Second Part

0:09:07 As a result of Bob’s absences I had quite a lot of freedom to do the things that excited me; there were a lot of interesting people in the lab so it was a rich environment; Richard Gardner was there and was just developing his micro techniques for looking at early mouse lineages which became very important subsequently towards understanding mammalian development; the particular contact I had was with Matt Kaufman; he was working on parthenogenetic development in mice; this was the area that excited me; parthenogenesis in plain English is virgin birth; what you can do is take mouse oocyte and put them in culture without fertilization and trigger the onset of early development; one of the things you can do to initiate development is to dunk (culture) them in 7% alcohol for seven minutes and they start developing as if they were fertilized; if you transfer some of these embryos back into foster mothers they would develop up to nearly mid-gestation before dying; the question that became intriguing was why did they stop at this particular point; there are other vertebrates like fish and frogs which had been shown to be capable of development right through to term and it was intriguing why mammalian embryos couldn’t do that; the main difference is that mammalian embryos grow in utero so have to have the placenta to support their nutrition and development; this became my main passion at this point; there were many theories at the time and one of the ideas was that somehow the sperm not only contributed the genetic material but also non-genetic material, and that somehow this was important for development; we did some experiments which disproved this; there were other experiments taking place at the time and papers published which made the claim that parthenogenetic embryos could develop to term, but this was still a big puzzle; around 1979 I had finished my PhD and was still in the Department of Physiology with a grant from the MRC to continue; when the grant ended I was thinking of going off to the States or Canada; by then my family had moved to Canada; in the meantime there was a job advertised at the Babraham Institute, or more strictly an institute on Huntingdon Road, a research unit of the Agricultural Research Council; they immediately offered me the job so I decided to stay on in Cambridge

7:58:09 At this point there were conflicting papers on parthenogenesis and I decided to pursue the subject further; I started to get some indications around 1982-3 that there was something very unusual and interesting going on; basically the experiment that we did was using micro manipulation we were able to create eggs which either had two maternal genomes or two paternal genomes with the control of one of each; we started to compare them, and found that you did require a maternal and paternal genome for normal development through to term; if you made embryos with two female genomes or two male genomes they died sometime after implantation; what was really important about these experiments was that genetically we could create an embryo with two maternal genomes which had come from different eggs so they were as diverse genetically as making an embryo of one male and female genome; we realized that there were functional differences in the two parental genomes; bringing all the data together we found that the maternal genome seemed to be much more important for the development of the embryo whereas the paternal genome seemed more important for the development of the placenta; this was quite amazing as it was not something that people were aware of, that the parental origin of the genome made a difference to development; we called this phenomenon ‘imprinting’ because what it seemed to suggest was that the parental genomes carried some kind of imprint of the parental origin and that this provided the information that made them functionally distinct from each other; the difference was not a genetic one but it was epigenetic, not in the DNA sequence but something else; this was the start of the work of investigating this additional layer that was necessary for development to take place; around 1983 people in Cambridge were starting to hear about these strange experiments and I was invited to give a seminar in the Department of Genetics; I could see they were very sceptical, but I was convinced; I didn’t know what the mechanism was but I was convinced that the observations were correct

13:47:05 I think that pursuing it was a risk; it could be a complete dead end and there might be some trivial explanation, and it wasn’t considered that important anyway; I was doing some other projects on the side which were safer while continuing with this risky pursuit; when I was doing my PhD I was given a lot of freedom to think and do things that I wanted to do so I believed that it was fine to ask questions if they interested you; somehow I felt that this was very important, and particularly when I got this job I thought I could now take a risk; I think that students starting now in science have less opportunity to do this; when I was doing my PhD I was not required to write reports each year; I went in the first day, had a chat with my supervisor, and then was more or less free until I finished my thesis three years later; nowadays I think the students are over-supervised so they are constantly worrying whether they have enough results for their yearly reports; there is also the phenomenon of getting publications in specific journals; this was not the case when I was doing my PhD; we did the experiments and when we had enough results we published them, and did not worry about where it was published

17:30:22 I have been offered various jobs in other places but have always found that Cambridge is a very special environment and I have really felt at home here; it is certainly a very beautiful place; the history gives a sense that you are somewhere very special; it is a small town with a very high density of scientists so you can have casual conversations with people about ideas and can have an impact on how you think about things; these are things that you can’t really quantify; in terms of the facilities and resources, there are many labs in the States which are much better; that might be an advantage for us; because we have limited resources we have to do much more lateral thinking; I talk to my colleagues in the States about this; their style of working is different because they have a lot of resources and money; what they tend to do is to cover a large area of the field they are interested in and make the assessment of what is important retrospectively once they have all the results; we can’t do that here as we don’t have that kind of money or manpower, so we have to think very hard first about what we want to do; it is a different way of working but it is a style that I prefer; I sadly don’t do experiments myself now because the nature of biological research has changed quite dramatically; the tools are much more sophisticated so it is much more of a group exercise; if you are head of a lab you have to get a team of people with different expertise and work as a group; this is what I am doing now, so sadly I am much more an administrator; there are so many regulations now including Home Office regulations to do with animals, health and safety regulations, plus the fact that I have to report on all my students which Bob never had to do; I don’t think he had to write a single report, but now I have write a report and read their reports every year; I have about five or six PhD students; I also lecture; I always grumble when the time comes but have always found the experience very enjoyable; I now only teach final year students and have found them extremely bright and interesting; I also do supervisions; I do about ten lectures a year so my teaching load is not very heavy; what I find increasingly is that my students will contact me by email so there is quite a lot of informal exchange

