A third MRT-baby is on its way

Written by César Palacios-González

It has been recently reported (link in Spanish) that a 32 year old Greek woman is 27 weeks pregnant with a child who was conceived after a mitochondrial replacement technique (MRT) – in this case Maternal Spindle Transfer (MST). If true this is really big news in terms of reproductive medicine and biotechnology, we are still waiting for data to be published. If successful, this would be just the third birth following a reproductive technique that mixes the DNA of three people (you will probably remember the big media buzz a couple of years ago about ‘three parent babies’). This newest feat was achieved by a group of Spanish and Greek scientists; the clinical trial was carried out in Greece due to the fact that in Spain MRTs are not on the list of authorised reproductive techniques.

Before discussing what I consider to be the main ethical issue with this case, let us talk a bit about mitochondria and MRTs. Every human egg contains thousands upon thousands of mitochondrion. These tiny organelles have the really important task of producing the energy (in the form of ATP) that first the egg, then the developing embryo, and finally the human adult need to adequately function. It is thus not strange that when mitochondria do not work as they should the human body ‘malfunctions’. And it is also not strange that mitochondrial dysfunction more significantly affects the organs that require the most energy, for example the brain and the muscles.

To understand, broadly, what can go wrong with mitochondria, we need to bear in mind two of their characteristics: a) that they have their own DNA, and b) that they are mostly solely maternally transmitted. Regarding the former, inside every nucleated human cell there is nuclear DNA (nDNA) and there is mitochondrial DNA (mtDNA).

Mitochondria can malfunction because of problems in the nDNA or problems in the mtDNA (for an illustrative video see here). Mutations in the mtDNA can cause: Leber hereditary optic neuropathy, Leigh syndrome, Pearson syndrome, Kearns-Sayre syndrome, and MELAS syndrome (mitochondrial myopathy, encephalopathy with lactic acidosis and stroke-like episodes). There is no cure for any of these conditions, which can be life shortening, and which negatively affect the wellbeing of those affected by them. At present, medical treatment just aims to alleviate the symptoms caused by them.

The fact that mitochondria are mostly solely maternally transmitted entails that if a woman has eggs that contain solely deleteriously mutated mitochondria, whichever of her eggs is fertilised, the resulting single cell embryo (and any future cell) will just contain deleteriously mutated mitochondria. This means that this woman will always pass the disease causing mutated mitochondria to her children.

Scientists have devised various techniques that can help women –whose eggs contain a high percentage of deleteriously mutated mitochondria– have genetically related children whose cells are free of such mutations. These techniques have been collectively called Mitochondrial Replacement Techniques (it is worth saying that there is an ongoing philosophical debate about what we should we call them, see here, here, and here).

The technique employed by the Spanish/Greek team works in the following way. MST: the nucleus of an egg which contains mutated mitochondria is removed, and then transferred into a previously enucleated egg which contains healthy mitochondria (for a detailed description of this technique, and all others, see here). In the end, any child produced with such a reconstituted egg would have DNA from three origins: the intended mother, the intended father, and the egg donor.

The fact that any such child would have this genetic composition has raised the question of whether it would have three (genetic) parents. I have argued elsewhere that this is the case. Furthermore, Giulia Cavaliere and I have defended that lesbian couples who wish to have children that are genetically related to both of them should be allowed access to mitochondrial replacement techniques.

In addition to some people arguing that we should ban these techniques because such children would have three parents, some have argued against MRTs on the grounds that: they are eugenic, would affect ancestry research, could harm egg donors,  could harm future generations, the resources employed for MRTs could be better employed, there are other reproductive alternatives, they would lead to other forms of germline modifications, they involve the destruction of human embryos, and they could harm prospective parents. All of these objections have been shown to be wanting.

Let us turn now to what I think will be the main ethical issue with the Spanish/Greek enterprise. But before doing that, I want to briefly revisit what happened the two previous times that a child was born after an MRT. The news about the first child born after an MRT (the technique was carried out in order to avoid an mtDNA disease) caused worldwide shock for two reasons. First, because it was proof of concept that a live human birth in humans could follow after an MRT. Second, because one part of the procedure happened in the US, and the other part (the embryo transfer) happened in Mexico. The former raised questions about the legality and ethics of the whole enterprise.

The news about the second child born after an MRT, this time in Ukraine, also caused a great stir in the scientific community. Scientists here used an MRT technique called Pronuclear Transfer (PNT), which employs single cell embryos. This time around the commotion was due to such techniques being used not to avoid a mitochondrial DNA disease, but to treat infertility. Scientists in the UK and US had mainly focused on using such techniques to avoid the passing of mitochondrial DNA diseases from mother to children. In their report on MRTs, the US Institute of Medicine concluded that “it is ethically permissible to conduct clinical investigations of MRT, subject to certain conditions” and then asserted:

“the committee recommends that any initial MRT clinical investigations

focus on minimizing the future child’s exposure to risk while ascertaining the safety and efficacy of the techniques. The recommended restrictions and conditions for initial clinical investigations include

limiting clinical investigations to women who are otherwise at risk of transmitting a serious mtDNA disease, where the mutation’s pathogenicity is undisputed, and the clinical presentation of the disease is predicted to be severe, as characterized by early mortality or substantial impairment of basic function; and”

Similarly, UK regulations on MRTs only allow MRTs to prevent the transmission of serious mtDNA diseases.Their use for treating infertility is not allowed (for a detailed account of UK legislation on MRTs see here, and for a contrast between UK and US legislation see here). The UK Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 assert:

            Permitted embryo: circumstances

8. The circumstances referred to in regulation 6(b) are that—

(a) the Authority has issued a determination that—

(i) there is a particular risk that any embryo which is created by the fertilisation of an egg extracted from the ovaries of a woman named in the determination may have mitochondrial abnormalities caused by mitochondrial DNA; and

(ii) there is a significant risk that a person with those abnormalities will have or develop serious mitochondrial disease; and

(b) embryo B was created by the fertilisation of an egg extracted from the ovaries   of the woman so named.

Now, the main ethical issue (or one of the main issues) that will arise from this Spanish/Greek enterprise is the same as that which arose from the Ukraine case: whether using MRTs for treating infertility that is not related to an mtDNA disease is morally permissible. In a news article by antena3 (also in Spanish), and a press release by Embrytools (that I have seen), we are told that this is the first time that a pregnancy ensues after employing MST to treat infertility problems that are not related to mitochondrial DNA mutations.

One of the ethical reasons presented so far against using MRTs for non-mtDNA related infertility hinges on the moral duty that doctors have not to offer futile courses of action. But whether MRTs (or some MRTs) can help to overcome certain types of infertility is an empirical question that is still open to empirical verification. And here is where a big difference between the Ukrainian case and the Spanish/Greek case seems to lie. Whereas there is no clear evidence (or at least no published evidence) that PNT, the technique that uses single cell embryos, can help to overcome infertility due to embryo arrest (for which it was used in the Ukraine instance), in the Spanish/Greek case, the scientists have already presented some evidence that MST “can enhance the potential of developmentally compromised oocytes to develop up to the blastocyst stage without compromising euploidy rates”. And these findings seem to support the use of such technique to help the 32 year old woman who suffers from poor ovarian reserve, which “indicates a reduction in quantity and quality of oocytes in women of reproductive age group”.

All this being the case, we can say that at least this first ethical hurdle (not offering futile treatments) seems to have been overcome. And in doing so we are once more invited to revisit the ethics of MRTs. Let us close here by stating the obvious: until we have more information about this case we will not be able to make a complete ethical assessment of it.