Genes interact with one another. If you think about it, that’s not really surprising – the complex range of processes that cells engage in, like respiration or cell division, are unlikely to be accomplished by single genes acting in isolation. So genes act in networks or pathways, each one contributing some particular component, frequently they contribute to multiple different networks or processes throughout the lifetime of an individual (e.g. development and immune system). Genes are also variable. This means that no two individuals are alike. As a consequence the outcome of a particular interacting pair of genes will sometimes differ between individuals. Geneticists call this kind of effect epistasis. It’s really the dark side of genetics, in the sense that it’s poorly studied and we know very little about how widespread it may be, but a recent study suggests it is important.
Epistasis can occur between individual genes, between sets of genes, or even between genomes. These kinds of epistasis are of relevance to the recent discussion regarding the safety and ethics of mitochondrial replacement therapy (MR; or 3-parent IVF as it’s sometimes referred to). I have written with colleagues about the safety aspects before. In this post I want instead to focus on the ethics of MR and the role of epistasis, which has so far been almost entirely ignored.
The ethical review of MR within the UK was carried out by the Nuffield Council on Bioethics in 2012. Their conclusion was: “Provided that the techniques are proved to be safe and effective, and an appropriate level of information and support is offered, it would be ethical for families to use these techniques as treatment” (summary report).
An important part of the review revolved around the question of identity: “A key area of discussion around proposed therapies for mitochondrial DNA disorders has been whether these treatments might alter, or otherwise affect, the resulting person’s identity in ways which might be ethically significant.” (section 4.5)
The report cites the view of the Medical Research Council and the Wellcome Trust that:
“We do not believe the transfer of mtDNA raises issues around identity, since it does not carry any genetic data associated with the normally accepted characteristics of identity. An analogy could be drawn with replacing the battery in a camera – the brand of the battery does not affect the functioning of the camera.” (section 4.5)
The rationale being that the mitochondrial genome contains only 37 genes, and that these genes “are thought to be restricted to governing the actions of the mitochondria” (section 1.6).
The Nuffield Council on Bioethics discussed four aspects of “identity”, including genetic identity. For the MRC and the Wellcome Trust then, genetic identity is limited to nuclear DNA (and apparently for the government too, see my recent post). Others see things differently, for example bioethicist Annelien Bredenoord argued that, in terms of a persons genetic identity, the distinction between the nuclear and mitochondrial genomes is a false one:
“No matter whether one modifies a (pathogenic) nuclear gene or a (pathogenic) mitochondrial gene, the identity of the future person will be changed” (section 4.26).
In the review, the action of genes within the mitochondrial genome – whether it be in terms of developing a disease, influencing genetic identity or individual characteristics or traits – was considered to be directly additive and the role of epistasis between the nuclear and mitochondrial genomes was not explored in depth. In fact, as far as I can see, the report addresses this issue in only two places, one of them was section 1.6:
“It is possible that mitochondrial DNA may have other influences, but this is the subject of ongoing scientific enquiry and debate. For example, some authors studying the mitochondria of mice have suggested a link between the functioning of their mitochondria and their cognitive capabilities.” (see also section 4.72)
By coincidence, the council published their annual report today and their director Hugh Whittall asked in a tweet: "Let us @Nuffbioethics know how you think we are doing.... http://www.nuffieldbioethics.org/2013/annualreport.php …"
Well, my answer is that the council was correct in stating that the role of variation within the mitochondrial DNA (mtDNA) on traits other than those encoded by the 37 genes it contains, is an active area of research. But it’s pretty well established by now that it does influence a range of important traits, and we pointed this out in our recent paper. The question is not really whether it has an effect or not, but what is the full impact of variation in mtDNA. This is a clear shortcoming of the ethical review, since they apparently did not explore in depth the substantial literature on this topic. The evidence indicates that the battery analogy is really an inaccurate simplification of how the mitochondrial genome exerts its influence.
In one sense, MR does not result in genetic modification – in terms of gene content the same set of 37 genes are being replaced in MR. But the sequence of DNA will be changed and as such the epistatic interactions between the novel mitochondrial genome and the mother’s nuclear genome will be modified. As a result, the individual embryo created through MR will, in all likelihood, not have the same identity as one created using the mother’s mitochondria (excluding of course the effect of any pathogenic mitochondrial mutations).
The Nuffield Council is not alone. So far I have not come across any discussion of how the ethics of these kinds of therapies (or others that may come in the future, such as gene editing) may be shaped by the effect of epistatic genetic variation. In my view it is important to realize that therapeutic efforts to replace or edit faulty genes may have knock-on and unpredictable effects on processes and traits that do not form the target of the intervention. That’s the reality of biological complexity. The ethics of that need to be included in those discussions.
This is a guest post by Ted Morrow, who is an evolutionary biologist and Royal Society University Research Fellow at the University of Sussex.