The Ethical Complexities of Mitochondrial DNA Donation

Margaret Somerville is Professor of Bioethics at the University of Notre Dame Australia School of Medicine (Sydney campus). She is also Samuel Gale Professor of Law Emerita, Professor Emerita in the Faculty of Medicine, and Founding Director of the Centre for Medicine, Ethics and Law Emerita at McGill University, Montreal.

A bill has been introduced in the Australian Parliament that, if it becomes law, would allow a genetic intervention on human embryos called “mitochondrial DNA donation”.

This means we have to decide on the ethical acceptability of this intervention. Good facts are necessary for good ethics and good ethics for good law. So, first, some facts relevant to deciding on the ethical acceptability of this procedure.

Some Relevant Facts

A human embryo is created when a sperm from a man fuses with an ovum (egg) from a woman. The sperm contributes DNA to the nucleus of the embryo (nDNA), but does not primarily, or even at all, contribute mitochondrial DNA (mtDNA). The ovum contributes both nDNA and mtDNA to the embryo.

Imagine the ovum as a hen’s egg; the yolk is the nucleus, which has nDNA, the white the cytoplasm, which has the mtDNA. The genes in the sperm and ovum that are passed to the embryo are called the human germline genome.

In short, “mtDNA is inherited only or at least primarily from the biological mother, nDNA is inherited from both biological parents. mtDNA contains 37 genes (approximately 0.1 per cent of our genes), nDNA contains 20,000 to 30,000 genes”, approximately half from our mother and half from our father. (Rebecca Storen and Elizabeth Smith, Mitochondrial donation in Australia)

“Three-Parent Human Beings”

One ethical argument against mtDNA donation is that it means creating “three-parent human beings”, which is inherently unethical. Another ethical argument is that it is harmful to the mtDNA recipients, because it causes “genetic bewilderment”, especially when they do not know who the anonymous mtDNA donor is.

We know from studies of people born from anonymous sperm or ova donation and adopted children that most people want to know where they came from biologically and to whom they are biologically related. This information is important in forming our own identity. Imagine, then, finding out that you are the manufactured product of three human beings, one of whom is anonymous.

Advocates of mtDNA donation respond to this objection by comparing the number of genes each parent contributes and arguing that the miniscule number contributed by the mtDNA donor means that the child does not have three parents, but only 2.0012 parents and the third parent can be ignored. The mtDNA contributes, however, to some characteristics of the resulting child and provides 90 percent of the energy for all of the child’s cells.

As well, in seeking to normalise mtDNA donation and its ethical acceptability, its advocates sometimes argue it is analogous to organ donation and transplantation, which is widely accepted as ethical. The latter can be distinguished, however, as not going to the intrinsic essence of the person, as mtDNA donation does. These advocates dismiss this distinction as “genetic reductionism”, that is, espousing the view that we humans are no more than the functioning of our genes — in short, that we are just “gene machines” — a stance that they are right to reject.

Mitochondrial Disease

In a blog posted by the Australian Parliamentary Library, Storen and Smith explain:

“Mitochondrial disease is a group of inherited conditions that can cause serious health issues and, in severe cases, can cause death in childhood. The disease is … [mainly] caused by mutations in mtDNA that impact the function of mitochondria, meaning it reduces their ability to produce energy.

The disease particularly affects organs that have a higher energy use, such as the heart, muscles and brain. Currently, there is no known cure and treatment is mostly limited to the management of symptoms.

In Australia, approximately:

• one in 200 babies are born with some level of mtDNA mutation that could lead to mitochondrial DNA disease in their lifetime
• between one in 5,000 and one in 10,000 Australians are estimated to develop severe or life-threatening mitochondrial DNA disease during their lifetime
• the average lifespan of children born with mitochondrial DNA disease is estimated to be between three and 12 years of age

… it is estimated that mitochondrial donation may be able to assist in the prevention of mitochondrial DNA disease in 60 births per year. (NHMRC Issues Paper, p. 12)”

Fertility specialists have developed various interventions to replace the cytoplasm with the faulty mtDNA with donor cytoplasm with healthy mtDNA. All of these interventions raise serious ethical difficulties and at present Australian law prohibits using them.

The Science

If mitochondrial donation were permitted in Australia, the technique most likely to be used would be pronuclear transfer or PNT. This involves creating two embryos with the father’s sperm, one with the ovum with the faulty mtDNA from the intending mother and one with the donor’s ovum with the healthy mtDNA.

The nucleus (nDNA) is removed from both embryos and the nucleus from the intending mother’s embryo is transferred to the enucleated healthy mtDNA embryo. In other words, the resulting embryo has the intending mother’s nDNA and donor’s healthy mtDNA.

The Australian Catholic Bishop Conference’s paper on mtDNA donation objects to this procedure on the grounds that

… two human embryos are destroyed in this process to create a third. The Conference objects to the disposing of any human embryos because such actions would instrumentalise human embryos, treating them as part of a production process where they can be kept or disposed of subject to arbitrary judgements. This of course does not show respect for the embryos’ inherent human dignity. … PNT is a form of human reproductive cloning prohibited in Australia. The Government is proposing to lift that prohibition.

