Three Parent Babies? Should we be concerned?
Headlines including the phrase “three-parent-baby” have appeared in the UK press this week after a report in the Guardian newspaper. [i] Journalists made a Freedom of Information request to the Human Fertilisation and Embryology Authority (HFEA) asking if any babies had been born who were conceived through a novel technique called Mitochondrial Donation Treatment (MDT) which results in them having genetic material from three people. In response, the HFEA confirmed that at least one, but fewer than five, such babies have already been born in the UK. This is not a world first – that was in the USA in 2016 – but it is the first confirmation that this has happened in the UK since 2015, when the UK became the world’s first country to approve techniques for MDT after a vote in Parliament.[ii] The technology has been developed and these babies conceived with the help of a team based in Newcastle Upon Tyne led by Professor Doug Turnbull and Professor Mary Herbert. It has been hailed as a breakthrough in treating mitochondrial diseases, which are rare but can be devastating, resulting in premature death or progressive illness.
The science behind MDT is truly astounding and not a little confusing for those who are not scientifically educated. I will do my best to explain it in accessible terms. DNA is a chemical from which genes, and the chromosomes that carry them, are made. Genes are pockets of information that code for the proteins that are the building blocks of bodies. In the natural process of procreation, we all inherit two kinds of DNA: nuclear, which is contained in the nucleus of the cell, and mitochondrial, which is contained in the mitochondria. The mitochondria are one of several kinds of organelles contained within cells, which are structures that fulfil various functions. Reports about children conceived through MDT have stressed that a tiny percentage (perhaps 0.1%) of the children’s DNA comes from the third person. This refers to the fact that the mitochondrial DNA is tiny compared to the DNA contained in chromosomes in the nucleus and, therefore, a small fraction of the total genetic material in our cells. The figure is, however, somewhat misleading for reasons I will explain below.
Nuclear DNA, along with influences from our environment, determines most of our inherited characteristics, from obvious things like hair and eye colour to non-visible things like our risk of developing many diseases. Half of it is provided by the father, in a sperm cell (spermatozoon), and half from the mother, in the nucleus of an egg cell (oocyte). The sperm and egg cells combine to form a new life, initially known as an embryo (or a zygote in the very beginning). This normally happens in the body during sexual intercourse, but it can also be done in a laboratory (as it is in cases of MDT) using sperm provided by a man and eggs harvested from the ovaries of a woman surgically after she has been treated with hormones to ‘ripen’ her eggs. Some mixing and mutations happen in the process, meaning that each embryo has some new variations in its DNA (on average around 200) that differ from either parent, but we can say that around 50% of our genes come from each of our parents. The sperm cell provides nothing other than the DNA, but the egg cell provides us with everything needed to begin life – it contains all the organelles needed to sustain life and facilitate the multiplication of the cell by producing proteins.
The egg cell, like all human cells except the sperm cell, is immensely complex. It can be likened to a miniature city, with each organelle having a specific function like the various buildings in a city. The egg cell is the largest cell of the human body and the only one large enough to be, theoretically at least, visible with the naked eye, being approximately the size of a small grain of sand. The specific function of a mitochondrion (plural mitochondria – each cell contains many) is to convert energy in nutrients obtained from food into a form usable by cells (the chemical adenosine triphosphate or ATP) through a process called cellular respiration. If the cell is a city, the mitochondria are the power stations.
Because the mitochondria are found in the egg cell but not the sperm cell, the mitochondria of the new embryo come only from the mother. Whether you are male or female, these powerhouses came from your mother. If you are a man you cannot pass them on but if you are a woman all your children, male or female, will receive their mitochondria from you. This makes the mitochondrial DNA an excellent tool for tracing descent through the female line. Biologically speaking, this means mothers have a special role to play in our ability to make use of nutrition. Mothers also have a special role in providing nutrition – initially to the early embryo through her blood supply, then via the placenta and, after birth, if she chooses and is able to breastfeed, through her breast milk. Biologically, motherhood entails protection and nurture.
The difference compared with this normal pattern in babies conceived through MDT is that they have nuclear DNA from one woman and mitochondrial DNA from another. MDT can be achieved through one of two mechanisms:
Maternal spindle transfer (MST) – the woman who carries a mitochondrial disease has her eggs harvested (woman a), as does another woman whose mitochondria are healthy (woman b). The nucleus is removed from an egg from each woman. The nucleus of the egg from woman b is discarded and replaced with the nucleus from woman a’s egg. We now have an egg with woman b’s mitochondrial DNA and woman a’s nuclear DNA. It can be combined with a sperm cell from the man of woman a’s choice (her partner or a donor) to produce an embryo.
