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Submission to the Nuffield Council on Bioethics on the ethics of mitochondrial donation

Published: 24th February 2012

The bypassing of inherited mitochondrial abnormalities using donor eggs to create embryos free of the disorder is an advancing area of research (creating so-called 'three parent embryos'). The Nuffield Council has been considering the ethical issues arising from these techniques to prevent the transmission of inherited mitochondrial disorders. The CMF response to this open Call for Evidence can be read below.

Nuffield Council on Bioethics

Emerging techniques to prevent inherited mitochondrial disorders: ethical issues

Response from The Christian Medical Fellowship

Summary

  1. Will these techniques work? We are highly sceptical
  2. Are they safe? No, it involves experimental reproductive cloning techniques and germline engineering, both outlawed and highly controversial
  3. Are they ethical? No, there are huge ethical issues generated by both techniques
  4. Is the debate being handled responsibly? No, there are huge vested interests and hype involved.

Introduction

CMF welcomes the opportunity to contribute to the ethical debate on mitochondrial manipulation through this consultation. CMF has regularly responded to Nuffield Council consultations.

The Christian Medical Fellowship (CMF) was founded in 1949 and is an interdenominational organisation with over 4,000 British doctor members in all branches of medicine and a further 1,000 student members. A registered charity, it is linked to about 70 similar national bodies in other countries throughout the world.

The CMF exists to unite Christian doctors to pursue the highest ethical standards in Christian and professional life and to increase faith in Christ and acceptance of his ethical teaching.

1. Will these techniques work?

1.1 We have significant reservations about the effectiveness of these techniques to prevent inherited mitochondrial disorders. As the powerhouses of cells, the correct assembly of mitochondria is vital for power to be generated, a process that relies on numerous interactions between nuclear DNA and mtDNA. Transplanting a nucleus from one mitochondrial background into that of another during pronuclear transfer (PNT) or maternal spindle transfer (MST) may result in nuclear-mitochondrial incompatibility, unhealthy mitochondria and symptoms reminiscent of mitochondrial disease, in any 'mitochondrial replacement' babies produced.

1.2 Nuclear-mitochondrial compatibility is essential for nuclear transfer. However individual humans are characterised by a complex mixture of related mitochondrial genotypes rather than a single genotype, which suggests that the application of this technology may be more unpredictable, complex and limited (to certain combinations of haplogroups) than is being suggested. (1)

1.3 There are numerous somatic and embryonic cell nuclear transfer animal studies that show mtDNA carry-over from the original cells to embryos, foetuses and offspring is a regular phenomenon (see appendix). mtDNA carry-over has been detected in 165 out of 204 (54 %) cases, with up to 59% mtDNA carry-over reported in one offspring. (2) Importantly, this amount was more than the amount present immediately after the somatic cell nuclear transfer, thus the authors suggested the mtDNA of the original somatic cell had been amplified during development.

1.4 Clearly not all studies have found high mtDNA carry-over. For example the Nature 2009 report on the birth of non-human primates (3) showed undetectable levels of spindle donor mtDNA, but there are sufficient studies showing carry-over for the effectiveness of this technique to be questioned, along with concerns for the outcomes when this is 'tested' out on humans. There is a high possibility that, despite best efforts, the unhealthy mitochondria will be carried over and amplified to levels that could cause mitochondrial disease in "mitochondrial-replacement" babies.

2. Are they safe?

2.1 PNT involves techniques akin to human reproductive cloning which has thus far failed to be proven to be either safe or effective. Cloned human embryos and animal-human hybrids produced by similar 'nuclear replacement' technology have not survived beyond blastocyst stage.

2.2 We know that cloning by nuclear replacement is difficult in mammals, hugely problematic in non-human primates and currently not possible in humans.

2.3 Studies of pronuclear transfer in rodents and maternal spindle transfer in macaques suggest that the procedure can work safely with respect to offspring born. However, if inbred mice or monkeys from the same strain were used throughout, then the lack of genetic variability does not provide much guarantee against nuclear-cytoplasmic incompatibility in other contexts.

2.4 It is clear that these techniques carry significant potential risks to human offspring. There is abundant evidence from animal studies that techniques for culturing and manipulating human embryos can cause major risks for offspring born as a result of these techniques. In general, the greater the amount of manipulation, the higher the frequency and severity of the problems in offspring.

