5
Cloning and Stem Cells

I doubted at first whether I should attempt the creation of a being like myself, or one of simpler organization; but my imagination was too much exalted by my first success to permit me to doubt of my ability to give life to an animal as complex and wonderful as man.

From Frankenstein, Mary Shelley (1818)

‘Ninety‐six identical twins working ninety‐six identical machines!’ The voice was almost tremulous with enthusiasm. ‘You really know where you are. For the first time in history.’ He quoted the planetary motto. ‘Community, Identity, Stability.’ Grand words.

From Brave New World, Aldous Huxley (1932)

The damaged brains of Alzheimer’s disease patients may be restored. Severed spinal cords may be rejoined. Damaged organs may be rebuilt. Stem cells provide hope that this dream will become a reality.

From The Biotech Investor’s Bible, George Wolff (2001)

5.1 Introduction

Fascination with human copies goes back a long way. In past ages, identical twins have been regarded as anything from sinister (especially if one of them was left‐handed) to magical or even divine,1 while stories of doppelgängers have appeared in a number of different cultures. The possibility of actually making human copies was typified in the 20th century by the 1978 film The Boys from Brazil in which the notorious Dr Mengele was depicted as directing the creation by cloning of several copies of Adolf Hitler. ‘Copying’ specific people was the theme of Fay Weldon’s 1989 novel, The Cloning of Joanna May. In the book, a man arranges that while his wife, Joanna May, is undergoing surgery, the surgeon will remove some cells from which the genetic material, DNA, may be extracted. This is then used to clone her, thus providing in the future ‘new’ versions of Joanna. Aldous Huxley’s dystopian novel, Brave New World (1932), imagined a world (in the year 2540) in which 96 clones, reared for specific purposes, could be obtained from one fertilised egg.

The cloning theme has even appeared in cartoons, through the activities of the little boy Calvin in Bill Watterson’s wonderful Calvin and Hobbes series. In 1990 the cartoon dwelt for several days on the theme of Calvin duplicating himself, urging the ‘doubting Thomases’ not to let ethics stand in the way of scientific progress while his toy tiger, Hobbes, expressed grave misgivings.2 This fascination with cloning has a broad basis that certainly includes our ideas of what makes us individuals and more recently on what role genes have in our development as persons. Neither is this fictional interest confined to writing about copying humans. The author Michael Crichton, probably aware of the well‐established procedure of cloning frogs (see below) based his 1980 novel Jurassic Park (made into a popular film by Steven Spielberg in 1993) around the theme of cloning dinosaurs from their DNA preserved in the bodies of bloodsucking insects trapped in amber.

Another common theme in the fictional presentation of cloning is that things can go badly wrong. In the Boys from Brazil, the misuse of science, albeit highly fictional science, was at the centre of the plot. In the Calvin and Hobbes cartoons, chaos ensues as Calvin uses his ‘duplicator’ to make more and more copies of himself. And in Jurassic Park, the warnings of a more cautious scientist that the dinosaur cloners were on dangerous ground went unheeded, only for major problems to occur when some particularly fierce carnivorous dinosaurs escaped from their enclosure. Of course, such themes are not uncommon in science fiction; what might go wrong with the use of science makes for exciting plots. Nevertheless, these ideas have entered the public debates about the applications of science; it is often said that scientists do not know enough about the systems they are manipulating and would be unable to prevent either misuse or potentially disastrous accidents but equally, some of the scenarios envisaged belong in science fiction rather than in science.

5.2 Frogs and Sheep

The examples mentioned above are all of course fictional but did the authors and scriptwriters have any factual basis at all for the development of their plots? It has been clear for at least four decades that most types of cell in a fully developed multicellular organism retain all their DNA – their genetic material – even though only a particular subset of the genes is active in any one cell. During development from the one‐celled embryo (zygote), there is a very complex programme of switching genes on and off. As investigations of gene activity gathered pace in the 1960s, one of the key questions in research was whether specialised cells retained the full genetic potential of the zygote,3 both in terms of the completeness of the information (is any lost during cell specialisation?) and in terms of its activity (would all the genes still ‘work’ if they were placed in a situation where development would start again?).

In plants, it was demonstrated by cell and tissue culture that differentiated cells, subjected to appropriate treatment, could give rise to whole plants. Indeed, this plasticity of plant development is very helpful in the generation of whole transgenic (genetically modified (GM)) plants from the initial transformed cells. But the organisation and growth patterns of plants are very different from those of higher animals and it took a different type of experiment to test the genetic potential of specialised animal cells. The question may be framed as ‘can the DNA, the genetic material, of a specialised cell function as if it was back in the zygote, the very first embryonic cell?’ Framing the question that way indicates how the experiments were done. Frog eggs are large and thus the nucleus containing the DNA is relatively easy to remove. In this state, emptied of genetic information, the egg cell is incapable of any further development. However, if the egg nucleus is replaced by the nucleus from a specialised frog cell, then, under particular experimental conditions, the egg will start to divide and may go on to develop into a tadpole and then even into an adult frog. This process is known as nuclear transfer and over the years its success rate with frogs has increased very significantly so that the procedure is now a routine part of particular research programmes on the regulation of gene activity during frog development. The procedure has been described in this way because the motivation for these experiments was based on this type of genetic research and the results clearly established, amongst other things, that the genetic material of a specialised cell retains its full genetic potential and can be persuaded to ‘start again’. Of course, it is also true that the frog that results from the nuclear transfer is a genetic copy, a genetic clone, of the individual from which the donor nucleus was obtained. Interestingly, however, this was very much a secondary consideration when the experiments were first done in the 1960s4 and indeed remained so until the cloning of Dolly.

Those nuclear transfer experiments in frogs were an important milestone in developmental biology. However, while experiments on frogs were becoming more and more sophisticated, all attempts at doing similar experiments with mammals failed. It looked very much as if the DNA of a specialised mammalian cell, although complete in terms of content, could not be reprogrammed to start again. In technical terms, it appeared that the epigenetic patterning that is involved in cell differentiation could not be reversed. Then, in February 1997, scientists at the Roslin Institute near Edinburgh in Scotland announced that Dolly the sheep, cloned from an adult cell, had been born some six months previously.5 For biologists, this was very exciting news: after over 30 years of trying, it had been shown that the genetic material of an adult mammalian cell (for Dolly, a cell derived from the mammary gland of a six‐year‐old ewe) could be reprogrammed to start again (albeit with great difficulty) – the changes were not after all irreversible. The major surprise was that this had been achieved not with the ubiquitous laboratory mouse, the subject of so much of the previous study, but with a large farm animal. And although this happened over 20 years ago, it is still very a ‘live’ issue, both in respect of the science itself and of bioethics.

