Background: Ethical questions arising

Ethical questions which may be considered as part of the project include:

1. Emerging techniques such as PNT and MST involve replacing the mitochondrial genes that a child would have received through natural conception, with mitochondrial genes taken from a healthy donor. Is it acceptable, in this instance, to select genes that will then be inherited by future generations?

2. PNT involves removing the two pronuclei from a very early embryo containing a significant level of mutated mitochondria, at the one-cell stage before the genetic material in the pronuclei of the sperm and egg cells merges to form the mature nucleus of the embryo. The pronuclei are transferred into another embryo at the same stage of development, which contains healthy mitochondria and which has had its pronuclei removed. From the two-cell stage of embryonic development onwards, the embryo’s cells contain one nucleus combining both parents’ DNA. What ethical distinctions can we make between prospective treatments which would:
   a. transfer pronuclei between embryos?
   b. transfer the nucleus of a cell between embryos1?
   c. seek to modify the nuclear DNA of an embryo?

3. All new techniques pass through research stages before being offered for treatment, but in the early stages of treatment might still be considered experimental. Is it reasonable to use experimental techniques such as these in treatment?

4. After the use of these techniques, children would inherit nuclear DNA (around 25,000 genes) from their parents, and mtDNA (13 genes) from the donor of the egg. What might the use of these techniques signify for the relationships of the resulting child to the three adults with whom it shares a genetic connection?

5. How might mitochondrial DNA be associated with a person’s identity?

6. Could the relationships created between the people involved in these new techniques- particularly between the mitochondrial donor and a person born with their donated mitochondria- be seen as similar to those involved in:
   a. organ or tissue transplantation?
   b. gamete donation?
   c. a donation of other bodily material?
   Or, should these relationships been seen as unique?

7. Only daughters born as a result of these techniques would be able to pass their mtDNA on to subsequent generations. Would it be reasonable to permit prospective parents using these technologies to also use pre-implantation sex selection (preferring male embryos), if they requested it in order to limit the risks of transmitting any adverse side effects of the techniques to future generations?

8. If mitochondrial donation were to be approved for medical treatment in the UK, what government or regulatory policies, and/or professional guidelines would be needed to promote ethically sound practices?

9. If mitochondrial donation were not to be approved for translation from research into medical treatment in the UK, what ethical concerns, if any, would follow?

10. Is it desirable for a record of the donation to be kept and managed by the relevant authorities, and if so, what should be recorded and to whom should this information be made available?

Why might these ethical issues arise from these techniques?

The nature of the pronuclear and maternal spindle transfer techniques means that any resulting children would be born with nuclear DNA (nDNA) from their parents’ sperm and egg, plus healthy mitochondrial DNA (mtDNA) taken from an egg donor who is not related to the mother. The effect of this is that the child would not inherit mtDNA from its mother, as would have happened naturally. This gives the resulting child a genetic connection to three people, albeit with a much smaller genetic contribution coming from the donor.

The law is very clear that an egg donor is not the legal mother of the resulting child2 because the legal mother is the woman who carries the child. However, egg donors may take on different social roles in relation to the children born and the recipient families, reflecting the diverse attitudes towards donation found in individuals and families.

The genetic link between a mitochondrial donor and the individual created using this donation has a relatively ambiguous social framework by which to contextualise it. There is not direct evidence on which to base assumptions about the perspectives of people born after the use of these techniques regarding any social role of the mitochondrial donor. Similarly it is an open question as to whether the donor giving an egg intending for her mitochondria (rather than her nuclear DNA) to be used might be approaching the donation with different expectations of its social meaning than a donor donating an egg in its entirety may do.

It may be relevant to note when considering the potential social meaning of mitochondrial connectedness, that the genetic link to the mitochondrial donor would be inherited by children descended from girls born via these techniques. This would give rise to a genetic link traceable back up the maternal line to the donor, whether or not she was identifiable. There is an online market for information about mitochondrial heritage but not a great deal is known about perceptions of any social meaning within this genetic relationship3.

Society is used to ascribing social meanings to the donation of human tissue according to its context, for example as seen in the different expectations around the subsequent social roles of blood, egg, sperm, or live kidney donors in relation to recipients and their families4. The possible ambiguity in the perception of the social relationship between the resulting child and the donating woman that would be brought about after the use of maternal spindle and pronuclear transfer is also seen in the range of language used to describe the parentage of people born after the use of these procedures.

