Disease Models & Mechanisms 2, 9-10 (2009) doi:10.1242/dmm.002014 A MODEL FOR LIFE

The birth of cloning: an interview with John Gurdon

Sir John Gurdon used nuclear transplantation and cloning to show that the nucleus of a differentiated somatic cell retains the totipotency necessary to form a whole organism. Here, he discusses model organisms, the future implications for his early work on medicine and his thoughts about scientific publishing.

ince our introduction to Dolly the tain frogs with mutations. Those were the sheep in the 1990s, it seems two main reasons for choosing Xenopus, somewhat logical that a whole or- and using it increased work efficiency ganism can be made from the enormously. nucleus of a mature somatic cell. SHowever, the idea defied dogma at the time When choosing a somatic cell nucleus for when John Gurdon, then a graduate experiments that would determine its student, first proved that an entire tadpole capacity for creating a whole new organ- could be made from combining a denucle- ism, you used a tadpole intestinal cell. ated embryonic cell with a somatic cell Was there a specific reason for thinking

DMM nucleus. From this discovery, cloning was that this cell nucleus would be totipotent born and he has extended his research to and work well in this experiment? the understanding of mRNA translation There was a good reason why I chose it. I and gene regulation. John Gurdon was started work with the tissue called endo- knighted in 1995 and has had an institute derm in the embryo. The endoderm frogs, eggs receiving transplanted nuclei named in his honour (the Gurdon Institute) happens to have very large cells, making it from a more mature cell type could not dif- for his unique contributions to science. convenient for this kind of work, and I kept ferentiate owing to the ‘specialised’ proper- finding that I could get normal development ties of the nucleus [King, T. J. and Briggs, When you designed your nuclear trans- of many tissues from these cells – even when R. (1955) Proc. Natl. Acad. Sci. USA 41, fer experiments, were there specific fea- the endoderm cells were close to being dif- 321-325]. After all, I was only a graduate tures that attracted you to the South ferentiated into gut epithelium. Having fol- student at the time and, as a graduate African clawed frog, Xenopus laevis, as a lowed that lineage, it made sense to go on to student, you shouldn’t contest the results of model organism? the intestinal epithelium, which is what the famous people in the field. There were un- There were indeed. The only previous work endoderm cells go on to form. It was a tissue derstandable reservations. of this kind had been done with an of choice because the convenience of large However, there was not too much risk in- American frog called Rana pipiens, which cells makes it easier to do the experiments curred in that particular bit of work as we Disease Models & Mechanisms has the disadvantage that it only lays eggs and, furthermore, the intestinal epithelium had the huge advantage of a genetic marker, for one or two months each year, usually in is a continuously dividing cell type and that’s which was not available in other species. March or April. You cannot obtain their more appropriate for these experiments This was important, because if you trans- eggs at other times of the year, whereas compared with cells which cease division al- plant a nucleus and get a normal animal out Xenopus will lay eggs whenever you inject together. For all these reasons, there was a of it, you really want to prove beyond doubt mammalian hormone into it, at any time of good rationale for choosing the intestinal that the animal has come from the trans- year. So, you have five to ten times more epithelium for this work. planted nucleus and not from the resident material with Xenopus than with other egg nucleus, which, occasionally, might not kinds of frogs. The availability of material is Your early cloning experiments made a have been removed. a good reason for choosing an animal. big splash and ignited some initial con- One further point is that the Rana frogs troversy. Do you feel like you had to take Do you think that cloning and our un- take about 4 years to reach sexual maturity, a calculated risk to achieve your eventual derstanding of stem cells will directly in- whereas the Xenopus frog reaches sexual success? fluence human health? maturity at between 6 and 12 months. With You’re right that the work was strongly crit- Yes, I think there are two ways in which it Xenopus, you can bring animals to sexual icised at an early stage. That was really might. One is that when you carry out a maturity quickly and it’s realistic to main- because it came to the opposite conclusion nuclear transfer experiment, moving the from that reached by Briggs and King who nucleus of a somatic cell into an egg, there first developed this methodology. is a remarkable re-programming effect. You Sir John Gurdon is Chairman of the Board of Directors at The Company of Biologists. Understandably people were critical. Briggs rather dramatically reset the pattern of gene (e-mail: [email protected]) and King reported that, in Rana pipiens expression of the somatic cell nucleus,

