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Science and Philosophy: Bridging the Two Cultures Divide
doi:10.1016/S0022-2836(02)00340-6 available online at http://www.idealibrary.com on
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J. Mol. Biol. (2002) 319, 907–915
Science and Philosophy: Bridging the Two Cultures Divide Justine Burley1* and Alan Colman2 1
Department of Government, University of Manchester, Manchester M13 9PL, UK
2
PPL Therapeutics, Roslin, Edinburgh EH 25 9PP, UK
*Corresponding author
Introduction The first success in cloning by somatic nuclear transfer announced in 1997 (Wilmut et al. (1997) Nature 385 810– 813) brought sharply into relief different aspects of the so-called two cultures divide. In his Rede Lecture, titled “The Two Cultures and the Scientific Revolution”, C. P. Snow opined that: “The intellectual life of the whole of western society is increasingly being split into two polar groups…Literary intellectuals at the one pole—at the other scientists, and as the most representative, the physical scientists. Between the two a gulf of mutual incomprehension” (Snow, C.P. The Two Cultures and the Scientific Revolution, Cambridge: Canto Books, Cambridge University Press, 1993). Despite, possibly in spite of F. R. Leavis’s salvo of devastating (and mostly apt) criticism of Snow’s essay, the phrase “the two cultures” entered common parlance (Leavis, F. R. “Two Cultures? The Significance of Lord Snow” in Nor Shall My Sword: Discourses on Pluralism, Compassion and Social Hope, New York: Barnes and Noble, 1972). It has endured as a helpful shortform with which to describe an ever-widening chasm between science and the humanities in a technologically advancing world. One of the senses of Snow’s two cultures thesis—that there is a growing knowledge gap between practitioners of science and the humanities, and that it makes talking together difficult—captures the attitudes and behaviour of some of the early participants in the controversy that erupted following Nature’s report of Dolly’s birth. Applied philosophers rushed out to purchase The Beginner’s Guide to DNA and the one to genetics as well, and they telephoned scientist friends, if they were lucky enough to have any, for “clarification”. Their self-abnegation in the face of science would continue but a more confident air was detectable—now they were really needed. E-mail address of the corresponding author: [email protected]
Meetings they attended confirmed their long-held suspicion that scientists were mere technicians, lacking the skill of lateral thought, people who could not advance a non-scientific argument to save their own lives. Scientists, on the other hand, already familiar with the word “ethics”, proceeded to employ it with abandon. Ignorant of an impressive body of established philosophical literature, they appeared to take the view that ethics was simply a matter of opinion. This was a further degradation of the idea that philosophy in general was either obvious, obviously wrong, or devoid of import. But there were deeper problems at issue between scientists and philosophers at the outset of the cloning debate than just that of divergent knowledge bases leading to an inability to communicate across disciplines. These problems are contemporary instances of two additional senses that can be gleaned from Snow’s two cultures thesis. The first involves a factual mistake. Snow and others labour under the misapprehension that the critical tools of the sciences and the humanities are always fundamentally different. Although Snow laments the rift between science and the literary arts, he was really concerned to emphasise the superiority of science when he wrote of the anti-intellectual biases of his colleagues. The standards of argument in science were of a higher and different order, he said, seeming to miss the fact that the analytical approaches taken in both science and certain branches of the humanities are one and the same. Snow does not mention “philosophy”, though he ought to have. Friedrich Nietzsche makes our point here neatly: “Science is totally dependent upon philosophical opinions for all of its goals and methods, though it easily forgets this.” Metaphysics and epistemology are, after all, the essence of scientific enquiry. (Good moral philosophical argumentation is not, but it exhibits a standard of argument more closely approximating that of science, than is often accepted.) Why is it that science and philosophy should stand apart today in the light of an
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intellectual tradition that includes Aristotle, Copernicus, Galileo and Kant? The second additional sense of Snow’s two cultures, taken up by his nemesis Leavis, concerns the normative role of science. Snow’s plug for science was over-enthused: scientists are forwardlooking, the key to raising the level of material well-being, hence science is the true path to social progress. Therefore, for Snow, science was the arbiter of value. Leavis rightly objected. By no means anti-science, Leavis was at once fighting against the debasement of culture as a form of entertainment, and the view that science was a guide to what we should do. Roger Kimball summarises thus: “What he [Leavis] denies is that science is a moral resource—he denies, that is to say, that there is any such thing as a “culture” of science. Science tells us how best to do things we have already decided to do, not what we should do with them. Its province is the province of means not ends. That is its glory—and its limitation” (Kimball, R. “The Two Cultures” Today’ The New Criterion vol. 12, 6, February 1994). Leavis’s defence of culture is infused with appeal to moral philosophical ideas. Culture, for him, is inextricably linked to human conduct. Science, according to his criterion, is not a culture. (Contra Leavis, here, a case could be made on other criteria for science being a culture.) The really important component of Leavis’s attack on Snow is that any intelligent assessment of the moral challenges posed by science, requires what the relatively unscientific literary arts have to offer. Far from being a form of entertainment the literary arts served a higher purpose. This stress of Leavis’s bears on the debate over cloning. Many seem blind to the fact that both science and philosophy are necessary conditions of any complex appreciation of the world as it is. Many more still are blind to the place of philosophy in thinking about how we might wish to direct it to become. Leavis’s preoccupation was not philosophy per se, rather it was the philosophical content of the high arts; culture furnished a richer deliberative context for the big questions in life. Few questions are bigger than the one that the possibility of human cloning poses: What sort of people should there be? When assessing the debate over human cloning, we can, pace Leavis, legitimately complain that the contributions of philosophers are, by and large, deemed superfluous. It is clear enough that since 1997, philosophers have played second fiddle to the lawyers and scientists. This is partly explicable by the fact that the currency of bioethics has become much devalued; it is sufficient to self-describe as a bioethicist to qualify as one. The other main explanatory factor is that, in our society, culture or philosophical reflection, call it what you like, is regarded as a side-show, peripheral to the real business at hand. The important overarching lesson to be drawn from the Snow/Leavis exchange, for our purposes,
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is that practitioners of both science and the humanities do themselves and everyone else a disservice by maintaining distance. When either is practised in isolation from the other, avoidable problems are created and/or inevitable problems are needlessly exacerbated. Not to mention the fact that both appear rather intellectually naked. The debate over human cloning has been plagued by mutual incomprehension on the part of scientists and philosophers, as Snow might have predicted. He did not deem the knowledge gap between science and the literary arts, in itself, to be necessarily worrisome. The cloning debate, however, shows the importance of trying, even in small ways, to close it. Snow did think improved communication to be desirable. In 1963, he published a new essay called “The Two Cultures: A Second Look” in which he envisages the emergence of a “third culture”, namely one in which there was a meeting of minds between the scientific and the literary owing to a willingness on the part of both to talk and make sense to one another (published in Snow, C. P. The Two Cultures and the Scientific Revolution, Cambridge University Press, 1993). What in reality has occurred is that both have by-passed their rightful first port-ofcall, namely, each other, and instead have gone directly to the public. This has impeded not aided the making of good science policy. These preliminary remarks now made, we set out below to put across our personal perspectives on the science and ethics of cloning, respectively, with a view to fostering, in however modest terms, the “third culture”. Part one of this article charts the evolution of cloning from the time of an exciting scientific collaboration up to the point it was made into a cause cele`bre for a multitude of different interests. It also highlights the naivete´ of the approach of the participating scientists to the ethical dimension of their work. The second section outlines the course of the ethical debate over cloning, and suggests, in conclusion, a more integrated approach to the planning, implementation and presentation of those scientific developments lying in sensitive areas of public concern. Part One by Alan Colman The cloning of mammals involves substitution of the genetic material of the unfertilised egg with the nucleus of an embryonic or somatic cell, technique known as somatic nuclear transfer. I first observed somatic nuclear transfer at close quarters during my PhD. My supervisor, John Gurdon, was the first scientist to clone a vertebrate (a frog) from a specialised somatic cell. His was a seminal contribution to our basic understanding of the genetic basis of cell differentiation. At a time well before the advent of recombinant DNA technology, it was not clear whether cell specialisation was accompanied by selective gene loss or permanent inactivation. After all, wholesale chromosome loss was frequently observed in the somatic cells of
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several invertebrate species, e.g. ascaris. John’s demonstration in 1962 (J. Embryol. Exp. Morph. 10 622– 640) that somatic cell nuclei taken from swimming tadpoles could support the development of a transplanted egg up to a fertile adult stage, proved unequivocally that the donor nucleus had retained all those genes necessary for complete vertebrate development. Even today, this method, when applicable, remains the best way of questioning the integrity of the genetic material in a somatic cell. Judged against this scientific tour de force, the recent successes in mammalian cloning epitomised so memorably in the form of Dolly the sheep, pale in comparison. However, the creation of Dolly incorporated a new element—a manipulation that had failed with frogs—the successful use of the nucleus from an adult somatic cell to make an adult animal. More than anything else it was this demonstration that ensnared the popular imagination and provided a catalyst for a revival of concerns about the pace of scientific developments especially in the sensitive area of human reproduction. As it turned out, the birth of Dolly uncorked a maelstrom whose reverberations continue today. If anything, my sojourn in John’s laboratory between 1971 and 1974 did not prepare me well for the events of the mid-1990s, either scientifically or from the standpoint of ethics (I doubt now that I even thought once about the latter back then). In that former period, the cloning work was designed to finally dispel any doubts that differentiated frog cell nuclei, rather than those from “contaminating” stem cells, were responsible for any successful outcome. This perennial concern was to come back to haunt us post-Dolly. I took no part in any cloning work; my own speciality concerned the micromanipulation of eggs and embryos for other purposes. However, I was knowledgeable of the significance of the results as well as the various caveats associated with their interpretation. Subsequent events also made it impossible to escape from the realisation that animal cloning fired the imagination of many both inside and outside of science. In 1971, one of the other PhD students in the Gurdon laboratory was Derek Bromhall. John had “inherited” Derek due to the premature death of David Kirby, Derek’s supervisor. His PhD project was to clone rabbits. At that time, and even today, this was an extremely difficult project. Nevertheless, he achieved success in this challenging area, publishing a paper in the journal Nature [(1975) 258 719 – 722] about the creation via nuclear transfer of an early cleavage embryo. In this case the donor cell was a blastomere from a four-cell embryo. Compared to the achievements in frogs, Derek’s contributions were modest yet the capacity for mammalian cloning attempts to seize and engage the most lurid imaginations soon became evident to me because of two events. First was 1976 novel by Ira Levin entitled “The Boys from Brazil”. The story line here held that white blood
