Second Part
0:09:07 Went to Trinity, Oxford in 1963 and was the only biologist in the College; I enjoyed myself and did no work whatsoever for two years because in those days there was no examination in the first two years; I was advised to take prelims before I went up and I passed; I acted and put the future out of my mind; however, I was fortunate in the third year to be part of a pioneering new course in zoology which was instituted by a man called John Pringle; think that that did change me; Pringle's view was that biology could be unified round the idea of information; information theory was one of the keys for everything we learnt; it was a radical change from a descriptive zoology to a much more analytical, reductionist, but at the same time a view of the animal world which was synthetic; we were taught by a glittering constellation of people; I was taught neuroscience by Pringle, animal behaviour by Nico Tinbergen, ecology by Charles Elton, developmental biology by John Gurdon; can't imagine a more privileged beginning; other teachers included Pusey who taught us about bones, Palin who taught us about fish, who were equally good; I was very stirred by Tinbergen and Gurdon; Tinbergen was inspirational because he provided a way of thinking about animal behaviour and about biological subjects in general; what Pringle said was that you don't understand a mouse until you can make one; Tinbergen emphasised that you wouldn't understand animal behaviour without understanding the underlying mechanisms; he would not hear of any distinction between neuroscience and ethology which was grounded in an understanding of how the nervous system works; you need to understand the mechanism and how it develops, how it evolved, what it is adapted to do; illustrated this with examples of his own work on gulls; John Gurdon was so clear as a lecturer brought order to something that was very difficult to get a grasp of; the idea of the emergence of order from simple beginnings; I did not want to do the sort of embryology that he did but I could see that logically if one wanted to understand how animals develop then one needed to pursue this sort of work; that led me when I came to think about doing a Ph.D. to follow the logic that I want to become a developmental biologist, I want to understand the patterns generated in developing organisms, so I had better go and study amphibian embryos; I had become quite an expert on fish and did very well in my exams; the external examiner approached me afterwards and asked what I was going to do; said I was going to do V.S.O. and organize fishermen's cooperatives in Burundi; he asked whether I was really interested in fish having deduced that I was not; said that if ever I wanted to do a Ph.D. I might consider doing it with him; I was struck by that as he was an amphibian embryologist called David Newth who worked in Glasgow; I was looking forward to going to Burundi but my father had had a recurrence of TB just before I took my finals; he went to a sanatorium in Sussex to recover; I had to take a test for TB for V.S.O. which I did at that sanatorium, and as a tiny hint was detected I was not allowed to go to Africa; I was supposed to take pills for six months which were so ghastly that I didn't take them; returned to the sanatorium for further tests to be told there was nothing there and that it was likely that there had been nothing in the first place; as a result I went to work with Newth in Glasgow but decided that I hated it; at that time had an important girlfriend in London and had the opportunity to become a journalist on 'Animals Magazine'; became assistant editor, living in a flat in Goodge Street, having a wonderful time; however felt pretty uneasy about what I was doing; remember sitting in my flat and reading something about the nervous system and its development; thought then that I wanted to study the development of behaviour; think it very important that when you decide to do research you really feel you must do it; I'd been reading a book by Martin Wells, 'You, Me and the Animal World'; knew that Wells was in Cambridge and I wrote to him asking if it would be possible to do a Ph.D. looking at the development of behaviour in some organism; this was a turning point for me; he was on sabbatical at the time but my letter was forwarded to him in America; he took the trouble to write an extended letter back to me saying that what I wanted to do was feasible and interesting; suggested I went to the Department of Zoology to see whether somebody would take me on to do a Ph.D.
