal Institution Christmas Lectures for children on the topic 'The secrets of life'.

In 2002, John Sulston was awarded the Nobel Prize for Physiology or Medicine jointly with Sydney Brenner and Bob Horvitz, for the work they had done in understanding the development of the worm and particularly the role of programmed cell death.

The Common Thread by John Sulston and Georgina Ferry, Bantam Press 2002.

Taken from: 9/2/09 - AC Written by: Georgina Ferry John Sulston-Biography