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From Nuclear Transfer to Nuclear Reprogramming: the Reversal of Cell Differentiation

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From Nuclear Transfer to Nuclear Reprogramming: the Reversal of Cell Differentiation ANRV288-CB22-01 ARI 28 September 2006 21:28 by b-on: Universidade de evora (UEvora) on 03/10/11. For personal use only. Annu. Rev. Cell Dev. Biol. 2006.22:1-22. Downloaded from www.annualreviews.org ANRV288-CB22-01 ARI 28 September 2006 21:28 From Nuclear Transfer to Nuclear Reprogramming: The Reversal of Cell Differentiation J.B. Gurdon Wellcome Trust/Cancer Research UK Institute, Cambridge CB2 1QN, United Kingdom; email: [email protected] Annu. Rev. Cell Dev. Biol. 2006. 22:1–22 Key Words First published online as a Review in nuclear transplantation, Xenopus, nuclear reprogramming, Advance on May 4, 2006 transcription The Annual Review of Cell and Developmental Biology is online at Abstract http://cellbio.annualreviews.org This is a personal historical account of events leading from the earli- This article’s doi: est success in vertebrate nuclear transfer to the current hope that nu- 10.1146/annurev.cellbio.22.090805.140144 clear reprogramming may facilitate cell replacement therapy. Early Copyright c 2006 by Annual Reviews. morphological evidence in Amphibia for the toti- or multipoten- All rights reserved tiality of some nuclei from differentiated cells first established the 1081-0706/06/1110-0001$20.00 principle of the conservation of the genome during cell differen- by b-on: Universidade de evora (UEvora) on 03/10/11. For personal use only. tiation. Molecular markers show that many somatic cell nuclei are Annu. Rev. Cell Dev. Biol. 2006.22:1-22. Downloaded from www.annualreviews.org reprogrammed to an embryonic pattern of gene expression soon af- ter nuclear transplantation to eggs. The germinal vesicles of oocytes in first meiotic prophase have a direct reprogramming activity on mammalian as well as amphibian nuclei and offer a route to iden- tify nuclear reprogramming molecules. Amphibian eggs and oocytes have a truly remarkable ability to transcribe genes as DNA or nuclei, to translate mRNA, and to modify or localize proteins injected into them. The development of nuclear transplant embryos depends on the ability of cells to interpret small concentration changes of signal factors in the community effect and in morphogen gradients. Many difficulties in a career can be overcome by analyzing in increasing depth the same fundamentally interesting and important problem. 1 ANRV288-CB22-01 ARI 28 September 2006 21:28 could have a place at Oxford so long as I did Contents not study the subjects in which I was exam- ined (Latin and Greek). I was allowed to study HOWNOTTOSTART............ 2 Zoology and was given an extra year in which NUCLEAR TRANSPLANTATION to make up for what I had not done at school. IN XENOPUS ................... 2 My parents were kind enough to pay for this, CLONING ......................... 4 in addition to the cost of the (private) school. OXFORD ZOOLOGY AND I had already acquired a great interest in CALTECH ...................... 6 the color patterns on the wings of butterflies TOWARD MECHANISMS OF and moths. How such intricate patterns are NUCLEAR formed developmentally with great precision REPROGRAMMING ........... 7 (Nijhout 1991), apparently by morphogen THE LABORATORY FOR gradient interpretation, is still a highly fasci- MOLECULAR BIOLOGY IN nating, unsolved problem (see below). In due CAMBRIDGE ................... 9 course, I applied to the Oxford Entomology CAMBRIDGE ZOOLOGY AND Department to do graduate work for a PhD. THE CANCER RESEARCH Fortunately, I was turned down, my student CAMPAIGN..................... 12 record being judged at that stage to be too THE WELLCOME weak. Later, I applied, and was fortunately TRUST/CANCER RESEARCH accepted, to do graduate work under the Em- CAMPAIGN INSTITUTE ...... 15 bryology lecturer at Oxford. This was Michail NUCLEAR REPROGRAMMING Fischberg, of Latvian descent, and a student AND THE PROSPECT OF of Hadorn, himself a student of Baltzer, who CELL REPLACEMENT ........ 16 studied under Spemann and Boveri (Buscaglia & Duboule 2002). Fischberg had done post- doctoral work in the Genetics Department in Edinburgh, headed by C.H. Waddington. At HOW NOT TO START that time, a very high proportion of all who Fortunately, the greater part of my career did were researching in the area of developmen- not follow logically from its exceptionally in- tal biology anywhere in Europe could trace auspicious beginning. At my school, students some part of their training back to the lineage were not taught biology until the age of 15. of Boveri in Germany. After just one semester of starting biology, my biology teacher reported at length on my ef- by b-on: Universidade de evora (UEvora) on 03/10/11. For personal use only. forts by saying, among other things, that “I NUCLEAR TRANSPLANTATION IN XENOPUS Annu. Rev. Cell