15:20:23 Thought Cambridge rather grey, quantitive and frightening, whereas Oxford was colourful and less serious; felt rather in awe when I came to Cambridge to be interviewed by the Professor of Zoology, Torkel Weis-Fogh, Danish, and a very interesting man, who suggested that I might like to work with him on locust flight; there was another man at the interview, John Treherne, who suggested I work on how a caterpillar becomes a moth, which has completely different behaviour; this excited me so decided to work with him; in October 1968 I came to Cambridge and started work on the way in which a caterpillar becomes a moth; got stuck instantly at the intervening stage, the pupa, which I found intensely interesting in its own right; it turned out that pupae far from being dormant organisms are actually intensely alive and have to defend themselves; the privet hawk moth that I looked at have a little defensive reflex called the gin-trap response in which they flex their abdomens in response to a tickle in a way that traps the creature in a pit between adjacent segments; I got very interested in this reflex; in the course of this I met Peter Lawrence who had just come back from America to work in the MRC at LMB; he had developed a very interesting set of ideas about how the insect segment is patterned; in fact there was a whole school founded by Wigglesworth to do with insect physiology and development; Wigglesworth had developed work on the segments to study the formation of patterns; Peter Lawrence had been Wigglesworth's student and had developed that notion that there was a gradient of positional information that extended from the anterior to the posterior of the segment and that cells could assess their position in this gradient and then decide what to do; this was very much in tune with ideas of Lewis Wolpert who was also influential at that time; it struck me that what I was studying in the segment was the little bit that would provoke a reflex when tickled and that there was something special about these cells which caused them to wire themselves in a particular way in the nervous system; I discussed these ideas with Peter and we developed a model for gradients in the segments specifying differences, not only between cells on the surface but differences between cells that would be then be reflected in their connections within the central nervous system; I was so fortunate in my Ph.D. because Treherne made everything fun, he was a fabulous person; he left me alone to get on with my work; when I had written my thesis he admitted he didn't understand it but that it was clearly good; what I was doing was in a great tradition started by Sperry who worked from the 1930's, and had developed the idea that connections were formed between nerve cells because they could recognise differences between each other in a systematic fashion; he worked on cells of the retina which he thought were distinguished from each other by a gradient, and that cells at one position on the gradient would connect with a particular bit of the brain called the tectum and with particular cells in the tectum that were identified by their position in the gradient; he did experiments that showed that the theory must be right in principle; my experiments with the gin-trap reflex are of that kind; experiments that were done after the fact so the connections had formed so tried to understand how they had formed; this worked out very well for me; I met Adrian Horridge who had started a lab in Australia which was very interested in the idea of differences between nerve cells and how connections were made between them; having met Horridge I applied to do a post doc with him; I went to Australia wanting to pursue my work with the gin trap; this led to a very unsatisfactory couple of years; I found myself at a loose end and thought it was my fault but in retrospect think the whole field was confused and depressed because we didn't know what to do next; I could not work with the gin trap because I couldn't bring experimental animals into Australia as they were reckoned to be a pest; I became quite famous for advertising for equivalent caterpillars in 'Sydney Morning Herald'; I offered 10c for every one and was deluged with caterpillars; I had a number of really good colleagues at A.N.U. in Horridge's group and we used to discuss endlessly what we should be doing; Ian Meinertzhagen and I were talking one day and he suggested that I go back to the beginning and look at the cells that make the nervous system; nobody had done that since Wheeler in the 1890's; thought this a fabulous idea; there were grasshoppers in culture in this laboratory; got myself some embryos, transparent creatures and beautiful; I rediscovered what Wheeler had shown that there were these very big cells which were repeated in segmental patterns and generated the segmentally organized nervous system of the insects; these were called neuroblasts; I mapped these cells and showed how they divided; at the same time I asked a very simple question - how do the very first nerve cells know where to put their axons?; Wigglesworth had shown that nerve cells love to grow their axons along the processes of other nerve cells; given the choice an axon will grow along another axon, but if they all follow each other who did it first; simply by studying the embryos I could show that there were cells out in the periphery, ones that would be the sensory cells of the animal in the future, which in pairs were putting nerves into the central nervous system; these nerves grew in a regular way which indicated that they were following cues and laying down the very first pathway; at the same time I made a map of the neuroblasts and showed where these so-called pioneer neurons came from and what their axons did and proposed a model for the way the foundations of the nervous system were being laid; I published the pioneer neuron material in 'Nature' and the neuroblast material in our house journal, 'The Journal of Embryology and experimental Morphology'; this work with the very beginnings of the nervous system was fairly revolutionary; it introduced the notion that if one really wanted to understand how the nervous system develops then you better go back to the beginning and see what actually happens rather than looking at it after the event and trying to work out what the rules are
