A practical barrier

The practical barrier concerns the risk that maintaining cell lines in vitro will lead to epigenetic changes that may be transmitted via gametes derived from these cell lines to the next generation of embryos.^vii The possibility of epigenetic changes impacting on gametogenesis is a barrier to the creation of gametes for reproductive purposes from stem cells. Scientists will need to be confident that the gametes they produce have normal chromatin and patterns of methylation before it would be ethical to contemplate using them for reproductive purposes.^viii However, the iterative process involved in in vitro eugenics raises the possibility that small changes that might not affect the viability of gametes produced in a single iteration might accumulate over multiple generations until gametogenesis is no longer possible or such that it would be irresponsible to use the embryos created for reproductive purposes.

It is obviously not possible to determine in advance whether such epigenetic changes will render in vitro eugenics impossible; we will have to wait and see what the science suggests. The fact that (most) epigenetic marks are reset in the development of the germline33 gives some cause to hope that epigenetic errors might be corrected each time a new generation is created—although there is no guarantee that errors will not creep into this process as well. However, it is worth observing that the fact that scientists will need to be able to evaluate the genetic and epigenetic quality of gametes produced by in vitro gametogenesis in order to use these for reproductive purposes does at least suggest that this same quality check could be employed to reduce the likelihood of the transmission of errors in each generation and also to check the quality of any gametes used to produce embryos for reproductive purposes at the end of the process.

An ethical barrier

The ethical barrier to in vitro eugenics arises because both the development and application of this technology would involve the deliberate creation of embryos for the purpose of research, something that is currently against the law in a number of jurisdictions.4 Human embryos are, of course, entities whose moral status is intensely contested. Even authors who have been inclined to deny that embryos should be granted the same moral status as (other) human beings have often allowed that there are some moral limits on the uses to which embryos may be put and, in particular, on the purposes for which they may be brought into existence.34 In many polities, the creation of embryos outside of the human body for reproductive purposes has been accepted, presumably because reproduction is seen as a project of great value, whereas the creation of embryos for other purposes has not been endorsed, because of concerns about the social consequences of the ‘commodification’ of embryos or because divorcing the creation of embryos from the context of reproduction would fail to demonstrate appropriate respect for the value of embryos.35 For this reason, research involving human embryos—including the derivation of stem-cell lines—has typically been carried out on ‘surplus’ embryos created for the purpose of reproduction in in vitro fertilisation (IVF) programmes and then donated for research.^ix

However, the development of the technology for in vitro eugenics would require the creation of embryos without any intention of using them in reproduction, in particular in order to show that the level of risk involved in bringing embryos created through this technology to term (of which, more below) is acceptable. Moreover, as I will discuss further below, one of the main applications of this technology would be for research, to learn more about human genetics and disease. Even where the intention of those employing in vitro eugenics was to bring new individuals into existence, this would still require the creation and destruction of multiple embryos in the course of the process of selective breeding. Thus, the prohibition of the creation of embryos for research purposes will stand as an insurmountable barrier to the development of the technology of in vitro eugenics in jurisdictions where it exists.

Yet the prospect of in vitro gametogenesis also provides us with strong reason to believe that this prohibition is likely to be eroded or abandoned in the not-too-distant future. In order to demonstrate that gamete-like cells produced from human stem cells are in fact capable of successfully fusing to create a new embryo, and in order to prove that embryos created using artificial gametes will develop normally, it will be necessary to create human embryos in vitro and examine them for karyotypic, genetic and epigenetic abnormalities. Such testing would be essential before it would be ethical to use artificial gametes for reproductive purposes.4 ^x Because of the potential of in vitro gametogenesis to serve as a powerful new technology to overcome infertility, especially for men who are unable to produce viable sperm, women who have undergone premature menopause, and for people who have lost their gonads due to injury or had them removed in the course of cancer treatment, there is likely to arise very significant political pressure to allow the creation of embryos for research purposes in order to test this technology.^xi Thus, it seems likely that, by the time in vitro eugenics becomes possible, any prohibition on the creation of embryos for research purposes will have already been rescinded.

