Three-parent embryos: can the end ever justify the means?
Every year, about one in 5,000 babies are born with a mitochondrial DNA (mtDNA) mutation, inherited from their mother, leading to incurable, life-changing, often life-shortening, diseases.
In 2013, Philippa Taylor wrote a CMF file commenting on a new IVF technique that could enable the creation of ‘three-parent embryos’ and avoid the transmission of mitochondrial disease from one generation to the next. Her file ended with this paragraph: It may be that one day some children might be born with three genetic parents. If so, we must treat them with the compassion we would show to any other human being. But it would seem wiser, given the scientific uncertainty, ethical problems and availability of alternative approaches, if we did not take a further step down that road.
Two years later, in 2015, in an attempt to reduce the risk of mtDNA disease in children born to women who carry high levels of pathogenic mtDNA mutations, the UK licensed that IVF-based technology, known as pronuclear transfer.
In this technique, an egg containing disease-causing mtDNA and a donor egg with unaffected mtDNA are fertilised. The nucleus from the unaffected zygote is then removed and discarded, and the nucleus from the affected zygote is transferred to the donor zygote. The resulting embryo thus inherits its parents’ nuclear DNA, and mtDNA from the egg donor – technically a three-biological-parent embryo.
There are just 37 genes in mitochondria, compared with 20,000 – 30,000 in the cell nucleus. The interactions between nuclear DNA and mitochondrial DNA are complex and poorly understood but for the very small number of children affected by inherited mitochondrial disease, the effects may be devastating.
Following the licensing of pronuclear transfer in the UK, a reproductive care pathway was implemented by a research team in Newcastle, under Prof Sir Douglass Turnbull, to provide women carrying pathogenic mtDNA variants with reproductive options, including mitochondrial donation.
Their results were published earlier this month in the New England Journal of Medicine. A total of 22 women with pathogenic mtDNA variants have commenced or completed pronuclear transfer (mitochondrial donation). There have been eight live births, including one set of identical twins. All eight children were healthy at birth, with no or low levels of mtDNA heteroplasmy in their blood. All are enrolled in an 18-month developmental study, and at the date of reporting, all the babies were meeting their relevant developmental milestones. Such clinical abnormalities as have arisen have proved treatable and transient and are not thought to have been related to the maternal mtDNA mutations, as the low levels detected in these babies would not be expected to cause disease symptoms.
Clearly, follow-up studies will be of paramount importance in detecting any patterns in childhood conditions, and the research team will continue to offer assessments up to the age of five years.
It would be hard to overstate the joy and relief these children have brought to their parents, or the hope they represent to more couples struggling with the knowledge that they would never be able to have a healthy child that was genetically their own. As long as no pattern of disease emerges among these eight children during follow-up, it seems likely that mitochondrial donation will become an option in the UK for women who carry high levels of pathogenic mitochondrial variants, regulated by the Human Fertilisation and Embryology Authority (HFEA).
So, is this a cause for undiluted rejoicing, a triumph of technology over the devastation of some rare inherited diseases? Or are there concerns we should not overlook amid all the backslapping?
Firstly, an observation. Twenty-two women underwent mitochondrial donation through pronuclear transfer. Only seven of them had live births (one delivering identical twins), a success rate of 36 per cent. Would a one-in-three success rate be deemed ‘good enough’ for the NHS to fund a nationally available pronuclear transfer service? IVF is an NHS-funded option for many couples or individuals in the UK seeking assisted reproduction (although eligibility requirements, funding availability, and wait times vary across regions), where the average success rate is only 31 per cent. On this basis, it would be difficult to withhold or restrict the availability of pronuclear transfer procedures. But what of the 64 per cent unsuccessful outcomes? Are these all to be attributed to the complexities of the procedure, an expected failure rate? Or might the interactions between donated and nuclear DNA be contributing? Further research data would be needed to draw a firm conclusion. It’s already clear, though, that the technique as it stands can’t promise all the prospective parents the baby they are seeking.
Secondly, and of greater concern, the procedure creates two embryos, but not with the intention of both being welcomed. The process is destructive and only the composite embryo will ever be offered hospitality and nurture. For those who believe that human life begins at fertilisation, the destruction of human life at any stage of development is ethically unacceptable. Whether for reasons of faith or not, the need to protect human life from the time of fertilisation to natural death is a conscientiously held belief of many. The deliberate destruction of embryos inherent in this procedure violates that belief.
