Catholic Medical Quarterly Volume 63(3) August 2013

The Moral Cost of Techniques for the Prevention of Mitochondrial DNA Disorder

Agneta Sutton,
Visiting Lecturer, Heythrop College, University of London.

The question:
Is germ-line gene therapy acceptable in order to avoid maternal transmission of mitochondrial disease?

Yes, said the Nuffield Council on Bioethics in its report Novel Techniques for the Prevention of Mitochondrial DNA Disorder: An Ethical Review, which was launched at a meeting on 12 June 2012. Later, on 17 September 2012, the Human Fertilisation and Embryology Authority (HFEA) launched a public consultation on the same issue. In January 2012 the Authority had been jointly asked by the Secretary of State for Health and the Secretary of State for Business, Innovation and Skills to seek public views on IVF techniques designed to prevent maternal transmission of mitochondrial disease. While four different techniques were envisaged by the Nuffield Council, the HFEA consultation sought the public’s views on only two of these techniques, namely pronuclear transfer and maternal spindle transfer.

In this paper I shall discuss all four techniques mentioned by the Nuffield Council. This is with focus on three techniques, namely pronuclear transfer, maternal spindle transfer and blastomere nuclear transfer, which I shall evaluate in the light of the intergenerational or parental attitudes they reflect. A central question is whether these techniques respect the human dignity of the child-to-be and nascent human life? Is the child-to-be treated as a neighbour? Are the techniques compatible with giving the child an unconditional welcome as a member of the human family? Or does the use of these techniques amount to treating the child-to-be as an artefact and a commodity? Finally, when these techniques are employed, who is the patient?

The four techniques

All four techniques involve germ-line gene modification. Their aim is to create healthy embryos. Three of the techniques, namely pronuclear transfer, maternal spindle transfer and blastomere nuclear transfer, lead to the creation of embryos free of faulty mitochondria. The fourth technique, mitochondrial transfer, involves adding healthy mitochondria to an egg before it is fertilised. The aim of the techniques may be good, but it will be argued that the means are controversial, especially in the case of the first three techniques.  

There is no denying the seriousness of mitochondrial disease.

Of course, there is no denying the seriousness of mitochondrial disease. Mitochondrial genes impact on cell metabolism. Faulty mitochondrial genes can cause serious and even fatal diseases. According to the HFEA, approximately 1 in 5000 babies are born with mitochondrial disease. This means that in the UK every year some 160 babies are born with such diseases. Depending on the particular illness in question, the symptoms vary from loss of motor control, to muscle weakness and pain and problems with digestion or difficulties in swallowing, impaired growth, heart problems and blindness. Obviously ways of avoiding maternal transmission of these kinds of disease would be welcome, but not at any price!

Genetic alterations of human egg, sperm and embryo are presently forbidden in the UK, other than for research. There is, however, a clause in the HFE ACT 2008, which grants power to the Secretary of Health to make an exception for germ-line gene therapy to overcome maternal transmission of mitochondrial disease. So from a legal point of view there is no problem. The problems with these techniques are of a moral nature.

Pronuclear transfer and maternal spindle transfer, the two techniques proposed by the HFEA, are similar to the cloning technique used to create Dolly the sheep in 1996. In the case of cloning, the cell nucleus from an adult somatic cell, such as a skin cell, is transferred to an enucleated egg (an egg whose own nucleus had been removed). This creates an embryo who is nearly 100% genetically identical to the individual whose adult somatic cell was used. That is, the only genetic difference between the embryo and the mature individual is that embryo carries mitochondrial genes from the donor egg, which genes are different from the mitochondrial genes of the mature individual.

In the case of pronuclear transfer the pronuclei of an embryo with faulty mitochondria genes are transferred to en enucleated embryo with healthy mitochondria. The result is a reconstructed embryo with healthy mitochondria. In other words, one embryo is created with the use of an egg from the intending mother and sperm from her partner. And another embryo with healthy mitochondria is created from a donor egg and (probably) sperm from the intending mother’s partner. The maternal and paternal pronuclei of are removed from both embryos. And the maternal and paternal pro-nuclei of the intending mother’s IVF embryo are transferred to the enucleated embryo created from the donor egg. The result, then, is a ‘combi-embryo’ free of mitochondrial disease.