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cells taken from Hitler had been preserved in a frozen state after his death. Nuclei from thawed cells were then used to create 54 Hitler clones. Clearly the author had put some thought into whether clones would display similar personality traits to the original cell donor since the cloned babies were subjected to similar familial circumstances as those accompanying the young Hitler. I found the book to be only vaguely entertaining but I was impressed with the author’s scholarship in citing John Gurdon as the pioneer of the enabling technology. The second event was litigation on grounds of defamation brought by Derek Bromhall against an author, David Rorvik and his publisher, JP Lippincott. Rorvik had cited publications and personal communications from Derek in “In His Image” a book describing the allegedly successful attempts of a wealthy American to clone himself. The action was settled out of court with apologies and payment to Derek. Needless to say, the cloning claims were fictitious. My interest in cloning, which had always been vicarious, subsided after this mild titillation. I took little interest in the scandal that erupted over the claims by Illmensee & Hoppe in 1981 (Cell 23 9– 18) to have succeeded in cloning a live mouse using a cell from a 5-day embryo as nuclear donor. No one was able to reproduce these data and the scientific fraternity generally discounted them. Meantime I was developing my academic career, which was focussing on the use of frog oocytes and eggs as in vivo test tubes for checking out theories of protein secretion. In the early 1980s this preoccupation allowed me to make a little consultancy income on the side. In 1984 with the help of Ron James who was to subsequently head up the company, now known as PPL Therapeutics, I came up with the idea of trying to make protein therapeutic drugs in the eggs of transgenic chickens. As a prelude to starting a company, we felt that we needed to establish some intellectual property, as well as checking that the technology could work. One way or another we were able to persuade a London-based venture capital outfit, Prutec (who Ron worked for at the time) and the pharmaceutical section of a large British company, ICI, to provide finance for a research project to be performed between the University of Glasgow (leader, David Onions) and the Institute of Animal Genetics and Physiology Research (later to be renamed the Roslin Institute) under the leadership of Helen Sang. The project unfortunately did not succeed, however during the three year funding period, Ron and I were appraised of some exciting technology being developed in the Institute which involved the generation of transgenic sheep that expressed human therapeutic proteins in their milk. Using technology licensed from the Institute, an independent company called Caledonian Transgenics was set up in 1987. I became its part-time research director. In 1989, this company changed its name to Pharmaceutical Proteins Ltd (PPL).
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In the early 1990s, the creation of transgenic livestock was a laborious, inefficient and expensive process. The method involved the microinjection of DNA into the pronuclei of fertilised embryos, followed by the implantation of the embryos into foster mothers. Very few of the resultant live-born incorporated the injected genes and the technique would only allow the addition of genes; it would not allow the removal or modification of host genes. Amongst mammals, this latter manipulation could only be done in mice via the use of embryonic stem (ES) cells. Mouse ES cells can be used to populate all the adult tissues including germ cells. ES cells with similar properties do not exist in other mammals despite many attempts to derive them. We were anxious to improve our transgenic success rates and, more importantly, we wanted a method to manipulate host genes. By 1994, our headquarters were situated in the grounds of the Roslin Institute and no more than 200 m away. We had always had ongoing scientific collaborations with the Institute and we were allowed to use their library and canteen facilities. As a result of these ongoing relationships, we became aware of some exciting new scientific developments concerning the use of nuclear transfer in sheep. Apparently in 1994, under the direction of Ian Wilmut and Keith Campbell, a lamb had been born from an embryo reconstructed using a donor cell nucleus taken from a very early passage, unsynchronised cell culture prepared from nine-day old sheep embryos. This male lamb survived for about six months but then died (possibly from kidney failure). Although lambs had been cloned from blastomere nuclei in 1986, this new demonstration was very significant because a later developmental stage was used and the appearance of the cultured cells indicated that they had acquired certain somatic cell characteristics. If such cell cultures could be expanded without losing their totipotent capabilities, we realised that these cells could provide the solution to the technical drawbacks to our transgenic technology. To learn more about the technical details behind this new advance, PPL seconded Angelika Schneike in 1994 to work in the Roslin Institute with Jim McWhir. It soon became clear that the technology mentioned above was not robust and that the particular cell cultures used could not be expanded further without loss of their totipotent properties. In 1995, Keith Campbell introduced serum starvation of cells as a means to synchronise their cell cycles at the G0 stage (he also believed G0 would be a better starting point for the reprogramming needed for successful nuclear transfer) and pregnancies were established with much later cell passages. These pregnancies were to result in the births of Megan and Morag in the summer. This work, published later in Nature [Campbell et al. (1996) 380 64 –66] was generally overlooked by the world’s press despite describing the same methodology later to prove successful with Dolly.
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Meanwhile, in early 1995, PPL and the Roslin Institute agreed to collaborate in a programme of nuclear transfer experiments. Unfortunately commercial issues clouded the early negotiations. In exchange for its scientific and financial involvement, PPL wanted to secure commercial rights to use the nuclear transfer technology in certain areas. These so-called Fields of use included the proteins in milk area and xenotransplantation. The Roslin Institute were unwilling to cede rights in the xenotransplantation believing (rightly) that they could obtain a better deal with another organisation. The negotiations stalled and there was a danger that the experiments would have to be postponed for a year because the breeding seasonality of the Scottish Blackface sheep which provided oocytes and foster mothers for the experiments. I broke the deadlock by agreeing on behalf of PPL to finance the programme in the absence of any commercial agreement whatsoever. PPL needed to know as soon as possible whether this technology could truly deliver its transgenic promise. We agreed to fund sufficient work to test four new embryonic cultures that we had derived from cultures from our own, Poll Dorset sheep. Roslin also wanted to test some new lines although they would not reveal the cell type (they later were revealed to be fetal fibroblasts). We established a programme management group consisting of myself, Angelika and Alex Kind from PPL together with Ian Wilmut, Keith Campbell and Jim McWhir from Roslin. The work began in October 1995 and went quite well to begin with. Unfortunately, two of the PPL lines failed to grow well in culture and we found ourselves with a gap in our experimental programme. It was at this point that Angelika Schneike suggested again that we should use some adult mammary cells which we had obtained two years previously from a pregnant, six year-old Finn Dorset ewe. The ewe had been sacrificed and the cells taken for a collaboration we had with the Hannah Research Institute some eighty miles away. Angelika had first suggested the use of these cells, many aliquots of which had been stored in liquid nitrogen, for nuclear transfer at an internal PPL meeting in Oct 1994 citing two reasons: First, despite their extended culture the cells had retained the normal diploid karyotype, an essential prerequisite to success in livestock nuclear transfer. Second, PPL’s core business revolved around high levels of protein expression in the mammary gland. If these cells would work in nuclear transfer, the possibility arose that we could genetically engineer the mammary cells and assess the level of expression from the added genes prior to making an animal. The expectation was that we could remove some of the empiricism from the process and unerringly make high expression animals. In principle, whilst this all seemed logical, the existing nuclear transfer literature taught against the use of adult cell donors. This was appreciated
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by all members of the group, particularly those of us with long memories like Keith, Ian and myself. I recall sharing my biases with the group and predicting failure. Ian Wilmut was non-committal, possibly because he accepted that PPL was financing this part of the programme. Although Keith did not accept the party line that adult cells would not work, even he was not sure that this cell type would provide the breakthrough. Nevertheless, we went ahead. Dolly was born on July 5, 1996. We were very lucky. A total of 277 embryos had been implanted into four temporary recipient sheep and 29 embryos developed successfully to the blastocyst stage. These were replaced into seven surrogate mothers and one pregnancy established. Given the provenance of the cells no one expected the pregnancy to go to term. This expectation of failure muted any growing excitement. Dolly developed a fever soon after birth and PPL staff mounted a 24-hour watch to assist the overburdened Roslin farm staff. Our chief vet, Denise Cottom, in consultation with the Roslin vet, prescribed a course of antibiotic treatment. As soon as Dolly and the six other nuclear clones were born we celebrated our success at a Nepalese restaurant in Edinburgh where we began to plan our next steps. We recognised that it was essential that we proved that Dolly had come from the Finn Dorset mammary cell. Dolly certainly looked like a Finn Dorset and was clearly of a different breed from the oocyte provider and surrogate mother (both Scottish Blackface) ruling out any trivial explanation for her appearance. We decided to perform microsatellite DNA analysis on samples taken from the various animals and the original cellular materials used in the transplantation process. At the time, we believed that this would be enough unequivocally to demonstrate that animal clone and cell cultures were genetically identical. The microsatellite analysis performed by Angelika gave the expected results and we set about writing a paper. Although Ian Wilmut did most of the writing, we all contributed suggestions and changes during the drafting process. We also considered the ethical implications of the work, armed as we were with many examples of disproportionate media and public reactions to theoretical or fictitious cloning claims (see G. Kolata (1997) Clone, Allen Lane, The Penguin Press). Looking back, it is embarrassing to realise how naı¨ve and superficial our “analysis” was. Almost single-mindedly, we concentrated on the “cloning Hitler” type objections. We unanimously agreed publicly to condemn outright what came to be known as reproductive cloning without ever considering or even recognising some of the problems or less desirable outcomes of natural procreation. Perhaps the fact that five of the management group had generated families without recourse to assisted reproduction methods had insulated us from the problems of the infertile. We did not have any ethicists at our meetings although