The science behind the cloning of Dolly is very important and perhaps it was for that reason that the press officers of the journal Nature, in which the paper announcing the birth of Dolly was published, included details of the paper in their weekly prepublication press release.6 However, it was the cloning aspects that clearly caught the imagination of the press and the editor of one major UK newspaper believed that the topic was so important that the paper broke Nature’s date embargo and ran the story several days before the edition of Nature was published. That in itself raises an ethical issue that readers may care to think about. Media interest in the story was huge, at levels of intensity that biologists had never encountered before; representatives of the press, TV and radio turned up at the Roslin Institute in large numbers (Figure 5.1). It was clear that the science of gene regulation was not the main topic on the minds of the reporters and news readers. Dolly was of course a genetic copy of the ewe from which the DNA had been obtained, that is, was a clone and this was the main focus of most of the media reports. Indeed, some of the media articles dwelt on the possibility of cloning humans, despite the clear statements from scientists at the Roslin Institute that this research was not intended as a step along that road (but the scientists also made it clear that Dolly was created as part of a programme to make genetic copies of valuable GM ewes, and so it is probable that the cloning of sheep figured as strongly in their motivation as much as solving problems of gene regulation). In a further frenzy of reaction around the world, the pope condemned cloning outright, the president of the United States (then Bill Clinton) requested that his Bioethics Advisory Committee should report on cloning as a matter of urgency, while the EU quickly enacted legislation to give all persons the right to their own genetic identity,7 in order to make illegal any attempt at reproductive cloning.

Image described by caption.

Figure 5.1 Micrograph of a human blastocyst.

(Source: Reproduced with permission from the National Institutes of Health, USA.)

The embryo now consists of an inner mass of cells (ICM) that will, if the embryo implants, become the embryo proper and an outer layer of cells, the trophectoderm (TE), from which the placenta will be derived if a pregnancy is established (see Chapters 3 and 4). Stem cell cultures may be established from the inner cell mass.

5.3 Genes and Clones

Before discussing specifically the ethical issues, it is necessary to consider the relationship in humans between genes and individuality. Identical twins, with identical genetic material, developing in the same womb and growing up in the same environment are not identical people. Anyone who wishes to clone a specific person will be disappointed. In Fay Weldon’s novel, The Cloning of Joanna May, the husband looking for a new youthful version of his wife did not find her despite the strong physical resemblance of the younger women to their ‘mother’. Similarly, cloning oneself or, even more tragically, cloning a dying child will not bring that person back again. Even at the physical level, the genetic clone may differ from the person from which the genes were obtained because of differing effects of environment, starting indeed with the uterine environment. Genetically identical twins may in some cases not look identical because the effects of epigenetic changes may be very marked. Further, it will also be impossible to mimic the factors that influence emotional and social development. Current views of the heritability of behaviour, personality and intelligence suggest that genes contribute significantly but to a variable extent to each of these features (e.g. heritability indices between 0.3 and 0.5 for a range of personality traits).8 However, that does mean that the inheritance is straightforward. Scores or even hundreds of genes (the identity of most of which we do not know) are involved and further, these are very much subject to environmental influences. The influence of either or both genes and environment may change with age but it is clear that environment, including nurture, plays a major role. Further, at least one ‘media‐famous’ British psychologist has suggested that these features are all moulded very much more by nurture than by genes.9 But whichever view one takes, it is clear that reproducing another person by cloning is not possible, except at the level of genotype.

5.4 It’s Not Natural: It Should Be Banned!

The heading of this section reflects what the philosopher Mary Warnock has called the morality of the pub bore for whom ‘It’s not natural’ apparently puts an end to the argument. However, as we have noted in Chapter 2, natural versus unnatural is not a good basis for ethical classification and in any case, none of us, the pub bore included, could live with such a basis for our moral decision‐making.

Cloning in order to bring into the world a genetic copy of another person is a reproductive procedure and indeed is often called reproductive cloning in order to distinguish it from ‘therapeutic cloning’ (discussed later in the chapter). It would involve the collection of donated ova from women, the manipulation of those ova in order to remove the genetic material and replacing it with the donated genetic material, which would lead to the creation of embryos, albeit by very unconventional methods, and the insertion of some of those embryos into women’s wombs. The result of this would be, if successful, the creation of a genetic twin of the person from whom the genetic material, the DNA, was obtained (the ‘clone donor’). Thus in the United Kingdom, cloning comes under the provisions of the Human Fertilisation and Embryology (HFE) Acts (1990 and 2008) as administered by the HFE Authority (HFEA). The Act and its interpretation by the HFEA are clear. Reproductive cloning is illegal in the United Kingdom. It is even illegal to split an embryo created by ‘normal’ in vitro fertilisation (IVF) in order to have identical twins (see Chapter 3).

The situation in the United States is somewhat different. Research on human cloning, including ‘therapeutic’ cloning, was banned by President George W Bush in all federally funded laboratories (Prohibition of Human Cloning Act, 2001) but it was not banned in laboratories that receive their funding from private industry, from charity or indeed from any non‐federal source. This did not mean that research on reproductive cloning has proceeded apace in the United States but it does mean that reproductive cloning could in theory happen there. Indeed, between 2002 and 2004 there were sensational claims, all unsubstantiated, from an organisation called Clonaid that several cloned babies had already been born in the United States. The refusal of Clonaid to produce DNA evidence throws this claim into great doubt and indeed, the claims have since just ‘faded away’. The great difficulty in cloning any primate (see below) is a further indication that Clonaid’s bizarre claims were simply not true and they have been generally rejected as nonsense.

The situation changed somewhat after the inauguration of President Barack Obama in 2009. Shortly after taking office he lifted the federal ban on research on embryonic stem (ES) cells and by implication on therapeutic cloning. However, he stated very clearly that he would never open the door on reproductive cloning of humans. It is, he said, ‘…dangerous, profoundly wrong and has no place in our society or any society’.10 Nevertheless there remains a suspicion that there are biomedical scientists, not necessarily in the United States, who sooner or later will be prepared to attempt reproductive human cloning (in one of the countries with no legislation in this area), however difficult it is (see below). Furthermore, it has been noted in both the United Kingdom and the United States that there are people who would like to clone offspring, while organisations like HumanCloning.com believe that it is inevitable that human reproductive cloning will occur (but see below).

At this stage we should ask whether there are in fact any intrinsic objections to human reproductive cloning, that is, objections that would make us say that it is our duty to ban it. Presumably those scientists who are prepared to try it cannot identify any intrinsic objections. Neither can the Manchester philosopher John Harris who believes that reproductive cloning should simply be evaluated as another reproductive technique. Indeed, cloning may be the only way for some couples, admittedly very few, to have a child that would be genetically related to at least one of them. The conditions that make this so are particular maternally inherited genetic diseases11 and certain forms of infertility. Further, some lesbian couples have suggested that having babies this way nicely bypasses the need for male gametes. Thus, it is argued that development of reproductive cloning would help couples who otherwise would remain childless. If this argument is accepted, then some would push to the conclusion that reproductive cloning is acceptable for any couple.