Maternal spindle transfer (MST) is another technique for ensuring that damaged mtDNA is not passed on to children. In this case, nDNA is moved from the intending mother’s unfertilised egg to the egg donor mother’s egg, which has had nDNA removed. The reconstructed egg is then fertilised with the father’s sperm to create a human embryo. [This avoids destroying two embryos, but] MST also involves three genetic parents and the difficulties that come from that confused parentage for the child.

We can add to the concerns that MST raises, arguably the most important one, that it too involves deliberately changing the human germline genome, the genes passed on from generation to generation.

The Present Law

The relevant laws are the Prohibition of Human Cloning for Reproduction Act 2002(Cth) and the Research Involving Human Embryos Act 2002 (Cth). They make it, respectively, an offence to create, for the purposes of reproduction, a human embryo that contains the genetic material of more than two people and an offence to create, for the purposes of reproduction, a human embryo that contains heritable changes to the genome. An mtDNA donation involves both of these presently illegal interventions.

It bears keeping in mind that legislators passed laws prohibiting these interventions because, as was the broad consensus at the time, they saw them as inherently wrong. That means they believed they could never be justified, no matter how much good they might promise, and that to undertake them would constitute very serious breaches of ethics. Those now wanting to legalise these interventions should have the burden of proving why that is no longer the case.

The Proposed Law

In March this year, the Government introduced a Bill, the Mitochondrial Donation Law Reform (Maeve’s Law) Bill 2021) to the House of Representatives. The Bill would amend “existing legislation to make mitochondrial donation legal for research and human reproductive purposes. The overall aim is for women at risk of passing on mitochondrial disease, to have reproductive options for [their own] biological children without the increased risk of their child having mitochondrial disease.” (Storen and Smith)

The Government recognises that deciding whether to allow mtDNA donation raises serious ethical issues. They include, for example, that mtDNA is medical research on unconsenting human subjects and that there are unknown risks and harms, especially long-term ones to any child born with donated mtDNA. It is not even certain that mtDNA replacement will avoid all mtDNA disease. Some faulty mtDNA might remain in the intended mother’s ovum.

Moreover, even politicians, who do not believe mtDNA donation is inherently wrong, face great uncertainty in deciding whether its benefits and potential benefits outweigh its risks and harms. Consequently, the Government has decided that a conscience vote on the proposed Bill, a rare event, is necessary.

The Ethical Issues

Modification of the Human Germline Genome

A major ethical issue, arguably the major one, is that mtDNA donation involves intervention on and alteration of the human germline genome, the genes passed on from generation to generation. All of the descendants of the genetically modified embryo will inherit the modifications. This opens the possibility of “designer children” and the tsunami of ethical issues associated with that, which we cannot explore in any depth here.

Briefly, prior to around 2015, when the first reports of the possibility of easily modifying the human germline genome with CRISPR-cas9 technology appeared, it was widely accepted that “the human germline was the common heritage of humankind and must be held on trust in its natural state for future generations”. In short, any intentional interference with it or its deliberate modification was considered seriously unethical.

As these new technologies such as CRISPR-cas9 became available, scientists wanting to “do good” and cure horrible diseases especially monogenic ones, those caused by a single gene, such as Huntington’s chorea, were strongly challenging this prohibition.

They argued that a distinction could be made between “therapeutic interventions” and “enhancement interventions” and the former should be permitted, for example, by allowing deletion of the one harmful gene responsible for a dread disease (Paul Root Wolpe, Karen S Rommelfanger & the Drafting and Reviewing Delegates of the BEINGS Working Groups, “Ethical principles for the use of human cellular biotechnologies”, Nature Biotechnology 35, 1050–1058 (2017) (Delegate)). Limited exceptions to the prohibition have been allowed, for instance, in the United Kingdom, but whether that is ethical is still a highly contentious issue.

Research on Human Embryos

mtDNA donation involves medical research on a living human being, the embryo. A central issue is the respect that we owe to this earliest stage of human life. We need to keep in mind in responding that we are all ex-embryos.

Those who believe that in vitro fertilisation (IVF) is immoral and unethical, because it contravenes the required respect, would stop their analysis of the ethical acceptability of mtDNA donation at the first step of the intervention, because it necessarily involves IVF and, therefore, is ethically unacceptable to them.

A caution is merited here: a stance that IVF is unethical should not be, as frequently happens, dismissed out-of-hand as ill informed, archaic and anti-scientific, or irretrievably naïve and simply religious dogma. We must be and remain open-minded to considering and reconsidering the ethics of how we use the knowledge gained from scientific research, especially, as is true of IVF, that which impinges on realities at the centre of what it means to be human.

If, however, we accept that some uses of IVF can be ethical, then we need further analysis to decide whether mtDNA donation falls within such ethical parameters. This requires examining the ethical acceptability of each of the components of the mtDNA donation procedures, two of which, PNT and MST, are described above.