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we did consult an external public relations company retained by PPL on how we should handle the release of the information. PPL decided to synchronise its press release with the expiry of a press embargo on the data, imposed by the journal Nature that had agreed to publish the paper. Unfortunately, there was a leak and the story got into a British Sunday newspaper four days before the Nature publication. Because of its obligations to immediately appraise the London Stock Exchange of any publicly released price sensitive information, PPL was forced to issue a press release on the following Monday morning. This ensured that the lead up to the expiry of the embargo was frenetic and confused. History will recall the deluge of newsprint and media comment that accompanied Dolly’s formal debut. [Wilmut et al. (1997) Nature 385 810 –813] From day one it was immediately evident that we had grossly underestimated the impact of the work on the public psyche. There were condemnatory cries, scientific praise, and amazement, in equal measure. Most concerns were directed at the possible extrapolation of these findings to humans and were intuitively formed and poorly thought out (see below). I confine my comments here to discussion of certain of the more substantive scientific criticisms. Criticisms were both of a general and specific nature. The work on Dolly was referred to as “anecdotal” because there was only one example of adult cell cloning-Dolly herself. There was, it was stated, an obligation on scientists to publish reproducible findings with the onus on the originating scientists, not those who follow, to supply evidence of reproducibility. Under normal circumstances I would agree with this. However, further delay (some critics felt we should have publicised the work as soon as Dolly was born) would have been accompanied by scientific leaks (academics are not good at keeping secrets) and accusations of unacceptable secrecy would have followed, compounding an already tarnished image of the way biological research is conducted. In addition, although Dolly was the only adult clone, six further somatic cell clones were mentioned in the paper and a repeated experiment would have taken a further 10 months at least due to seasonality in sheep breeding cycles. More worrying was the technical criticism that Dolly could have come from a rare fetal cell donor that had contaminated the mammary cell culture due to the fact that Dolly’s mother was pregnant at the time the cells were removed. This could have been immediately discounted had the fetus been male but we had no record of its sex. Although we had performed microsatellite DNA analysis, it was argued that this might not have had the resolution to rule out a fetal cell origin, particularly if the male parent was from the same (inbred) flock. To resolve this, I contacted Alex Jeffreys, the pioneer of DNA fingerprinting, and his lab agreed to perform the world’s first DNA
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fingerprinting on a sheep. The results published in Nature [Signer et al. (1998) 394 329– 330] were unequivocal. Our claims to the provenance of Dolly had been vindicated though of course we should have performed this type of test earlier. It is now over five years since Dolly was born and despite frequent claims about her demise, Dolly is alive, healthy and the mother of six offspring. In the time intervening, three other mammalian species have been cloned using adult somatic cells (cows, mice and pigs) and the number of cloned livestock is in the hundreds. We still do not know why livestock experiments which had been in progress since 1986, only succeeded in 1996. There was an initial insistence that only quiescent (G0) nuclei would work, however this does not seem to be the case and diploid, cycling cells (G1) also seem to work. The technique still remains very inefficient and generates high levels of pre- and post-natal mortality. Nevertheless some of the initial promises of the technology have been fulfilled: it has proved possible to make livestock with predetermined genetic changes [gene targeting—see McCreath et al. (2000) Nature 405 1066 – 1069]. It has proved possible to expand elite genetics in cows [Wells et al. (1999) Biol. Reprod. 60 996– 1005]. And, it has proved possible to rescue endangered species (the Mouflant to name one). However, many eyes are focused on the human arena. Whilst there is widespread agreement amongst scientists that reproductive cloning should not be attempted, a variation termed therapeutic cloning has attracted many advocates. With this technique, reconstructed embryos serve as a source of embryonic stem cells, which ultimately would be used to the medical benefit of the cell donor. Cloning opened the proverbial Pandora’s box to many ethical challenges for which scientists and society were woefully unprepared. Part Two by Justine Burley In November 2001, five and half years after the birth of Dolly, the first human embryos were cloned by somatic cell nuclear transfer (SCNT) to the four and six-cell stages respectively (Cibelli, J. B. et al., “Somatic Cell Nuclear Transfer in Humans: Pronuclear and Early Embryonic Development” J. Regen. Med. 2, 26 November 2001, 25 –31). Although the objective of this research effort was the derivation of autologous embryonic stem (ES) cells, inferences were immediately drawn from the data for the case of human reproductive cloning. Already an inefficient technique in non-human animal models (see above, see also Colman, A. (2001) “Somatic Cell Nuclear Transfer in Mammals: Progress and Applications”. Cloning 1 185 – 200) it would appear that creating viable embryos using SCNT is not straightforward. The concern that human reproductive cloning would involve huge wastage of oocytes, articulated back in 1997, seems to have been confirmed. Moreover
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to understand the root of the problems will require further research on human embryos. Whether and in what ways these two facts matter morally is, of course, open to debate. In 1997, in those countries where some embryo research is permitted few relished the thought of revisiting the questions of whether and under what circumstances it should be permitted. This reluctance was thought justified for reasons of expediency but the net result of it, was impoverished governmental policy, policy which scientists were instrumental in shaping, and which would, in some countries, back-fire when the relatively more important issue of embryonic stem cell research arose. This was particularly evident in the USA. The National Bioethics Advisory Commission (NBAC) chose to bypass the issue of embryo research in its hastily prepared report (Cloning Human Beings: Report and Recommendations of the National Bioethics Advisory Commission, Rockville, MD, June 1997: http:// bioethics.gov/pubs.html). Lack of discussion and the concomitant absence of guidelines for such research undermined the NBAC’s own pronouncement in favour of a continued moratorium on public funding for reproductive cloning-related research on the grounds of safety. On the basis of cloning experiments in non-human animal models scientists raised the prospect at every available opportunity, of human clones suffering severe abnormalities in the early and late fetal stages and also in infancy. How can the health risks to human clones be assessed and/or minimised without research in the area? Scientists informing the policy debate in the USA mentioned repeatedly the fact that the reproductive systems of mammalian species differ, sometimes greatly. This should have led them to call for research on human embryos to establish properly the risks of harm to human clones. Most did not (see, for example, Colman, A. “Why Human cloning should not be attempted” in Justine Burley ed. The Genetic Revolution and Human Rights Oxford: Oxford University Press, 1998, pp. 14 –18). A total ban on human cloning (i.e. in both the public and private sectors) might be indicated were research to show that even at the early stages of human fetal life embryos cloned by SCNT are consistently defective. The NBAC omitted any recommendations to address scientifically the problem of harm, in effect leaving it to the unregulated private sector, where human cloning still is not illegal (this may soon change depending on the fate of Bill H.R. 2505 in Senate, see below), to supply this information. The lack of focus on the moral permissibility of embryo research would also prove deeply problematic for the NBAC (as well as other bodies like the National Institutes of Health (NIH)) when it was charged with pronouncing on ES cell research. From the outset, most of the scientists opposed to human reproductive cloning sought to distinguish it from so-called therapeutic cloning, the latter being a possible source of ES cells which would
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have the advantage of being immuno-compatible with the patient. Not only has the wider public had difficulty keeping the two separate, so too have policy-makers, as evidenced by the recent Congressional debate over Bill H.R. 2505 (Human Cloning Prohibition Act 2001, House of Representatives—July 31, 2001: http://thomas.loc.gov/ cgi-bin/query/D?c107:1:./temp/~c107a953ZK::). Research on embryos in the public sector has been outlawed since 1996 in the USA. The failure of scientists and moral philosophers to tackle the issue from then on, in concert with one another, contributed to the current unsatisfactory situation in which urgently needed public funding for ES cell research is sorely constrained. (See President George W. Bush’s address on stem cell research, August 9, 2001: http://cnn.net/2001/ ALLPOLITICS/08/09/bush.transcript/index.html.) The remit of scientists who self-elected to be public spokespeople ought much earlier to have been educating the public about the importance of embryo research for a number of different purposes, and in this they should have had more assistance from moral philosophers. As noted, taking their cue from scientists, the NBAC justified its policy on human cloning by referencing the notion of harm to future children. Their well-intentioned message, however, without accompanying philosophical reflection has compromised emerging policy in a number of countries. The concentration on physical safety by scientists and the policy-makers they have informed, whilst appropriate, has been philosophically naı¨ve. As I have argued elsewhere, the appeal to harm made by scientists against human clones is exclusively framed in “vulgar” consequentialist terms. This philosophical approach looks at what outcomes can be reasonably predicted, and shapes policy accordingly. If the foreseen outcome is, on balance, a negative one, then the action is proscribed. A ban on human cloning is thought to be justified according to this line of thinking because it is likely that a clone would be physically abnormal. But, if the technique of SCNT ever is perfected someday, somewhere, do we not, on this kind of blunt consequentialist reasoning, find ourselves committed to recommending cloning over natural procreation? On balance, natural procreation would carry more risk for future children simply because the genetic make-up of any embryo so conceived would not be knowable to the same extent as would that of a cloned embryo. Moreover, and more importantly, what if all decision-making about human reproduction were made in this way? Should not people who possess dominant genes for serious disorders be banned from procreating owing to the high risk they have of transmitting that gene to their offspring? Should all prospective parents be obliged to undergo genetic testing? Should all embryos be tested prior to implantation, and only the “healthy” ones placed in utero? If the physiological welfare of future