33:19:24 Horridge, was rather like Treherne, didn't understand what I was doing, although he did understand the paper in 'Nature'; I wanted to do experiments for which I needed a laser and needed to learn about embryos; the obvious place to go was Germany where the great insect embryologists were; there was a laser in Freiburg where I applied; I left Australia, which I have regretted ever since because I loved it; went to Germany in 1976 where, with apologies to my German colleagues, I found myself in winter, in a very conservative institute; although I had done German at school I didn't really speak a word of it, so I was pretty unhappy; the experiments didn't work, but in the following year I encountered a woman called Janni Nüsslein-Volhard; she was brilliant, smoked and whistled endlessly, and persuaded us in this Freiburg lab that the way forward was genetics which was the key to understanding things in biology; she had dedicated herself to a project which was to take Drosophila (fruit fly) and to use it to make a genetic analysis of the mechanisms that are involved in forming patterns; I had come from a lab that was deeply neuro-scientific and gone to a lab that was deeply embryological and very classical, then I encountered this woman with her revolutionary notion; she got funding to pursue this project in the European Molecular Biology labs in Heidelberg; the essence of the project was that if there are mechanisms which operate in animals then they must be encoded in the genome; if we want to discover the nature of these mechanisms, and whether they exist, we must make mutations; if the mechanisms are there they are encoded in the genome and it will be possible to disrupt them with mutations; if we cannot, they don't exist, but if we can we will reveal the nature of these mechanisms by discovering and mapping the genes that encode them; many people said she was mad; her notion was that she could find all the mechanisms necessary to make a pattern by looking for embryos that couldn't make patterns; she claimed that they would fail to make patterns in discrete steps; it would not be that everything would be a mess but it would be an interpretable mess; she went out with huge dedication with colleagues to create mutations in Drosophila quite systematically until she had a collection of mutations affecting the formation of patterns in embryos; she would go on creating such mutations until she achieved saturation which was when she started to get the same mutations again and again; this was in the era when molecular biology was just beginning and genetics was the key; within a few years molecular biology would allow you to go from the genes to the proteins that the genes encoded; indeed, she discovered a great slew of genes that were required for making patterns for which she got the Nobel Prize in 1997; the genes she discovered were as relevant to humans as to fruit flies; the effect of all this was to make me learn genetics and to become serious about trying to understand how genes make brains; understood, in principle, that development was about translating genetic information into neural networks and behaviour; question was how does one go about doing that; first thing that I did was to suggest we followed Janni's line and work on fruit flies; that was the moment I abandoned grasshoppers and I became more of a developmental geneticist than I had been
42:28:11 Another influential thing for me was that I gave a seminar in Berkeley on my work on the grasshopper and met Corey Goodman; he liked what I was doing and my use of insect embryos; we collaborated and continue to be good friends; as far as I am concerned, the success of this project depended on the excellence of the work that Corey did based on what I had done; he took the field forward by leaps and bounds; together we spawned a large industry; one of the most awful things that has happened to our particular little branch of science in recent times is the fact that he went off to work for a biotech company and stopped working in science; I work on how genes make brains; the essence of the project is to understand how genetic information is used to build the neural networks that underlie behaviour; when I was in Germany I was invited to apply for a job in Cambridge and came here in 1980; after Freiburg I was recruited by Friedrich Bonhoeffer who was a Max Planck director in Tübingen in 1978; I was allowed to do what I liked; I was then offered a job in Cambridge, a lectureship in Zoology, at the same time and turned it down; then realized I did not want to stay in Germany for the rest of my life; I changed my mind on the understanding that it could be postponed for two years during which I would come and give lectures; from 1980 I came full time; that was when Gabriel Horn was Professor