Dev. Biol. 2006.22:1-22. Downloaded from www.annualreviews.org believe Gurdon has ideas about becoming a scientist; on his present showing this is quite Fischberg was an excellent choice of mentor. ridiculous; if he can’t learn simple biological Within a few months after I started work un- facts he would have no chance of doing the der him in 1956, he encouraged me to try work of a specialist, and it would be a sheer to achieve nuclear transplantation in Xeno- waste of time, both on his part and of those pus, following the first real success in trans- who would have to teach him.” At that post– planting living cell nuclei to eggs, reported World War time (1947), there were no text- in 1952 by Briggs & King. It is important to books; we were supposed to remember what appreciate that a major question in develop- the teacher said, but I have a bad memory. For mental biology at that time was whether the the rest of my school time I studied Latin and genome of cells undergoes any stable changes ancient Greek. At that time, the universities in the course of cell differentiation. The im- were short of applicants, and I was told that I portance of this question had been already 2 Gurdon ANRV288-CB22-01 ARI 28 September 2006 21:28 clear to Weissmann, who in 1892 had pro- extremely elastic jelly, not shared by other posed that as cells embark on a defined devel- amphibian eggs, might have completely pre- opmental pathway, they lose genes no longer vented success. needed to be expressed (Weismann 1892). By another piece of good luck, Fischberg Spemann (1928) made an early attempt to test was also supervising a graduate student work- this idea; his hair loop constriction of a sala- ing on ploidy, for which the number of nu- mander egg at the eight-cell stage demon- cleoli is a reliable guide (i.e., two nucleoli per strated that at least up to this stage, nuclei diploid nucleus). The anomalous results ob- are totipotent. But this did not at all exclude tained (one nucleolus in diploid cells) would the possibility that genetic changes could take normally be attributed to the inexperience of place subsequently when cells start to differ- a new student. Greatly to his credit, Fischberg entiate. Briggs & King’s (1952) experiment, traced the particular frog that produced these in which 30% of transplanted blastula nuclei inexplicable results and found that it always yielded apparently normal tadpoles, was the produced one-nucleolated diploid embryos first to provide a clear test of the genome (Elsdale et al. 1958). This phenomenon later equivalence in development. However, Briggs turned out to be due to a mutation that had & King (1957) subsequently found that at the deleted one complete set of ribosomal genes relatively early tail-bud stage, endoderm nu- (Brown & Gurdon 1964, Wallace & Birnstiel clei no longer supported normal development 1966), but at the time (1958), it was an in the way in which blastula nuclei could, lead- extremely useful genetic marker of nuclear ing to the conclusion that irreversible nuclear transplantation, enabling us to prove be- changes do in fact take place as cells begin to yond doubt that the original nuclear trans- differentiate. fer embryos obtained in Xenopus were from Michail Fischberg was well aware of the the implanted nucleus (Figure 1a) and not value of genetics in developmental biology, from a failed UV enucleation of the egg and when I joined him, he had just started chromosomes. using Xenopus as a laboratory animal, on the We soon obtained numerous fertile adult grounds that it could be grown to sexual ma- male and female frogs from transplanted en- turity within a year and that, as it is wholly doderm nuclei (Gurdon 1962a) (Figure 1b). aquatic, it is easy to keep in the laboratory. My Xenopus nuclear transfers, like those of Xenopus can deliver eggs throughout the year, Briggs & King (1957), showed that as cells dif- in contrast to the limited-season availability ferentiate, their nuclei become progressively of eggs from Rana and European newts, the less able to support normal development of organisms of choice for European embryolo- enucleated eggs. However, more important by b-on: Universidade de evora (UEvora) on 03/10/11. For personal use only. gists. The history of how a frog that naturally in my view was the result that even the fully Annu. Rev. Cell Dev. Biol. 2006.22:1-22. Downloaded from www.annualreviews.org occurs only in Africa has come to be one of the differentiated cells of the feeding tadpole in- half-dozen most used animals for research is testine contained nuclei capable of yielding bizarre (Gurdon & Hopwood 2000). fertile male and female adult frogs (Gurdon My first attempts to inject Xenopus eggs 1962b, Gurdon et al. 1958). I believed that the were frustrated by impenetrable jelly. By good derivation of entirely normal adult frogs was fortune, Michail Fischberg had just bought a more significant result than a large number a new UV microscope.
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