The Nobel Prize in Physiology or Medicine 2002
Sydney Brenner, H. Robert Horvitz, John E. Sulston
On my mother's side I come from Midlands engineers and on my father's from tenant farmers near Oxford. As far back as I remember, and earlier, I was an artisan, a maker and doer. Mechanically minded, my parents said.
Ted, my father, was an Anglican priest; after serving as an army chaplain in the second world war he joined the missionary society SPG (later USPG) and spent his life as an administrator, though he was active in the local parish at weekends. He had a great interest in the natural world, and was a keen gardener. When young I was mainly interested in the physical world, especially anything to do with electricity, but I think something of his love for living things may have rubbed off on me. He brought me up as a Christian, and it was a source of distress to him that I lost my faith, as they say, during my adolescence. That was a hard struggle, one of the hardest I've had. When I tried to talk to my fellow students about it at Cambridge I found them uncomprehending, not seeing it as very important in the scheme of things: but I had had to choose between my judgement and my father. It was a slight worry to me that our children were raised faithless - not prohibited, just not encouraged - in case the religious upbringing was essential to their moral development. Great relief that they've got on fine! Daphne said don't be silly, and of course she was right.
Muriel, my mother, was my main confidant. She was a teacher of English at Watford grammar school, but took a break while my sister Madeleine and I were children. She held court in the kitchen, and we talked about everything. Questions, help with homework. She was more subtle than my father, and it was only after her death that I opened a letter from her and realised that she too desperately wanted me to have continued in the Christian faith.
From them both I gained a sense that there is not, or need not be, any clear distinction between work and play, and that one has a duty both to serve others and to do the best one can in everything.
They believed in private education, and at five I was sent to the local preparatory school. It was just round the corner. The classroom work was easy enough and I got on well with that, but I absolutely loathed games at which I was hopeless. Whether it was eyesight, reflexes or just daydreaming I don't know, but it just didn't turn out well. Cricket was the worst because it went on so long, on beautiful summer afternoons when there were so many better things to do. Once we had catching practice and the ball hit me in the forehead because I was thinking about something else to pass the time. It knocked me over and there was some concern about safety - rather embarrassing for my teacher.
From there I got a scholarship to Merchant Taylors at Northwood, which was a financial relief for my parents, who were not particularly well off. I could have gone to a grammar school like Madeleine, but I'm ashamed to say that there was the sense that the boy had to have the "best". One can't blame them too much - that was the tenor of the age. School gradually became more interesting because I was able to specialise in science. Games continued to be a nightmare for a while, but that gradually faded as I realised that one didn't have to take them seriously and began to discover the joy of hill walking on my own.
When it came to choice of subjects, science was obvious - since I was uninterested in anything else - but a decision that caused consternation in some eyes was my demand to take biology for A-level. I was told that this was not sensible at all and would lower my chances, upon which what had initially been more or less a whim on my part hardened into determination. So biology, physics and chemistry it was, with maths abandoned. Not sensible at all, but I had tremendous fun dissecting animals and sectioning plants and wondering about their workings. This was the late 50's, and the molecular biology revolution was getting under way with reports from the front starting to trickle back to us. And we had great support: my enthusiastic zoology teacher, Richard Stokes, wrote to me regularly until his death last year.
In 1960 I arrived in Cambridge, with a scholarship to read Natural Sciences at Pembroke College. The first year was easy because those of us with scholarships had a head start, but the second year was a grind. I wasn't enjoying my course work much, because biology wasn't fulfilling its promise, and anyway I'm not a books person but a hands person, but mainly because by then I had become distracted by other activities, especially theatre lighting at the ADC. Meredith Dewey, my tutor, warned me that those who went into the theatre seldom did well at anything else, but of course that was of no great concern to me. I also became fairly depressed at my lack of social graces and everything seemed pretty pointless. It culminated in a night of drunken disorder that ended in the police station, and poor Meredith was hauled out to retrieve me. Covered in shame, I felt nobody would ever speak to me again. Of course my misdemeanour was hardly noticed, but it did have the effect of motivating me to make some sort of effort in my final year. I plumped for organic chemistry, reasoning that at least I could get a job with it, found it interesting because of my sparky supervisor Ian Fleming, and ended up with a 2.1, though without tremendous enthusiasm.
My only attempt at job-seeking had been an application to VSO, and I was actually expecting to join a scheme that summer. However it fell through at the last moment, and so with my 2.1 in hand I went along to see Alexander Todd at the chemistry department in Lensfield Road, on the off chance of being taken on as a research student. To my amazement I was taken on immediately and handed over to Colin Reese, who put me to work on his research into oligonucleotide synthesis.
And that was the beginning of my scientific career, if you can call it that. No more text books, just my own lab books, and the toys, the lovely toys, to play with. I was put in a large lab, sharing a long bench with Mike Tanner, swarthy and amiable. Life was simple, revolving largely around the lab and the Panton Arms where Iris Ambrose dispensed beer, egg on toast with beans (or sometimes as a variant beans on toast with egg), sympathy, and cashed our cheques.