24:59:15 I became a Fellow of King’s in 1994; it has been both enriching and enjoyable; I am slightly sad that I haven’t spent as much time actively at King’s as I would have liked; my research takes up quite a lot of time and I like to be close to the lab; I leave my door open so my students can come and talk to me, thus I am in my lab many hours a day; I also travel quite a bit to meetings; since 2000 I have been quite heavily involved trying to get a stem cell institute established in Cambridge; that has now been set up successfully; I am on the advisory board but there are other people in charge of it; a lot of the meetings I go to are in the States but I also go to Japan quite a bit; I have also been to India and Singapore; China is also beginning to emerge as a big player; they have large resources but haven’t quite found their direction yet; I have not been to Africa since 1973 when my father died; I would like to go back but have mixed feelings about it as it must have changed a lot; I have very happy memories of growing up there; if I don’t go back to Kenya I might go to another part of Africa; I am married and have two teenaged daughters; my wife trained as a speech therapist and worked for many years with children; when we had children she decided to stop working for a while, and then she decided she didn’t want to work with children any more

30:09:08 This is the twenty-fifth anniversary of the paper we published in ‘Nature’ in 1984 on imprinting; that has become much more important than even I had thought; there is now a whole field of epigenetics which has grown up and that phenomenon is central to it; the human genome has been sequenced and we know what the genetic code looks like, but it is important to figure out how this genetic code is then translated into various cells and tissues; although each cell contains the same genetic material the cells themselves are very different; this is where the research on epigenetics is important because this area of research is to do with understanding how different genes are selected for expression and repression to create the diversity of cell types; this is one of the major areas of research and it also has implications for stem cell research; if you are starting with an embryonic stem cell there is a potential to give rise to all the different types; we really have to know how these cell fate decisions are made which requires an understanding at the epigenetic level, how the cell deals with selecting the right set of genes to be turned on and off; it is also the area which can inform us about when you have a terminally differentiated cell, what are the mechanisms that can take it back to be more like an embryonic cell; these mechanisms operating in cells, especially in early stages where the decisions are being made in response to signals that come from outside and are then converted into this epigenetic form, are quite central to many areas of research now; there is also increasing awareness that some of the things that go wrong, for example when some cells become cancerous, also could be examined from the perspective of the epigenetic mechanisms that have gone wrong; instead of these cells behaving normally they have got locked into a particular state and are just continually proliferating rather than stopping and differentiating; I think that this may also have some value in trying to design various therapeutic agents to combat diseases; there are a large number of pharmaceutical companies that are exploring epigenetic mechanisms to understand what these key enzymes are that are involved in this kind of modification and trying to find agents which can stop these enzymes from malfunctioning; I am funded by the Wellcome Trust and about eight years ago some people from the Trust came to see me; they thought that some of the work that I was doing was important and could be useful in the context of some translational research; through their encouragement we set up a spinout company called CellCentric; the lab is now trying to understand the detailed mechanisms involved in epigenetics, and trying to find the key molecules and genes; the understanding we get from this basic research is then used by the company to see if some of the genes might also feature, particularly in cancers; the idea is that once we identify these genes then we can maybe look for therapeutic agents that interfere with their activity; if the work that we do is interesting we will publish it anyway so it will come into the public domain; I was reluctant to get into any kind of commercial things myself for quite a long time, but I certainly now think that it is very important to use discoveries if they are exploitable especially in trying to deal with nasty diseases; as a University spinout company I don’t own it although I have shares in it, and I don’t have day to day dealings with it and I am not a director; I sit on the board as an observer but don’t try to influence what they do, neither do they try to influence me; as far as the intellectual property is concerned it is very clear that it is owned by the University unless they didn’t want it; one of the criticisms that used to be made of the Wellcome Trust was that they were funding basic research for millions of pounds and what was the UK getting out of it; the Trust responded by going round to the people they funded to see if there was anything that could be spun off into a company

41:09:05 Of the big Cambridge figures, Sydney Brenner comes to mind as hugely inspiring with such originality; John Gurdon is another; also when I was working at Babraham I had interactions with both Aaron Klug and César Milstein; I remember very interesting discussions with César although our fields were diverse; Anne McLaren was another very close colleague and when she retired she came to Cambridge and her lab was next door to mine; she came to all our group meetings and we had really good discussions; leaving aside big names, what is very interesting is bumping into post docs and people just starting up new groups; some of my students are inspiring and come up with amazing observations and reflections; it is on many levels and the whole thing is very special; for young hopeful scientists, the key thing that they must sort out in their heads is what is it that excites them; the next question is why is it important; if they can sort that out then they are on their way