John Sulston on YAC Clones Worm Map
  John Sulston     Biography    
Recorded: 15 Jun 2005

JS: So Alan and I had been working on these clones, these 40,000 base-pair chunks, which are called cosmids, which is a nice name. And we got now a new bottleneck. We’d managed to make the jigsaw, that’s to say map the genome, into something like 700 bits. But there were gaps, and we could not find those gaps. There were all sorts of speculations; various people came and looked and played around with their own experiments to see if we could find a way of bridging them. But we began to think that maybe the reason was that these particular bits in the gaps would not grow in bacteria. We had no way of proving that, because we hadn’t got hold of them, so we couldn’t do anything. But we thought that might be the case. The problem was solved, as it turned out, quite wonderfully by Bob Waterston, who came to join us on sabbatical. He actually hadn’t intended to come to work on the map at all, but he came to join us on sabbatical and was so entranced by what we were doing with the map that he started to join in. And the key thing was that while he was with us in Cambridge, back at his place in St. Louis, the guys in the lab next door, in Maynard Olson’s lab, were in the process of inventing yeast artificial chromosomes, which are now called YAC. YAC clones.

Narrator: Are you talking about David Burke?

That’s right, exactly. And they were—so, when Bob got back, the YAC technology was established and Bob immediately had the chance to try out whether this new way of cloning might perhaps clone the bits that were missing from the worm genome. Well, obviously it took a few months, perhaps the best part of a year, to prove it, but by then it was all in the bag, because it turned out that the pieces of DNA grown in yeast included those gaps. And we were able to knit the whole thing together into, with a mixture of cosmids and YACs – it was good to have both because the cosmids actually were very convenient and they also contained most of the genes, it turned out, so it was good to have both, it was not a loss – but we had this combined map. One little point about science, at least in genome science, it’s not true of all science, is that it was very good that we collaborated, because it turned out there’s a number of other organisms that had by now picked up on the technology and realized that this was a good thing to do – had actually fallen to squabbling among themselves. There would be people cloning in cosmids, and people cloning in YACs, and they wouldn’t talk to each other. So the result was that these organisms actually didn’t get complete maps. Whereas the worm, we quite deliberately said, yes, we’re going to do a collaboration. We agreed to a 50-50 collaboration between these two labs, the Cambridge and St. Louis labs, and the result was that our map knitted together. And in a couple of years, towards the end of the ’80s, it really was a complete map of the worm and it was it.

Narrator: So what are we talking about, a year, when its completion came?

Well, all of these things are asymptotic, because you always struggle with end-gaps and so on. But they key year where we knew we pretty much had it together, and it was being used by the worm community—I mean, people were, people who had, as I said, sort of felt we were just nutters at the beginning of the ’80s and thought this was a crazy thing and it would never work, now were bringing bottles of whiskey for us to the meetings because they had cloned their genes much faster than they could have done before. So everybody was very happy, and the worm map was a great success. And in 1989 we, at the worm meeting—all through the ’80s we were having, every two years, we had an international worm meeting at Cold Spring Harbor, and 1989 meeting, we pasted the map up in six long strings corresponding to the six chromosomes, on the end of Blackford.

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