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Gamete derivation from stem cells: revisiting the concept of genetic parenthood
  1. Heidi Mertes
  1. Correspondence to Dr Heidi Mertes, Bioethics Institute Ghent, Ghent University, Blandijnberg 2, Ghent 9000, Belgium; Heidi.Mertes{at}ugent.be

Abstract

Genetic parenthood is usually portrayed as a value-neutral concept that can be confirmed or rejected based on objective, scientific tests. However, on inspection, it is exposed as a very complex idea that we might need to consider as something that comes in different shapes and forms and that is open to interpretation rather than being clearly defined and fixed. Different people may therefore also desire different aspects of the general concept of genetic parenthood, which implies that some may not even be satisfied with gametes that have all the properties that their own natural gametes would have, whereas others may be satisfied with a much simpler solution. Encouraging infertility patients to gain insight into what it is exactly that they hope to gain by pursuing genetic parenthood (rather than choosing for donor conception or adoption) may lead them to recognise that the added advantage may be limited and may be acquired in other ways as well. Nevertheless, many people will find it difficult to let go of the desire for genetic parenthood as it is deeply rooted in our genes. Infertility is experienced as a grave medical condition and entails an intense grieving process for many. For that reason alone it is important that the medical and research community develop and apply methods to help people in their quest for genetic parenthood. On the other hand, it is important not to reinforce the dogma that genetic parenthood is ‘the best kind of parenthood’.

  • Reproductive Medicine
  • Stem Cell Research

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INTRODUCTION

As is the case for most interventions in the field of medically assisted reproduction, the goal of creating stem cell-derived gametes is not merely to allow people to have children but very specifically to allow people to have genetically related children. If not, adoption or donor conception would be safe and available alternatives. Developing this new technology will require a great research effort and more importantly, may carry considerable risks and uncertainties for the resulting offspring. Therefore, a legitimate concern should be whether or not this is outweighed by the value of genetic parenthood. In light of this question, I argue that there is no straightforward account of what genetic parenthood is. This implies that rather than focusing on achieving genetic parenthood as the ultimate goal of reproductive medicine, it may be more useful to uncover which (possible) characteristics of genetic parenthood are important to infertile patients and whether we might be able to convince them that there are other ways of obtaining these important aspects besides having a child that shares 23 of their chromosomes.

When is a child ‘my’ genetic child?

It is important to clarify from the onset that what we are looking for is not a biology textbook definition of genetic parenthood. Rather, we need insight into the perception of stakeholders in this concept of genetic parenthood, most notably of people who are infertile. This may strike some as unscientific and unimportant, but it would not be very useful to go to great lengths to establish de facto genetic parenthood, if those who we are trying to help do not recognise it as such. The most common answer to this first question will be that a child is my genetic child when it has 50% of my DNA or when it has 23 of my chromosomes. This 50% overlap of genetic material is, for example, what is looked into when performing a paternity or maternity test. Still, this is not a straightforward answer. My siblings also share 50% of my DNA, as do my parents, and yet, the relationship I have with my parents and siblings differs profoundly from the one I have with my children. Moreover, almost all (99.9%) of nucleotide bases are exactly the same in all humans, so we may wonder whether it even makes sense to say that we share 50% of DNA with our genetic children. We are in fact very closely genetically related to all other humans, so does that little ‘extra’ connection really have a great impact? Another definition of genetic parenthood that has been advanced is that X is a genetic child of Y if X is directly derived from Y's genes.1 The fact that derivation enters the definition here is important to rule out parents and siblings and the fact that the derivation needs to be direct is important to distinguish parents from grandparents.

At first glance, these two definitions are compatible and thus we might decide that they are both useful. However, they conflict when we are dealing with (hypothetical or possible) new means of assisted reproduction such as reproductive cloning or pronuclear transfer (PNT)/maternal spindle transfer (MST) and even with a very common situation, namely, reproduction by monozygotic twins. Let us first consider this last example. When X and Y are monozygotic twins and X conceives child Z, then not only X, but also Y will pass a maternity/paternity test for Z with flying colours. Thus, according to the first definition, Y is a genetic parent of Z. According to the second definition, however, as Z is not directly derived from Y's genes, Y is not a genetic parent of Z. In this case, the latter definition matches our intuitions best: Y is an aunt or uncle of Z, not a parent. Yet our intuitions may become less convincing when we consider a situation in which X donates egg cells to Y (in case they are female) or a situation in which X donates ovarian or testicular tissue to Y who then conceives a child (natural or through IVF). The fact that several infertile patients have opted for this last procedure rather than relying on gametes donated by their twin siblings indicates that at least in people's perception there may be a relevant distinction between the two scenarios.2