Disease Models & Mechanisms 9 A MODEL FOR LIFE Sir John Gurdon

changing it from the specialised type of the carried out through a route of understand- a good tearoom. The best example of this differentiated cell back into the stem cell ing nerve fibre growth in chick embryos – is the Medical Research Council Laboratory type of an embryo. So in effect, you are de- the work then focused on snake venom, fol- for Molecular Biology, Cambridge, riving stem cells from an adult cell and if lowed by rats and higher mammals. So, this England. It is uniquely famous, having pro- one thinks of that in mammalian terms then is a very good example of choosing the most duced some 15 Nobel Prize winners, you can take, for example, a skin cell (or any tractable system and then switching to the despite being quite a small institute. They other kind of adult cell) and create embry- one of most practical relevance after you’ve have a lovely room where people like to go onic cells from it. By applying Martin Evans’ more or less answered the outstand- for their coffee, tea or lunch and talk over famous embryonic stem (ES) cell method- ing questions or identified the important experiments quite extensively before they ology, these cells can then be expanded into molecules. actually plan or do them. So, to have a place a large number of cells and, subsequently, where people like to communicate is, in my directed to a cell type of choice. This is a po- The Wellcome Trust/Cancer Research view, a great asset and not as trivial as it tential route towards cell replacement. I UK Institute for Cell Biology in Cancer sounds. should emphasise that this procedure gives was renamed in your honour and is now you the same genetic type as the source of the Gurdon Institute. Are there any par- You are the Chairman of the Board for the donor cells. They call it person-specific ticular qualities that you, and the The Company of Biologists (COB). Why cell replacement. Institute, look for in young investigators do you choose to invest so heavily, in The second area where this technology when recruiting new faculty. terms of time and effort, in this scientific might influence human health is through We particularly like any new group to have publishing group and charity? the creation of disease models for testing, something in common, scientifically, with I am a keen supporter of COB because sci- which is very relevant to DMM. If you have other existing groups. For new group leader entists own the company. Scientists are the a diseased individual, you can derive prolif- positions, we purposely select people who directors of the company and they deter-

DMM erating cells from a diseased somatic tissue. have an obvious overlap of interest with at mine policy entirely. Because of this struc- This nuclear transfer ES route allows you to least one, and preferably more than one, of ture, it is a charity. The scientists who kindly create a large number of the groups in the give their time to managing the company, cells in culture, which [Nuclear transfer] Institute. What we do many of them highly distinguished re- can then be analysed to not do, is find that we searchers, give their time for free because determine what is technology can influence have nobody here they feel they are serving the community. wrong with them and models for disease and working with yeast or The profit from the journals that we publish possibly whether there perhaps provide a route fish or something else, goes back into science in the form of grants are any agents available and then attempt to fill a and awards. I would like to see this as an ul- that can alleviate the towards trying to alleviate gap. A biochemist might timate model for all scientific publishing. At problem. So, this tech- disease say ‘we don’t have anyone present, the big-journal-owning businesses, nology can influence working on lipid metab- of course, take a healthy profit. You could models for disease and perhaps provide a olism so we’ll choose a lipid biochemist next view this as a case where the scientists are route towards trying to alleviate disease. time round’. We do the opposite. the ones who do the experiments, submit Of course, we look at any very good can- their papers to the journal, referee the What do you believe the future impact of didates, but we are particularly attracted to papers and get the grants to do all of this – Disease Models & Mechanisms model organism research will be on med- ones that would connect with a couple of the scientists do everything – and the profit icine and patient care? other groups who are interested in a some- goes to someone who is not a scientist. My I think that there is a great future for model what related area. We purposely choose view is that it would make the best sense if organism research because it’s not always people with an interest in ongoing work in the major scientific journals were in fact easy or satisfactory to do everything with the Institute because, in most cases, work owned and run by scientists for the benefit human cells. Often, it’s better to choose the progresses particularly well when you have of the scientific community. That is what most tractable system to answer a question collaborations between people. the COB is doing. So many of us are keen to and then switch to humans. One might support it for that reason and, indeed, that work with mice or frogs or something else, Within the Institute, how do you facili- is how it came into existence in the first to find important processes or genes. Once tate collaboration rather than competi- place. you’ve found the genes or their products in tion? DMM greatly appreciates Sir John a model organism, it’s not so difficult to find We don’t really experience significant com- Gurdon’s time and willingness to share his the equivalent human ones. So, there’s a petition because it is not a very large insti- personal story about how cloning became great logic in working with whatever organ- tute. We have 15-16 groups and all of us possible and how this important technology ism or system is most tractable. I could realise that our viability depends on the might impact patient care in the future. We quote the famous case of Rita Levi- success of the Institute. People are not com- are pleased to present his story as a DMM Montelcini and Stanley Cohen who discov- peting against each other, but rather against Model for Life. ered the nerve growth factor (NGF), which the rest of the world to try and make a mark. Sir John Gurdon was interviewed by is of great importance. They received a However, there’s an additional comment Kristin Kain, Associate Reviews Editor for Nobel Prize for it. The work was actually that’s not as trivial as it sounds – you need DMM.

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