However, even if one holds this view, it is clear that caution is still very necessary. Twenty‐one years after the birth of Dolly, no primate has yet been cloned, notwithstanding that a few clones of both rhesus monkey and human have been developed as far as the blastocyst stage (see below).12 In the work with monkeys, attempts have been made to establish pregnancies with some of the cloned embryos but with no success. Attempting to undertake reproductive cloning of humans at this stage in the development of the procedure would be to treat humans and women especially, as experimental objects. In particular, any woman who becomes pregnant as a result of implantation of a cloned embryo carries a significant risk of experiencing the spontaneous abortion of a malformed foetus or, perhaps worse, of bringing to term a seriously malformed baby. Many people, even those who do not have any intrinsic objections to reproductive cloning, would find it unacceptable to use women in this way, effectively as experimental material. Indeed, most scientists, including those who cloned Dolly, suggest that, notwithstanding any other arguments, these grounds alone are enough to prevent attempts at human cloning. Further, in terms of conventional medical ethics, the very high risks of this procedure are not at present justified by the possible benefits.

The objections set out above are essentially based on risk and in particular on the very high risks of failure, failure of a type that may prove very traumatic. No specific intrinsic objections are raised. Thus, some would argue that the way is left open for reproductive cloning, should the risks become low enough and the success rate high enough to be acceptable at least in the context of offering help to certain infertile couples. Indeed, this type of argument has often been presented in the media. However, there are other risks that are not reduced by improvements in the cloning procedure per se and these are the risks to the clone himself or herself. Unlike IVF, cloning bypasses the coming together of gametes (eggs and sperm) of different genetic make‐up that sets up a new genetic mix (which is one of the functions for which sexual reproduction is believed to have evolved). Routine IVF techniques (Chapter 3), although they separate the act of sexual intercourse from the process of procreation, preserve this coming together of the genetic material from the two parents. Again it is emphasised that naturalness or unnaturalness are not in themselves strong factors in the ethical argument but this very marked biological difference between cloning and sexual reproduction may be a factor in discussion. Further, the DNA that is used to support the development of the egg is the result of a long biological history and often needs unusual treatment in order to reverse its developmental state. It is not at all clear that these processes are risk‐free or ever will be. Has the DNA accumulated a lifetime’s worth of unrepaired damage? If so, will the new embryonic environment enable the DNA to be repaired? At present there are no generally applicable answers to these questions: the situation seems to vary from species to species. Dolly, the first mammal cloned from an adult cell, suffered early onset of degenerative disease, as if she was as old as her clone donor but it is not clear whether this is a widespread problem. Further, some other cloned mammals have died soon after birth (see Section 5.6), while others do not appear to suffer health problems. Human clones are thus exposed to unknown and unquantifiable health risks (i.e. if human cloning is ever actually achieved). What has become clear as research on cloning of non‐human animals has continued is that cloning of primates is very difficult indeed.

For further consideration of the ethics of cloning, it is helpful to think of the reasons (other than helping couples to overcome fertility problems) there may be for cloning a human. As mentioned already, some of the earlier enthusiastic and positive responses to the possibility of cloning humans were based on the wish to recreate a specific person such as a loved one. The mistake inherent in this idea has already been dealt with: a clone will reproduce a genotype (i.e. a specific set of genes) with no guarantee of how that clone will turn out as a person. Our personhood relies on very much more than our genes. We cannot manufacture a particular person by copying a particular genotype. However, because the genetic material used to create a cloned embryo is taken from a cell in an adult, it would be possible to have a good idea of how the genotype will be translated into the physical phenotype – in other words, how the clone will ‘turn out’ physically. Even this aspect of development is subject to environmental influences, again including the environment in the womb, but nevertheless, the likelihood of physical resemblance to the DNA donor might provide enough incentive for some people to try (as in the fictional situation presented in Fay Weldon’s novel; Section 5.3). Having said that much it also must be emphasised here that mammalian cloning is not mass technology; furthermore, based on 60 years’ experience of cloning frogs and 40 years’ experience of human IVF, it is very unlikely to become so. The projected scenario is not one of creating armies of drones to carry out menial jobs as in Brave New World, nor of creating football teams. The film The Boys from Brazil often crops up in discussions of cloning but the plot, although good fiction, is very far‐fetched. Nevertheless it is clearly possible to think of reproducing a specific genotype with characteristics desired by those attempting to bring a cloned child into the world, even if at the present time (mid‐2017) it seems very improbable.

This possibility of cloning to copy a specific genetic make‐up raises a number of questions, one of which has been posed immediately above. Another question is whether the procedure makes the cloned child a commodity in that there is the attempt to fulfil the specific wishes of other people. Whatever one thinks about treating the rest of the living world in this way (e.g. in the use of farm animals), treating another human as a commodity, that is, in a specifically instrumental way, again contravenes any ethical code based on the autonomy, dignity and worth of the individual. However, it is also true that people have children for a variety of reasons, some of which certainly look as if the child is indeed a commodity (as discussed more fully in Chapters 3 and 6). This issue is not therefore specific to cloning but has more general applications to the reasons for choosing to have children and to ways in which humans treat each other in general.

This leads us to think about the emotional/mental health of any child who is born as a result of these cloning procedures. Will their very unconventional origin have any psychological effects? We simply do not know, although we can say that it is likely to vary from person to person. For people produced by cloning, the genetic mother and father are one generation further back than in normal sexual union; the clone did not arise from a conventional fertilisation and did not therefore have a mother and father in the biological sense, at least in the way in which we normally use those terms. Knowledge of this may well be disturbing. Further, the clone will have been created specifically to fulfil the wishes of others, leading to social and emotional pressure that some will find hard to deal with. However, the latter point is not specific to cloning. Many parents place expectations on their children and may make arrangements on their children’s behalf to push them towards fulfilling those expectations, even to the extent of living emotionally through their children. While some children cope with this with no apparent difficulty, others rebel against fulfilling the wishes of their parents, while yet others may believe themselves to be failures or even experience feelings of rejection if they do not (or in their own minds do not appear to) live up to their parents’ expectations. Would a person feel any greater pressure if those expectations were based on the fact that they were genetic copies of another person? Again we do not know.