Pronuclear transfer (PNT) – the difference from MST is that sperm is injected into an egg from woman a (who carries a mitochondrial disease), beginning the process of fertilisation that leads to a new embryo. The nuclei of the sperm and egg will become pronuclei – the phase before the genetic material combines together – and these pronuclei will be removed and injected into an embryo produced using woman b’s egg which has already had its nucleus removed.
The end result is the same in both cases – we now have an embryo with DNA from three people. This can be implanted into the womb of woman a so that she can carry the baby and give birth to it.
As indicated above, advocates of MDT tend to play down the significance of the combination of three people’s DNA, for example by emphasising that only a small percentage comes from woman b. The 0.1% headline is misleading, however, because it considers the mitochondrial DNA only as a percentage of the total genetic material in the cell. When we consider the nuclear DNA and mitochondrial DNA separately, we should say that these embryos will have 50% of their nuclear DNA from each of two individuals – one man and one woman – and 100% of their mitochondrial DNA from another woman. The term “Mitochondrial Donation Treatment” (MDT), although used by the HFEA,[iii] is also somewhat misleading, since what has been donated is not only the mitochondria, but the whole of the egg cell minus the nucleus. Whilst the mitochondria contain the only genetic material, which is what will be replicated and passed on to other cells and down the generations, the other organelles have been created in the body of the third person. Since they are also essential for life, she has played a crucial part in the conception of the new embryo.
The mitochondrial diseases MDT has been developed to treat result from mutations in the mitochondrial DNA. These mutations can occur in a single egg cell or the new embryo, but they are often inherited from the mother, being present in the mitochondria in all her eggs. Women who discover they are carrying a severe mitochondrial disease are often advised not to have further children as mitochondrial diseases are incurable. The new technologies of MST and PNT open the possibility that women carrying mitochondrial DNA can have children who are genetically related to them because they provide their half of the nuclear DNA. As with any new medical technology, however, we must consider the safety and ethical implications of MDT.
Perhaps the most obvious concerns about this technology relate to its safety. Will the babies conceived through MDT be healthy? Might the process create other problems not yet anticipated? As with any scientific development, the effects and side effects of MDT can only be measured accurately over a long period of time after multiple uses of the technique. As Professor Robin Lovell-Badge, from the Francis Crick Research Institute, is quoted as saying: "It will be interesting to know how well the mitochondrial replacement therapy technique worked at a practical level, whether the babies are free of mitochondrial disease, and whether there is any risk of them developing problems later in life”.[iv] We must remember that real individuals are in view here. Only as they develop to and through adulthood will we be able to tell if MDT has had a negative impact.
This risk of harmful consequences is all the more important when we remember that the embryo’s genes will be inherited by the individual’s children. Any problems arising from MDT will be passed on to future generations too. This amplifies the safety concerns and may cause some people to be wary of such new technologies, especially since they had had limited testing in non-human primate species (those whose genes share the most commonality to ours) before being used in human beings. Some medical ethicists argue that this concern alone should mean that medical scientists should never edit the DNA of embryos. Some may add that it is unacceptable to do something to an individual before a point when he or she can consent (as an embryo clearly cannot) that may have a lasting effect on his or her health. I am not convinced that we must be as restrictive as that, but we certainly should be extremely cautious, and I am not certain that enough research was done into MDT before beginning to use it in human beings.
So far, I have commented primarily on safety concerns. Some geneticists suggest those are “the only serious ethical issue” with this technology.[v] But there are other ethical considerations besides the risk of harm. Our view towards MDT will depend on what we believe to be right or wrong concerning the use of embryos and the nature of families and parenting.
Concerning the use of embryos, the key question is what the status of an embryo is. Science confirms that an embryo is a genetically unique, living, human individual. Some ethicists suggest it should not be regarded as a human person because it has no self-awareness and therefore argue that experimentation on, and destruction of, embryos is acceptable. But they have created a category of “human non-persons”, to which it could be argued that other human beings belong, for example those with severe intellectual disabilities or advanced dementia. The definition of personhood cannot be established through science. It is a philosophical or religious question.
Within a biblical worldview, there can be no such thing as a human non-person. Every living human being descended from the first human beings who were created in the image of God is a human person in relationship to God and bearing his image. The dignity that identity confers does not lessen due to disability or age. Every embryo is, therefore, a human individual known and loved by its creator, God, and afford embryos should be afforded the same value and dignity as any human being. If this is correct, then the PNT technique is problematic because the nucleus from one embryo is destroyed. Killing one individual to allow another individual to be conceived without disease cannot be ethical. This objection does not apply to the MST technique, in which an egg cell nucleus is discarded rather than an embryonic nucleus, but what about the ethics of family and parenthood?
