Page URL: https://www.progress.org.uk/ncobmtdna

Response to a Call for Evidence issued by the Nuffield Council on Bioethics as part of its project Novel Techniques for the Prevention of Mitochondrial DNA Disorders: An Ethical Review

13 February 2012
This policy document is a response by the Progress Educational Trust (PET) to a Call for Evidence (.pdf 189KB) issued by the the Nuffield Council on Bioethics (NCoB), as part of the latter's project Novel Techniques for the Prevention of Mitochondrial DNA Disorders: An Ethical Review.
Responses to this consultation were summarised and responded to by NCoB (.pdf 1.13MB) in June 2012.
PET has also responded to public consultations on mitochondrial donation conducted by the Human Fertilisation and Embryology Authority (HFEA) in December 2012 and by the Department of Health in May 2014, has responded to a survey on mitochondrial donation conducted by the HFEA in July 2015, and has drafted briefings for MPs and Peers on the science and ethics of mitochondrial donation.
PET is grateful to John Parsons and Professor Marcus Pembrey for their contribution to this document.

Summary
We use the term 'mitochondrial exchange', because it has the advantage of describing an outcome rather than a process.
It would be unethical not to permit the use of techniques involving mitochondrial exchange to prevent the transmission of inherited mitochondrial DNA (mtDNA) disease.
There is no reason to think that techniques involving mitochondrial exchange raise any particular ethical problems in respect of translational treatments.
There is no association between mtDNA and a person's identity, and this is the case even if we take the epigenetics of mitochondria into account.
Mitochondrial exchange can be characterised accurately as a form of human germline genetic modification, but this does not make it ethically problematic.
Permitting maternal spindle transfer (MST) while prohibiting pronucelar transfer (PNT) could appear politically expedient, but would in fact be completely wrongheaded.
A record of mtDNA donation should be kept and managed by the relevant authorities, and an (immortalised) cell line should be created from the mtDNA donor, but mtDNA donors should not be identifiable to patients (unless they choose expressly to waive their anonymity).
The use of PGD for sex selection, in order to mitigate hypothetical risks by ensuring that recipients of donated mtDNA are male, would not be reasonable.

Response
In this response, we refer collectively to pronucelar transfer (PNT) and maternal spindle transfer (MST) as 'mitochondrial exchange'. This term has the advantage of being a description of the outcome, rather than the process, of these techniques, and could be used to refer to any other techniques developed in future that result in the same outcome – namely, a situation where a nucleus and mitochondria come to occupy the same cell, when they did not do so previously.
The most urgent ethical issue arising from new techniques to prevent the transmission of inherited mitochondrial DNA (mtDNA) disease is the harm that will result from not permitting the use of these techniques, if they can be demonstrated to work. A 2008 study of the working-age population of the North East of England found that 9.2 in 100,000 people have clinically manifest mtDNA disease, making it one of the commonest inherited neuromuscular disorders and a common cause of chronic morbidity ('Prevalence of mtDNA disease in adults', Schaefer et al, 2008, Annals of Neurology).
mtDNA disease can affect the bone marrow, brain, ears, endocrine and exocrine pancreas, eyes, gut, heart, kidney, liver, muscles and peripheral nerves. Generic symptoms include deafness, diabetes, fatigue, neuropathy, movement disorders, myalgia, seizures, stroke-like episodes and visual impairment ('The neurology of mitochondrial DNA disease', McFarland et al, 2002, Lancet Neurology).
If we do not permit the use of new techniques to avoid the transmission of mtDNA disease, then we will be forced to continue relying on old techniques. These are severely flawed, consisting as they do of preimplantation genetic diagnosis (PGD, only reliable and suitable in a minority of instances), prenatal diagnosis (also unreliable and involves contemplating a termination of pregnancy), requiring the patient(s) to use an egg donor (when the latest HFEA figures confirm that there remains a national shortage of donors), or requiring that the patient(s) abandon all hope of having children to whom they are biologically related. If it is within our means to offer aspiring parents better options than these, then it would be unethical not to do so.
NCoB's Call for Evidence suggests that 'in the early stages of treatment' new techniques 'might still be considered experimental'. All medical treatment is experimental, in the broad informal sense that it stands to be improved or supplanted pending the emergence of further evidence. But treatment is only 'experimental' in a formal sense if patients receiving it are knowingly participating in an experiment. Granted, the transition from laboratory to clinical use is not instantaneous, and the category of 'translation' is useful in describing this transition and ensuring that patients are duly appraised of what it entails. But there is no reason to think that techniques involving mitochondrial exchange raise any particular ethical problems in respect of translational treatments.
