In early February, the Minister for Health, Greg Hunt, announced that Australia’s federal government intends to introduce legalisation to permit the procedure called “mitochondrial replacement”. It says it will do this in a “staged and closely monitored” way.

The Government intends to relax two laws -- the Prohibition on Human Cloning for Reproduction Act and the Research Involving Human Embryos Act -- so as to permit assisted reproductive technology clinics (initially, only one) to offer the service to families who suffer from the effects of severe forms of mitochondrial disease. The research and experimentation will be monitored and evaluated before other clinics will be allowed to offer the service.

Women who carry a mitochondrial genetic defect risk passing on severe mitochondrial disease to their biological children. The term “mitochondrial donation” refers collectively to a number of techniques aimed at avoiding the transmission of abnormal mitochondrial DNA.

Mitochondrial donation techniques

There are two main techniques.

One is called “pronuclear transfer” or PNT. In PNT, two embryos are created, one with mother’s egg which contains abnormal mitochondria, the other with a donor egg which contains normal mitochondria. The nuclear DNA is removed from each embryo. The nuclear DNA from the abnormal embryo is then transferred to the healthy embryo. The two original embryos are destroyed in the process of creating the third.

The other method is called “maternal spindle transfer” or MST. In MST, the nuclear DNA is removed from the intending mother’s unfertilized egg and inserted in the donor’s egg which has had its nuclear DNA removed. The reconstructed egg is then fertilized to create an embryo free of abnormal mitochondria.

In both processes, human embryos will be deliberately destroyed. This is part of the process of PNT and will be part of the embryo experimentation involved in preparing for, and undertaking, MST. In addition, and if it is decided to implant only male embryos -- because mitochondrial disease follows the maternal line -- then female human embryos will also be destroyed as part of the process.

Severe mitochondrial disease can have devastating effects which include the premature death of children, painful and debilitating and disabling conditions, and long-term ill-health and poor quality of life. It is hoped that mitochondrial replacement could prevent some children from suffering from a potentially very severe and sometimes life-threatening disease.

So we should certainly look for ways to help couples who want to avoid passing on mitochondrial disorders to their children.[1] Their desire for healthy children to whom they are biologically related is goes deep and is easily appreciated.[2]

Other possibilities

That said, over the last ten years the significant advances in therapy development for mitochondrial diseases raise a serious question about why the law should be changed now to permit such an ethically-troubling solution to the problem faced by these couples.

The synopsis of one report states:

“Decades of work elucidating mitochondrial disease mechanisms have culminated in the commencement of several clinical trials of novel pharmaceutical agents that may herald the discovery of urgently needed disease-modifying therapies.” [3]

Another report contrasts mitochondrial replacement which could ultimately “benefit ‘a slice of a slice of the affected communities’, namely women with mutated mitochondrial DNA who want to have genetically related children”, with gene therapies which offer hope to everyone with mitochondrial disease. [4]

Perhaps the results of these clinical trials of pharmaceutical agents may be some way off. Perhaps the trials will not be successful.

For one reason or another, the government has decided to endorse mitochondrial replacement as a solution to mitochondrial disease.

Objections and risks

I suggest that there are two in-principle (or intrinsic) objections to mitochondrial replacement treatment, as well as many attendant risks.

The procedure involves creating human life not for its own sake but for the purposes of experimentation, extraction and then destruction. In PNT, this is part of the process itself. In MST, it will be part of the research involved in testing the procedure.

In addition, mitochondrial replacement arguably violates what in the ethical literature is referred to as the child’s entitlement to a natural biological heritage, that is, his or her entitlement to be conceived from untampered-with biological origins, in particular, from a natural sperm from one, identified, living, adult man and a natural ovum from one, identified, living, adult woman. [5]

In the light of these two in-principle objections, I think we should not pursue this solution to mitochondrial disease. However, once the parliament legalized the creation of human embryos for purposes other than implantation in a woman, that is, once it legalized the creation of human embryos for research, experimentation and subsequent destruction, the door was opened to this kind of technology.

But it is associated with serious risks.

Mitochondrial donation risks creating confusion with respect to personal identity, parentage and kinship. Both the US national academies and the English Nuffield Council have acknowledged that mitochondrial DNA might contribute to personal characteristics in ways that are not yet well understood.[6] Given that the child will inherit DNA from three people, the procedure risks causing “genealogical bewilderment”, the discovery that one’s origins are fragmented. [7] This has implications for what it means to obtain consent from participating parties, which include not only the adults involved but also the to-be-born children.

Mitochondrial replacement raises difficult challenges to the principle of “informed consent”, the principle that, except in cases of emergency treatment, physical treatments should not be administered to any competent person until all relevant information has been discussed and considered and the person’s free and adequately informed consent has been given. But it raises much more difficult challenges to the principle of “anticipatory consent”, the principle that, if we cannot reasonably assume that someone -- for example, the “to be born child” -- affected by our decision, who is not present, would consent if present, it is not ethical to proceed.[8]

Mitochondrial donation risks changing the human germline in ways which we do not as yet understand. It therefore constitutes a technology with unknown long-term results.