2.5 Moreover, two of the main drugs commonly used in MST and PNT are potentially toxic - cytochalasin and nocodazole.

2.6 Our current state of understanding of how embryo manipulation leads to abnormalities in gene expression is very rudimentary. As a result, there is still an extremely long way to go before it will be possible to reduce these risks.

2.7 The first attempts to create children using these techniques will be experiments because testing of the safety of new reproductive technologies such as this can only be done by actually creating new human individuals.

2.8 The only justification for submitting a child to serious risk is that the mother wishes to be the nuclear genetic parent of the child. We do not consider that the risks to the child from these experimental techniques are justified by this desire.

2.9 Both methods involve germline genetic engineering. The proposed alteration of the germline would mean that unforeseen medical problems would affect not only children born via these procedures, but also be inherited by future generations.

2.10 Profound safety and ethical concerns about germline alterations in many countries - including the UK – have made it illegal to offer treatments which make such changes, yet such concerns are being ignored and overridden.

3. Are they Ethical?

3.1 Both PNT and MST generate very serious ethical problems.

3.2 As noted above, PNT employs reproductive cloning techniques using the original embryo of the woman who wants a baby. This embryo is destroyed when its nuclear genetic material is removed and placed in the 'shell' of a largely-gutted second embryo. Generating embryos exclusively to be used as cytoplasmic donors disrespects nascent human life, and any child born from this particular technique is actually formed from the bodies of two embryos created and destroyed as 'building blocks' for hers.

3.3 Even leaving aside concerns about the welfare of individual embryos, it appears to be a strikingly uneconomical procedure if at least two embryos must always be destroyed in order to create one that is intended for transfer to a womb, and in reality probably many more than two destroyed due to inefficiency.

3.4 There has been little public concern voiced about the acquisition of sufficient numbers of eggs from women for these procedures, particularly MST. However large number of women's eggs will be required to generate embryos 'free' of unhealthy mitochondria. We would like to know how many eggs the Newcastle team have already required to date, to generate embryos via PNT – some have been used in the project but it is far from clear how many have been used, and little has been publicly said about the amount needed to progress this research and 'treatment'.

3.5 Egg donation raises significant ethical – and safety - concerns. Women are increasingly being offered inducements to 'donate' their eggs, through cut price IVF treatment. This is offered alongside promises of potential 'cures' for diseases. This encourages vulnerable women undergoing IVF treatment, and other potential providers of eggs for research, to take known and unknown health risks for ethically dubious research. In our view, encouraging healthy women to risk damage to their own health by providing 'spare' eggs for treatments for others is not medically, ethically or socially justifiable.

3.6 Even with MST, where nuclear material is exchanged before fertilisation and the ethical concerns about embryo destruction are therefore reduced, the child will face the physical risks of the procedure in addition to the identity issues of knowing that she has, in this case, three genetic parents.

3.7 Sir Mark Walport, in an article in The Times argued that: "Medical procedures that introduce a donor's biological material into the body are … long accepted. If a child with donated mitochondria can be said to have three parents, then the recipient of a heart transplant could be said to have four." (4)

3.8 This is disingenuous. Neither MST or PNT can be compared to heart transplants, nor to bodily structural repairs, as they do not involve genetic transfer, nor are inheritable and neither generate ethical questions regarding identity.

3.9 In contrast, the resulting embryo from MST and PNT will have nuclear DNA from a man and a woman and mtDNA from a second woman. This is effectively three genetic parents, despite the contribution from the second woman being very small in terms of genetic diversity. (5)

3.10 Headlines along the lines of 'three-parent embryos' and 'three-parent babies' may not appeal to scientists, but they are accurate. We may not know exactly how the mitochondrial DNA will be associated with a person's identity but we do know there will be three adults with whom it shares a genetic connection. Therefore we have to question what will be the psychological effect on any child of the fact that their DNA is derived from three separate 'parents'?

3.11 The Nuffield consultation paper claims that: 'there is no 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'. This is correct, and illustrates just how the whole experimental process is proceeding far ahead of any research into the social and ethical implications for those who may be born of such experiments.