47:05:11 Started badly as I arrived late, my letter having gone astray; Gabriel Horn was furious; he may have thought I was a bit of a waste of space at the beginning but was always very supportive, particularly after the first couple of years; his stewardship of the Department of Zoology was amazing; fantastic at proselytizing for zoology although he was not really a zoologist at that time; had known Gabriel when in Cambridge before when John Treherne had swapped me with Gabriel on the understanding that Gabriel's post doc would teach me to how make a certain sort of electrode and I would teach Gabriel how to dissect grasshopper brains, or something; he was extraordinarily nice to me then; we had a neurophysiology discussion group in Zoology when I was a Ph.D. student where I met Pat Bateson and Gabriel; got to know Pat better and we did have a small seminar here in King's; to begin with I had no college affiliation but came to King's in 1992; to begin with I had a slightly bruising encounter as I was asked whether I would be interested in a Fellowship; to begin with I knew nothing about the supervision system or anything and said I wanted more information; at that point I was told they were no longer interested in me; in 1992 Chris Gilligan encouraged to come when Gabby Dover left; don't think I realized how you are cut off from a whole part of life without a college affiliation in Cambridge; I have enjoyed being at King's; discovery of an intense feeling of belonging and loyalty which came slightly later; there have been irritating experiences as well; I used to supervise the first year biologists in a cells course which I enjoyed; since I became a professor, the understanding that professors don't teach has stopped me supervising for King's; this is not something I relish and am glad the situation has now changed; look forward to doing more teaching for King's; I am a good lecturer and enjoy doing it
53:33:20 I never married; I bitterly regret not having children; I could have probably married a very dear girlfriend in Australia; I have a partner who is delightful, but had I married years ago I would probably have had children and life would be very different; on other people, Sydney Brenner was extremely influential when I was a Ph.D. student; he used to give wonderful lectures on zoology; rather like Sidney Pask, he would come into a crowded lecture theatre and ask what he should talk about; suspect that he talked about what he wanted to talk about but it was enthralling; I still am swept away by him when he talks; do remember him talking about the nematode project, explaining why he was doing what he was doing; remember Peter Lawrence asking him what the point was; Sidney said they were going to solve the nervous system; immediately felt the rug being pulled from under my feet; actually, just for once, I think he is wrong; I don't think they did, though it may have been a fruitful project
57:30:02 On Cambridge, it is a wonderful place for me to work; I think partly because I know it so well, things are possible, I don't have to think what to do in order to do X; vital to have had stimulating colleagues, but the key events for me have had more to do with people from outside; in 1983 Corey Goodman came to visit me here; I had just discovered a way of doing something we did routinely with grasshopper embryos, to dissect them, lay them out flat on a piece of glass and put them under a microscope; we could do the same with drosophila embryos; I showed it to Corey and he became hugely excited; we then went home and Corey had no outlet for the surging emotion; he needed to eat instead and shoved toast into my toaster in a frenzy until he broke it; I feel that this was a moment of high drama where emotion really manifested itself in a scientific enterprise; on the scientific enterprise - when I was doing work as a Ph.D. student I was doing things for the sake of doing them; I then went to Australia and met Ian Meinertzhagen and were talking about my work on the gin trap; he said it was interesting but not exactly main stream; that was not an idea I had come across before; that became more apparent as life went on and is now the dominant thing; people do what everybody else does and you can only get money to do certain things; that has two corollaries; one is that I found competitiveness amongst scientific colleagues focuses on the science; for me, that has never been the case; I value the friendship of people I work with not the science that they do; that seems to be against the grain; the other corollary is the question of being allowed to do what you want to do; this again I first perceived in Australia because I realized that my life as a scientist was a wasting asset, that it was expensive and an incredible privilege to do these things; like an artist craves a studio and materials, a scientist you need a laboratory; if those are taken away how difficult life would be; that has always remained with me; I don't care about being paid to do something, what I do care about is being given the opportunity to do it; retirement is an interesting thought; I cannot leave the microscope; in retirement, if it is possible to continue, that is good and I can't think of anything better; not sure of that attitude is the same with everybody; finally, films are things that are important to me; I love cinema; in Australia I was offered a job as film critic for the Australian Broadcasting Commission; I had a weekly programme when I broadcast to Canberra about films and got free tickets to go to drive ins to see films like 'Last Tango in Paris' and comment on them; the film that made me realize this was something important was 'The Seventh Seal', shortly after which I saw 'Last Year at Marienbad' and I have never recovered