Practical limits

The first practical limit concerns the amount of time that is likely to be required to move forward a generation ‘in vitro’. While this will undoubtedly be an order of magnitude less than the ∼13 years that is currently required to produce a new generation of human beings, the power of in vitro eugenics will be significantly affected by just how much time is involved. There are four processes that will need to take place in each generation, each of which may be expected to take a certain amount of time. First—assuming that we identify the beginning of the process as the derivation of gametes—it will be necessary to derive gametes from stem cells that are being maintained in vitro. As we do not yet know the details of a reliable protocol for in vitro gametogenesis from human cells, it is not possible to place a precise figure on how long this is likely to take. However, as spermatogenesis takes approximately 70 days in vivo, this suggests an upper limit on this process: it is possible that in vitro derivation of sperm might be achieved in as little as 35 days. Derivation of oocytes may take significantly longer, as the maturation of oocytes in vivo takes approximately 6 months.37 However, again, it is possible that in vitro derivation might be possible within a shorter timeframe.38 Second, sperm and egg must be united, fuse, and a new embryo develop until the blastocyst stage in order that new stem cells may be derived from this embryo. This will require 7 days. Third, the stem cells taken from the inner cell mass of the embryo must be coaxed into developing into a colony suitable for use in the derivation of further gametes. Again, precisely how long this will take will depend upon the details of the protocols for the derivation of gametes and, in particular, how many stem cells are required and of what quality. A plausible estimate of the minimum time it might take to produce the required stem cells is 28 days, but if a stable and well-characterised line of stem cells is required, this may require a number of months. Fourth, researchers must characterise the genotypes of the embryos (or stem-cell lines) created in each generation and decide which embryos should be selected to be used to begin the task of breeding the next generation. Modern gene-sequencing technologies mean that it should be possible to characterise the genotype concurrently with the third process, but how long it will take to decide which genetic lines to cross will depend on the skills and resources available to the scientific team conducting the breeding.

Although there are significant uncertainties in several of the estimates provided above, ‘4–6 months’ seems plausible as an initial estimate of the amount of time that might be necessary to proceed forward a generation ‘in vitro’. If this is correct, researchers could produce two or three generations of human embryos each year using the procedure I have described. While this figure places significant limits on how radical a transformation of the human genome might be possible through selective crosses using this technology, it is also clear that an in vitro breeding programme of this sort would give future eugenicists a power undreamed of by governments and would-be genetic reformers of the past. In a 10-year research programme, scientists might produce 20–30 generations of human beings in vitro—enough to achieve significant changes in genotype. Advances in cell culture technology and in the science of gametogenesis might increase this figure still further. Obviously, the more generations it is possible to proceed through each year, the more powerful this technology will become.

The second practical limit on the technology arises out of the difficulties involved in performing the last task described above—that is, in deciding which embryos to use in selective breeding once several generations have been produced. It is one thing to be able to identify—or even cross in vitro to produce—certain genotypes, it is quite another to know which genotypes we should be aiming to produce. The power of in vitro eugenics will therefore be a function of our ability to understand specific genotype/phenotype correlations and, more generally, of our understanding of human genetics. Of course, our understanding of human genetics has increased rapidly over the last several decades, especially since the completion of the human genome project, and is likely to increase further over coming years. Indeed, as I will discuss below, one application of in vitro eugenics is precisely to serve as a valuable tool to investigate the operation of particular genes. Nevertheless, the utility of in vitro eugenics for producing a desired phenotype will be limited unless we know what genes—and in which combinations—are involved in producing it.^xii

Research into the heredity of genetic disorders

The most immediate scientific application of this technology—and the reason why it is likely to be developed—is for research into the heritability and development of various genetic disorders.4 Rather than—or perhaps more realistically, in addition to—relying upon epidemiological and historical evidence, which is often difficult to gather and unreliable when it does exist, to investigate the transmission of genes suspected of involvement in the aetiology of a particular disorder, researchers could perform genealogical experiments in the laboratory. Fusing gametes derived from stem cells derived from embryos that carry a gene that is known to be associated with a particular genetic disorder would allow researchers to investigate how such disorders are inherited and to investigate the contribution that different genes make to the disorder. Indeed, by allowing researchers to breed embryos with different genotypes, this technique would allow them to test hypotheses about the role of different genes in various disorders. In vitro eugenics might therefore make a valuable contribution to our understanding of genetics and disease and thus to the quality of genetic counselling and therapeutic interventions available in the future.