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children is a sufficient reason to ban cloning, it should also be sufficient to support these draconian procreative policies as well (Colman, Alan and Burley, Justine (2001) “A Legal and Ethical Tightrope: Science, Ethics and Legislation of Stem Cell Research” EMBO Reports 2 2 –5). Timely consultation with philosophers might have alerted those advancing the harm objection to human cloning of the logical implications of their argument. It might also have been helpful had, what is called, the non-identity problem, been broached by opponents of human cloning (this is Derek Parfit’s name for it, see his Reasons and Persons Oxford: Clarendon Press, 1984). Again, as I have argued elsewhere, the harm objection to human cloning is stated in a fashion that implies that for clones non-existence is preferable to existence [Burley, J. & Harris, J. (April 1999) “Human Cloning and Child Welfare” J. Med. Ethics 25(2) 108– 113]. The problem with this is that when someone does not exist, doing or refraining from an action that prevents that someone from existing does not make that someone better off. If we do not clone, no particular child is better off because this child never existed. Likewise, if a child is brought into the world using SCNT and is physically impaired as a result, it is most unclear that, on balance, this child has been harmed by the action of cloning. This particular child would not have existed had he or she not been cloned in the first place. The NBAC thought about this problem but decided that it should be left to the obscure deliberations of philosophers (and presumably scientists share this attitude). However, in the light of the fact that the proverbial Pandora’s Box that was opened in 1997 relates to the question of what kind of people should come to exist, it would seem necessary to address properly the non-identity problem. It is not posed solely by human cloning, many reproductive cases can be envisaged where the usual person-affecting notion of harm does not capture the core difficulty. A possible solution to the non-identity problem has been proposed by Ron Green. He argues that we should avoid before-after comparisons when thinking about birth outcomes, because never having existed is not a state to which one can ascribe anything negative to (The Human Embryo Research Debates Oxford: Oxford University Press, 2001, pp. 126 –129). Instead, we should concentrate on the reasonable expectations of the child and/or parents. In this way we can protect the interests of children who have been harmed through others’ negligence. If, for example, a child is born with a physical defect due to the failure of its parents to take precautions that they could easily have, he or she can reasonably claim to have been harmed. However, the duty of parents to ensure that their offspring have roughly the same prospects as other children around them, does not apply independently of other considerations. The right of parents to be free to choose to have a
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biologically-related child will also be relevant. Moral choices involve competing rights and claims, Green reminds us, so it will not always clearly be wrong to bring a child into existence knowing that it will be damaged in the process. With regard to cloning, Green’s stance is therefore permissive in those cases where a child could not have been conceived in any other way. Green’s proposed alternative to the non-identity problem, I think, begs the question of whether it is reasonable to attempt to have a child by whatever means (i.e. natural or artificial) when the risk of harm to it is substantial. I fail to see how the desire for a biologically-related child trumps our moral concern for the physical well-being of a child whenever that level drops below a certain threshold (cf. Burley & Harris). Thus whilst Green is on the right track, further refinements of the position are required. The scope of this piece does not permit in depth analysis of the problem. The preceding discussion does, however, serve to demonstrate why the sledge-hammer safety objection to human cloning is deficient, and therefore why it might have been of benefit to the policymaking process had scientists and philosophers put their heads together earlier. One of the main reasons that scientists have been sceptical about what philosophers have to offer is the fact that amongst themselves philosophers often do not agree on what should be done. But this does not necessarily lead to an impasse. Moral philosophy as a whole involves two broad kinds of inquiry. The first concerns the status of moral values themselves: are they objective or subjective, and in what sense of either might they be so? This sort of inquiry, otherwise known as meta-ethics, is all about the locus of authority of moral values. The second type of moral philosophical inquiry concerns conduct at the levels of the individual or society. The question: What do we owe to one another? is its chief preoccupation. Political philosophy is a sub-branch of this kind of moral philosophy, that part of the discipline devoted to discussion of the appropriate relationship between the state and the individual and/or groups of individuals. It asks, amongst other things, about the legitimate bounds of state intervention in individuals’ lives. In the debate over human reproductive cloning, whenever advocates of a particular religion make their case by appeal, for example, to some higher authority, e.g. the teachings of the Bible, they are engaging in meta-ethical argumentation. The values championed are held to be true, objective in the sense that God is the ultimate moral arbiter. It is plain that when people disagree at this level of moral inquiry, there is no way, short of simply insisting on one’s own view, to convince others of it. Discussion ends where it began. This is why the inclusion of people who in essence are members of religious lobby groups, in the policymaking arena, in the capacity of “expert” bioethicists, is misguided. They may be very know-
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ledgeable about, e.g., Christian ethics, but their mission will always be to assert the rightness of their own meta-ethical view, from which it will be impossible to shift them. They demand not tolerance but respect for their position. However, not all moral philosophy, indeed very little applied philosophy, relies on meta-ethical arguments. Bioethics, for the most part, circumvents entirely metaphysical questions and focuses instead on supplying independent arguments (perhaps consequentialist in style, perhaps deontological, perhaps both) for why we should or should not, for example, clone humans or engage in research involving embryos for research purposes. Although there often is disagreement between philosophers at this level of moral inquiry, it is possible nevertheless to assess the relative strengths of the different positions taken. Moral deliberations of this ilk, in short, are amenable to reason in multicultural societies. It really is crucial to be aware of which approach is being taken in any argument about the morality of a given scientific advance. Understanding the way in which we arrive at an ethical view bears directly on the questions of whether and how differences between views can be accommodated in a pluralistic society. This is where political philosophy comes in. At the heart of the debate over both human reproductive and therapeutic cloning are many competing views about when a human life should be accorded moral status, and also about the wider question of what sort of people should come to exist. In a pluralistic society policy must be derived by reference to the reigning public political culture as well as to citizen’s shared principles and conceptions of practical reason. In the cases of human cloning and embryo research, the first step towards an acceptable policy is to identify the diversity of moral doctrines touching on these areas that are held by citizens. These should then be reflected in relation to shared values and laws in conceptually related areas, the purposes of the research, whom it might benefit, whether and how much the suffering of people who might be helped by the research matters to us, and so on. What should emerge, after such reasoning, is a policy that can be accepted in a pluralistic society by reasonable individuals. The requirement of reasonableness demands that we understand that on subjects where people have divergent, deep-seated moral convictions, a policy may never fully reflect all the respective particularities of citizen’s moral doctrines, but it will fit sufficiently with their commonly held values to stand as legitimate public policy. The moral principles at stake in cloning and embryo research, are not, in fact, novel ones. A careful look reveals that they underpin a good many cultural norms and laws that people not only accept but believe to be the cornerstone of any liberal democracy. The secular liberalism of
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our society makes diversity possible, and it is the only approach to resolving differences of opinion on cloning and research on embryos that we can all agree on, if we think hard about it, that is.
Conclusion In closing we quote F. R. Leavis: “The advance of science and technology means a human future of change so rapid and of such kinds, of tests and challenges so unprecedented, of decisions and
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possible non-decisions so momentous and insidious in their consequences, that mankind—this is surely clear—will need to be in full intelligent possession of its full humanity…” We contend that “full” in both of Leavis’s phrases, in the context of the debate over human cloning, is a prescription for a greater joint role for scientists and philosophers in guiding science policy. We hope that our discussion above renders this conclusion. And also that others will identify with the project of bridging the two cultures divide for this is the responsibility of us all.
Justine Burley received an Honours BA from the University of Western Ontario, Canada, prior to reading an MPhil in Politics, an MSc in Neuroscience and a DPhil in Political Philosophy at the University of Oxford. She is currently Lecturer at the University of Oxford, and Simon Fellow at the University of Manchester. She is the editor of “The Genetic Revolution and Human Rights” (OUP, 1998), “A Companion to Genethics” (Blackwell, November 2001) and “Ronald Dworkin and His Critics” (Blackwell, forthcoming 2001). Her first monograph is titled “Genetic Justice” and is forthcoming with OUP. From 1987– 2002, Alan Colman was research director of PPL Therapeutics, a biotechnology firm based in Edinburgh, Scotland (PPL Ltd), Blacksburg, Virginia, US (PPL Inc.) and New Zealand (PPL NZ) which specialises in the production of foreign (usually human) proteins in the milk of transgenic livestock (particularly cows and sheep), as well as having a broad programme in the area of organ transplantation from pigs. Alan Colman obtained a BA degree in Biochemistry in Oxford (1971) and a PhD under John Gurdon, a pioneer of the field of nuclear transfer, at the Laboratory of Molecular Biology in Cambridge, UK (1974). After a series of academic appointments in Oxford and Warwick Universities, he became Professor of Biochemistry in the University of Birmingham. The focus of his academic career was the area of eucaryotic protein secretion, with a particular emphasis on the use of frog oocytes and eggs as in vivo test tubes. Along with Ron James (current managing director of PPL) he has been involved with PPL since its inception in 1987, first as part-time research director, becoming full-time (and leaving Birmingham) in 1993. Alan has just left PPL to join ES Cell International, a company specialising in the generation and use of human embryonic stem cells.