In our second example, that of reproductive cloning, we can also envisage two different (currently hypothetical) scenarios. In a first scenario, a couple (Mr and Mrs X) may become infertile after already having conceived one genetically related child (Y). As they long for a second child, they opt to clone their existing child Y, which results in the birth of Z. If we apply the rule that genetic children share 50% of DNA with their parents, then Z is a genetic child of Mr and Mrs X and a sibling of Y. We might conceptualise this situation as Y and Z being identical twins born years apart from each other. However, if we apply the rule that genetic children are directly derived from the genes of their parents, then we must conclude that Y is not a sibling of Z, but the genetic parent. In this first scenario, it is most likely that Mr and Mrs X will ‘feel’ like the genetic parents of Z, whereas Y is unlikely to think of herself as Z's mother. Let us now consider a second scenario in which Mr and Mrs X decide to clone Mr X instead of Y, resulting in child Q. According to our second definition, Mr X is the genetic parent of Q, as Q is directly derived from Mr X's genes. However, they do not share 50% of DNA, but 100%. The people who would pass a maternity/paternity test would be the genetic parents of Mr X. In this second scenario, both Mr X and his parents might consider themselves as Q's genetic parents and both would have good arguments (either a contribution of 50% DNA or direct derivation) to support their claim.

A similar ambiguous situation could arise regarding PNT or MST, which both result in a situation in which a child inherits the nuclear DNA (nDNA) of one woman and mitochondrial DNA (mtDNA) of another. In a first scenario, woman X has a mitochondrial disease and therefore her friend Y donates an egg cell so that X can have a child Z that has X's nDNA and Y's mtDNA. It is very unlikely that Y will consider herself to be the genetic parent of Z. That is not to say that there may not be a special sort of connectedness between Y and Z, but this is more likely to resemble that of a known organ donor and the donor recipient than that of a gamete donor and the resulting child, as Y only contributed a very limited part to Z, namely, 0.15% of Z's total genome.3 Based on the first definition of genetic parenthood that holds sharing 50% of DNA as an important criterion, Y can thus be dismissed as a genetic parent. We might, however, also imagine a second scenario in which Mrs X is in a relationship with Mrs Y and as they long to have a child that is genetically connected to both of them, they decide to create a child with X's nDNA and Y's mtDNA, resulting in child Q. Although also in this scenario Y's contribution to the genome of Z is minimal compared with that of X, this small contribution may be enough for Y to consider herself as a genetic parent of Z and to obtain some sort of ‘legitimacy’ in the child's life. Based on the 50% DNA criterion, she could be said to be wrong, but based on the criterion that children are directly derived from the genes of their genetic parents, Y does qualify as a genetic parent. Unlike in the previous example of reproductive cloning, in this example it seems to make sense to acknowledge all genetic parent-candidates as being genetic parents, but to regard one as ‘more’ of a genetic parent than the other, depending on the amount of DNA that was contributed by each of them.

The concept of genetic parenthood revisited

What do these examples teach us about stakeholders’ and laypeople's perceptions of the concept of genetic parenthood? Rather than being a black-or-white concept (either one is a genetic parent or one is not), it appears that there is also a grey area in which some people may be more or less of a genetic parent than others. There is no fixed, scientific, everlasting criterion of genetic parenthood that everyone can agree upon. Quite on the contrary, the concept is increasingly challenged by new and hypothetical interventions in reproductive medicine. Thus, just as social parenthood and even biological parenthood (with surrogates and gamete donors in mind) are concepts that are open to interpretation, also the term genetic parenthood is not value-free, but dependent on personal intuitions, intentions or judgements. No matter how precisely we might define genetic parenthood, these definitions will always fail to resonate with people in very specific situations who will ‘feel’ like the genetic parent of a child, despite not fitting neatly into the definition. At the same time, there may be people who do fit into a certain definition, but who do not feel like a genetic parent, which is illustrated by the examples outlined above. In many cases, what people want is a child to be theirs (and their partner's), without necessarily being able to say what that means or why that is important. Maybe genetic parenthood is in fact not what is important, but rather the absence of other parent-candidates (besides the partner). In this regard, it would, for example, be interesting to see whether the replacement of donor gametes by (hypothetical) gametes of which the DNA was randomly assembled through synthetic biology or by gametes derived from embryonic stem cells from spare IVF embryos would be welcomed by infertile people. There would probably still be a preference to use gametes that contain half their own DNA, but it might well be a more acceptable alternative.