The creation of a human embryo with the intention of killing it in order to use it for spare parts for another embryo or for research, as occurs in PNT, is, in my view, seriously unethical. In other words, transmitting human life with no intention that that human life will have a chance to survive is wrong and sets a dangerous precedent about what is required to maintain respect for human life, both in relation to each individual human life and in society as a whole.

I simply note here that so-called “spare” or “leftover” embryos from IVF undertaken for reproductive purposes also raise serious ethical issues, but they are not created — or at least they should not be — with the intention of killing them or using them other than to try to achieve a pregnancy.

The Failure to Relieve Suffering

The strongest argument for allowing mtDNA donation and by far the most difficult to counter, is that it is necessary for the relief of suffering, both of the affected children and their parents. I know this difficulty from personal experience, because I have participated in debates in which I was called on to make such counter-arguments. One was the 2015 meeting in Atlanta, Georgia, reported in the Nature Biotechnology article referenced above (Wolpe et al.).

I argued against allowing alteration of the human germline genome with CRISPR-cas9 technology, which, at that time, had just become available. That prohibition would include banning mtDNA donation. My principal objections were that, for a variety of reasons, it was unethical to alter the human germline genome and that every human being has a fundamental human right to come into existence with an untampered with genome. In short, everyone has a right not to be designed by another human being or, as philosopher Hans Jonas described it, they have “a right to their own unique ticket in the great genetic lottery of the passing on of human life”.

Two renowned Harvard professors, who were also invited presenters at the meeting, cognitive psychologist Stephen Pinker and geneticist, molecular engineer, and chemist George Church, were appalled that I would want to see them prevented from relieving serious suffering, which would include that of everyone affected either directly or indirectly by mtDNA disease.

Pinker proposed that if bioethicists, such as Margaret Somerville, would recommend preventing the use of these technologies, then the solution was not to stop using them, but to get rid of the bioethicists, a sentiment he expressed again in an opinion piece in the New York Times.

It is, indeed, very difficult to deny people something that they see as their only hope of avoiding severe suffering and deciding to take such a stance requires the utmost integrity, self-reflection and understanding of the other person’s situation. It brings to mind an encounter I had with a woman who sat in my office sobbing and saying to me, “How can you be so cruel?”

I had publicly recommended against repealing the law that prohibited commercial surrogate motherhood in Canada and she wanted me to change my position. She had had five miscarriages and desperately wanted a child created from her ovum and her husband’s sperm, including because she thought it would save her marriage. It was very difficult to deny her request.

That said, in the context of seeking to do good and claiming that goal justifies our actions as ethical, we need to keep in mind that just because we want to relieve suffering and do good does not guarantee that we will achieve that goal or that we are acting ethically.

Funding

Finally, funding of medical research also raises ethical issues. If we believe mtDNA donation is unethical, we would oppose funding it as also being unethical. That brings into question the Government’s allocation of $4.4 million of taxpayers’ money over four years (part of a $10.3 million commitment over ten years) in the 2021–22 Federal Budget (pp. [223–4]) “to support the implementation of mitochondrial donation in Australia’s research and clinical settings” (Storen and Smith, supra). A common saying is that “money talks”. Sometimes it talks ethics or, sometimes, the lack thereof.

A Momentous Decision

Whether to allow mtDNA donation is a complex ethical decision that could also be styled as a court case: In the matter of: The relief of suffering (plaintiff) vs. The ethics of genetically designing our descendants (defendant). It is no accident that both ethics and law are central in this debate.

Just because we can do something does not mean that we should do that or that it is ethical. The most difficult decisions about ethics arise when we are in “a world of competing sorrows”, that is, there are no “no harm options” and we must decide on whom we will inflict the harm. The decision whether to allow mtDNA donation is of this nature.

To prohibit mtDNA donation is a serious harm to parents wanting to use it hoping to have a healthy child and to their children born with mitochondrial disease. It is to choose not to prevent both the parents’ suffering and that of their affected children, and the suffering of the descendants of those children.

As well, some scientists would argue that prohibition is an unwarranted restriction of scientific research into human reproduction and the earliest stages of human life, which could result in great benefits.

On the contrary, to allow mtDNA donation through PNT involves creating human embryos, with the intention of destroying them by using them as therapeutic products. This means we must decide whether this form of mtDNA donation breaches respect for both the transmission of human life and for human life, itself, at both the individual and societal levels at which this respect is required.

Then we need to ask, what precedent allowing mtDNA donation would establish. What would be the wider uses and impacts of this precedent? Would it affirm that it can be ethical to design our descendants? Should we humans set out on a path of displacing and taking over our own genetic evolution?

We are the first humans to face this decision, because genetically manipulating our own evolution was never possible in the past. With the powers that genetic and molecular biology research and technologies have given us, we hold the essence of life, including human life, in the palm of our collective human hand. We need to act wisely and ethically in how we use those powers.

This article was first published in News Weekly.

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