This new embryo has two genetic mothers, the intending mother and the egg donor. According to the Nuffield Council, there is, however, only one ‘real’ genetic mother. And this is the intending mother, the woman with the mitochondrial disease. The Council’s view is based on the argument that the intending mother provides the ‘combi-embryo’s’ pronuclei DNA and, therefore, most of the embryo’s DNA--and the DNA thought most important for the phenotype of the child-to-be.

As shown, the technique involves the sacrifice of two embryos. Both the intending mother’s original IVF embryo with faulty mitochondria and the egg donor’s IVF embryo with healthy mitochondria are destroyed in the process. The end-product, the ‘combi-embryo’, with healthy mitochondria is thus constructed from bits and pieces of the two sacrificed embryos.

Like the aforementioned technique, maternal spindle transfer requires an egg donor free of mitochondrial disease. The spindle of chromosomes (in effect, cell nucleus) from an unfertilised (healthy) donor egg is removed and replaced by the spindle of chromosomes from the intending mother’s egg, that is, the woman who is suffering from mitochondrial disease. The result of maternal spindle transfer, then, is a’ combi-egg’ with healthy mitochondrial genes. This healthy egg can then be fertilised in vitro, thus allowing the woman with mitochondrial disease to have a baby free of the disease. No embryo is destroyed in the process. But again the hoped for baby would have two genetic mothers, the ‘real’ mother being, according to the Nuffield Council, the one with mitochondrial disease. And again, the embryo resulting from the ‘combi-egg’ is effectively a fabricated bit of brickwork.

The two other techniques discussed by the Nuffield Council, but not by the HFEA, are blastomere nuclear transfer and cytoplasmic transfer. In the case of blastomere nuclear transfer an egg from the intending mother is fertilized with sperm from her partner. At day five after fertilization, when the embryo has turned into a multi-celled blastocyst, a number of blastomeres, are removed. The nucleus of each of these blastomeres is then extracted and transferred into enucleated eggs from a donor free of mitochondrial disease. This then results in embryos with the intending mother’s nuclear DNA and healthy mitochondria from the donor eggs. The father of the embryo—or embryos—is the intending mother’s partner.

Like pronuclear transfer, the technique involves embryo destruction. It results in destruction of the intending mother’s original IVF embryo. In addition, it involves the destruction of many of the donor eggs. And the end-products, the resulting embryos, are constructs assembled from parts of the original embryo and the donor eggs. As in the cases of blastomere transfer and maternal spindle transfer, the resulting embryos are artefacts created by human hands. In addition, as in the case of blastomere and maternal spindle transfer, they have two genetic mothers

Cytoplasmic transfer is the least manipulative of the four techniques. Cytoplasm from a healthy donor egg is injected into an egg of the intending mother, the woman with mitochondrial disease. The result, then, would be an egg with both healthy and unhealthy mitochondria. Unlike the other techniques, this technique has already been used, but not to avoid maternal transmission of mitochondrial disease. The aim has been to rejuvenate eggs of women with problems to conceive. It would appear, however, that not all offspring generated by the eggs with added donor mitochondria carry mitochondria from the donor. The Nuffield Council writes: ‘The technique can potentially create germline changes in resulting offspring, because a small amount of the donor’s mitochondria may be found in the person’s cell cytoplasm as well as their mother’s mitochondria, although this was not shown to occur in all documented cases’ (NCB, 2012, p. 38). [1] In view of the last-mentioned observation, it seems doubtful that the technique could be of use in order to avoid maternal transfer of mitochondrial disease. Furthermore, Nuffield Council reports that the technique ‘has been largely discredited in the scientific community because of safety concerns’. [2] For these reasons I shall not say much more about this technique.

The moral quandaries

The questions to be raised now about the other three techniques do not relate to safety or efficiency issues. They relate to inter-generational relationships and attitudes towards the child-to-be. As shown, the techniques involve destructive and reconstructive procedures. This raises anthropological and ethical questions about inter-generational attitudes. In other words, is the child-to-be treated and respected as a neighbour and a member of the human family, or is it treated as an artefact and commodity? Furthermore, can the discussed mitochondrial replacement techniques be described as healing? If so, who is healed?

Of course, there are also concerns relating to the egg donors. First of all there is the question of to what extent egg donation involves exploitation of women. Do women who come forward for egg donation really understand what they are doing? Are they aware of the risks? Are they doing it for money? To be sure, egg donation raises significant moral and social questions relating to the dignity and health of women, even if the donors come forward voluntarily to offer their services.