(Received and Accepted 11 April 2002)
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J. Mol. Biol. (2002) 319, 907–915
Science and Philosophy: Bridging the Two Cultures Divide Justine Burley1* and Alan Colman2 1
Department of Government, University of Manchester, Manchester M13 9PL, UK
2
PPL Therapeutics, Roslin, Edinburgh EH 25 9PP, UK
*Corresponding author
Introduction The first success in cloning by somatic nuclear transfer announced in 1997 (Wilmut et al. (1997) Nature 385 810– 813) brought sharply into relief different aspects of the so-called two cultures divide. In his Rede Lecture, titled “The Two Cultures and the Scientific Revolution”, C. P. Snow opined that: “The intellectual life of the whole of western society is increasingly being split into two polar groups…Literary intellectuals at the one pole—at the other scientists, and as the most representative, the physical scientists. Between the two a gulf of mutual incomprehension” (Snow, C.P. The Two Cultures and the Scientific Revolution, Cambridge: Canto Books, Cambridge University Press, 1993). Despite, possibly in spite of F. R. Leavis’s salvo of devastating (and mostly apt) criticism of Snow’s essay, the phrase “the two cultures” entered common parlance (Leavis, F. R. “Two Cultures? The Significance of Lord Snow” in Nor Shall My Sword: Discourses on Pluralism, Compassion and Social Hope, New York: Barnes and Noble, 1972). It has endured as a helpful shortform with which to describe an ever-widening chasm between science and the humanities in a technologically advancing world. One of the senses of Snow’s two cultures thesis—that there is a growing knowledge gap between practitioners of science and the humanities, and that it makes talking together difficult—captures the attitudes and behaviour of some of the early participants in the controversy that erupted following Nature’s report of Dolly’s birth. Applied philosophers rushed out to purchase The Beginner’s Guide to DNA and the one to genetics as well, and they telephoned scientist friends, if they were lucky enough to have any, for “clarification”. Their self-abnegation in the face of science would continue but a more confident air was detectable—now they were really needed. E-mail address of the corresponding author: [email protected]
Meetings they attended confirmed their long-held suspicion that scientists were mere technicians, lacking the skill of lateral thought, people who could not advance a non-scientific argument to save their own lives. Scientists, on the other hand, already familiar with the word “ethics”, proceeded to employ it with abandon. Ignorant of an impressive body of established philosophical literature, they appeared to take the view that ethics was simply a matter of opinion. This was a further degradation of the idea that philosophy in general was either obvious, obviously wrong, or devoid of import. But there were deeper problems at issue between scientists and philosophers at the outset of the cloning debate than just that of divergent knowledge bases leading to an inability to communicate across disciplines. These problems are contemporary instances of two additional senses that can be gleaned from Snow’s two cultures thesis. The first involves a factual mistake. Snow and others labour under the misapprehension that the critical tools of the sciences and the humanities are always fundamentally different. Although Snow laments the rift between science and the literary arts, he was really concerned to emphasise the superiority of science when he wrote of the anti-intellectual biases of his colleagues. The standards of argument in science were of a higher and different order, he said, seeming to miss the fact that the analytical approaches taken in both science and certain branches of the humanities are one and the same. Snow does not mention “philosophy”, though he ought to have. Friedrich Nietzsche makes our point here neatly: “Science is totally dependent upon philosophical opinions for all of its goals and methods, though it easily forgets this.” Metaphysics and epistemology are, after all, the essence of scientific enquiry. (Good moral philosophical argumentation is not, but it exhibits a standard of argument more closely approximating that of science, than is often accepted.) Why is it that science and philosophy should stand apart today in the light of an
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intellectual tradition that includes Aristotle, Copernicus, Galileo and Kant? The second additional sense of Snow’s two cultures, taken up by his nemesis Leavis, concerns the normative role of science. Snow’s plug for science was over-enthused: scientists are forwardlooking, the key to raising the level of material well-being, hence science is the true path to social progress. Therefore, for Snow, science was the arbiter of value. Leavis rightly objected. By no means anti-science, Leavis was at once fighting against the debasement of culture as a form of entertainment, and the view that science was a guide to what we should do. Roger Kimball summarises thus: “What he [Leavis] denies is that science is a moral resource—he denies, that is to say, that there is any such thing as a “culture” of science. Science tells us how best to do things we have already decided to do, not what we should do with them. Its province is the province of means not ends. That is its glory—and its limitation” (Kimball, R. “The Two Cultures” Today’ The New Criterion vol. 12, 6, February 1994). Leavis’s defence of culture is infused with appeal to moral philosophical ideas. Culture, for him, is inextricably linked to human conduct. Science, according to his criterion, is not a culture. (Contra Leavis, here, a case could be made on other criteria for science being a culture.) The really important component of Leavis’s attack on Snow is that any intelligent assessment of the moral challenges posed by science, requires what the relatively unscientific literary arts have to offer. Far from being a form of entertainment the literary arts served a higher purpose. This stress of Leavis’s bears on the debate over cloning. Many seem blind to the fact that both science and philosophy are necessary conditions of any complex appreciation of the world as it is. Many more still are blind to the place of philosophy in thinking about how we might wish to direct it to become. Leavis’s preoccupation was not philosophy per se, rather it was the philosophical content of the high arts; culture furnished a richer deliberative context for the big questions in life. Few questions are bigger than the one that the possibility of human cloning poses: What sort of people should there be? When assessing the debate over human cloning, we can, pace Leavis, legitimately complain that the contributions of philosophers are, by and large, deemed superfluous. It is clear enough that since 1997, philosophers have played second fiddle to the lawyers and scientists. This is partly explicable by the fact that the currency of bioethics has become much devalued; it is sufficient to self-describe as a bioethicist to qualify as one. The other main explanatory factor is that, in our society, culture or philosophical reflection, call it what you like, is regarded as a side-show, peripheral to the real business at hand. The important overarching lesson to be drawn from the Snow/Leavis exchange, for our purposes,
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is that practitioners of both science and the humanities do themselves and everyone else a disservice by maintaining distance. When either is practised in isolation from the other, avoidable problems are created and/or inevitable problems are needlessly exacerbated. Not to mention the fact that both appear rather intellectually naked. The debate over human cloning has been plagued by mutual incomprehension on the part of scientists and philosophers, as Snow might have predicted. He did not deem the knowledge gap between science and the literary arts, in itself, to be necessarily worrisome. The cloning debate, however, shows the importance of trying, even in small ways, to close it. Snow did think improved communication to be desirable. In 1963, he published a new essay called “The Two Cultures: A Second Look” in which he envisages the emergence of a “third culture”, namely one in which there was a meeting of minds between the scientific and the literary owing to a willingness on the part of both to talk and make sense to one another (published in Snow, C. P. The Two Cultures and the Scientific Revolution, Cambridge University Press, 1993). What in reality has occurred is that both have by-passed their rightful first port-ofcall, namely, each other, and instead have gone directly to the public. This has impeded not aided the making of good science policy. These preliminary remarks now made, we set out below to put across our personal perspectives on the science and ethics of cloning, respectively, with a view to fostering, in however modest terms, the “third culture”. Part one of this article charts the evolution of cloning from the time of an exciting scientific collaboration up to the point it was made into a cause cele`bre for a multitude of different interests. It also highlights the naivete´ of the approach of the participating scientists to the ethical dimension of their work. The second section outlines the course of the ethical debate over cloning, and suggests, in conclusion, a more integrated approach to the planning, implementation and presentation of those scientific developments lying in sensitive areas of public concern. Part One by Alan Colman The cloning of mammals involves substitution of the genetic material of the unfertilised egg with the nucleus of an embryonic or somatic cell, technique known as somatic nuclear transfer. I first observed somatic nuclear transfer at close quarters during my PhD. My supervisor, John Gurdon, was the first scientist to clone a vertebrate (a frog) from a specialised somatic cell. His was a seminal contribution to our basic understanding of the genetic basis of cell differentiation. At a time well before the advent of recombinant DNA technology, it was not clear whether cell specialisation was accompanied by selective gene loss or permanent inactivation. After all, wholesale chromosome loss was frequently observed in the somatic cells of
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several invertebrate species, e.g. ascaris. John’s demonstration in 1962 (J. Embryol. Exp. Morph. 10 622– 640) that somatic cell nuclei taken from swimming tadpoles could support the development of a transplanted egg up to a fertile adult stage, proved unequivocally that the donor nucleus had retained all those genes necessary for complete vertebrate development. Even today, this method, when applicable, remains the best way of questioning the integrity of the genetic material in a somatic cell. Judged against this scientific tour de force, the recent successes in mammalian cloning epitomised so memorably in the form of Dolly the sheep, pale in comparison. However, the creation of Dolly incorporated a new element—a manipulation that had failed with frogs—the successful use of the nucleus from an adult somatic cell to make an adult animal. More than anything else it was this demonstration that ensnared the popular imagination and provided a catalyst for a revival of concerns about the pace of scientific developments especially in the sensitive area of human reproduction. As it turned out, the birth of Dolly uncorked a maelstrom whose reverberations continue today. If anything, my sojourn in John’s laboratory between 1971 and 1974 did not prepare me well for the events of the mid-1990s, either scientifically or from the standpoint of ethics (I doubt now that I even thought once about the latter back then). In that former period, the cloning work was designed to finally dispel any doubts that differentiated frog cell nuclei, rather than those from “contaminating” stem cells, were responsible for any successful outcome. This perennial concern was to come back to haunt us post-Dolly. I took no part in any cloning work; my own speciality concerned the micromanipulation of eggs and embryos for other purposes. However, I was knowledgeable of the significance of the results as well as the various caveats associated with their interpretation. Subsequent events also made it impossible to escape from the realisation that animal cloning fired the imagination of many both inside and outside of science. In 1971, one of the other PhD students in the Gurdon laboratory was Derek Bromhall. John had “inherited” Derek due to the premature death of David Kirby, Derek’s supervisor. His PhD project was to clone rabbits. At that time, and even today, this was an extremely difficult project. Nevertheless, he achieved success in this challenging area, publishing a paper in the journal Nature [(1975) 258 719 – 722] about the creation via nuclear transfer of an early cleavage embryo. In this case the donor cell was a blastomere from a four-cell embryo. Compared to the achievements in frogs, Derek’s contributions were modest yet the capacity for mammalian cloning attempts to seize and engage the most lurid imaginations soon became evident to me because of two events. First was 1976 novel by Ira Levin entitled “The Boys from Brazil”. The story line here held that white blood