5.5 The Ethics of Human Cloning: An Overview

In the previous section we have raised a number of problems, risks and unresolved questions relating to human cloning. The key points may be summarised as follows:

  • It is a technique with a very variable success rate, depending on species.
  • Until this is resolved, women who take part in cloning procedures would be subjects of highly experimental and very controversial procedures.
  • There are unresolved questions about the health of some cloned animals; these may also apply to humans but we just do not know.
  • The risks far outweigh any supposed benefits.
  • Except in instances where cloning is used as a last‐resort procedure in fertility treatment, there will be questions about the motivation of those who wish to bring clones into the world.
  • The view that cloning can recreate a specific person is mistaken.
  • These may be emotional problems for cloned children who will be under pressure to live up to particular expectations.
  • The unusual origins and the uncanny resemblance to the clone donor may be emotionally and/or psychologically harmful.

In summary then, it is clear that from the start of the cloning procedure through to the life of the cloned person themselves, there are several serious unresolved (possibly unresolvable) problems and risks. Although these may not be specific to cloning per se, they are enough for many people reason to support a ban on reproductive cloning. However, as pointed out earlier in the chapter, there are some who argue that there are no intrinsic ethical objections to human cloning. Their position on the problems summarised above is that to ban cloning for these reasons would be to do so on consequentialist grounds. In other words it would be concerns about the consequences that might lead to a prohibition. And of course, some of the problematic consequences may melt away as the biomedical community improves the procedures used in cloning. However, there are other views in this debate.

For Roman Catholics and for some other Christians, cloning is forbidden specifically because it is one of several procedures that separates sexual activity from procreation (a position that we also encounter in Chapter 3). This is a deontological viewpoint based on what are perceived to be the teachings of the Bible as interpreted by the Roman Catholic Church. Moving into the cloning methods themselves, it is likely that in any cloning procedure, attempts will be made to create several embryos and of those that reach the blastocyst13 stage, some will be rejected. This will raise objections from anyone who holds a strictly conservative ethical view of the early embryo, however it comes into being; for example, some believe that the very early embryo, even before implantation in the womb, is a human person (or at least, should be treated as a human person). To reject and destroy an embryo is, in this view, to reject and destroy a person. (We discuss this view more fully in Section 5.7.2.)

Thinking now of more widely held ethical positions, we have suggested that currently, any woman undertaking to carry a cloned embryo and any cloned person who is born would firstly be ‘experimental material’ and secondly would be exposed to several types of risks, risks that cannot be evaluated or quantified until several ‘experiments’ had run their course. In Kantian ethics, one of the categorical principles is that one human does not use another as a means to an end and this deontological position is obviously applicable to cloning. Further, this is similar to the virtue ethics principles of treating others as we would be treated ourselves that are embedded in the practice of several religions and also in humanism and in the Victorian ‘golden rule’. In respect of virtue ethics, we can also bring in specific virtues: firstly, there is the virtue of wisdom and secondly the virtue of empathy; the latter translates into concern for others about the outcomes/consequences of cloning. Both these sets of principles (Kantian categorical principles and virtue ethics) also come into play in dealing with motivations for making a specific genetic copy of any person.

Two other ethical positions must be mentioned. The first of these is moral repugnance, a widespread feeling, perhaps based partly on the ‘yuk factor’, that this is wrong. We have argued elsewhere in this book that ethics based purely on the yuk factor does not work but in some instances, repugnance goes deeper than the yuk factor. Thus, ethicists in both the United Kingdom and the United States have suggested that repugnance about human cloning reflects a position, based on our common humanity (as emphasised by humanism and by most religions), that to try to make another copy of another person is simply wrong. The second position is based on human rights. Thus the EU now has legislation that asserts the right of every person to their own genetic identity. One wonders whether, prior to enacting this legislation in the months following the birth of Dolly, there had been enough thinking about, for example, identical twins, or about those people who receive many copies of another’s genome in the form of an organ transplant. Nevertheless, the message is clear: according to this legislation, cloning is not compatible with the human rights of an individual.

5.6 Reproductive Cloning of Non‐human Mammals

The list of mammals that have been cloned grows relatively slowly but now includes sheep, cow, cat, dog, mouse, mule, horse, pig, deer, coyote and water buffalo. Even though some of these, such as dog, have been cloned hundreds of times, the procedure cannot yet be described as routine for all of these species. Difficulties may occur at any stage, including creation of the initial embryo, formation of a blastocyst, establishment of a pregnancy, foetal development, birth and lifespan. Further, the extent to which any of these is a problem varies greatly between different groups of mammals. Thus, once conditions had been optimised, cloning of dogs and cows has proved quite straightforward, while at the other end of the range, primates have proved very difficult to clone. Indeed, to date, no primate clone has survived beyond the early pregnancy stage and most have not lived past the embryo stage. Nevertheless, work on mammalian cloning continues, with four main purposes.

Firstly, there is a wish to achieve a greater understanding of developmental genetics, epigenetics and imprinting.

Secondly, cloning is a way of multiplying useful or valuable genotypes. These may include elite strains of cattle, GM animals that produce pharmaceuticals in their milk (as with Dolly) and animals that are useful but sterile (such as mules). With cattle, this is now a commercially viable procedure; in the United States, the meat from cloned cattle was, in 2008, declared to be safe for human consumption and is in the human food chain. In China, a pig cloning ‘factory’, producing about 500 animals per year, has been in operation at Shenzhen since 2014. More recently, in order to meet the growing demand for consumption of beef, a huge cattle cloning facility has been set up in Tianjin and started production in 2016.14 The project is a joint venture between a Chinese company, BoyaLife, and a South Korean Company, Sooam Biotech, and when fully functional, the facility is expected to produce 100,000 beef cattle per year, plus some ‘sniffer’ dogs and some elite racehorses. The director of the project and the CEO of BoyaLife, Xu Xiaochun, says that the factory could also make a valuable contribution to saving endangered species from extinction.

These cloning ‘factories’ represent a large‐scale application of scientific knowledge in response to a clear market demand. Most of us are amazed that it can be done on this scale. However, two notes of caution needed to be sounded. First, even if several different genotypes are being cloned at any one time, large numbers of each genotype will be generated. If a particular genotype is or becomes susceptible to, for example, a new strain of virus, it may well be disastrous for all who are using that particular genotype for meat production. Secondly, as noted above, these cloning facilities are partly a response to increased demand for meat, especially beef. This raises environmental concerns. Because the cattle feed on plants or plant products, land must be devoted to growing their food, whether it is grass or feed derived from farmed crops. On average it takes six times as much land to feed humans on beef than on a vegetarian diet, notwithstanding recent improvements in farming efficiencies and in the breeding of cattle that better utilise nutrients in their feed.15 This clearly has implications in respect of land availability for feeding a growing world population (Chapter 15).