Production of cell lines with specific genotypes

According to Mathews et al,4 in vitro eugenics might also serve as a valuable tool for producing cell lines containing a particular genetic mutation or set of mutations, which could in turn serve as a means to study the progression of the resulting genetic condition or to test drug therapies to ameliorate it. Similarly, researchers might be able to develop (through selective crossing) cell lines suitable for use for therapeutic purposes in a wide range of individuals by virtue of having appropriate human leucocyte antigen tissue-typing or other desirable properties.4 According to Mathews et al4, then, in vitro eugenics holds out the prospect of results that may translate into clinical applications, in the form of drug and cell therapies, with significant benefits to future generations. If this is true, the possibility of these future benefits is a strong argument in favour of pursuing in vitro eugenics.^xiii

Breeding better babies

Once researchers have succeeded in creating several generations of embryos in the laboratory in the course of researching the genetics of disease, a question will inevitably arise about implanting embryos created through in vitro eugenics into the womb of a woman in order to bring a new individual into the world. Moreover, this question is likely to arise with some urgency because of the potential of in vitro eugenics to serve as a powerful technology of ‘human enhancement’. If it becomes possible to breed human beings in vitro, it will be possible to use all of the techniques of artificial selection to produce embryos with desirable genomes. In effect, scientists will be able to breed human beings with the same (or greater) degree of sophistication with which we currently breed plants and animals. Importantly, there are currently several influential bioethicists who argue that we are morally obligated—or, at least, have strong moral reasons to—enhance future human beings.39–42 Implanting embryos that have been bred for above-species-typical capacities into the wombs of willing women would be one way to achieve this goal.

In vitro eugenics would be most powerful if it becomes possible to produce viable gametes from iPS cells. In this case, it would be relatively straightforward to gather a suitable ‘stock’ with which to begin the breeding programme—and from which to introduce new genes into the process at any point as required in order to avoid concerns about ‘inbreeding’—by sourcing somatic cells from a large number of individuals with desirable genetic traits and then deriving stem cells and then gametes from these. However, it would also be possible—although more difficult—to gather the stock for the breeding programme in the form of embryonic stem-cell lines created by other researchers or in the form of embryos donated through IVF programmes. Indeed, presuming the restriction on the creation of embryos for research is lifted, it would also be possible to begin (or to introduce new sources of genetic diversity at any stage) simply by using donated gametes.

Again, it is important to acknowledge that there are likely to be significant limits on our capacity to use this technology to produce intended outcomes because of the limits of our knowledge of human genetics. As the vast majority of desirable phenotypes will be the result of complex interactions involving multiple genes in particular environments, it may be very difficult to determine what genotypes we should be aiming to produce in vitro. Attempts to combine genes associated with desirable phenotypes in one genome may have unanticipated consequences because of interactions between the genes or other sequences that may have been combined alongside them. Moreover, while it may be possible to glean some information about the phenotype likely to result from a given genotype by using theoretical models of gene activity and by drawing upon population-level studies of genetics, ultimately the only way to determine whether a given genome will produce a child with enhanced capacities will be to bring a child into existence and study them over their lifetime.^xiv

Despite these caveats, in vitro eugenics is likely to be superior to the other technologies that have been proposed as methods to enhance the genetics of future human beings—namely preimplantation genetic diagnosis (PGD), SCNT cloning and recombinant-DNA technology.

PGD allows prospective parents to choose from amongst embryos they have created via IVF on the basis of their genetics before implanting their chosen embryo(s) into the woman's womb; they may therefore use PGD to ‘enhance’ their children if they are able to select embryos with genes for above-species-typical traits. SCNT cloning would facilitate enhancement by allowing scientists to bring children into the world who have the same genome as an individual identified as possessing a superior genotype. Yet both these technologies are limited in so far as the range of enhancements they make possible is restricted to those that arise by chance through the recombination of genes during meiosis and the mixing of the recombined genomes at fertilisation.^xv In vitro eugenics would allow researchers to consciously shape the human genome by combining (through selective breeding) desirable traits that arise in different embryos.^xvi