Implications for stem cell-derived gametes

As scientists and clinicians are trying to accommodate infertile patients who long for genetic parenthood, they should be conscious of the fact that even if gametes are produced that have all the properties that the patient's own gametes would have, this may not necessarily satisfy all of their patients. At the same time, some may already be pleased with interventions that allow them to contribute a small fragment of their DNA rather than 50% of the child's genome. One might say that this is irrational, but in this context rationality might not matter all that much. Adoptive parents or parents of donor-conceived children are already legally recognised as legitimate parents. If a big research effort is invested in helping people become genetic parents, then this is to accommodate their personal desires, not because of a well-argued necessity that parents and children should be genetically connected. Let us clarify this subjectivity in the case of, for example, gamete derivation from patient-matched embryonic stem cells. The procedure would consist in creating a cloned embryo, deriving stem cells from that embryo and deriving a gamete from that stem cell line. This procedure could be described in two different ways to a patient: (a) “Your skin cells will be reprogrammed to become stem cells, which will then be turned into germ cells” or (b) “Your skin cells’ DNA will be used to make a clone of you. Gametes will then be derived from that clone”. Scenario (a) may be interpreted by the patient in the following way: “My cells are made into gametes, so these are my gametes. I am therefore the genetic parent of the resulting child”. Scenario (b), on the contrary, may be perceived quite differently: “Gametes are derived from my clone (= identical twin), so my clone (although microscopically small) is the genetic parent of the resulting child”. Researchers and clinicians should thus not merely focus on creating gametes that contain 23 of the prospective parent's chromosomes, but should also take the subjective and possibly irrational perceptions of stakeholders and the lay public into account.

At the same time, it would be interesting to see how patients would react when confronted with these examples and whether they would be able to formulate explicitly what it is that they are seeking when pursuing genetic parenthood. I suspect that few would be able to do so. The desire for genetic parenthood can be perfectly explained by Dawkins’ selfish genes theory, which predicts that the genes of people who value genetic parenthood over childlessness or adoption (even if this is merely based on a ‘gut feeling’) are more likely to survive.4 However, evolutionary biology does not provide us with good reasons to give in to this desire. What sets humans apart is that by reasoning we are able to question our evolutionary urges and act against them if they are not in our personal interest. For example, as it is in the interest of their genes’ survival that married men produce as many children as possible (with as many women as possible), these men will not only feel aroused in the presence of their wives but also in the presence of other young, beautiful women. However, rationality and good judgement will lead (most) men to suppress these urges, as restricting their number of offspring and number of bedpartners will lead to a greater long-term benefit for them as individuals (as opposed to gene-vehicles). Thus, although evolutionary urges may help us understand people's behaviour, they are not accepted as reasons to act.

Moving back to the importance of genetic parenthood, I do not wish to deny that there is an added value in parents and children sharing genes. The fact that children resemble their parents creates a bond, the fact that children are made out of their parents’ ‘flesh and blood’ provides a very strong connection and the idea that a couple's genomes are mixed together into one new individual is a romantic thought. At the same time, a genetic link is neither a sufficient nor a necessary condition for a loving parent–child relationship. A genetic connection may put you one step ahead, but a good relationship is largely dependent on parenting, not just parenthood. In this regard, it is interesting to note that lesbian couples using donor sperm to conceive redefine kinship to a certain extent. On the one hand, they tend to downplay both the importance of the genetic link between the donor and the child and the importance of the absence of this link between the non-birth mother and the child. On the other hand, they do seek resemblance and kinship in a number of ways. For example, it is common that lesbian couples match the donor to the non-birth mother (both for looks and for aptitudes) and prefer to use the same donor for multiple children so that they are full genetic siblings if the same birth mother conceives or half-siblings if both partners conceive.5 Also, there seems to be a considerable interest in meeting half-siblings of donor-conceived offspring through donor sibling registries.

