The Nobel Prize in Physiology or Medicine 2007
Mario R. Capecchi, Sir Martin J. Evans, Oliver Smithies
I was born on the first day of January 1941 in the front bedroom of my grandparents' house in Rodborough near Stroud in Gloucestershire where my mother had come to escape the bombing in London. "A fine strapping lad" was the news my grandfather received as Dr Mold came to the top of the stairs. Later my father's factory was bombed out and evacuated from East London to Hertford where they continued to manufacture military transport vehicles. My parents found a tiny rural cottage to live in near Wareside. It was here that I have my first memories. We had mains water but nothing else. I remember the grand acquisition of a paraffin stove for easier cooking and also after the war helping my father to install some 12 volt battery operated lights and a generator. The switches were from motor vehicles and the wires were ex army telephone cable. In the few hours he was not at work my father ran the local communication signals for the Home Guard. Starting with nothing eventually they had their own telephone network covering Hertfordshire and run from our living room. I remember a slit trench in front of the house as an emergency shelter and seeing the local fields being tilled by prisoners of war. It was here that I remember what I have described as my first experiment - covert mixing of sand cement and water because I couldn't understand how adding water could make it become solid. It didn't work (as any good experimental first attempt!) because I added too much water; but it is a vivid memory.
After the war we moved to live in Raynes Park and it was there that, on what should have been my first day at school, I suffered a burst appendix and had it not been for the first antimicrobial drugs (M&B 693) would not have survived. I remember vividly seeing the low winter sun, red through the darkened glass of the ambulance, and hearing its shrill bell. I was awakened by a beautiful nurse with a sip of juice – of elixir! Maybe that's why I have since always loved nurses.
I contracted mumps in hospital and thereafter throughout the next 18 months suffered most available childhood infections. I hardly got to school and spent long periods in bed with various books and toys including meccano. When I was seven we moved to Orpington and in my new school I was kept in for extra lessons to learn "joined-up" writing instead of playing football. I still think that my poor handwriting and lack of soccer skills date from that period.
When I try to think back to my favourite toys, books and activities I do see now that perhaps I did naturally become a scientist. I made pressed flower collections at about the age of eight, later I learned about wild orchids and became adept at finding all the species in Kent. I loved old science books – e.g. "Moving things for Lively Youngsters". I was bought a job – lot of very early wireless construction materials from a house sale including a crystal and catswhisker and beautifully-made hexagonal, plug-in, air filled coils bearing the inscription "What are the Wild Waves saying?"; my father and I were able to make a working crystal set from these. We had an old model steam engine "Puffing Billy" and I still remember the smell of the methylated spirit burner. One Christmas I was fortunate enough to be given the electric experimental set for which I had yearned and in which the main item was an induction coil to generate high voltage shocks for all. I build a tesla coil and other static electric gadgets. I kept aquaria. My father had a mechanical workshop and trained me in operating the metalwork lathe. I used it to make cannons and first of all filled them with matchheads for powder. Then one of my greatest amateur passions began with a chemistry set of the sort which is nowadays (on account of Health and Safety!) unobtainable and I slowly learnt quite a bit of basic chemistry. It was possible to buy supplementary chemicals from helpful chemist shops and I even had a can of metallic sodium. The weak cannon filling matcheads were replaced by a variety of improved explosives and I spent a long time trying to perfect a rocket – most of my attempts failed to lift off and several underwent spectacular explosive failures! I was, however, careful with these explosive mixtures but probably my most dangerous experiment was when I attempted to make a large batch of urea formaldehyde resin in the fireplace of my bedroom; the reaction suddenly took off and overheated, nearly suffocating me. In this and other aspects – when only 10 or 12 I was able to spend all day alone miles from home collecting fresh water fish and specimens, with no-one worrying – my personal explorations seem to have been remarkably fostered and unfettered compared with today's children who are often constrained by our safety-conscious society. I was a boy who dreamt long and hard and could spend all day wondering how to join two cans to make a cylinder.
By the time, therefore, in the middle school of St Dunstan's College we started Chemistry and Physics lessons I was ready, I was keen. I even remember the sudden shock of hearing some of the technical words I had only up to that time read being actually pronounced.
In the prep school I had been taught biology by the Reverend Toller, a wonderful man who used his classes to give us foundation in plant and animal science and cosmology. I still remember the start of one term of lessons when he said "Go out tonight and look up at the stars – look carefully they are not all the same colour". In the middle school we didn't do Biology before the sixth form but in my year we had the opportunity to start by dropping Maths after the O level exam in the fourth year. Although my main subjects were Chemistry and Physics I chose to do Biology probably just because it had been denied. This meant that because I had dropped the Maths the only choice I had for advanced level in the sixth form was Chemistry with Botany and Zoology.