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cells taken from Hitler had been preserved in a frozen state after his death. Nuclei from thawed cells were then used to create 54 Hitler clones. Clearly the author had put some thought into whether clones would display similar personality traits to the original cell donor since the cloned babies were subjected to similar familial circumstances as those accompanying the young Hitler. I found the book to be only vaguely entertaining but I was impressed with the author’s scholarship in citing John Gurdon as the pioneer of the enabling technology. The second event was litigation on grounds of defamation brought by Derek Bromhall against an author, David Rorvik and his publisher, JP Lippincott. Rorvik had cited publications and personal communications from Derek in “In His Image” a book describing the allegedly successful attempts of a wealthy American to clone himself. The action was settled out of court with apologies and payment to Derek. Needless to say, the cloning claims were fictitious. My interest in cloning, which had always been vicarious, subsided after this mild titillation. I took little interest in the scandal that erupted over the claims by Illmensee & Hoppe in 1981 (Cell 23 9– 18) to have succeeded in cloning a live mouse using a cell from a 5-day embryo as nuclear donor. No one was able to reproduce these data and the scientific fraternity generally discounted them. Meantime I was developing my academic career, which was focussing on the use of frog oocytes and eggs as in vivo test tubes for checking out theories of protein secretion. In the early 1980s this preoccupation allowed me to make a little consultancy income on the side. In 1984 with the help of Ron James who was to subsequently head up the company, now known as PPL Therapeutics, I came up with the idea of trying to make protein therapeutic drugs in the eggs of transgenic chickens. As a prelude to starting a company, we felt that we needed to establish some intellectual property, as well as checking that the technology could work. One way or another we were able to persuade a London-based venture capital outfit, Prutec (who Ron worked for at the time) and the pharmaceutical section of a large British company, ICI, to provide finance for a research project to be performed between the University of Glasgow (leader, David Onions) and the Institute of Animal Genetics and Physiology Research (later to be renamed the Roslin Institute) under the leadership of Helen Sang. The project unfortunately did not succeed, however during the three year funding period, Ron and I were appraised of some exciting technology being developed in the Institute which involved the generation of transgenic sheep that expressed human therapeutic proteins in their milk. Using technology licensed from the Institute, an independent company called Caledonian Transgenics was set up in 1987. I became its part-time research director. In 1989, this company changed its name to Pharmaceutical Proteins Ltd (PPL).
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In the early 1990s, the creation of transgenic livestock was a laborious, inefficient and expensive process. The method involved the microinjection of DNA into the pronuclei of fertilised embryos, followed by the implantation of the embryos into foster mothers. Very few of the resultant live-born incorporated the injected genes and the technique would only allow the addition of genes; it would not allow the removal or modification of host genes. Amongst mammals, this latter manipulation could only be done in mice via the use of embryonic stem (ES) cells. Mouse ES cells can be used to populate all the adult tissues including germ cells. ES cells with similar properties do not exist in other mammals despite many attempts to derive them. We were anxious to improve our transgenic success rates and, more importantly, we wanted a method to manipulate host genes. By 1994, our headquarters were situated in the grounds of the Roslin Institute and no more than 200 m away. We had always had ongoing scientific collaborations with the Institute and we were allowed to use their library and canteen facilities. As a result of these ongoing relationships, we became aware of some exciting new scientific developments concerning the use of nuclear transfer in sheep. Apparently in 1994, under the direction of Ian Wilmut and Keith Campbell, a lamb had been born from an embryo reconstructed using a donor cell nucleus taken from a very early passage, unsynchronised cell culture prepared from nine-day old sheep embryos. This male lamb survived for about six months but then died (possibly from kidney failure). Although lambs had been cloned from blastomere nuclei in 1986, this new demonstration was very significant because a later developmental stage was used and the appearance of the cultured cells indicated that they had acquired certain somatic cell characteristics. If such cell cultures could be expanded without losing their totipotent capabilities, we realised that these cells could provide the solution to the technical drawbacks to our transgenic technology. To learn more about the technical details behind this new advance, PPL seconded Angelika Schneike in 1994 to work in the Roslin Institute with Jim McWhir. It soon became clear that the technology mentioned above was not robust and that the particular cell cultures used could not be expanded further without loss of their totipotent properties. In 1995, Keith Campbell introduced serum starvation of cells as a means to synchronise their cell cycles at the G0 stage (he also believed G0 would be a better starting point for the reprogramming needed for successful nuclear transfer) and pregnancies were established with much later cell passages. These pregnancies were to result in the births of Megan and Morag in the summer. This work, published later in Nature [Campbell et al. (1996) 380 64 –66] was generally overlooked by the world’s press despite describing the same methodology later to prove successful with Dolly.
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Meanwhile, in early 1995, PPL and the Roslin Institute agreed to collaborate in a programme of nuclear transfer experiments. Unfortunately commercial issues clouded the early negotiations. In exchange for its scientific and financial involvement, PPL wanted to secure commercial rights to use the nuclear transfer technology in certain areas. These so-called Fields of use included the proteins in milk area and xenotransplantation. The Roslin Institute were unwilling to cede rights in the xenotransplantation believing (rightly) that they could obtain a better deal with another organisation. The negotiations stalled and there was a danger that the experiments would have to be postponed for a year because the breeding seasonality of the Scottish Blackface sheep which provided oocytes and foster mothers for the experiments. I broke the deadlock by agreeing on behalf of PPL to finance the programme in the absence of any commercial agreement whatsoever. PPL needed to know as soon as possible whether this technology could truly deliver its transgenic promise. We agreed to fund sufficient work to test four new embryonic cultures that we had derived from cultures from our own, Poll Dorset sheep. Roslin also wanted to test some new lines although they would not reveal the cell type (they later were revealed to be fetal fibroblasts). We established a programme management group consisting of myself, Angelika and Alex Kind from PPL together with Ian Wilmut, Keith Campbell and Jim McWhir from Roslin. The work began in October 1995 and went quite well to begin with. Unfortunately, two of the PPL lines failed to grow well in culture and we found ourselves with a gap in our experimental programme. It was at this point that Angelika Schneike suggested again that we should use some adult mammary cells which we had obtained two years previously from a pregnant, six year-old Finn Dorset ewe. The ewe had been sacrificed and the cells taken for a collaboration we had with the Hannah Research Institute some eighty miles away. Angelika had first suggested the use of these cells, many aliquots of which had been stored in liquid nitrogen, for nuclear transfer at an internal PPL meeting in Oct 1994 citing two reasons: First, despite their extended culture the cells had retained the normal diploid karyotype, an essential prerequisite to success in livestock nuclear transfer. Second, PPL’s core business revolved around high levels of protein expression in the mammary gland. If these cells would work in nuclear transfer, the possibility arose that we could genetically engineer the mammary cells and assess the level of expression from the added genes prior to making an animal. The expectation was that we could remove some of the empiricism from the process and unerringly make high expression animals. In principle, whilst this all seemed logical, the existing nuclear transfer literature taught against the use of adult cell donors. This was appreciated
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by all members of the group, particularly those of us with long memories like Keith, Ian and myself. I recall sharing my biases with the group and predicting failure. Ian Wilmut was non-committal, possibly because he accepted that PPL was financing this part of the programme. Although Keith did not accept the party line that adult cells would not work, even he was not sure that this cell type would provide the breakthrough. Nevertheless, we went ahead. Dolly was born on July 5, 1996. We were very lucky. A total of 277 embryos had been implanted into four temporary recipient sheep and 29 embryos developed successfully to the blastocyst stage. These were replaced into seven surrogate mothers and one pregnancy established. Given the provenance of the cells no one expected the pregnancy to go to term. This expectation of failure muted any growing excitement. Dolly developed a fever soon after birth and PPL staff mounted a 24-hour watch to assist the overburdened Roslin farm staff. Our chief vet, Denise Cottom, in consultation with the Roslin vet, prescribed a course of antibiotic treatment. As soon as Dolly and the six other nuclear clones were born we celebrated our success at a Nepalese restaurant in Edinburgh where we began to plan our next steps. We recognised that it was essential that we proved that Dolly had come from the Finn Dorset mammary cell. Dolly certainly looked like a Finn Dorset and was clearly of a different breed from the oocyte provider and surrogate mother (both Scottish Blackface) ruling out any trivial explanation for her appearance. We decided to perform microsatellite DNA analysis on samples taken from the various animals and the original cellular materials used in the transplantation process. At the time, we believed that this would be enough unequivocally to demonstrate that animal clone and cell cultures were genetically identical. The microsatellite analysis performed by Angelika gave the expected results and we set about writing a paper. Although Ian Wilmut did most of the writing, we all contributed suggestions and changes during the drafting process. We also considered the ethical implications of the work, armed as we were with many examples of disproportionate media and public reactions to theoretical or fictitious cloning claims (see G. Kolata (1997) Clone, Allen Lane, The Penguin Press). Looking back, it is embarrassing to realise how naı¨ve and superficial our “analysis” was. Almost single-mindedly, we concentrated on the “cloning Hitler” type objections. We unanimously agreed publicly to condemn outright what came to be known as reproductive cloning without ever considering or even recognising some of the problems or less desirable outcomes of natural procreation. Perhaps the fact that five of the management group had generated families without recourse to assisted reproduction methods had insulated us from the problems of the infertile. We did not have any ethicists at our meetings although