That first year my lodging was in a bedsit on the other side of town. For the second year I arranged with another research student Henry Chan to share a flat. We advertised for a third, and a geophysicist Bob Grasty replied. Most Tuesdays we shared a meal, to which Bob brought two women from his group - Monica Dirac and Daphne Bate. We were all very cheerful together, and when the year ended we seemed to disperse.
But that autumn we went to London for Bob's wedding to his long standing girl friend Jenny. I sat behind Daphne, and she turned and smiled at me. I asked her if she wanted a lift home, and we haven't really been apart since. And Mike, Henry and Bob are our lifelong friends.
Meanwhile, thanks to Colin's efficient organisation and my love of playing with the toys, my labwork was trundling along nicely, and already it was time to be writing up and moving on. Colin suggested that I should take a post-doc position with Leslie Orgel at the Salk Institute, and Daphne agreed to get married. And so we whooshed away to California, where Daphne intended to get a job too but then found she was pregnant. So Ingrid was born there, and though at first we feared destitution it turned out to be idyllic. The lab was a great place, and we spent holidays travelling around the western states; shores, deserts, forests and mountains - an earthly utopia.
With Leslie's prebiotic chemistry I felt I was beginning to get back towards biology. It was through the discussions there that I really grasped the power of evolution for the first time. And Leslie spoiled me terribly, frequently inviting us to dinner when he had visitors, and making me feel pretty important. I fear that I became rather obnoxious as a result. In my second year there Leslie introduced me to Francis Crick, who interviewed me on behalf of Sydney Brenner. All I really knew at the time was that Sydney had picked a small animal to study neurobiology. There were lots of jokes about Sydney's worm, and general scepticism about its chances of coming to anything. This seemed a pretty good recommendation to me: there's little point in doing what everybody else is doing. In fact, Leslie suggested that I could just go away for a year and then apply for a junior fellowship at the Salk Institute. The buzz word was neurobiology, and the place was full of meetings and discussion about this next step in molecular biology. One of the events was a summer programme run by Steve Kuffler and Ed Furshpan from Harvard Medical School, and I was invited to join in. They put me on to studying the formaldehyde-induced- fluorescence of catecholamines, a method for revealing these neurotransmitters in sections of frozen tissue. Although I was not deeply involved in their objectives, learning this technique was to make a difference in my life. In the spring of 1969 the three of us took our last holiday, swinging around Mexico and then departed on an extended break, travelling overland to the east coast via Florida and Canada. After the open spaces of America, southern England felt pretty cramped, but in no time we were settled again in Cambridge, I joined Sydney's group, and Adrian was born.
The group was housed in the Cell Biology Division of the Medical Research Council's Laboratory of Molecular Biology in Cambridge, where so many of the basic mechanisms of molecular biology had been worked out: a rather awe-inspiring place to arrive as a junior staff member. Space was at a premium, as it is in any successful institute, and I ended up in the "big lab". Hugh Robertson, Sidney Altman and Mary Osborn were all there. Next door was Mike Wilcox working on Anabaena, later switching to Drosophila. Our families became great friends, and we often shared weekend trips as the children grew up. His death from cancer in 1992 was a great loss.
My first years there were devoted to exploring all manner of things to do with the worm: it was a largely virgin field, and so one didn't have to know much in advance. I worked on neurotransmitters, and, because of my background, I spent some time on the DNA using the global methods of hybridisation that were all we had available at the time.
But as a side project I tried out the FIF method, and got it to work on the tiny cells of the worm. The neurons I discovered have not proved especially important in themselves, but they led me to start looking at the cellular anatomy as a whole. And so, quite by chance, I was the one who began to watch the cell divisions unfold. For a decade I became essentially a pure zoologist, and with several colleagues worked out the entire cell lineage of the animal. My key colleagues at this time were Bob Horvitz and John White, and after Bob returned to the US for a tenure track post at MIT I felt distinctly bereft. But there was Judith Kimble as my first post-doc, and Marty Chalfie with Sydney, and Jonathan Hodgkin as Sydney's research student, so we continued as a vigorous little group. It suited me very well not to be in charge, so that I was free to go on playing. The LMB gave me a junior staff position, for which I am immensely grateful. To set up a formal research programme would have been impossible for me then.
The last and most difficult stage of the cell lineage to be completed, that of the embryo, was an important accomplishment for me. It quickly secured my election to the Royal Society, proposed by Sydney, and is now a factor in bringing me to Stockholm. Later, better methods of observation were devised, which to some extent are superseding direct observation. Of course one has to begin somehow, and that beginning then stimulates the development of new approaches, so that what had been difficult becomes routine. I was lucky to have the chance to start it off.
Another feature of the community that was instigated by Bob Edgar was the series of international worm meetings. The first was at Woods Hole in 1977, then it moved to Cold Spring Harbor, then to Madison. The meetings played a vital role in holding together and nurturing the growing C. elegans community, and for me they were particularly important when I moved on in 1982 to map and eventually sequence the worm's DNA. This was no longer to be a solitary endeavour for me. It began with new partnerships - Alan Coulson and Bob Waterston - and continued with an increasingly large group.