I won a major scholarship to Christ's college in Cambridge. The Cambridge Natural Science Tripos has the great advantage of allowing breadth and choice. I embarked on Zoology, Botany and Chemistry with the clear intention of following specialisation in Chemistry. After the first term, however, I found that the Zoology course which was a dry systematics was not for me, whereas the Botany in which plant physiology and function illuminated the adaptive radiation and speciation lit my fire. I took a drastic change in my planned courses, dropped Zoology started Biochemistry and doubled the Botany. Chemistry, my erstwhile love, was becoming less of an option for although my Maths and Physics could just manage to mid degree level I was probably going to struggle too much at Part 2. Biochemistry part 2 was the option I had never anticipated but suited me perfectly. In the days I was there it was taught magnificently at the highest level. Enzyme function was taught by the world expert Malcolm Dixon, by then seemingly a quiet, mumbling old man. (Younger then than I am now!) One day I arrived late for the 9am lecture and had to sit in the front row. I heard what he was saying fully for the first time and he was giving us the most exquisite analysis of a paper published that week in Nature! Ever after I made sure of a front seat! Molecular Genetics was just starting, Sanger had sequenced Insulin, the principles of protein synthesis were being established and the genetic triplet code was being solved. Jacob and Monod won the Nobel Prize and Monod gave an illuminating series of lectures which together with a seminar series organised by Sidney Brenner in his College rooms in Kings, inspired me in the new concepts of control of genetic readout through messenger RNAs.
Sadly, I was never able to sit my final exams for which I had been working so avidly as I succumbed to Glandular Fever. This effectively scuppered my chances of acquiring the postgraduate position and grant I wanted and so I took a post as a research assistant with Dr Elizabeth Deuchar at University College in London – a most fortunate choice. She was an excellent supervisor who encouraged but didn't direct, a policy I have myself followed in supervising graduate students. For some it works most excellently and I am justly proud of many of my students. It was just what I needed. It did result in my taking a long time to complete the PhD and in a lot of non realised innovation. I experimented, I developed techniques, I learnt skills – viewed coldly I probably wasted a lot of time but I was not under the pressure that so many are today.
My ambition was to isolate developmentally controlled m-RNA but at that time none of the cloning tools or probes upon which we now rely were available. All I could look at were double reciprocally labelled (14C and 3H) profiles of polyribosomes and messenger RNA from dissected blastula and gastrula ectoderm by Sucrose Density Gradient centrifugation and RNA by agarose electrophoresis. In modern terms I was looking at animal cap development in culture before induction and after commitment to either a neural or an epidermal ectoderm.
At that time I saw two impediments to further progress: the difficulty of getting enough material for biochemical analysis, and the lack of any foreseeable genetics. In discussion with Robin Weiss and Ann Burgess I cast around for a more tractable system and Robin suggested looking at mouse teratocarcinomas. In 1966 Leroy Stevens and Barry Pierce both published reviews of their formative studies. Stevens had developed a strain of mice with a high incidence of spontaneous testicular teratomas (129 Sv) and demonstrated that the tumours depended upon "Pluripotent embryonic cells (that) appear to give rise to both rapidly differentiating cells and others which, like themselves, remain undifferentiated." Pierce had, importantly, demonstrated the clonality of these multiply differentiating tumours. Stevens generously sent me stocks of mice and tumours and Robin, who was at that time setting the foundations of his pivotal studies on retroviral tumour viruses, together with Pavel Veseley, who was visiting from Prague, taught me tissue culture.
When I was in Cambridge I had met Judith and we were now married with two small boys. I am blessed with a wonderful, interesting, intelligent, independent and supportive wife. By then I had become an assistant lecturer and was teaching an intensive course in molecular developmental biology. I have always found during my academic career that investment in home and family life together with the imperatives of teaching provide the necessary counterbalance to the inevitable slow progress of research. One is doing a good job, at the University, at home and can therefore take the extensive rough with the occasional smooth of research.
The science progressed towards every goal and is related elsewhere. Memorable highlights include my trips to Oxford visiting Richard Gardner to make chimaeras. On one occasion I remember our workshop had rigged up an old black wax-oven with a huge battery connected by curly red wires as a temperature-controlled transport vessel and I carried this object, which had all the appearance of a cartoon bomb, home on the crowded tube – with no notice taken, or complaints, by fellow passengers. This was at the height of bomb attacks by the IRA!
When I was approaching the salary bar from lecturer to senior lecturer at UCL I was wondering about my future and I applied for a post at the Genetics department in Cambridge. I remember at the interview under extensive cross examination by the whole department that I told them that I would be aiming to use mouse teratocarcinoma stem cells as a vector to mouse genetics. I don't think they believed that it would become possible. After many months and when I had virtually forgotten about my application I received a phone call assuming I would take the job, which (after a little hesitation) I did. I later learnt that I was not their first choice - I don't know who got away! Cambridge was a difficult move for me but eventually good. It was a good time to move my children. The boys had not yet started secondary school and we were very worried by the available schools where we lived in London. Clare was just four and therefore needed to start primary. Judith had been working in family planning in London but there were virtually no positions available in Cambridge so when the opportunity came she moved into general practice nursing. This was a newly developing field and over the years she was instrumental in helping to set up local groups and training. It was a very proud moment for us all when she was awarded an MBE for services to practice nursing.