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we did consult an external public relations company retained by PPL on how we should handle the release of the information. PPL decided to synchronise its press release with the expiry of a press embargo on the data, imposed by the journal Nature that had agreed to publish the paper. Unfortunately, there was a leak and the story got into a British Sunday newspaper four days before the Nature publication. Because of its obligations to immediately appraise the London Stock Exchange of any publicly released price sensitive information, PPL was forced to issue a press release on the following Monday morning. This ensured that the lead up to the expiry of the embargo was frenetic and confused. History will recall the deluge of newsprint and media comment that accompanied Dolly’s formal debut. [Wilmut et al. (1997) Nature 385 810 –813] From day one it was immediately evident that we had grossly underestimated the impact of the work on the public psyche. There were condemnatory cries, scientific praise, and amazement, in equal measure. Most concerns were directed at the possible extrapolation of these findings to humans and were intuitively formed and poorly thought out (see below). I confine my comments here to discussion of certain of the more substantive scientific criticisms. Criticisms were both of a general and specific nature. The work on Dolly was referred to as “anecdotal” because there was only one example of adult cell cloning-Dolly herself. There was, it was stated, an obligation on scientists to publish reproducible findings with the onus on the originating scientists, not those who follow, to supply evidence of reproducibility. Under normal circumstances I would agree with this. However, further delay (some critics felt we should have publicised the work as soon as Dolly was born) would have been accompanied by scientific leaks (academics are not good at keeping secrets) and accusations of unacceptable secrecy would have followed, compounding an already tarnished image of the way biological research is conducted. In addition, although Dolly was the only adult clone, six further somatic cell clones were mentioned in the paper and a repeated experiment would have taken a further 10 months at least due to seasonality in sheep breeding cycles. More worrying was the technical criticism that Dolly could have come from a rare fetal cell donor that had contaminated the mammary cell culture due to the fact that Dolly’s mother was pregnant at the time the cells were removed. This could have been immediately discounted had the fetus been male but we had no record of its sex. Although we had performed microsatellite DNA analysis, it was argued that this might not have had the resolution to rule out a fetal cell origin, particularly if the male parent was from the same (inbred) flock. To resolve this, I contacted Alex Jeffreys, the pioneer of DNA fingerprinting, and his lab agreed to perform the world’s first DNA
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fingerprinting on a sheep. The results published in Nature [Signer et al. (1998) 394 329– 330] were unequivocal. Our claims to the provenance of Dolly had been vindicated though of course we should have performed this type of test earlier. It is now over five years since Dolly was born and despite frequent claims about her demise, Dolly is alive, healthy and the mother of six offspring. In the time intervening, three other mammalian species have been cloned using adult somatic cells (cows, mice and pigs) and the number of cloned livestock is in the hundreds. We still do not know why livestock experiments which had been in progress since 1986, only succeeded in 1996. There was an initial insistence that only quiescent (G0) nuclei would work, however this does not seem to be the case and diploid, cycling cells (G1) also seem to work. The technique still remains very inefficient and generates high levels of pre- and post-natal mortality. Nevertheless some of the initial promises of the technology have been fulfilled: it has proved possible to make livestock with predetermined genetic changes [gene targeting—see McCreath et al. (2000) Nature 405 1066 – 1069]. It has proved possible to expand elite genetics in cows [Wells et al. (1999) Biol. Reprod. 60 996– 1005]. And, it has proved possible to rescue endangered species (the Mouflant to name one). However, many eyes are focused on the human arena. Whilst there is widespread agreement amongst scientists that reproductive cloning should not be attempted, a variation termed therapeutic cloning has attracted many advocates. With this technique, reconstructed embryos serve as a source of embryonic stem cells, which ultimately would be used to the medical benefit of the cell donor. Cloning opened the proverbial Pandora’s box to many ethical challenges for which scientists and society were woefully unprepared. Part Two by Justine Burley In November 2001, five and half years after the birth of Dolly, the first human embryos were cloned by somatic cell nuclear transfer (SCNT) to the four and six-cell stages respectively (Cibelli, J. B. et al., “Somatic Cell Nuclear Transfer in Humans: Pronuclear and Early Embryonic Development” J. Regen. Med. 2, 26 November 2001, 25 –31). Although the objective of this research effort was the derivation of autologous embryonic stem (ES) cells, inferences were immediately drawn from the data for the case of human reproductive cloning. Already an inefficient technique in non-human animal models (see above, see also Colman, A. (2001) “Somatic Cell Nuclear Transfer in Mammals: Progress and Applications”. Cloning 1 185 – 200) it would appear that creating viable embryos using SCNT is not straightforward. The concern that human reproductive cloning would involve huge wastage of oocytes, articulated back in 1997, seems to have been confirmed. Moreover
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to understand the root of the problems will require further research on human embryos. Whether and in what ways these two facts matter morally is, of course, open to debate. In 1997, in those countries where some embryo research is permitted few relished the thought of revisiting the questions of whether and under what circumstances it should be permitted. This reluctance was thought justified for reasons of expediency but the net result of it, was impoverished governmental policy, policy which scientists were instrumental in shaping, and which would, in some countries, back-fire when the relatively more important issue of embryonic stem cell research arose. This was particularly evident in the USA. The National Bioethics Advisory Commission (NBAC) chose to bypass the issue of embryo research in its hastily prepared report (Cloning Human Beings: Report and Recommendations of the National Bioethics Advisory Commission, Rockville, MD, June 1997: http:// bioethics.gov/pubs.html). Lack of discussion and the concomitant absence of guidelines for such research undermined the NBAC’s own pronouncement in favour of a continued moratorium on public funding for reproductive cloning-related research on the grounds of safety. On the basis of cloning experiments in non-human animal models scientists raised the prospect at every available opportunity, of human clones suffering severe abnormalities in the early and late fetal stages and also in infancy. How can the health risks to human clones be assessed and/or minimised without research in the area? Scientists informing the policy debate in the USA mentioned repeatedly the fact that the reproductive systems of mammalian species differ, sometimes greatly. This should have led them to call for research on human embryos to establish properly the risks of harm to human clones. Most did not (see, for example, Colman, A. “Why Human cloning should not be attempted” in Justine Burley ed. The Genetic Revolution and Human Rights Oxford: Oxford University Press, 1998, pp. 14 –18). A total ban on human cloning (i.e. in both the public and private sectors) might be indicated were research to show that even at the early stages of human fetal life embryos cloned by SCNT are consistently defective. The NBAC omitted any recommendations to address scientifically the problem of harm, in effect leaving it to the unregulated private sector, where human cloning still is not illegal (this may soon change depending on the fate of Bill H.R. 2505 in Senate, see below), to supply this information. The lack of focus on the moral permissibility of embryo research would also prove deeply problematic for the NBAC (as well as other bodies like the National Institutes of Health (NIH)) when it was charged with pronouncing on ES cell research. From the outset, most of the scientists opposed to human reproductive cloning sought to distinguish it from so-called therapeutic cloning, the latter being a possible source of ES cells which would
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have the advantage of being immuno-compatible with the patient. Not only has the wider public had difficulty keeping the two separate, so too have policy-makers, as evidenced by the recent Congressional debate over Bill H.R. 2505 (Human Cloning Prohibition Act 2001, House of Representatives—July 31, 2001: http://thomas.loc.gov/ cgi-bin/query/D?c107:1:./temp/~c107a953ZK::). Research on embryos in the public sector has been outlawed since 1996 in the USA. The failure of scientists and moral philosophers to tackle the issue from then on, in concert with one another, contributed to the current unsatisfactory situation in which urgently needed public funding for ES cell research is sorely constrained. (See President George W. Bush’s address on stem cell research, August 9, 2001: http://cnn.net/2001/ ALLPOLITICS/08/09/bush.transcript/index.html.) The remit of scientists who self-elected to be public spokespeople ought much earlier to have been educating the public about the importance of embryo research for a number of different purposes, and in this they should have had more assistance from moral philosophers. As noted, taking their cue from scientists, the NBAC justified its policy on human cloning by referencing the notion of harm to future children. Their well-intentioned message, however, without accompanying philosophical reflection has compromised emerging policy in a number of countries. The concentration on physical safety by scientists and the policy-makers they have informed, whilst appropriate, has been philosophically naı¨ve. As I have argued elsewhere, the appeal to harm made by scientists against human clones is exclusively framed in “vulgar” consequentialist terms. This philosophical approach looks at what outcomes can be reasonably predicted, and shapes policy accordingly. If the foreseen outcome is, on balance, a negative one, then the action is proscribed. A ban on human cloning is thought to be justified according to this line of thinking because it is likely that a clone would be physically abnormal. But, if the technique of SCNT ever is perfected someday, somewhere, do we not, on this kind of blunt consequentialist reasoning, find ourselves committed to recommending cloning over natural procreation? On balance, natural procreation would carry more risk for future children simply because the genetic make-up of any embryo so conceived would not be knowable to the same extent as would that of a cloned embryo. Moreover, and more importantly, what if all decision-making about human reproduction were made in this way? Should not people who possess dominant genes for serious disorders be banned from procreating owing to the high risk they have of transmitting that gene to their offspring? Should all prospective parents be obliged to undergo genetic testing? Should all embryos be tested prior to implantation, and only the “healthy” ones placed in utero? If the physiological welfare of future