NCoB's Call for Evidence asks how mtDNA might be associated with a person's identity. In our view, there is no association between mtDNA and a person's identity, except in the narrowest technical sense of the word 'identity'. To wit, mtDNA sequence variation can be of practical utility in tracing the matrilineal 'ancestry' of cytoplasm, and from this an element of a person's familial ancestry might be inferred. But this fact, while interesting and useful to those with an interest in genealogy, does not confer any profound significance upon mtDNA.
What is generally meant by a person's 'identity' is their essential and distinguishing characteristics, their ipseity. Properly functioning mtDNA is irrelevant to a person's ipseity. The one and only circumstance in which the genetic makeup of a person's mitochondria can have a distinct bearing on their life, is if pathogenic mtDNA mutations compromise the generation of intracellular energy, resulting in mtDNA disease.
This situation does not constitute an identity with cultural value deserving preservation (as some would argue in relation to the culture and customs that have developed around deafness and dwarfism), but rather is precisely the debilitating situation that mitochondrial exchange seeks to avert. Indeed, in most contexts it is nowadays thought dubious to define people in terms of a disorder they happen to have, and doing so is actively discouraged.
The argument above still stands, even if we take the epigenetics of mitochondria into account. Epigenetics is the science of enduring changes in the pattern of gene activity that do not involve alteration of the DNA sequence. Recent evidence suggests that mtDNA can be methylated, meaning that the expression of mtDNA can be epigentically modified. But this is not thought to have any impact upon the expression of nuclear DNA, except inasmuch as late onset complications in mtDNA disease can be mediated by an epigenetic response ('Epigenetics, epidemiology and mitochondrial DNA diseases', Chinnery et al, 2012, International Journal of Epidemiology). mtDNA can therefore be said to be both genetically and epigenetically tangential to a person's ipseity.
One reason why it is sometimes wrongly assumed that mtDNA is bound up with a person's ipseity, is because of a more general misapprehension that DNA per se is inseparable from identity. This notion has been promulgated widely in recent years, with the forensic use of DNA variation to identify individuals among populations, and with public dissemination of the results of the Human Genome Project. But despite the popularity of this notion, it is far from being a generally applicable truth, and mtDNA is one of the starkest examples of an instance where it does not apply.
For this reason, and contrary to what has been suggested in much of the media coverage of mitrochondrial exchange, the word 'parent' is in no way a helpful or accurate description of someone's relationship to another person to whom they have donated solely mtDNA. It is worth recalling that 'parent' is a generic and informal rather than a scientific term – if it were used in a scientific study, it would require elaboration to specify what it meant. Inasmuch as the generic term 'parent' relates to our biology, it is of no use in describing a person from whom we inherit solely mtDNA.
NCoB's Call for Evidence asks what techniques involving mitochondrial exchange 'signify for the relationships of the resulting child to the three adults with whom it shares a genetic connection'. For the reasons stated in the preceding paragraphs, our answer to this question is that the techniques signify nothing. As ever, a child's genetic connection to those adults from whom it has inherited nuclear DNA is coterminous with the connection between a child and a parent. And as ever, a child's genetic connection with the adult from whom it has inherited mtDNA is tangential to the connection between a child and a parent.
In other words, the provenance of mtDNA is irrelevant, beyond the importance of the mitochondria functioning properly. Neither a person conceived using mitochondrial exchange nor anyone who knew them would notice any difference, if one mtDNA donor was chosen rather than any one of a thousand others.
This helps to answer the question of whether mitochondrial exchange is ethically problematic due to the fact that the inherited mtDNA is not only replicated throughout the tissues of the recipient's body, but will (if the recipient is female) be inherited by any children the recipient conceives. In other words, mitochondrial exchange can be characterised accurately as a form of human germline genetic modification, albeit a form of modification where DNA molecules are left completely intact (thereby avoiding risks posed by intervening in the gene sequence within the molecule). Because the provenance of properly functioning mtDNA is irrelevant to an individual's identity, altering mtDNA's provenance in a way that endures across generations is not ethically problematic.
However, such enduring alteration will come to seem ethically problematic, if the proponents of techniques involving mitochondrial exchange seek to avoid the characterisation of these techniques as germline genetic modification. The only reason this characterisation gives an inaccurate impression is because the function and significance of mtDNA is easily misconstrued. The solution to this problem is to better explain the function and significance of mtDNA, rather than reinforcing the misapprehension that germline gene modification is intrinsically problematic. In other words, this is a nettle that needs to be grasped.