Egg donation also raises questions about the egg donor’s relation to the children-to-be. Under current UK law, on reaching the age of 18, a child created by egg or sperm donation has a legal right to learn the donor’s identity. If the donation is registered with the HFEA and performed in an HFEA licensed clinic, he or she can approach the HFEA and ask for this information. The Nuffield Council recommends, however, that in the case of germ-line gene therapy to avoid mitochondrial disease the child should have no such right. As I shall argue, the rationality and justice of this recommendation is questionable.

To turn first to the intergenerational and ethical issues raised by embryo destruction and construction. Both pronuclear and blastomere nuclear transfer involve embryo destruction in order to fabricate embryos free of disease. As has been shown, in the case of pronuclear transfer two sacrificial embryos are used to assemble one healthy embryo, while in the case or blastomere nuclear transfer an embryo free of disease is put together at the expense of an original human embryo and the destruction of numerous donor eggs.

Of course, if human embryos are seen as mere inanimate biological material, there is nothing wrong in treating them as disposable matter. If the embryo is seen as mere inanimate matter there is as yet no child. There is nobody! The child-to-be is something yet to be constructed from the given raw material. If you cannot see the image of God in the embryo, or if you cannot see it as your neighbour, what can be wrong with destroying it or using parts of it for making other embryos? Indeed, if you fail to recognize the spiritual dimension of embryonic human life--or that the embryo actually is a live human--you may find no wrong with pronuclear and blastomere nuclear transfer.

The intergenerational attitudes reflected in the generation children as if they were artefacts are materialistic. In the case of these procedures, both the embryos that are destroyed and the constructed healthy embryos are treated as mere biological material. So to treat the human embryo and child-to-be is to show a materialistic understanding of human life. It is to forget that the embryo is the beginning of human life. Every one of us started life as an embryo. And since you and I are more than mere matter, how could the embryo not be more than mere matter? The embryo ready to undergo cell division, or undergoing cell division, is not inanimate matter. Alive and human, it is already at this stage a member of the human family, and so is our neighbour. Because every one of us started life as an embryo, the human embryo deserves to be counted as one of us from the very beginning.

As alive and human, the human embryo whatever its provenance, has a dimension that transcends mere physical being.

That neither pronuclear transfer, nor blastomere nuclear transfer, reflects neighbourly attitudes towards the human embryo is obvious. It is obvious in the case of those embryos that are destroyed. It is also obvious in the case of the embryos constructed as children-to-be. Both in the case of pronuclear transfer and in that of blastomere nuclear transfer the resulting aggregate embryos--and hence the children-to-be--are assembled like manufactures. In the case of pronuclear transfer the building material are two sacrificed embryos. In the case of blastomere nuclear transfer the building material are embryonic cells and egg cells. In both cases the production of the resulting ‘combi-embryos’ is totally depersonalising. For, to come into being as a manufacture by aggregation is depersonalising, because it is to enter the world as an artefact. Neither the embryos produced (the children–to-be) nor the sacrificed embryos are treated as our neighbours.

As alive and human, the human embryo whatever its provenance, has a dimension that transcends mere physical being. To use Aristotelian and Thomist language, inasmuch as the embryo is alive and human, it possesses a human nature. It shares our nature. If we have a spiritual and (more or less) rational and social nature, so too does the embryo, even if its spiritual, rational and social nature is dormant and yet to be expressed. Already at this stage the healthy embryo has it in itself to become like us, people looking for love and companionship. This is why the human embryo deserves to be respected as our neighbour, as another who like us is more than mere matter, as another who like us is created for brotherly companionship. The processes involved in pronuclear and blastomere nuclear transfer represent, however, total failures to see the human embryo as other than mere biological tissue.

On a Christian understanding it is difficult to see how parents and medical doctors could think they have a right to destroy some embryos and use parts of them in order to construct other embryos. It is, however, easy to see why those who are unable to see the human embryo as a neighbour and a gift might think that they have a right and even a duty to manipulate and treat it as they see fit in order to create a healthy embryo - and child. A parent or a ‘medical technician’ who sees the embryo as mere biological material has no reason to be concerned about its destruction or worry about the manner of its creation. What matters is the end not the means.