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children is a sufficient reason to ban cloning, it should also be sufficient to support these draconian procreative policies as well (Colman, Alan and Burley, Justine (2001) “A Legal and Ethical Tightrope: Science, Ethics and Legislation of Stem Cell Research” EMBO Reports 2 2 –5). Timely consultation with philosophers might have alerted those advancing the harm objection to human cloning of the logical implications of their argument. It might also have been helpful had, what is called, the non-identity problem, been broached by opponents of human cloning (this is Derek Parfit’s name for it, see his Reasons and Persons Oxford: Clarendon Press, 1984). Again, as I have argued elsewhere, the harm objection to human cloning is stated in a fashion that implies that for clones non-existence is preferable to existence [Burley, J. & Harris, J. (April 1999) “Human Cloning and Child Welfare” J. Med. Ethics 25(2) 108– 113]. The problem with this is that when someone does not exist, doing or refraining from an action that prevents that someone from existing does not make that someone better off. If we do not clone, no particular child is better off because this child never existed. Likewise, if a child is brought into the world using SCNT and is physically impaired as a result, it is most unclear that, on balance, this child has been harmed by the action of cloning. This particular child would not have existed had he or she not been cloned in the first place. The NBAC thought about this problem but decided that it should be left to the obscure deliberations of philosophers (and presumably scientists share this attitude). However, in the light of the fact that the proverbial Pandora’s Box that was opened in 1997 relates to the question of what kind of people should come to exist, it would seem necessary to address properly the non-identity problem. It is not posed solely by human cloning, many reproductive cases can be envisaged where the usual person-affecting notion of harm does not capture the core difficulty. A possible solution to the non-identity problem has been proposed by Ron Green. He argues that we should avoid before-after comparisons when thinking about birth outcomes, because never having existed is not a state to which one can ascribe anything negative to (The Human Embryo Research Debates Oxford: Oxford University Press, 2001, pp. 126 –129). Instead, we should concentrate on the reasonable expectations of the child and/or parents. In this way we can protect the interests of children who have been harmed through others’ negligence. If, for example, a child is born with a physical defect due to the failure of its parents to take precautions that they could easily have, he or she can reasonably claim to have been harmed. However, the duty of parents to ensure that their offspring have roughly the same prospects as other children around them, does not apply independently of other considerations. The right of parents to be free to choose to have a
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biologically-related child will also be relevant. Moral choices involve competing rights and claims, Green reminds us, so it will not always clearly be wrong to bring a child into existence knowing that it will be damaged in the process. With regard to cloning, Green’s stance is therefore permissive in those cases where a child could not have been conceived in any other way. Green’s proposed alternative to the non-identity problem, I think, begs the question of whether it is reasonable to attempt to have a child by whatever means (i.e. natural or artificial) when the risk of harm to it is substantial. I fail to see how the desire for a biologically-related child trumps our moral concern for the physical well-being of a child whenever that level drops below a certain threshold (cf. Burley & Harris). Thus whilst Green is on the right track, further refinements of the position are required. The scope of this piece does not permit in depth analysis of the problem. The preceding discussion does, however, serve to demonstrate why the sledge-hammer safety objection to human cloning is deficient, and therefore why it might have been of benefit to the policymaking process had scientists and philosophers put their heads together earlier. One of the main reasons that scientists have been sceptical about what philosophers have to offer is the fact that amongst themselves philosophers often do not agree on what should be done. But this does not necessarily lead to an impasse. Moral philosophy as a whole involves two broad kinds of inquiry. The first concerns the status of moral values themselves: are they objective or subjective, and in what sense of either might they be so? This sort of inquiry, otherwise known as meta-ethics, is all about the locus of authority of moral values. The second type of moral philosophical inquiry concerns conduct at the levels of the individual or society. The question: What do we owe to one another? is its chief preoccupation. Political philosophy is a sub-branch of this kind of moral philosophy, that part of the discipline devoted to discussion of the appropriate relationship between the state and the individual and/or groups of individuals. It asks, amongst other things, about the legitimate bounds of state intervention in individuals’ lives. In the debate over human reproductive cloning, whenever advocates of a particular religion make their case by appeal, for example, to some higher authority, e.g. the teachings of the Bible, they are engaging in meta-ethical argumentation. The values championed are held to be true, objective in the sense that God is the ultimate moral arbiter. It is plain that when people disagree at this level of moral inquiry, there is no way, short of simply insisting on one’s own view, to convince others of it. Discussion ends where it began. This is why the inclusion of people who in essence are members of religious lobby groups, in the policymaking arena, in the capacity of “expert” bioethicists, is misguided. They may be very know-
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ledgeable about, e.g., Christian ethics, but their mission will always be to assert the rightness of their own meta-ethical view, from which it will be impossible to shift them. They demand not tolerance but respect for their position. However, not all moral philosophy, indeed very little applied philosophy, relies on meta-ethical arguments. Bioethics, for the most part, circumvents entirely metaphysical questions and focuses instead on supplying independent arguments (perhaps consequentialist in style, perhaps deontological, perhaps both) for why we should or should not, for example, clone humans or engage in research involving embryos for research purposes. Although there often is disagreement between philosophers at this level of moral inquiry, it is possible nevertheless to assess the relative strengths of the different positions taken. Moral deliberations of this ilk, in short, are amenable to reason in multicultural societies. It really is crucial to be aware of which approach is being taken in any argument about the morality of a given scientific advance. Understanding the way in which we arrive at an ethical view bears directly on the questions of whether and how differences between views can be accommodated in a pluralistic society. This is where political philosophy comes in. At the heart of the debate over both human reproductive and therapeutic cloning are many competing views about when a human life should be accorded moral status, and also about the wider question of what sort of people should come to exist. In a pluralistic society policy must be derived by reference to the reigning public political culture as well as to citizen’s shared principles and conceptions of practical reason. In the cases of human cloning and embryo research, the first step towards an acceptable policy is to identify the diversity of moral doctrines touching on these areas that are held by citizens. These should then be reflected in relation to shared values and laws in conceptually related areas, the purposes of the research, whom it might benefit, whether and how much the suffering of people who might be helped by the research matters to us, and so on. What should emerge, after such reasoning, is a policy that can be accepted in a pluralistic society by reasonable individuals. The requirement of reasonableness demands that we understand that on subjects where people have divergent, deep-seated moral convictions, a policy may never fully reflect all the respective particularities of citizen’s moral doctrines, but it will fit sufficiently with their commonly held values to stand as legitimate public policy. The moral principles at stake in cloning and embryo research, are not, in fact, novel ones. A careful look reveals that they underpin a good many cultural norms and laws that people not only accept but believe to be the cornerstone of any liberal democracy. The secular liberalism of
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our society makes diversity possible, and it is the only approach to resolving differences of opinion on cloning and research on embryos that we can all agree on, if we think hard about it, that is.
Conclusion In closing we quote F. R. Leavis: “The advance of science and technology means a human future of change so rapid and of such kinds, of tests and challenges so unprecedented, of decisions and
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possible non-decisions so momentous and insidious in their consequences, that mankind—this is surely clear—will need to be in full intelligent possession of its full humanity…” We contend that “full” in both of Leavis’s phrases, in the context of the debate over human cloning, is a prescription for a greater joint role for scientists and philosophers in guiding science policy. We hope that our discussion above renders this conclusion. And also that others will identify with the project of bridging the two cultures divide for this is the responsibility of us all.
Justine Burley received an Honours BA from the University of Western Ontario, Canada, prior to reading an MPhil in Politics, an MSc in Neuroscience and a DPhil in Political Philosophy at the University of Oxford. She is currently Lecturer at the University of Oxford, and Simon Fellow at the University of Manchester. She is the editor of “The Genetic Revolution and Human Rights” (OUP, 1998), “A Companion to Genethics” (Blackwell, November 2001) and “Ronald Dworkin and His Critics” (Blackwell, forthcoming 2001). Her first monograph is titled “Genetic Justice” and is forthcoming with OUP. From 1987– 2002, Alan Colman was research director of PPL Therapeutics, a biotechnology firm based in Edinburgh, Scotland (PPL Ltd), Blacksburg, Virginia, US (PPL Inc.) and New Zealand (PPL NZ) which specialises in the production of foreign (usually human) proteins in the milk of transgenic livestock (particularly cows and sheep), as well as having a broad programme in the area of organ transplantation from pigs. Alan Colman obtained a BA degree in Biochemistry in Oxford (1971) and a PhD under John Gurdon, a pioneer of the field of nuclear transfer, at the Laboratory of Molecular Biology in Cambridge, UK (1974). After a series of academic appointments in Oxford and Warwick Universities, he became Professor of Biochemistry in the University of Birmingham. The focus of his academic career was the area of eucaryotic protein secretion, with a particular emphasis on the use of frog oocytes and eggs as in vivo test tubes. Along with Ron James (current managing director of PPL) he has been involved with PPL since its inception in 1987, first as part-time research director, becoming full-time (and leaving Birmingham) in 1993. Alan has just left PPL to join ES Cell International, a company specialising in the generation and use of human embryonic stem cells.
(Received and Accepted 11 April 2002)