This observation might be an argument for the creation of stem cell-derived gametes, as it shows that even for those people who are most likely to downplay the importance of the genetic link, it does remain important to a certain extent. On the other hand, it is an illustration of how flexible the concept of genetic parenthood really is, and of how people who feel strongly about kinship and about connectedness between generations can achieve this without being the genetic parent of their children.

How far should we go in accommodating the desire for genetic parenthood?

In principle, the optimal scenario would be that people who are infertile can be convinced that they overestimate the importance of genetic parenthood and that there are other equally valuable means of constructing a family—or building a meaningful life without children—thus changing their desires. However, it is most doubtful that many infertile people would come to this conclusion. Research shows that a diagnosis of infertility often has a tremendous psychological impact and that in this respect it is similar to the diagnosis of other severe diseases.6 Ignoring the psychological distress that these people and their partners face while a medical intervention (IVF) is available would not be considered as good clinical practice. The mere fact that these people suffer is therefore in itself a sufficient reasons to help them, and if this cannot be done with counselling, then a medical intervention is warranted.

However, even if one accepts the moral duty of helping infertile people based on this argument, it does not logically follow that all possible means of assisted reproduction should be offered. Alleviating the pain of infertile couples should always be balanced against the risks involved for themselves and their future offspring and against other needs in society that may have a more convincing claim on the healthcare budget. In other words, the interventions that are offered need to be safe and cost-effective. While standard IVF procedures largely meet these criteria, stem cell-derived gametes are currently a long way from doing so. The manipulations that are needed to create these gametes are extensive and many questions linger regarding successful reprogramming and epigenetic changes. As the safety concerns reach much further than the first generation of children that might be created in this way, proving the safety of this new innovation before introducing it into the clinic will be very difficult if not impossible. In regard to the condition of cost-effectiveness, we can equally wonder if stem cell-derived gametes will be affordable at any point in the future.

Besides the issues of safety and cost-effectiveness, an additional argument against the creation of artificial gametes is that the undertaking itself reinforces the idea that genetic parenthood is something that we ought to be pursuing. Some people who are currently happy with the (safe and relatively cheap) solution of using donor sperm (eg, lesbian couples) will get the message that this is inferior to having their ‘own’ lab-created gametes. This is not only a wrong message to send but also creates a situation in which this new innovation not only meets demand but creates demand. This last argument may not in itself be a sufficient reason not to pursue the creation of stem cell-derived gametes, but it deserves some attention nonetheless.

Conclusion

Genetic parenthood is usually portrayed as a value-neutral concept that can be confirmed or rejected based on objective, scientific tests. However, on inspection, it is exposed as a very complex idea that we might need to consider as something that comes in different shapes and forms and that is open to interpretation rather than being clearly defined and fixed. Different people may therefore also desire different aspects of the general concept of genetic parenthood, which implies that some may not even be satisfied with gametes that have all the properties that their own natural gametes would have, whereas others may be satisfied with a much simpler solution. Encouraging infertile patients to gain insight into what it is exactly that they hope to gain by pursuing genetic parenthood (rather than choosing for donor conception or adoption) may lead them to recognise that the added advantage may be limited (as compared with the necessary investments, which will be considerable if gametes can one day be derived from stem cells) and may be acquired in other ways as well. Nevertheless, many people will find it difficult to let go of the desire for genetic parenthood as it is deeply rooted in our genes. Infertility is experienced as a grave medical condition and entails an intense grieving process for many. For that reason alone, it is important that the medical and research community develop and apply methods to help people in their quest for genetic parenthood. On the other hand, it is important not to reinforce the dogma that genetic parenthood is ‘the best kind of parenthood’ and to realise that sometimes a gratifying feeling of kinship can be created in a safer and more accessible way than by ‘full’ genetic parenthood (whatever that may be). This is illustrated by donor matching, by women who receive egg cells from their sisters, by mothers who freeze their egg cells for their daughters with Turner syndrome, by people connecting with half siblings through the donor sibling registries and so on. These ‘easy’ answers to not being able to have genetically related children stand in sharp contrast to the enterprise of creating stem cell derived gametes, which is somewhere on the crossroads between reproductive cloning and germline gene modification, two areas of research that are heavily criticised due to important safety concerns. Instead of losing ourselves in the hope and hype of a possible revolution in reproductive medicine, it may therefore be wise to first consider whether the pros of this revolution would really outweigh the cons.

References

Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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