FORTPFLANZUNG UND WOHLTUN / LA BIENFAISANCE PROCREATIVE / PROCREATIVE BENEFICENCE Original article Mitochondrial donation – birth of a policy Andrea Büchlera, Karène Parizera a University of Zurich, Collegium Helveticum ETH/UZH drial diseases affect parts of organs that use a lot of Abstract energy, causing problems such as loss of muscle co­ Mitochondrial donation (or mitochondrial replacement techniques, ordination, heart disease, liver disease, neurological MRT) is a special form of in vitro fertilisation involving the mitochon­ problems, diabetes mellitus, deafness and dementia, drial DNA (mtDNA) of a third (donor) party. This technique eliminates leading to morbidity and in some cases to premature the risk of severe mitochondrial pathologies, genetically inherited from death. In fact, patients can be mildly, severely or fatally the mother, by replacing part of her mtDNA with healthy mtDNA from affected, depending on which organs are dysfunctional another woman, the donor. and to what extent. According to the Human Fertilisa­ tion and Embryology Authority (the UK regulator of the This paper explores the ethical dimensions of this technique and their use of gametes and embryos in assisted reproduction impact upon policy decisions. In particular, it is argued that despite the and research), in the UK, one in 200 children is born spectacular fact that a child might have three genetic sources, the bi-­ with mitochondrial disease each year, with symptoms parental paradigm is not truly challenged. The most important issue ranging from light to severe,1 whereas in the scientific surrounding mitochondrial donation is the fact that it involves germ­ literature it is estimated that one in 400 persons carries line modification. To this extent, approval of such a technique sets a a disease­causing mitochondrial mutation [1]. How­ precedent. There is a wide and traditional international consensus on ever, the probability of a child being born with mito­ prohibiting human germ­line modification, and this paper examines chondrial disease is difficult to evaluate [2]. It is esti­ whether the specific procedure of mitochondrial donation falls within mated that the number of women likely to be eligible this logic. for the procedure under consideration will be around Key words: mitochondrial donation, mitochondrial replacement tech­ 150 per year in Britain [3] and about 800 per year in niques (MRT), medical assisted procreation, germ­line modification. the United States [4]. Both sexes can inherit a mitochondrial disease, but it is only women who are at risk of transmitting the disease to their children. The two most common techniques A. Introduction used for mitochondrial transfer are maternal spindle transfer (MST) and pronuclear transfer (PNT). In the Mitochondrial donation (or mitochondrial replacement first method, MST, a patient’s nuclear genetic material techniques, MRT) is a special form of in vitro fertilisa­ is removed from her eggs and transferred into donated tion involving the mitochondrial DNA (mtDNA) of a eggs once their nuclear genetic material has been re­ third (donor) party. This technique eliminates the risk moved. The eggs containing the patient’s nuclear ge­ of severe mitochondrial pathologies, genetically inher­ netic material and the donor’s healthy mitochondria ited from the mother, by replacing part of her mtDNA are fertilised with the intended father’s (or a donor’s) with healthy mtDNA from another woman, the donor. sperm to create embryos. In the second method, PNT, This implies that the future child will have DNA from the patient’s eggs are fertilised with the intended both parents, as well as some DNA from a healthy fe­ father’s (or a donor’s) sperm in a laboratory to create male donor of mitochondrial contents. embryos. The nuclear genetic material within each Mitochondria are small structures contained in the cy­ embryo is then transferred into embryos created using toplasm of human cells, including eggs. They generate donated eggs and sperm from the sperm provider, once the majority of a cell’s energy supply which powers the nuclear genetic material has been removed. In both every part of our body. The genetic contribution of MST and PNT, the resulting embryos containing the mitochondria is small, both qualitatively and quantita­ female patient’s and her partner’s (or sperm donor’s) tively. Qualitatively, because they do not transmit any of genetic material as well as the mitochondria donor’s the traits that confer the usual family resemblances healthy mitochondria are transferred to the patient’s and distinctive personal features. Quantitatively, mito­ womb and hopefully implant and develop into a foetus. chondria constitute approximately 0.1% of the human There is a wide and traditional international consensus genotype. Nevertheless, for any cell to function, the mi­ on prohibiting human germ­line modification,2 and in tochondrial genes need to work properly, so the impact when they fail to function is considerable. Mitochon­ 1 Confer www.hfea.gov.uk/7517.html (accessed 30/1/2017). 