John Sulston on Nobel Prize Research: Cell lineage of the nematode C. elegans
  John Sulston     Biography    
Recorded: 15 Jun 2005

Well, it really was the cell lineage. I came to be working on that, my—I came to be working on it very, very accidentally. The thing is, since Sydney’s original proposal to the MRC that suggested that we should do the cell lineage, he and others had gotten equipment, they had microscopes for doing this. And other people elsewhere in the world; there were people in Germany working on it, people in Japan working on it, to try to establish the cell lineage. And they were all looking at the egg, because they all thought, start at the beginning, very sensible, and also the egg doesn’t move so they could take pictures of it with cameras. And so a lot of people were trying to do this. So this was all going on anyway, but it was only getting up to a certain point because the cells were very tiny, it was very hard to resolve. I came at it a completely different way, just by chance, because I was working on—I was using a technique actually I’d learned from guys at Harvard who I worked with in Leslie Orgel’s lab in California. This is—well, Furshpan and Potter came to visit, and they had this technique that they were applying, where you react a biological specimen with formaldehyde gas, and if you get all the conditions just right – it’s one of these lovely old fiddly techniques involving Kilner jars and ovens and pumps, all sorts of things – anyway, if you get it just right, you get these beautiful intense fluorescent patterns wherever there’s a neuron or indeed anything else that contains one of the catecholamines, these are among the neurotransmitters. The particular one the worm turns out to have is dopamine, which is actually very important in our own brains. It’s I guess lack of dopamine that’s involved in Parkinson’s disease, for example. It’s an important neurotransmitter in the brain. Anyway, I had a go with the worm just because it was fun. The wonderful thing about Sydney’s group was that we all tried different things, you know, whatever we wanted to do we had a go with, because we all worked long hours and whatever our day job was on the worm, we could do other things as well. So anyway, I tried out this, and I got some nice patterns. I saw that there were a small number of neurons that had dopamine in them. Didn’t know what they did at that point. We can talk about, that’s another story. But as far as the lineage was concerned, I just wished to know which cells these were in the thousand or so cells of the worm. So I started using, borrowing these microscopes when other people weren’t using them to have a look and see where the cells were. And bit by bit I found myself looking at these cells, and then I also noticed by chance that some of these neurons were only produced after the worm had hatched out of the egg. Now, it happened, there was a mistake in the review literature – not in the original primary literature about the worm, but in the review literature – people had said, oh, the nervous system doesn’t develop after the worm hatches from the egg. So we thought, huh, that’s strange, you know, surely they should have known this. But anyway, as a result I started to look and to see where these cells came from after hatching. And so bit by bit I found myself watching cell divisions. And bit by bit I looked more and more, and then finally, eventually sort of worked backwards into the egg, where it was the most difficult because the cells were very tiny and all looked the same. Along with other people, particularly Bob Horvitz, Einhard Schierenberg from Germany, and Judith Kimble, who looked at the gonad, we put together the entire cell lineage of the nematode. I think the thing I was particularly cited for then was sort of leading on this in the sense of writing the first paper that showed that one could follow cell lineages using Nomarski optics, and also observing for the first time programmed cell death. I came across this phenomenon, I was watching a cell and all of a sudden it would go very sort of glistening, highly refractive object, and then just disappear. And it turned out I was actually viewing a programmed cell death. And it was easy to watch, because the whole death process would only take about half an hour from beginning to end. Knowing the position of these deaths, knowing which cells were going to die, because the program of the cell lineage of the worm is almost invariant, it meant that one could then start looking for mutants and the genes therefore that controlled this process of death. And this turned out in the end to be very important.

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: http://genome.wellcome.ac.uk/doc_WTD021047.html 9/2/09 - AC Written by: Georgina Ferry John Sulston-Biography