For example, the media have frequently heralded ‘three-parent embryos’ and ‘three-parent babies’5,6,7  in discussing these techniques. Other commentators have compared aspects of the procedures to bone marrow donation8,  which also incorporates third-party genes into patients’ bodies in order to improve health, although these changes are not inherited by the patients’ children. Elsewhere, MST and PNT techniques have been described as being like structural repairs to functional objects, such as ‘changing the batteries in a laptop’9  or like ‘changing the bacteria in our intestines’10, the provenance of which are not usually seen as having any resonance for social relationships.

MST and PNT would also alter the germline of the resulting child. Changing the germline means that changes made would be passed on via the resulting person’s sperm or eggs to the generations descended from them. Based on safety and ethical concerns about germline alterations, in many countries including the UK it would be illegal to offer treatments which make such changes. It is a question for debate as to whether MST and PNT should be regarded as ethically different or acceptable in altering the germline by using mitochondria from a donor’s egg in an embryo, in the place of the mutated mitochondria that the mother would otherwise have provided.
 
Unlike nuclear genes, which come from both parents, only mothers can pass on their mitochondrial genes to their children. In human embryos, mitochondria are passed on from the woman’s egg because the sperm’s mitochondria degenerate as the male pronucleus forms in the fertilised egg. Therefore, while all children of a woman who has mutated mitochondria will inherit them, only her daughters will pass on the mutated mitochondria to their children and to future generations. In the same way, all children born after the use of these techniques would inherit healthy mitochondria taken from an egg donor, but only the daughters that were born could pass on copies of the donated mitochondria to their children.

This alteration of the germline could also mean that, if any unforeseen medical problems were to result from these techniques, they could affect not only children born via these procedures, but also their descendants. It is possible that because of the inheritance of mitochondrial genes down the maternal line, some prospective parents might request sex selection, preferring to put back only male embryos (if a choice of healthy embryos is available), based on a concern to prevent potential grandchildren’s exposure to any safety risks that might be incurred by these techniques. Whether or not such medical problems eventuated, parents might also be concerned that daughters born after the use of such techniques may also face difficult reproductive decisions about whether to use their own eggs to have children. Using sex selection would not, however, limit potential health risks to the parents’ own children, which is the grounds on which the procedure is usually offered. Both sexes are likely to be equally affected if problems were to be passed on alongside the healthy donated mitochondria.

Researchers have strongly recommended that families using this technique commit to allowing very long term follow-up of their children over generations, in order to further our knowledge about the outcomes of these techniques. However, this expectation may prove difficult to fulfil on the part of both families and the research community over several decades. The voluntary nature of the research relationship can make it difficult to anticipate what level of short or long-term follow up data may be able to be gathered from families.

Next: The role of genetic testing

Previous: What are mitochondria?

1It does not currently appear that nuclear transfer techniques (similar to those used to produce cloned embryos for research) would be technically the most straightforward to use in the reconstruction of eggs or embryos to render them unlikely to transmit inherited mitochondrial disorders: see Brown DT, Herbert M, Lambe VK et al. (2006) Transmission of mitochondrial DNA disorders: possibilities for the future The Lancet 368(9529): 87-9.

2s.47of the Human Fertilisation and Embryology Act 2008, is headed: ‘Woman not to be other parent merely because of egg donation’ and follows: ‘A woman is not to be treated as the parent of a child whom she is not carrying and has not carried’, before listing some exceptions which would not usually be engaged in this context.

3See, for example commercial websites, Genetree.com (http://www.genetree.com/mtdna) and Ancestry,com (http://dna.ancestry.com/learnMoreMaternal.aspx)

4See, for example, the Nuffield Council’s recent report Human bodies: donation for medicine and research

5BBC News Online (5 February 2008) Three-parent embryo formed in lab, available at: http://news.bbc.co.uk/1/hi/7227861.stm;

6New Scientist (20 April 2011) Three-parent babies on their way, available at: http://www.newscientist.com/blogs/shortsharpscience/2011/04/three-parent-babies-on-their-w.html.

7Daily Mail (12 March 2011) Babies with THREE parents and free of genetic disease could soon be born using controversial IVF technique, available at: http://www.dailymail.co.uk/health/article-1365287/Babies-THREE-parents-born-years-controversial-IVF-technique-gets-ahead.html#ixzz1iaiH7Ylk.

8BioNews (3 May 2011) IVF and the prevention of mitochondrial DNA disease: the moral issues, available at: http://www.bionews.org.uk/page_94023.asp. 

9The Guardian (19 April 2011) Scientists seek to implant embryos with genetic material from three parents, available at: http://www.guardian.co.uk/science/2011/apr/19/scientists-embryos-three-parents

10BBC News Online (26 August 2009) Genetic advance raises IVF hopes, available at: http://news.bbc.co.uk/1/hi/health/8220553.stm