2 The Universal Declaration on the Human Genome and Human dria with gene abnormalities can cause severe medical Rights (UNESCO) indicates in Art. 24 that “Germ­line interventions” disorders known as mitochondrial diseases. Mitochon­ could be “contrary to human dignity”. Bioethica Forum / 2017 / Volume 10 / No. 1 15 FORTPFLANZUNG UND WOHLTUN / LA BIENFAISANCE PROCREATIVE / PROCREATIVE BENEFICENCE this paper we will examine whether the specific proce­ this breakthrough technique has gained the support of dure of mitochondrial donation falls within this logic. a number of scientific reviews [7, 4], as well as some Initial projects involving gene editing with the CRISPR/ academics [8–11]. On the other hand, there has been Cas9 method have prompted extensive discussion of much reluctance, mostly due to the third party’s contri­ its various dimensions. Consensus has been reached bution and a lack of long­term experiments [25]. In this among many scientists that a moratorium on germ­line paper we will discuss the ethical aspects of this tech­ interventions is needed to reflect on their medical and nique and their impact on policy decisions. In particu­ ethical implications [5, 6]. This is not the place for lar, we argue that despite the spectacular fact that a extensive discussion of the various issues; instead, we child might have three genetic sources, the biparental would like to highlight the special features of mitochon­ paradigm is not truly challenged. The most important drial donation versus germ­line editing with CRISPR/ issue surrounding mitochondrial donation is the fact Cas9, for example. that it involves germ­line modification. To this extent, To date, the United Kingdom is the first and only coun­ approval of such a technique sets a precedent. try to have set a regulatory framework,3 enabling women who are at significant risk of passing a mito­ chondrial disease onto their children to receive treat­ B. Ethical considerations and public interest ment at a clinic which has been granted a specific licence to carry out this new technique.4 The UK is An important general ethical consideration underlying known for its forefront approach in reproductive tech­ any decision in the field of reproductive technologies is nologies (including the birth of the first IVF baby, reproductive autonomy. The other ethical considera­ Louise Brown, 1978) and genetics (Dolly, the cloned tions and aspects of public interest are more specific to sheep, 1996), as well as its liberal policy: it is one of the the mitochondrial donation procedure. few countries where the creation of embryos for research,5 including mixed human­animal embryos6 is 1. Reproductive autonomy allowed. Whereas infertility is recognised as pathology by the As for other countries, this prohibition is often subject World Health Organisation (WHO), procreation is con­ to debate with no policy change in sight, including in sidered to be an element of the physical and mental the US where a cautious approach has been adopted. well­being of a person. The wish to have a child has Before analysing the various attitudes, we would like to long been considered by the Swiss Federal Court as a draw attention to a semantic difference: whereas in the basic expression of personality development, and the UK, this technique is usually named ‘mitochondrial Court placed it under the protection of the fundamental donation’, highlighting the altruistic dimension of such right to personal liberty enshrined in Art. 10(2) of the a procedure, US scholars and policy makers tend to use Swiss Constitution.8 The reason given by the Court was a more general term, namely ‘mitochondrial replace­ that the decision to have and raise children belongs, for ment technique’ (MRT). many people, to the essential elements that give mean­ The technique of mitochondrial donation has attracted ing to their lives. The inability to procreate is seen as a intense media interest, even before the first babies burden by people who cannot have children for biolog­ were born through this procedure.7 On the one hand, ical reasons, or who, because of a genetic predisposi­ tion or risk to the health of the unborn child, do not consider natural childbearing as responsible.9 Accord­ 3 Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015. ing to this jurisprudence, State regulations that limit 4 Confer www.hfea.gov.uk/9942.html (accessed 30/1/2017). access to medically assisted procreation and thus hin­ 5 Contrary to the Convention for the Protection of Human Rights and der the achievement of the desire for children, infringe Dignity of the Human Being with regard to the Application of Bio­ logy and Medicine: Convention on Human Rights and Biomedicine, on a fundamental right [12, 13]. Whereas this position according to which: “The creation of human embryos for research was not widely shared initially [14, 15], the desire to purposes is prohibited” (Art. 18­2). This is one of the reasons that the UK has never signed this so­called Oviedo Convention.