One proposal is that only male embryos, created using this technology, should be implanted. For, if female embryos were implanted, the new mitochondrial DNA would pervade every cell of the body of the child so produced, who would then pass that on to her children. That is certainly germ-line modification.

Merely to stipulate that the technology does not constitute germ-line modification (in legislation permitting the procedure) would be both unethical and unpersuasive.

However, if to avoid such germ-line modification only male embryos were to be implanted, this would involve the destruction of even more human embryos -- the female ones -- and according to one scientist, a 50 percent reduction in the efficiency of IVF. [9]

And there are other risks.

One is that we shall return to the bad old days of anonymous gamete donation (to avoid the “three parent” problem). This must be resisted. We should not backslide on this significant Australian ethical achievement: the prohibition of anonymous donation of gametes in IVF. People want to know “where they came from”.[10] In addition, whether they want that information or not, the history of adoptions and of anonymous donation of sperm underscores the community’s obligation to ensure that identifying information remains available.

Another is the possibility that the mother’s damaged mitochondrial DNA may be carried over into the reconstituted donor ovum.[11] Unless the haplotype of the donor is matched to the haplotype of the commissioning couple, there is a (theoretical) risk that the mitochondrial DNA will not be compatible with the nuclear DNA, and that incompatibility itself may cause disorders.[12]

There is also the prospect of further commercializing assisted reproductive technologies, and thus adding to the inequities in the medical system. For this reason, clinics should be prohibited from charging anything over “cost-recovery”. Nor should we forget that the procedures used to obtain eggs from the donor are invasive and associated with risks.[13]  

The government must be truthful

If, as seems to be the case, the government is intent on legalizing the procedure, it should be truthful about the technology.

It should not describe the technology as a cure for mitochondrial disorders.

It should not imply that mitochondrial donation is comparable with organ donation and transplantation (as is sometimes suggested by its proponents).[14]

It should not obfuscate the fact that use of the technology will occasion unresolved questions of kinship and parentage associated with mitochondrial donation.[15]

It should outlaw the use of the technology for any purpose other than circumventing severe mitochondrial disorders (eg to circumvent age-related infertility).

And it has to find a way to balance respect for the privacy of couples who make use of the technology with the community’s entitlement to require follow up studies which evaluate the uses of the technology: no easy task.

Notes

[1] Other options are available: IVF with donor egg, adoption, fostering, etc.

[2] It is sometimes claimed that the desire is based on mere cultural conventions.

[3] Pitceathly, Robert D.S. et al. Moving towards clinical trials for mitochondrial diseases. Journal of Inherited Metabolic Disease, 2021, 44: 22-41

[4] Dolgin, Elie. Beyond three-parent babies: new drugs offer hope for mitochondrial disease, https://www.statnews.com/2016/02/11/mitochondrial-disease-therapies/ accessed 23 Feb 2021

[5] Somerville, M. Children’s Human Rights to Natural Biological Origins and Family Structure, International Journal of the Jurisprudence of the Family, Vol 1, 2010.

[6] Senate Community Affairs Reference Committee. Science of mitochondrial donation and related matters, Thursday 17^th May 2018: Dr Newson, University of Sydney, Hansard: p 52

[7] Nicholas Tonti-Filippini. Submission No 2 to NSW Parliamentary Inquiry into Inclusion of Donor Details on the Register of Births, 18 November 2011

[8] Somerville, M. op cit.

[9] Professor Thorburn, Murdock Children’s Research Institute: Hansard, op cit. p 15.

[10] Ironically, the arguments for anonymity inadvertently reveal (contrary to what is sometimes claimed) just how significant is the donor’s mitochondrial DNA.

[11] “Even with efficient techniques, invariably mutant mitochondria will be transferred to the donor oocyte.” Prof Dowling, Hansard, op cit, p 52

[12] Professor Thorburn, Hansard, op cit, p 15; An analysis across studies conducted in animals suggests that the effects of creating new mitochondrial-nuclear interactions are more often negative than positive. Professor Dowling, Hansard, op cit, p 53

[13] Scientists say that fresh eggs will be needed. So, the introduction of this technology will in no way reduce the thousands of stored and frozen human embryos.

[14] In standard organ transplants, any new DNA which is introduced into the recipient’s body is unlikely to persist in the long term and is unlikely to enter the germ-line and be passed on to the organ recipient’s children.

[15] This was acknowledged by Professor Dowling, who points out that in debates about the technology, the part that mitochondrial DNA plays in human characteristics is sometimes “underplayed”. Hansard, op cit, p 50

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