3.12 However, we do have increasing anecdotal evidence about the importance of genetic heritage for those born from donated gametes and their desire to know about their full genetic heritage. (6) Some have described anger at feeling like a medical experiment and cited problems with understanding identity for themselves and their own children. (7)

3.13 Vested interests and narrow experimental agendas are driving the way ahead, with the ethical concerns lagging behind. The precautionary principle is being ignored. Concerns about the long-term psychological effects on children born of experimental techniques should take highest priority. At the minimum, Nuffield should wait for the conclusions of its own working group on donor conception. (8)

3.14 Claims that the genetic impact of inheriting a third person's mitochondrial DNA would be as minimal as 'changing the batteries in a camera' (9) are only based on current understanding. In reality our understanding of the amount, influence and purpose of mitochondria is still limited and therefore claims such as this are based on supposition.

3.15 None of the safety concerns noted above will be able to be answered without research on hundreds, if not thousands, of human embryos, all of which will be destroyed in the process. We question the justification for the destruction of hundreds of human embryos that have already been destroyed in this research and the many more that will be destroyed in the future. We do not consider that the hunt for 'therapies' that might prevent a small number of disabled children (with mitochondrial disease) being born justifies the destruction of hundreds if not thousands of embryonic human lives.

3.16 We are not alone in holding this concern. Even Sheila McLean has commented: 'there is probably a majority of people (for whom) the deliberate discarding of human embryos is morally troubling' (10).

3.17 Should we be able to choose effectively not to allow disabled children, who would have been otherwise born by natural means, to be born? Why should parental preference for a 'normal child' take precedence over an (equally valuable) disabled child? We should be concentrating on finding treatments for disabling conditions, not preventing those who suffer from them from being born or conceived.

3.18 It is suggested that it would be reasonable to permit prospective parents using these technologies to also use pre-implantation sex selection (preferring male embryos), to limit the risks of transmitting adverse side effects of the techniques to future generations. Once the process is started, it will be difficult to end the selection process. PGD will be permitted for prospective parents to avoid the birth of female embryos, but where will boundaries for this be drawn? How severe would the mitochondrial disorder have to be? How great the risk? (It is claimed that when mutated mtDNA copies make up around 60% or more of the total of mtDNA copies in a cell, this causes serious health problems. What will the risk be for 50% of mutated mtDNA? Will this be permitted? And what is a 'serious' health problem?). Once we have judged some disabled babies not worthy of being conceived, where do we draw the line, and who should draw it?

4. Is the debate being handled responsibly?

4.1 This new 'treatment', even it were eventually to be shown to work (and there is considerable doubt about that), is not actually 'treatment'. It will do nothing for the thousands of people already suffering from mitochondrial disease or for those who will be born with it in the future.

4.2 This is not about research into mitochondrial disorders - which we would support – but is primarily about trying to prevent people being born, or at least helping a very small number of mothers who carry the gene to have their own genetic children who are unaffected.

4.3 There is always in this country huge media hype about supposed breakthroughs in biotechnology and the IVF industry (especially the Newcastle group) is very skilled in generating media interest. We have been here before with human reproductive cloning, so-called therapeutic cloning for embryonic stem cell research (which has thus far failed to deliver) and animal hybrids now a farcical footnote in history.

4.4 The Newcastle scientists have a huge financial and research-based vested interests and getting the regulatory changes and research grants to continue and extend their work is dependent on them being able to sell their case to funders, the public and decision-makers. Yet what is currently being proposed and researched on in Newcastle may be legal in Britain but is illegal in almost every other Western country for good public safety and ethical reasons. Britain is regarded by many as a rogue state in all this.

4.5 Whilst we understand that parents would like to be the nuclear genetic parents of their children, an absolute insistence upon this is unreasonable. There are already some solutions available for those couples who find themselves in the tragic position of carrying genes for mitochondrial disease – including adoption and egg donation (although we have serious ethical reservations about the latter). Adoption is a far better solution to their quandary than these dehumanising and experimental options.

References

1.See the non-confidential evidence to Mitochondria Review, HFEA, 2011.