The worm genome work was funded throughout by the Medical Research Council, but in 1992 the Wellcome Trust accepted a proposal for tackling the human genome and under Michael Morgan's management built a new laboratory, the Sanger Centre, to house worm, human and other projects. From then until I stepped down in 2000 I found myself to my astonishment being an actual director. Thanks to a close knit group of colleagues (Alan Coulson, Jane Rogers, Richard Durbin, David Bentley, Bart Barrell and Murray Cairns) we succeeded in our aims, and it all seems to have worked out well enough, but it was a strange time.
The human sequence is being brought to completion this year through the international consortium of the human genome project. More than half the effort is in the US; the central management is there - initially under Jim Watson, then under Francis Collins from1992 - as are other leading figures including Bob Waterston, Eric Lander, Maynard Olson and Phil Green. Outside the US are several groups, including Jean Weissenbach in France, and others in Germany, Japan and China. Michael Morgan is a key organiser of the international aspects.
It all took a lot of work, organisation, and of course money. Despite helping to set up the UK side of it, I didn't expect to be playing a visible role myself. But in 1999 we were drawn into defending our position against a vigorous bid, by Celera Genomics, to take over the project for profit, and it fell to me to be a major UK spokesman.
Having to deal with this extraordinary dispute, at what turned out to be a moderately unpleasant level of public acrimony, was quite a shock. It seemed to me self-evident that on both moral and practical grounds the human genome itself (as opposed to inventions that may be made from a knowledge of it) is an inappropriate subject for commercial investment and ownership. It was not just the commercial bid itself that shocked, what was worse was that it gained support from all sorts of people for whom I'd previously had respect. I still don't exactly know why, but part of the reason seems to be a business-style way in science nowadays of following bandwagons and avoiding controversy in case things turn out politically against you.
During these events, I thought all the time that I would return to my lab bench once we'd got the episode over with. It had never been my ambition to run a large enterprise, and the thought of returning to play with the toys buoyed me along. Well, get over it we did - Celera collapsed, and the human, mouse and other genomes are firmly in the public domain. It's immensely exciting to reflect that the plan has worked out, and that all these sequences are quietly providing a new and firm foundation for biological research. But I found myself impelled further away from practical science rather than returning.
First, I felt it important to write an account of what had happened. Other books had already been published, and more were to come, but all were written by journalists who drew on the press accounts, largely from the US where for no solid reason the balance of opinion had been in favour of the private effort. So I thought someone should provide an accurate record of events. Bob Waterston and I discussed writing something, but we were neither expert nor free enough to get it done in a reasonable time. So at Daphne's suggestion I got together with Georgina Ferry, a very accomplished science writer. I found it an enormously rewarding undertaking, and a wholly novel experience. Georgina drew on my email records, interviewed many people, and did the greater part of the actual writing, but I wrote some parts and we finished it off jointly, merging our ideas as we went (Sulston and Ferry, 2002).
The exercise had a great influence on me, because it forced me to examine some of the premises under which I had been working all my life. Like many scientists I had felt that my job was to get on with my work, and leave the world to be run by politicians who have the skills and experience to do it properly. Indeed while writing these words I've had a conversation with a colleague who argued exactly that. She feels that to stray from one's expertise is to become second rate.
However, it's become apparent to me that the problems that we encountered over the human genome are much more widespread than I had realised. The researchers at Oxfam, in particular, have educated me in the global consequences of ignoring common goods in the quest for short term profit. These issues are not simple, but I do think we would benefit from a greater and genuine involvement by us non-professionals in deciding the sort of world we want. Many people say: "Yes, I agree with you, but what can I do?". For me, it's been like climbing up from a valley and reaching a col: suddenly you can see new territories, stretching away into the distance, and you wonder.
At present, of course, I'm indeed second-rate in these matters - an amateur. But one should not be afraid of being an amateur if one is willing also to be a student. Has my head been turned by the Nobel prize? No, this happened to me two years ago. But getting the prize provides us all with a higher platform from which (if we don't fall off through excessive gesticulation) we can have more influence than we did before. So it changes our lives.
It remains for me to say thank you to my family for putting up with me, and for all the talking. Daphne retires this year from her duties as librarian at DAMTP. Through her I've had a lot of interaction with the staff there, and shall miss seeing them at parties. After taking her PhD at Berkeley Ingrid went into interactive museums. She lives in New York with her husband Paul Pavlidis, and son Micah. Adrian is in Edinburgh, and works in software. Madeleine worked for many years in the Gray Lab at Mount Vernon Hospital; now retired, she lives with her husband John Harvey near Lewes. We all met in Stockholm on 7 December, and had a marvellous week together.
Sulston, J. and Ferry, G. (2002) The Common Thread - a story of science, politics, ethics and the human genome. Bantam Press, February 2002; Joseph Henry Press, October 2002
From Les Prix Nobel. The Nobel Prizes 2002, Editor Tore Frängsmyr, [Nobel Foundation], Stockholm, 2003
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.
Copyright © The Nobel Foundation 2002
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