This leads neatly to the third main motivation for pursuing mammalian cloning, namely, to multiply endangered or recently extinct species. A very rare Asian wild ox, the gaur, has been cloned although the animals died within a day of birth. More successful was the cloning of another rare bovine species, the banteng, and of a wild sheep, the mouflon, where the cloned animals survived at least into young adulthood. With African wildcats, use of domestic cats as surrogate mothers initially led to the birth of 17 kittens,16 of which ‘seven were stillborn, eight died within hours of delivery or up to six weeks of age and two remained alive and healthy’. There has been some success with grey wolves17 in that three healthy pups were born from domestic dog surrogate mothers, but this was a very small proportion of the 372 embryos introduced into 17 surrogates. The first extinct animal to be cloned was the Pyrenean ibex (a subspecies of the Spanish ibex).18 Fibroblasts from the last known individual (a female) were frozen when it died in 2000 and these cells were used in cloning procedures with Spanish ibex or ibex–goat hybrids being used as surrogate mothers. One kid was born but it only lived for seven minutes. Hopes of resurrecting the thylacine or Tasmanian tiger were dashed at an even earlier stage. The project started in 1999 but was abandoned in 2005 because the DNA of preserved specimens was too degraded. However, efforts were renewed in 2013 with the availability of new DNA sequencing and DNA repair methods (but, in early 2017, still with no success). In the meantime, it is likely that attempts to clone mammoths will also run into problems relating to DNA integrity.

We should note that because cloning is a difficult procedure with a low success rate it seems unlikely that enough individuals of a given species could be reproduced this way to achieve the aim of saving a species. Further, it would create a population with very little genetic variation that, as occurs in many inbred groups, may lead to a high frequency of genetic disease. Many conservationists believe that for endangered species it is better to deal with the factors that have caused them to become endangered, for example, habitat degradation or loss, rather than using a sophisticated and difficult technique in order to increase numbers. Nevertheless there are some who are enthusiastic about cloning both of endangered species and in efforts to bring back extinct animals.19

The fourth main reason for continuing work on cloning is the replication of cherished pets. In South Korea a cloned Afghan hound (‘Snuppy’) was produced in 2005 and now the team that produced him, led by Hwang Woo‐suk (see Section 5.7.3) at a privately funded research institute, produces cloned dogs at a price of around $90,000–$100,000 each. He had planned to provide the service in the United Kingdom and to publicise this he offered, early in 2014, a free clone as a prize in a competition. Rebecca Smith will thus be remembered as the owner of the United Kingdom’s first cloned dog, born in March 2014, which is a copy of her pet dachshund. However, the planned UK facility did not materialise but several British dog owners have used the service in South Korea. Hwang uses the money from these commercial ventures to offset the cost of the more medically oriented work at his institute. There has also been some cloning of pet cats, mainly in the United States but not on the same scale as dogs.

For all these applications, there are issues related to animal welfare. The likelihood of the mother experiencing difficult pregnancy and birth and of the offspring suffering developmental abnormalities and health defects remains very high for some of these species. Even for easy‐to‐clone species, birth defects occasionally occur. We are thus faced with the question that is common to any use by humans of animals: how far should we expose non‐human animals to suffering in order to supply human needs? This topic is covered in depth in Chapter 13. Here we just need to say that there are some people who would include cloning in their opposition to all activities that treat non‐human animals merely as commodities. Others may take the line, adopted by the United Kingdom’s Research Defence Society, that some use of animals in research is justified if it contributes to a decrease in human suffering. On this view, some applications of cloning may be acceptable but essentially trivial ones are not. This view is echoed, for example, by the Science, Religion and Technology Project of the Church of Scotland, which is highly critical of the cloning of pets.

5.7 Unlocking the Genetic Potential of Stem Cells

5.7.1 Embryonic Stem Cells

At the time of writing the first edition of this book, one of the more controversial developments in biomedical science was research on human ES cells, a topic that, as will become apparent, is related to cloning. In the United Kingdom, the topic continued to be debated vigorously as a result of the provisions for this work in the 2008 version of the HFE Act. Although the heat of the discussion has somewhat declined over the last few years, the topic remains controversial for some people. The research is aimed at making it possible to use particular cells in the early human embryo as sources of ‘spare parts’ for tissue and organ repair. To understand this, it is necessary to describe the early stages of mammalian embryonic development (see also Figure 4.1). The zygote, the fertilised egg, contains all the genetic information necessary for the complete development of the adult mammal. The zygote is thus said to be totipotent. This totipotent state is retained by all the embryo cells through the first few rounds of cell division until the blastocyst stage is reached at about five or six days after fertilisation. As shown in Figure 5.1, the embryo is at this stage a hollow ball in which a dense group of cells, the inner cell mass, hangs from the outer cell layer. During normal development, the inner cell mass grows out through the outer cell layer (‘hatches’) and begins to attach to the lining of the uterus, thus establishing a pregnancy. These cells of the inner cell mass go on to develop into the foetus. Meanwhile, the cells of the outer layer of the blastocyst give rise to the placenta. Thus, at the blastocyst stage, the outer cell layer has lost the potential to develop into a fully formed mammal and the inner cell mass has lost the potential to form the placenta but it does of course retain its much wider potential of being able to grow into the whole living mammal. At this stage, therefore, the cells of the inner cell mass are stem cells, cells that have the developmental potential to form many different types of cell and, in this particular instance of ES cells, all the different types of cell that occur in the mammalian body. In genetic terms these cells are totipotent but because at this stage of embryonic growth they have lost the developmental capacity to form the placenta, they are not developmentally totipotent.20 They are thus described as pluripotent stem cells.

The terms of the original HFE Act in the United Kingdom allowed the creation of embryos in vitro not only to enable subfertile couples to have babies but also for specific research projects relating to human reproduction (see Chapter 3). However, in practice such research is mostly carried out with ‘spare’ embryos from IVF rather than with embryos created specifically for research, the latter amounting to less than 1% of the total. Nevertheless, following the recommendations of a committee chaired by the United Kingdom’s chief medical officer, Professor Liam Donaldson, the HFE Act was amended in 2001 to extend the research use of in vitro embryos to include research on ES cells. This legislation was further clarified and strengthened in the 2008 version of the Act (as mentioned above). However, although this opened the door to the creation in vitro of embryos specifically in order to generate ES cells, in practice much of the research on human ES cells is still carried out with spare embryos from IVF treatments.

5.7.2 Therapeutic Potential

Developmental biologists have had some success in persuading mouse ES cells to grow into particular cell types in the laboratory. This led the United Kingdom’s HFEA to grant licences to particular laboratories for the culture of human ES cells, derived from the blastocyst. As with mouse, it has proved possible to induce the formation of a range of specialist types of cell from these human ES cells. This reinforces the idea that ES cells may in the future be used to repair tissues and organs damaged by disease or accident. However, even in 2017 such treatment would still be very much an experimental procedure and both clinicians and patients need to be aware of the possibility that stem cells may revert to a tumorous phenotype, which may lead to the formation of teratomas.