2. Takeda, K., S. Akagi, et al. (2003). "Proliferation of donor mitochondrial DNA in nuclear transfer calves (Bos taurus) derived from cumulus cells." Mol Reprod Dev 64(4): 429-37.

3. Tachibana et al, Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009;461;367-72

4. http://www.thetimes.co.uk/tto/opinion/columnists/article3292262.ece

5. The genetic contribution of the maternal mtDNA is understood to be small (even trivial), however why is mitochondrial disease so devastating? There does seem to be some irony whereby mitochondria are considered, by proponents of these procedures, to be both essential and insignificant at the same time.

6. Note the court case by Joanna Rose in the UK. http://www.dailymail.co.uk/health/article-115840/Sperm-donor-children-launch-court-fight.html See also 'Who Am I? Experiences of donor conception' Dr A McWhinnie. 2006.

7. 'I wasn't the person I thought I was!' Inside Story DVD, www.concordmedia.org.uk

8. http://www.nuffieldbioethics.org/donor-conception

9. http://www.telegraph.co.uk/science/science-news/9025121/Babies-with-three-parents-possible-within-three-years.html

10. Sheila McLean, New approach could ease the stem-cell fears, The Scotsman, 25/08/06.

Appendix

  1. Do, J. T., J. W. Lee, et al. (2002). "Fate of donor mitochondrial DNA in cloned bovine embryos produced by microinjection of cumulus cells." Biol Reprod 67(2): 555-60.
  2. Takeda, K., S. Akagi, et al. (2003). "Proliferation of donor mitochondrial DNA in nuclear transfer calves (Bos taurus) derived from cumulus cells." Mol Reprod Dev 64(4): 429-37.
  3. Han, Z. M., D. Y. Chen, et al. (2004). "Mitochondrial DNA heteroplasmy in calves cloned by using adult somatic cell." Mol Reprod Dev 67(2): 207-14.
  4. Inoue, K., N. Ogonuki, et al. (2004). "Tissue-specific distribution of donor mitochondrial DNA in cloned mice produced by somatic cell nuclear transfer." Genesis 39(2): 79-83.
  5. Steinborn, R., P. Schinogl, et al. (2002). "Coexistence of Bos taurus and B. indicus mitochondrial DNAs in nuclear transfer-derived somatic cattle clones." Genetics 162(2): 823-9.
  6. Steinborn, R., P. Schinogl, et al. (2000). "Mitochondrial DNA heteroplasmy in cloned cattle produced by fetal and adult cell cloning." Nat Genet 25(3): 255-7.
  7. St. John, J. C. and G. Schatten (2004). "Paternal mitochondrial DNA transmission during nonhuman primate nuclear transfer." Genetics 167(2): 897-905.
  8. Hiendleder, S., S. M. Schmutz, et al. (1999). "Transmitochondrial differences and varying levels of heteroplasmy in nuclear transfer cloned cattle." Mol Reprod Dev 54(1): 24-31.
  9. Steinborn, R., V. Zakhartchenko, et al. (1998). "Composition of parental mitochondrial DNA in cloned bovine embryos." FEBS Lett 426(3): 352-6.
  10. Steinborn, R., V. Zakhartchenko, et al. (1998). "Non-balanced mix of mitochondrial DNA in cloned cattle produced by cytoplast-blastomere fusion." FEBS Lett 426(3): 357-61.
  11. Lloyd, R. E., J. H. Lee, et al. (2006). "Aberrant nucleo-cytoplasmic cross-talk results in donor cell mtDNA persistence in cloned embryos." Genetics 172(4): 2515-27.

For further information:

Dr Peter Saunders (CMF Chief Executive) 020 7234 9660
Philippa Taylor (CMF Head of Public Policy) 020 7234 9664
John Martin (CMF Head of Communications) 020 7234 9665

Media Enquiries:

Alistair Thompson on 020 3008 6063 or 07970 162 225

About CMF:

Christian Medical Fellowship (CMF) was founded in 1949 and is an interdenominational organisation with over 4,000 British doctor members in all branches of medicine. A registered charity, it is linked to about 65 similar bodies in other countries throughout the world.

CMF exists to unite Christian doctors to pursue the highest ethical standards in Christian and professional life and to increase faith in Christ and acceptance of his ethical teaching.

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