Recombinant-DNA technology would also allow scientists to achieve enhancements that have not arisen (and perhaps would not have arisen) by chance. However, the utility of this technology as a method of human enhancement is constrained by the difficulties involved in introducing new genes into a location in the genome where they will achieve their intended results without disrupting the activities of other genetic systems, and of being confident of their effects in the functioning organism. The development of iPS cells has, admittedly, greatly increased the potential of recombinant-DNA technology. If they wished, researchers could now attempt to introduce novel or trans-species genetic sequences into human cells maintained in a colony of stem cells, vastly increasing the chances that some cells at least will integrate the desired sequence into the target location. Cellular marking technology would allow researchers to identify and cultivate these cells, which could then be fused into tetraploid embryos in order to create a clone of the individual from whom the original stem cells were sourced, but with a modified genome. Alternatively, once genetically modified stem cells have been created, gametes could then be derived from these and fused with other gametes to create embryos that would include the modified gene.19 ,20 Even with these advances, however, the use of recombinant-DNA technology to modify the human genome will remain an extremely uncertain and risky proposition.

In vitro eugenics is, in theory, a less powerful technology than recombinant-DNA technology—the latter would allow scientists to engineer modifications by using genes drawn from other species—but is likely to be a much more reliable technology in practice and one that will still allow significant modification of the human genome. The practical advantages of in vitro eugenics derive from the fact that (most) genomic imprints are reset in the course of the formation of the germline and in the early stages of the development of the zygote33 and from the capacity of the processes of meiosis and fertilisation to screen out (some of the) genetic errors that would be lethal to the organism. In choosing at each stage to proceed with viable gametes derived from viable embryos, researchers would introduce a crucial selective process that could function to reduce the probability that epigenetic changes or novel combinations of genes would have deleterious effects on the functioning of the organism. Moreover, in so far as in vitro eugenics would mimic sequences of fertilisations that might have occurred in the natural course of human reproduction, researchers have more models and a better evidence base to draw upon to try to evaluate the impact of novel combinations of genes produced by this technique. In vitro eugenics is therefore likely to be less risky than the use of recombinant-DNA technology to modify embryos.^xvii

Safety

Although in vitro eugenics has these advantages over PGD, SCNT and recombinant-DNA technology, there remains an obvious objection to the creation of new individuals by in vitro eugenics—as there is to any new reproductive technology—that derives from the experimental nature of the technology when it is first used. How can we know that this technology is safe? That is, how can we know that it will be possible to bring the embryos created through in vitro eugenics to term and that the individuals who develop from these embryos will not suffer increased risks of ill health as a result of the circumstances of their conception? These questions loom especially large because of the concerns about possible variations in the epigenetics of embryos created via in vitro eugenics, discussed above. While it may be possible to check that embryos created via in vitro eugenics develop ‘normally’ in vitro and to go some way towards trialling the technology in animal models, the first use of embryos created by in vitro eugenics to try to achieve a live human birth will necessarily be experimental.

However, there are a number of reasons to believe that concerns about safety and risk are unlikely to prove an insurmountable barrier to the ethical creation of designer babies by in vitro eugenics. To begin with, as I noted above, these concerns arise regarding every new reproductive technology involving the manipulation of embryos. Until a generation of children produced by IVF (or intracytoplasmic sperm injection or cytoplasmic transfer) have lived out their natural lifespan, we will not know whether IVF (or any of these other technologies) is safe—and we certainly did not know this at the time at which those technologies were first trialled.^xviii Thus, in vitro eugenics would not raise any issues we have not confronted before. Moreover, it seems unlikely that we must be sure that in vitro eugenics must be completely devoid of risk before it would be ethical to trial it. ‘Natural’ conception and pregnancy involves many risks, but we do not think it unethical to seek to become pregnant by natural means.19 Finally, although the claim is controversial, it may be argued that it would be ethical to use even reproductive technologies with significant risks given that, as long as children are born with sufficient quality of life that it is not rational for them to prefer to be dead, these individuals will not be able to claim that they were harmed by the mechanism of their birth—on the grounds that they would not have existed at all except for the use of the technology.45 Concerns about safety and risk are therefore unlikely to rule out the ethical creation of children by in vitro eugenics, once animal and laboratory testing has shown that the technology has a reasonable chance of producing children with a reasonable quality of life.