It was at Cambridge that I met Matt Kaufman who provided the vital trick of using delayed blastocysts for our isolation of ES cells. This was a very productive collaboration of the best sort where we were able to combine our complementary approaches and expertise and I was later sorry to see him go when he left to take the prestigious chair of Anatomy in Edinburgh.
I had an excellent laboratory including Robin Lovell-Badge, David Latchman, Liz Robertson and Allan Bradley among others. Later, when they had all left, I remember a colleague saying, "... you'll never be able to rebuild it now ...". It was a challenge, but slowly and in particular with Bill Colledge and Mark Carlton we started to be able to use the genetic promise of the ES cells. Because we mutated, trapped and targeted somewhat eclectically we were drawn into a number of fascinating fields of biology and medicine. I am glad to have seen our work with cystic fibrosis and breast cancer moving from mouse models to potential therapeutic application but I do feel that the major contributions are in fundamental understanding of biology.
I have always been interested – indeed waylaid – by the leading edges of technology even during my PhD years when I pioneered (but did not publish) agarose gel electrophoresis for RNA fractionation. Also, much later, I was instrumental in showing that Green Fluorescent Protein and RNAi could be made to work in mammalian cells.
I have spent a long time with personal computers starting with the Olivetti programmer 101 which was a programmable calculator with (as far as I remember) a memory of eight numbers in an acoustic delay loop and the ability to store its programme on a magnetic card. I was able to program this to replace the use of the University's IBM mainframe to normalise dual label results with only two separate entries of the data compared with preparation of a suite of punched cards. I later progressed through machine language programming to the use of Basic on a Hewlett-Packard calculator - an amazing advance. Hooked, I used an Apple II with an attached CP/M card as a word processor and later was responsible for Cambridge University using the Torch box addition to the BBC microcomputer as the standard word processing system. This came about from a fairly drunken presentation where on the basis of an order for just two units I persuaded the manufacturers to give the University a main dealer discount! I subsequently became enamoured with (and wasted a lot of time on) UNIX on the desktop.
When I took ES cells to Oliver Smithies he introduced me to PCR and his own amazing thermal cycling system. I needed to source the Taq Polymerase and make my own thermal cycler. It was then that I made acquaintance with Dr Peter Dean who has since become a lifelong friend. He was just in the process of setting up his own molecular biologicals supply company and I was able to find him a source of Taq Polymerase and together in discussion we invented a much neater thermal cycler which, by using a low heat capacity block was able to be heated rapidly by a quartz halogen lamp and cooled by a fan. We established a company and went into manufacture and it was, for some years, the best thermally performing machine on the market. This was an adventure into commerce. I was also a co-founder of a biotechnology company with much larger aspirations (Animal Biotechnology Cambridge Ltd) and here learnt a lot about business management.
At a time when funding was at a very low ebb I was visited by Michael Morgan of the Wellcome Trust and in conversation asked him how, if ever, will we be able to retain the best postdocs in the UK? Would it be possible to set up an institute of developmental biology? To my amazement he just said, "Send the Welcome Trust an outline proposal". Brigid Hogan and I had discussed the need for an institute of mammalian developmental biology and so together with her we put together a proposal. Although I didn't know it at the time and Michael was quite unable through confidentiality to tell me there was a potential institute in discussion and the one component missing was mammalian. Brigid in London kept getting rumours that John Gurdon was planning something and eventually these rumours became so insistent that, although it appeared that there was nothing whatsoever happening in Cambridge, I phoned him. There was a long pause and John then said – "you'd better come to talk with me". It transpired that he together with Ron Laskey had prepared a proposal which, when we cautiously swapped them, proved to be closely comparable to ours. This was the start of the Welcome/ CRC Institute for Cancer and Developmental Biology which became such a success and which was such a joy to be part of.
In 1999, I moved from leading a personal research group in a scientifically buzzing Institute to heading a large and newly formulated School of Biosciences in Cardiff University. This was a huge change of role but one which I found I was rather better prepared for than I might have anticipated. All my experience both in Cambridge Departmental and University committees as well as my wrangles with commercial management had prepared me well. I was also pleased to be able to help facilitate scientific careers on a wider scale than hithertofore and to help lead and develop a newly re-energised Welsh University into the 21st century. It was hard but extremely rewarding.
A Lasker Prize, Knighthood and now the Nobel Prize brings recognition and quiet, unexpected satisfaction. I have always been a bit outside the mainstream and I have been outspoken and opinionated with a wide interest in science but I'm still at heart that small thoughtful enquiring boy.
From Les Prix Nobel. The Nobel Prizes 2007, Editor Karl Grandin, [Nobel Foundation], Stockholm, 2008
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 2007
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