John Sulston on Biology of the Worm
  John Sulston     Biography    
Recorded: 15 Jun 2005

With the worm genome? Well, you have to step back slightly and see else what I was doing before. And so, after joining Sydney Brenner’s group in 1969, and then a number of other people joined, including Bob Horvitz, for example. We were working on the biology of the worm, but also, and particularly, the program was working on the genetics of the worm. And the idea was to link the genetics to biology. How do the genes control, how do they drive development, and ultimately behavior of this animal? And in order to make that link, obviously you have to find some clues. Now the clues that were available at that time were the clues of classical genetics. And this was Sydney’s program, really, he started in the mid ’60s, was to pick funny worms. You mutagenize the worms; that’s to say you chemically alter their DNA, or alter the DNA some other way, but at random create mutations and then look as the worms breed for worms that behave in some strange way. For example, worms that can’t go backwards when you touch them, or worms that roll, or worms that are a funny shape, and so on and so on. And as time went on, Sydney starting initially on his own, and then working with more and more postdocs and students as they came in, collected a large number of these mutations. And I guess by the end of the ’70s, during which time I’d started the cell lineage and other things, by the end of the ’70s, they, collectively we had hundreds of genes, and thousands of mutants affecting them. But the problem was this: in order to take the next step – we had the clues – but in order to take the next step we have to actually isolate the genes. And that, although we understood because of the success of molecular biology starting in the early ’50s, we knew in principle what to look for – we were looking for pieces of DNA, which were the genes, and we wanted to know what they were; what was the DNA sequence of those genes and then we wanted to manipulate and learn how the whole thing worked. But we had to first isolate the genes. And this was proving to be a real bottleneck. So the worm genome consists of, as we now know, about 100 million base pairs, and that’s a pretty big haystack for looking for a few thousand base pairs, which is the content of a single gene. And people were digging around in this and spending weeks, months, years looking for genes in very laborious way. And it was clear that we had to overcome this bottleneck. We could get the clues; we had to convert those clues into real molecular biology. So that was the beginning of the genome project. It wasn’t clear what one should do. It was clear there was a bottleneck. Now, people didn’t all agree what one should do. And in fact, those of us that started working on the genome at that time were pretty widely regarded as a bit crazy, because people said, why do you want to look at the whole genome?

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