Concerns about safety have been amongst the reasons for the slow progress in developing therapies based on ES cells.21 Across the world, there exist several hundred human ES cell lines but despite this there have been very few clinical trials of therapies based on these cells. A trial initiated in 2011 by a US company, Geron, on the use of ES cells to cure spinal cord injuries was discontinued on grounds of cost. In 2012 through to 2016 further trials had been initiated by another US company, ACT, in relation to curing conditions of the retina. These have been at least partially successful.22 Other applications include repair of damaged heart muscle – cardiac cells have been developed from ES cells – and reversal of neurological degeneration, albeit that these are at an early stage of research. Thus, progress seems very slow after the wave of optimistic predictions at the beginning of the century. Indeed, as recently as 2016, it was suggested that ‘The large‐scale availability of treatments involving pluripotent stem cells remains some years away…’.

5.7.3 Embryonic Stem Cells and the Ethical Status of the Early Human Embryo

As mentioned above, ethical discussions in the United Kingdom about this work have largely disappeared from the public domain but from time to time resurface. Nevertheless, differences of opinion remain.

Firstly, as we have already noted in Section 5.5, there are those who view the earliest human embryo, the one‐celled zygote, as a human person or at least suggest that it should be treated as if it was a human person (see also Chapters 3 and 4). The following points are often made in support of this position:

  • Each zygote has a unique human genotype that has never existed before and will never exist again (unless the embryo splits to form identical twins).
  • Given the right conditions in the womb, the embryo will develop into a foetus and thence into child.

On these grounds there can be no such thing as a spare embryo; it would like saying that a fully formed human was a spare person. Based on this view, IVF treatments should only involve creating one embryo at a time, with each embryo thus created being given a chance to establish a pregnancy by implantation in the womb. Further, the deliberate diverting of embryonic development to establish a stem cell culture is regarded as destroying a human life (and some would go as far as defining this act as murder). According to this view, it matters not whether the embryos are ‘spare’ ones from IVF treatment or have been created specifically for establishing a stem cell culture, their use in this way is wrong.23 It will be obvious to our readers that this is a deontological position.

On the other hand, the majority view in the United Kingdom does not bestow human personhood on the early human embryo. Thus it is pointed out that in nature, 70–80% of very early embryos do not implant into the lining of the womb and thus do not establish a pregnancy. If all these early embryos are lost then, the argument goes: it is difficult to regard each one as a human person even though each one has a unique set of genes. They also point out the following features of early development:

  • It is not until several rounds of cell division have occurred that the allocation of specific cell lineages to placenta and to embryo is made.
  • Even after this, the embryo itself may split to form identical twins, suggesting that the early embryo cannot yet be regarded as a human individual.
  • There is evidence that, as has been observed in other mammals, two very early non‐identical embryos may on rare occasions merge to form one that develops normally.

On these grounds, the use of early embryos to create stem cell lines does not mean ending the life of another human person. Further, the use of spare embryos may be regarded as an ethical good: these spare embryos, unless the ‘parents’ had given permission for research use, would, after several years of deep‐frozen storage, be discarded. Their use for stem cell research can instead bring major benefits to existing humans and thus to society at large. This is a view strongly espoused by the Australian philosopher and bioethicist Peter Singer (based at Princeton University, United States). Readers will recognise this as a consequentialist and, more specifically, a utilitarian argument.

While the previous paragraphs have set out the two main positions in the debate about stem cells, there are others who ask whether a middle course is possible. Dame Mary Warnock was the chair of the committee whose recommendations led to the HFE Act (1990) and to the establishment of the HFEA. At face value, the Warnock Report, published in 1984, supports a very utilitarian view of the early embryo:

‘According to the majority view, the question was not, as is often suggested, whether the embryo was alive and human or whether, if implanted, it might eventually become a full human being. We concluded that all these things were true. We nevertheless argued that, in practical terms, a collection of 4 or 16 cells was so different from a full human baby or a fully formed foetus, that it might quite legitimately be treated differently. Specifically, we argued that, unlike a full human being, it might legitimately be used as a means to an end that was good for other humans’.24

However, the same report urged ethical respect for the human embryo and suggested that it ‘ought to have a special status’ under English law. This would mean that early embryos were not be used for trivial research.

Of course, use of human embryos to create stem cell cultures was not envisaged when the Warnock Report was written nor when the HFE Act was established in 1990. This topic was however very much part of the amendment to the Act, debated in 2000 and 2001 and passed in 2001. Mary Warnock voted against the amendment in the House of Lords on the grounds that, despite her views as set out in the quotation above, she believed that to create embryos as sources of stem cells would be a step too far in their commodification. She has since changed her view and supported the 2008 version of the Act, which further clarified the law on human ES cell research. Nevertheless, there are people who do not believe that early human embryos are human persons but still have misgivings about their use to generate stem cells. They suggest that this use is so far from their natural course of development (even given that 70–80% fail to undergo this) that it does indeed represent a step too far in their commodification. However, this is certainly a minority view in the United Kingdom, with most of the debate occurring between the proponents of the two main views set out above.

This section would not be complete without a brief discussion of the situation in the United States. During the first term of office (2001–2005) of President George W Bush (Republican), use of human embryos for stem cell research was banned, except that a limited number of embryos, held frozen for possible future research, were exempted. Scientists wishing to embark on this type of research therefore had some, albeit very limited resources, at their disposal. As with the ban on reproductive cloning mentioned earlier, it applied only to federally funded laboratories. In theory, non‐federally funded scientists could be very active in this area. In general though, the debate has been along to the two main lines that were set out above, the main difference being that a larger proportion of the US population than the UK population ascribe human personhood to the very early embryo. Nevertheless, ES cell research had and still has some high‐profile supporters in the United States, including the actor Michael J Fox; Ronald Reagan Jr, son of a former Republican president; and perhaps most famously, the former actor Christopher Reeve (‘Superman’). Reeve, who was extensively paralysed after a riding accident (and who eventually died in 2004 from complications arising from his paralysis), was convinced that such research would one day enable him to walk again. He was angry about the federal ban, stating, for example, that ‘bigots are delaying my recovery’. The stem cell debate even featured in the 2004 US presidential election campaign with the Democrat challenger Senator John Kerry publicly supporting such research (and it is interesting that a Roman Catholic should take this view), while the Republican incumbent, President George W Bush, well known as a Protestant Christian, maintained his opposition to it. However, the ban was lifted in March 2009 when the newly elected President, Barack Obama (Democrat), signed an Executive Order ‘Removing Barriers to Responsible Scientific Research Involving Human Stem Cells’. Nevertheless, even now in 2017, the debate continues, with the ‘religious right’ in particular remaining opposed to this work.