A 2015 BBC headline about MDT read, “Three-person babies - not three-parent babies”.[vi] This confident declaration was apparently intended to allay fears raised by headlines that referred to “three-parent babies”, but is it correct? The article was based on comments by Professor Turnbull, who pioneered MDT. It describes those who provide the nuclear DNA as ‘parents’ and the woman who provides the mitochondrial DNA as a ‘donor’. It also introduced the misleading 0.1% figure and quoted Prof Turnbull describing “three-parent-baby” as “a catchy headline”, adding, “Do I think it's accurate? Of course I don't”. But on what basis does Turnbull make this assertion? Simply because he says that a woman who provides mitochondrial DNA to a child should not be seen as a parent? The article does not provide a definition of a parent. How can we judge if someone is a parent if we do not have a clear definition?
Parenthood is comprised of various elements – both biological and sociological. We may think of those who raised us as our parents even if we are not biologically related to them, but we still had biological parents. Normally, people have a biological father, who provided the sperm cell, and a biological mother, who provided the egg cell and bore the embryo through pregnancy and gave birth to the child. With modern medical techniques, these two aspects of biological motherhood can be separated, as an embryo formed with one woman’s egg can be implanted into the womb of another woman. So, we can speak of a genetic mother and a birth mother. Normally, people have two genetic parents as all of their genetic material comes from one man and one woman. Indeed, definitions of genetic parents tend to describe them as the man who provided the sperm and the woman who provided the egg, but such definitions are made without considering MDT. A more accurate definition of a genetic parent is a person who passes genetic material to an embryo that shapes its development. By that definition, people conceived through MDT do have three parents.
At this point, someone might accuse me of semantics. What does it matter, they might say, if the embryo has DNA from a third person? Surely such a small amount of DNA (0.1%) can make little difference and is basically negligible? To answer that objection, we need to understand more about what mitochondrial DNA does. The mitochondrial DNA contains 37 genes. [vii] In total, the human genome has somewhere between 20,000 and 25,000 genes, so the mitochondria carry at most 0.19% of our genes. Since the mitochondrial genes are, “principally concerned with the integrity of the respiratory (energy producing) chain”, some geneticists liken MDT to, “changing the batteries”.[viii] I find this analogy concerning for three reasons. Firstly, I object in principle to any parallel between human beings (or any created organism, for that matter) and machines. Changing the batteries in a device is clearly not of the same ethical significance as altering the genes of a person. Secondly, the analogy is misleading because PNT and MST do not simply change the mitochondria. The new embryo will have all the constituent elements of the egg cell of the third person, so this is a little more than simply a battery change. Thirdly, and most significantly, the suggestion that the mitochondrial DNA does not do anything other than ensure the provision of energy is wrong.
Advocates of MDT have suggested that it will have no impact on the characteristics of the resulting children other than to free them from the mitochondrial disease. In 2015, Prof Turnbull told the BBC, “Those mitochondria are not going to influence any of the characteristics of these children, they're going to provide healthy mitochondria”.[ix] This claim is in direct contradiction to findings from medical science, which is rapidly discovering more about how the mitochondrial DNA interacts with the nuclear DNA in our development. For example, Fabrizio Ghiselli and Liliana Milani write that, “Mitochondria have a central role in many fundamental processes of eukaryotic life, well beyond energy production”.[x] This is because the mitochondrial genes interact with the nuclear genes, affecting how they are expressed. Researchers have already discovered connections between variations in the mitochondrial genes and characteristics like adult height and liver and kidney function as well as certain diseases.[xi] The field of research is rapidly developing, and many more connections are likely to be discovered in coming years. Our analogy of the cell as a city may help explain this point. The parts of a city will inevitably affect one another – roadblocks in one place will create congestion elsewhere and products produced in one place will be distributed to others. If there are two sources of authority in a city (for example a mayor and a police chief), their policies will affect each other. So it is with the mitochondrial genes and the nuclear genes.
I do not mean to accuse Turnbull of dishonesty in 2015 when he dismissed the idea that mitochondrial DNA impacts characteristics of individuals beyond cellular energy production, since the reports I have cited in contradiction to his claim are from 2020 and 2021. Turnbull may have been ignorant of these facts when he made his statement to the BBC as the evidence may not yet have become clear. Even if that is the case, however, it is still concerning that he was ready to press on with his research and to make such an emphatic statement in the absence of any clear understanding of how mitochondrial DNMA influences development. This correction to a statement made in 2015 – the year when Parliament gave approval for the techniques Turnbull was eager to develop – shows, I suggest, that Parliament was premature in giving its approval. It should be a basic principle of medical ethics that no genetic alterations can be made to human DNA in living individuals without a very clear understanding of how the DNA that is to be altered affects the characteristics of the individuals. That is not the case with MDT.