Some may consider that because human embryos are tiny, physically insignificant and utterly dependent, they are expendable. However, others argue that we owe these most vulnerable of human lives the utmost respect, that a society should measure itself by the care and protection it affords to its most vulnerable members.
Next, the procedure suggests that the end justifies the means. It never does. It is not possible to add together two ethical ‘wrongs’ and make one ethical ‘right.’ Noble work must be achieved by noble means. The alleviation or prevention of disease and suffering is a noble aspiration, but not at any price, and certainly not if it entails the deliberate destruction of another human life. Pronuclear transfer wastes some embryos to create other ones, so that would-be parents can have a genetically related child of their own.
This is surely to commodify human embryos. A child is a gift from God, a mysterious bundle to be accepted and cherished, not a made-to-order acquisition. The Christian gospel declares that a person’s worth depends not upon their abilities, achievements, or productivity, but upon their being made in the image of their Creator.
Other avenues of curative research might be tried. Maternal spindle transfer (MST) has been suggested as another way to avoid transmission of mitochondrial diseases; The procedure has the ethical advantage of transferring eggs rather than embryos. More evidence of safety and efficacy is required.
Even now, a couple, where the woman carries affected mtDNA, but who wish to become parents, have another option – adoption. Adoption is a mutually beneficial act that provides a loving home for a child who is already in need. It also allows a childless couple to enjoy the loving service of parenthood. It makes the best of a difficult situation, whereas creating children with DNA from three different ‘parents’ (at the expense of a discarded sibling) knowingly introduces identity problems and confusing parentage for the child.
Also, pronuclear transfer is a novel form of assisted reproduction (more correctly described as selective reproduction) that undermines a key pillar of marriage – that it is an exclusive relationship between one man and one woman. The procedure introduces a third party into the marriage. This is not to question the noble intent of the egg donor to alleviate fear and anxiety for the couple facing the birth of a child with a potentially life-threatening disease. But it does mean that a third party will contribute her DNA into the genetic mix that will shape that baby, even if the proportion of DNA involved may be less than one per cent.
IVF, when it uses donor gametes, mitochondria, and (in a different way) surrogacy, introduces a third party into what should be an exclusive relationship. Interfering with the genetic relationships between a child and his or her parents and, in this case, creating a child with a link to three genetic ‘parents’, would knowingly disrupt the symmetry of family relationships and the complex interrelatedness of the extended biological family, though perhaps to a lesser extent than when donor gametes are used. This would be no one-off experiment as it would impact the child’s own female descendants for generations to come. There are similar effects with surrogacy and the use of donor gametes; however, the concerns in this case are compounded by the deliberate manipulation of the inherited germline.
Looking further ahead, what happens as the three-parent child reaches late teens and wants to know the woman from whose enucleated egg he or she was formed? At present, the HFEA will not divulge that information. We suggest that children born by donated mitochondria be treated in the same way as those born by donated gametes. Within current policy, donors give their consent for any children born using their donated egg or sperm to contact them when they reach the age of 18. Under this model, only the donor-conceived child has the right to initiate contact. Our proposal is that a child born from donated mitochondria should enjoy the same provision, regulated by the HFEA. The adult child should have the right to know their genetic heritage.
Once again, the emotional and psychological impacts on recipients, donors and their families are complex, involving a mix of guilt, anxiety, confusion and regret, along with the more well-publicised joy, relief and altruism. Navigating the delicate line between secrecy and privacy, trying to balance the needs and comfort levels of everyone affected, and setting appropriate boundaries can be very difficult and stressful. The implications of these complexities for the matter of informed consent must also be considered. What do we really know about the potential emotional or social consequences of mitochondrial donation for the couples and/or individuals who are involved in these therapies, for their marriages and extended family units, or for the lives and self-perceptions of the children born as a consequence? How can the various parties involved be fully informed of both short- and long-term risks so that their consent to the procedure is meaningful?
Twelve years ago, long before any babies had been born following pronuclear transfer, Philippa concluded that it would be wiser not to take a further step down this path. In this, as in other areas, the ability to ‘do’ that science and technology have given humankind has proved reason enough to do it. We rejoice with those who cherish the children they had almost lost hope of having. But perhaps we should also tremble as we take yet another step in the direction of commodifying children and introducing germline therapies, straining for biological perfection in the attempt to eradicate suffering by any means.