Another nettle that needs to be grasped relates to the difference between the two techniques involving mitochondrial exchange that are currently being investigated. Each method entails discarding a cell containing mutated mtDNA once its karyoplast has been removed, but in the case of PNT the discarded cell is a zygote, whereas in MST the discarded cell is a gamete. One could therefore form the superficial impression that PNT is more ethically problematic than MST, because a higher moral status is generally ascribed to zygotes and embryos than to gametes. Permitting MST while prohibiting PNT could therefore appear expedient to policymakers who seek to appease simultaneously the interests of those who have mtDNA disease, and the interests of those who oppose the destruction of embryos. But far from being expedient, such an approach would in fact be completely wrongheaded.
It is crucial that all avenues of research into avoiding the transmission of mtDNA disease be kept open, and this must extend to permitting both PNT and MST. For one thing, the comparative efficaciousness of these techniques remains an open question, pending further research. For another thing, insights gained from investigating one technique can benefit our understanding of the other technique, because scientific knowledge is not neatly partitioned according to what is most politically palatable. It is worth learning from the experience of research into embryonic, adult and induced pluripotent stem cells – these are closely interrelated and interdependent fields, and yet they have suffered from being divisively politicised.
NCoB's Call for Evidence asks whether it is 'desirable for a record of the donation to be kept and managed by the relevant authorities'. In our view, the answer is clearly yes. The provenance of mtDNA is medically useful knowledge in relation to the long-term follow-up of those receiving donated mtDNA, and may also have some as yet unanticipated medical utility. By contrast, the provenance of the sperm used to create the enucleated zygote into which the karyoplast is transferred in PNT is unlikely to be of any medical utility, but this information is also worth recording in the interests of comprehensiveness.
We would also suggest that an (immortalised) cell line be created from the donor at the time of mitochondrial exchange, so that the relationship between the cell nucleus and the donated mitochondria can be studied in the original cellular environment. Such a resource would be as important as long-term follow-up of the health of the recipient and their progeny.
NCoB goes on to ask: 'To whom should this information be made available?' This relates to an earlier question in the Call for Evidence, about possible analogies between mtDNA donation and donation of other human bodily material. While some analogies can be drawn, ultimately we believe that mtDNA donation is sui generis. A limited analogy with egg donation is justifiable, inasmuch as mtDNA is obtained by retrieving eggs from the donor. But in our view, this analogy should not extend to making mtDNA donors identifiable to patients, unless such donors choose expressly to waive their anonymity. (If donor sperm is used to create the enucleated zygote into which the karyoplast is transferred in PNT, then we do not believe there are any circumstances in which the sperm donor should be identifiable to the patient.)
In our view, the concerns that motivated the 2005 removal of the entitlement to anonymity of UK gamete donors are not pertinent to mtDNA. These concerns were predicated on questions of identity, whereas as we argue above, mtDNA is not and should not be associated with a person's identity. While the method of obtaining mtDNA is analogous to egg donation, the ramifications of mtDNA donation for a person's identity are more analogous to tissue or organ donation, which are anonymous. Indeed, there may be mileage in referring to mitochondrial exchange as an 'organelle transplant' in public discourse, in order to reinforce the analogy with organ transplantation.
NCoB's Call for Evidence asks whether the use of PGD for sex selection would be reasonable, in order to ensure that recipients of donated mtDNA are male, and therefore that any as yet unforeseen problems arising from mitochondrial exchange would not be transmitted to subsequent generations via maternal mtDNA. We do not think that this would be reasonable.
As mentioned above, the most significant risks associated with human germline genetic modification do not apply in this instance, as molecules of donated mtDNA remain completely intact. Inasmuch as the possibility of any unforeseen risk needs to be anticipated, long-term follow-up of the recipients of donated mtDNA, together with the resource of an (immortalised) cell line for monitoring, are sufficient for this purpose. Similar measures have been sufficient to monitor the health of those conceived in vitro, many of whom have gone on to conceive their own children (both naturally and via IVF) during the past two decades.
Furthermore, for the same embryo to undergo the processes of mitochondrial exchange and PGD, or for both an egg cell and the embryo it goes on to form to undergo these processes, poses its own risks to the health of the embryo and the chances of successful transfer and pregnancy. Mitochondrial exchange and PGD both involve insertion of a needle into the cell, and time spent with the cell under a microscope. Such procedures put the integrity of the embryo at risk, and multiple procedures compound this risk.
There may be circumstances in which having the same egg/embryo undergo both mitochondrial exchange and PGD is justified. However, we do not believe that mitigating hypothetical risks of as yet unproven and unforeseen problems arising from mitochondrial exchange constitutes such justification.