5.7.4 Therapeutic Cloning

Research on ES cells has the immediate scientific aims of discovering what factors maintain cells in this juvenile state where they can give rise to all other cell types and of discovering the factors that control this formation of specialised cells. It also has the medical aim of using this scientific knowledge in providing tissues for transplant into patients in order to effect repairs. One of the problems with transplants is that of rejection and for this reason, the clinicians and scientists in the transplant team will seek tissue that is as close an immunological match to the recipient as possible. It can be readily understood therefore that using cloning methods to create embryos as sources of stem cells may have significant advantages. A person who needed a particular transplant could be ‘cloned’ by nuclear replacement but without the aim of implanting the embryo into a womb. Instead, it would be used to generate stem cells that would be immunologically matched to the patient and thus any transplanted tissue or organ derived from those cells is unlikely to be rejected.

The difficulties involved in cloning have already been noted as has the fact that those difficulties begin at the very start of the process. Further, as we have mentioned already, there seem to be particular problems with primates. The report in 2004 – that human stem cell cultures had been established from cloned embryos in Professor Hwang Woo‐suk’s laboratory in South Korea – was thus received with great acclaim. That acclaim grew further in 2005 when the same team announced that they had established stem cell lines from patients with degenerative conditions. However, despite the fact that both papers had come through the peer review process in the prestigious American journal Science, it became apparent that most of the data had been made up. The only thing that the team had achieved was the creation of some cloned embryos, several of which reached the blastocyst stage. This was clearly a case of major scientific fraud. The journal retracted the papers,25 and Professor Hwang lost his job (although he now heads a privately funded cloning laboratory, still in Korea; see Section 5.6). The stem cell community returned to their efforts to create cloned human embryos with, for a long time, very limited success. However, in 2013, a group in Oregon, United States, announced that they had established human stem cell lines from cloned embryos that had reached the blastocyst stage26; this time it was for real. Use of such cell lines in therapy is still a long way off, but this is a start. Since then, there have been just a few more reports of the establishment of cell lines from cloned human blastocysts; one of these cell lines was from a patient with type I diabetes.27 However, the procedure has not been used therapeutically.

Most of the ethical reactions have been very much along the same lines as the two main positions relating to ES research in general, with those who hold that the early human embryo is a full human person being firmly opposed to this work. Indeed, when the first UK licence for therapeutic cloning was issued in 2004, a legal challenge to that decision was made by a group of lawyers acting on behalf of a conservative Christian organisation; the challenge was unsuccessful. However, in addition to the clear positions set out previously, we encounter another less definable reaction, namely, that if we accept cloning technology in order to generate stem cells, then it will make easier to accept reproductive cloning. This of course is an example of the slippery slope argument, an argument that is rejected by many ethicists, including Mary Warnock, but accepted by others, including, in the United States, the influential commentator Leon Kass, a former chair of the President’s Advisory Committee on Bioethics.

5.7.5 Adult Stem Cells

Although ES cells have the widest potential for development into many different types of cell (because that is their function in normal embryonic development), they are not the only type of stem cells. Fully formed mammals also have stem cells, different populations of which are responsible for replenishing cells that have short lives (such as blood cells), wound healing and tissue repair. For example, the stem cells in bone marrow give rise to all the different types of blood cell and to some cells of the immune system. They differ from ES cells in that they can only give rise to a limited range of cell types. Further, some tissues have only a limited capacity for repair. Nevertheless, there is active research on adult stem cells and especially on the process of trans‐differentiation, that is, the ‘persuasion’ of one type of stem cell to undergo a developmental pathway that is not its normal one. Indeed, there have been some success with this and a small number of clinical trials, involving several types of adult stem cells, have been carried out. Details lie outside the scope of this chapter except to say that it now appears possible that there may be the potential to generate, from a small range of adult stem cell types, a bank of stem cells for use in tissue repair and transplant therapies.28

One further issue relating to adult stem cells needs to be discussed. The successes, albeit limited in number, in using adult stem cells in various clinical trials (as mentioned above) has led in several countries, including the United States and the United Kingdom, to the current potential of stem cell therapy being very much exaggerated. In some instances this comes from those opposed ethically to the use of ES cells who will look to any possible alternative. However, perhaps more worryingly, it has also led to the commercial provision of effectively untried stem cell therapies, offered for a wide range of conditions and usually at a high price. Further, in many countries, the regulation of clinics offering these therapies may be lax. Even in the United States this may be true: a 2016 survey29 revealed a ‘burgeoning, huge industry from coast to coast’ of 570 clinics that were offering stem cell therapies without approval from the Food and Drug Administration (FDA). Further, in Australia, one clinic was showing the ‘Hallmarks of quack medicine’ according to the coroner dealing with the death of a woman who had undergone stem cell treatment.30 Patients are clearly at risk because of the lack of clear regulation. Perhaps the inclusion of stem cells in The Biotech Investor’s Bible (see quotation at the head of the chapter) raises the possibility that commercial considerations sometimes override other issues. Nevertheless, as pointed out by the authors of the 2016 survey, this should not deter research into the development of treatments using adult stem cells.

Of course, one of the factors that will influence answers to that question is one’s view of the early human embryo. Those who hold an ethically conservative view of the early embryo will press for research on adult rather than ES cells, and such views have certainly been expressed publicly in the United Kingdom and United States. Further, they may argue that if more resources were put into such research, adult stem cells may turn out to have at least the same potential as ES cells and will point out some of the successes reported so far. People holding opposing views will suggest that adult stem cells may have some potential but that there can be no denying the natural broad potential of ES cells. If resources are limited, it is the latter that should be prioritised for funding. This is thus just one more element in a debate that seems set to run and run.

5.7.6 Novel Sources of Stem Cells

It will be very obvious from what has been written so far that some people will continue to find the use of ES cells ethically unacceptable. For that reason there has been pressure on medical researchers to find other sources of cells that have the same potential as ES cells. In other words, are there any other types of cell that are pluripotent? In respect of mammalian development, the simple answer is No. However, it has been possible to generate pluripotent cells from other cell types. In 2006 and 2007, scientists in Japan31 and in the United States announced that they had succeeded in transforming fibroblasts, a type of adult stem cell, into pluripotent stem cells, similar to ES cells.32 The key to converting the fibroblasts back to the ‘youthful’ state was the insertion of four genes that are active in ES cells but are switched off in adult stem cells. The cells are called induced pluripotent stem cells (iPS cells) and have the added advantage that a cell line can be made from the specific individual who is in need of stem cell therapy, thereby avoiding the need for therapeutic cloning (see Section 5.7.4). Indeed, one commentator stated that the development of iPS cells meant that ‘therapeutic cloning is dead’. No wonder then that people and organisations opposed to the use of human embryos dubbed these cells ‘ethical stem cells’.