To turn now to maternal spindle transfer, again the child-to-be is put together like a collage. The procedure involves the destruction of two eggs, the intending mother’s egg and a donor egg. And parts of these two eggs are combined, in order to create a healthy ‘combi-egg’ to be fertilised in vitro. The aggregate egg to be fertilised is, as I said, effectively a bit of brickwork. And because the ‘combi-egg’ is a bit of brick-work or an aggregate, so too is the IVF embryo. In this situation too, the end-product, the embryo created as a result of the procedures, is a product of homo faber. And as such it is not treated as a neighbour.

Another point of note is that maternal spindle transfer brings sharply to the fore both the status of gametes and the inherently deceptive nature of any procedure involving the replacement of maternal mitochondrial genes. That in the case of maternal spindle transfer some eggs are destroyed in order to assemble healthy eggs to be fertilised, may at first sight not seem to be much of an issue. Separately neither the egg nor the sperm can give rise to life. Moreover, sperm and eggs are subject to natural loss all the time, so why should we not treat them as disposable pieces of raw material. What complicates the matter, however, is that the human egg, like the human sperm, carries a code. Put together, two such codes form what we might call the code of life.

In the case of maternal spindle transfer the DNA code of the egg is split up. Partial codes from two different eggs are pasted together when the nuclear DNA from the intending mother’s egg and the mitochondrial DNA from the donor egg are housed together. The fertilised egg, that is, the embryo, carries a paternal DNA code and two partial maternal DNA codes. Since the DNA codes of sperm and egg can be said to represent the man and woman from which they originate, the splitting up and mixing of such codes is not insignificant.

When in 2005 English law recognized the right of the donor child to know its genetic origins, it was implicitly recognized that the donor’s relation to the child is parental

That said, it is noteworthy that when in 2005 English law recognized the right of the donor child to know its genetic origins, it was implicitly recognized that the donor’s relation to the child is parental--and so that the genetic heritage of egg and sperm are representative of the adults from which they originate. This shows that the mixing and matching of bits and pieces of human eggs is actually a matter of concern.

Indeed, the status of egg and sperm cells is special not only because together such cells can give rise to life, but also inasmuch as they point backwards to the men and women from which they originated. Indeed, mitochondrial genes, which are passed down from generation to generation by means of the maternal eggs, could even be used to trace one’s genetic and ethnic origins, on the maternal side, backwards thousands of years. When the nuclear DNA from an egg is separated from the egg’s mitochondrial DNA and placed with mitochondrial DNA from another egg and made to form a new egg, the DNA of the resulting egg no longer serves as a true pointer backwards. It is not that it gives a mixed message. It gives a false message.

Of course, pronuclear and blastomere nuclear transfer techniques of mitochondrial replacement are equally deceptive. All three processes of mitochondrial replacement are deceptive. The mitochondrial genes of the offspring will give a false reading in all three cases.

The three procedures also raise the question: Who is the patient? Take the case of pronuclear transfer. Who is the patient? Not the intending mother’s IVF embryo. It is destroyed. Not the egg donor’s IVF embryo. It is also is destroyed. Nor is the end-product of the procedures, the ‘combi-embryo’ the patient. It was not there when the ‘treatment’ began. The situation is similar in the case of blastomere nuclear transfer. The destroyed embryo cannot be seen as the patient. Nor can the embryos constructed in the process. They were not there when the ‘treatment’ began. The dilemma is no less acute in the case of maternal spindle transfer. The ‘combi-egg’ constructed from intending mother’s egg and a donor egg cannot be seen as a patient. And the IVF embryo cannot be the patient, since it was not itself undergoing the crucial ‘treatment’. In none of the situations is the child or child-to-be, who is meant to gain from the procedures, given medical treatment to improve its health. Nor is the intending mother being treated for her mitochondrial disease. For short, there is no obvious patient or subject of healing.

What is taking place in the case of all three procedures is construction coupled with destruction. The ultimate hoped for end-product, the child, might be healthy and it might come to be loved like any other child, but it was not given therapeutic treatment. Mitochondrial replacement technologies are beyond the pale of conventional medicine. What is taking place is best described as a kind of engineering. And as argued, fabrication of embryos by aggregation of embryonic and/or gametal parts is a depersonalising technology. Pronuclear transfer, blastomere nuclear transfer and maternal spindle transfer fail to respect not only the humanity of the human embryo, but also the human dignity of the child or child-to-be. These technologies distort intergenerational relationship inasmuch as nascent human life is treated as mere inanimate matter and the child-to-be as a construct.