However, there are also ethical issues relating to iPS cells, mainly in the area of risk. In particular, the genetic modification techniques used in generating these cells increase the possibility of activating oncogenes, genes involved in the formation of cancers. Indeed, the risk of inducing cancer was regarded as too high for these cells to be considered for medical use. This of course stimulated further research and at the end of 2009 a method had been developed to introduce not genes but the relevant proteins themselves into the cells32. The first clinical trial of these cells, to repair macular degeneration in the eye, was initiated in Japan in 2014.33 However, the trial was halted in 2015, after just one patient had been treated, because there were concerns that subtle genetic changes had occurred in the cells. To date, this remains the only clinical trial of iPS cells, although there are several treatments ‘in the pipeline’. And actually, for many developments in medicine, it takes about 20 years to go from the scientific discovery to clinical applications, so the ‘timeline’ for iPS cells is not unusual.

iPS cells obviously offer the possibility of stem cell therapies tailored for individual patients. However, the procedure for making them is not straightforward. Because of this, the biomedical community and the world’s media thus reacted very enthusiastically to a paper published early in 2014 in the prestigious UK journal Nature, showing that pluripotent cells could be generated by a much simpler method.34 The claim was that mouse spleen cells could be induced to become pluripotent by 30 min dip in weak acid. The cells were then able to grow into any type of cell in the body, as if they were ES cells. These cells were named STAP cells (stimulus‐triggered acquisition of pluripotency). In addition to spleen, the method apparently worked with several other types of mouse cell and there were indications that it also worked with human fibroblasts. But then questions started to be asked. Some of the data in the paper seemed to have been ‘improved’; other researchers could not repeat the results. Just a few weeks after publication, the lead author on the paper, Haruko Obokata, was deemed to have committed gross scientific misconduct and the papers describing the work were withdrawn. The head of the research group (at the RIKEN Centre in Japan), an author on the paper, committed suicide.

However, after extensive investigation, it eventually became clear that, although there had been some possibly unwarranted image manipulation, Obokata had not committed a deliberate scientific ‘crime’. The truth was much more mundane: her cultures were contaminated with stem cells. It was carelessness, not misconduct.

5.8 Concluding Remarks

This is a long and complex chapter that has explored the genetic potential of somatic and embryonic cells in the contexts of cloning and stem cell therapies. As has been made apparent, these topics are intertwined and raise ethical issues, both on their own and when considered together. In respect of medical therapies, there is, in the ‘developed’ countries of the world, a widely perceived need to widen the scope and potential of regenerative medicine. Some of this need arises because of our increasing lifespans. The fact that we are living longer (see Chapter 8) is generally regarded as a good thing. However, it does mean that degenerative conditions, including some forms of dementia, are becoming more widespread, although a healthy and active lifestyle may stave off some of them. The development of a routinely workable ‘tissue repair kit’ has become a major prize. Inevitably, with research of a complex nature, there have been several false starts. Earlier hopes have not been fulfilled. For example, applications that seemed to work in some patients did not work in others, while clinical trials have been halted because of safety concerns. Further, this area of research has been associated with incidences of scientific misconduct including falsification and/or ‘improvement’ of data; some medical practitioners have cut corners or offered commercially untried procedures. The advancement of scientific knowledge and of its application in medicine relies on the integrity of scientists and clinicians; otherwise the whole edifice would collapse. However, when the prizes are glittering enough, people in these professions may be as prone as anyone else to succumb to temptation.

Key References and Suggestions for Further Reading

  1. Bouchard TJ (2004) Genetic influence on human psychological traits: a survey. Current Directions in Psychological Science 13, 148–151.
  2. Cyranoski D (2007) Cloned monkey stem cells produced. Nature, 14 November 2007. http://www.nature.com/news/2007/071114/full/news.2007.245.html (accessed 23 September 2017).
  3. Folch J, Cocero MJ, Chesné P, et al. (2009) First birth of an animal from an extinct subspecies (Capra pyrenaica pyrenaica) by cloning. Theriogenology 71, 1026–1034.
  4. Garg A, Yang J, Lee W, Tsang SH (2017) Stem cell therapies in retinal disorders. Cells 6, 4. doi:10.3390/cells6010004.
  5. Gómez MC, Pope CE, Giraldo A, et al. (2004) Birth of African wildcat cloned kittens born from domestic cats. Cloning and Stem Cells 6, 247–258.
  6. Graf T (2011) Historical origins of transdifferentiation and reprogramming. Cell: Stem Cell 9, 504–516.
  7. James O (2016) Not in Your Genes. Penguin/Random House, London.
  8. Kennedy D (2006) Editorial retraction. Science 311, 335.
  9. Nuffield Council on Bioethics (2002) Genetics and Human Behaviour: The Ethical Context. Nuffield Council, London.
  10. Oh HJ, Kim MK, Jang G, et al. (2008) Cloning endangered gray wolves (Canis lupus) from somatic cells collected postmortem. Theriogenology 70, 638–647.
  11. Phillips T (2015) Largest animal cloning factory can save species, says Chinese founder. The Guardian, 24 November 2015. https://www.theguardian.com/world/2015/nov/24/worlds‐largest‐animal‐cloning‐factory‐can‐save‐species‐says‐chinese‐founder (accessed 23 September 2017).
  12. Quill E, Shapiro B (2015) These are the extinct animals we can and should resurrect. Smithsonian Magazine, May 2015. http://www.smithsonianmag.com/science‐nature/these‐are‐extinct‐animals‐we‐can‐should‐resurrect‐180954955/ (accessed 23 September 2017).
  13. Scudellari M (2016) How iPS cells changed the world. Nature 534, 310–312.
  14. Smith A (2014) Cell biology: potency unchained. Nature 505, 622–623.
  15. Tachibana M, Amato P, Sparman M, et al. (2013) Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153, 1228–1238.
  16. Trounson A, DeWitt MD (2016) Pluripotent stem cells progressing to the clinic. Nature Reviews: Molecular Cell Biology 17, 194–200.
  17. Turner L, Knoepfler P (2016) Selling stem cells in the USA: assessing the direct‐to‐consumer industry. Cell: Stem Cell 19, 154–157.
  18. University of Turku (2017) New insights into mechanisms regulating gene expression in embryonic stem cells. Science Daily, 31 May 2017. www.sciencedaily.com/releases/2017/05/170531103319.htm (accessed 23 September 2017).
  19. Willmott C (2016) Biological Determinism, Free Will and Moral Responsibility: Insights from Genetics and Neuroscience. Springer, Basel.
  20. Wilmut I, Schnieke AE, McWhir J, et al. (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813.
  21. Yamada M, Johannesson B, Sagi I, et al. (2014) Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells. Nature 510, 533–536.

Notes