Mitochondrial replacement and the ‘slippery slope’ trope

14 July 2013 by Lee Turnpenny, posted in Uncategorized

Ethical arguments are conveniently bracketed under the 'Slippery Slope' trope when their empirical and logical predictions are summarily of the form: 'Acceptance and moral justification of X will inevitably lead to, and automatically imply acceptance of, (undesirable) Y. Therefore, ban X.' In an article in the latest edition of Nature, Marcy Darnovsky, executive director of the Center for Genetics and Society, argues that it is not mitochondrial replacement technology per se, but the UK government's acceptance of the Human Fertilisation and Embryology Authority's advice on it which constitutes the slope towards germline modification. Because she is adamant that the envisaged technology, which could (theoretically) prevent the hereditary transmission of mitochondrial disease, is itself germline modification. So, to be clear (because the title of the piece is potentially mis-readable), her concern is not that mitochondrial replacement technology (as X) will lead to something else (more) sinister (as Y); it is that the accepted 'recommendation' for further research is the X that leads to inevitable mitochondrial replacement as the Y. And hence that the HFEA advice's inclusion of suggestions for regulation to prohibit other genetic modification is tantamount to trying to shut a horseless stable door. And she makes a fair case. Certainly one necessary in order to provide perspective on the media's painting of an apparently done deal.

Mitochondria (‘thread-like granules’) are cell organelles present in cytoplasm in high but varying number, depending on cell type. Essential for cell function and normal development, they contain their own DNA, comprising genes which encode proteins crucial to the maintenance of energy levels, without which cells degenerate and die – we all age as our mitochondrial 'batteries' wear out. Mitochondria tend to be present in larger number in cell types with greater energy requirements, such as those of the nervous system or muscle. Mitochondrial gene defects can thus give rise to disease conditions which, being more dependent upon mitochondrial function, tend to afflict those same tissues. And some of those conditions are severe.

Whereas the sexual process results in equiparental contribution to a unique chromosome complement in the fertilised egg, the transmission of mitochondrial DNA is asexual, being provided solely by the mother. Hence, disease caused by mutation in mitochondrial DNA is inevitably transmitted from carrying mother to offspring. To enable an affected woman to have unaffected children, it is proposed that her eggs' chromosomal DNA could direct development of healthy offspring if supported by 'healthy' mitochondria. There are (at least?) two approaches: following fertilisation, paternal and maternal pro-nuclei are transferred to a pre-fertilised and enucleated donor egg ('embryo repair'); or, maternal chromosomes are transferred to an enucleated donor egg ('egg repair'), with subsequent fertilisation of the composite cell. Either way, the envisaged result is ultimately – dependent upon successful culture, implantation and gestation – healthy offspring whose cells contain genetic material from three individuals: a haploid chromosome set each from mother and father; and mitochondrial DNA from the donor.

Therein lies the knee-jerker: the third 'parent' – the procedure requires healthy mitochondrial DNA-containing eggs from a separate donor individual. And there are those, who cannot – or just refuse to – get beyond this 'Yuck Factor.' Although generalisation, we might reasonably predict that those who object (on religious grounds) might also air dissension to, eg, nuclear transfer technology (encouraged by media misuse of its misnomer 'cloning'); and to human embryonic stem cells; and to abortion; and even IVF. Not all objectors would tick all on that list, grant you; though most would likely object to more than one. Certainly, those indisposed toward IVF will hardly countenance the laboratory manipulation of human cells being considered here. (However, in my experience, the accusation that scientists are 'playing God' is not levelled by the majority of people, religious or otherwise. Which is refreshing, because after all, whether prompted or not, it is a stance from creationist-level inconsideration.)

There is, however, an irony in the (usually religious-based) 'ethical' concerns here: labelling nuclear transfer with that bastard word 'cloning' (in order to spark emotive reaction) conveniently overlooks the mitochondrial DNA in the donated egg, which, as it is also distributed throughout the body by replication and cell division, would contribute to an individual with a unique total DNA complement. In other words, not a 'clone.' Yet with mitochondrial replacement technology, such objection is turned on its head because this scenario relies on recognition of this other 'third parent' DNA, which is not insignificant. And advocates of the technique attempting to dismiss its significance are criticised by Darnovsky, who writes:

'Supporters argue that these concerns [about the genetic modification of gametes or early embryos and the consequent manipulation of the characteristics of future children] do not apply to modifications of mitochondrial DNA, which they characterize as an insignificant part of the human genome that does not affect a person’s identity. This is scientifically dubious.'

Which it is. Whilst mitochondrial DNA carries a small number of genes, there is a not insubstantial amount of it. And it is not being merely 'modified'; it is being replaced – wholesale. Any scientist making absolutist statement as to the absence of any effect on identity should at the very least be met with a concerned and quizzical frown. Yet, questionability aside (See 'Misconception 6' here), isn't such a statement a misleading attempt to assuage the protests of those who instinctively react to the other 'third parent' DNA? A problem that those directly affected and considering the technique have presumably resolved.

Surely the more plausible and applicable ethical objections are not those ingrained from a faith perspective. A real, important and sticky matter is the procurement of donated eggs. Darnovsky does not go there (here); it would be interesting to learn her opinion of the researchers' offer of £500 to egg donors. Is that per egg?! Is this the going rate? At what level was this decided as sufficient recompense? Oughtn't that particular committee to perhaps have sat a while longer? However, Darnovsky does legitimately voice concern as to the riskiness of the technique, rightly pointing out that such concerns are not the sole preserve of the moralising religious. Which is a good point to make in order to counter the (religious) perception that religious perspective is necessary in order to pronounce on bioethics.

I have previously pondered aloud on the real ethical reason why the reconstructed cell that is the product of nuclear transfer should not be introduced into a uterus for implantation and gestation and eventual parturition of a new individual. Because, the only test of whether it would work – and by 'work', I mean a life lived without health complications consequent on the technique by which that life was engendered – is the healthy longevity (or longevous health) of the resultant individual.

Following public consultation last year, the HFEA has provided advice to the UK government. It is a long document, which I've only skim-read. But my eye was caught on page 4 by:

1.7          Our advice to Government, set out in this report, is that there is general support for permitting mitochondria replacement in the UK, so long as it is safe enough to offer in a treatment setting and is done so within a regulatory framework. Despite the strong ethical concerns that some respondents to the consultation expressed, the overall view is that ethical concerns are outweighed by the arguments in favour of permitting mitochondria replacement.

Since when did 'general support' (a claim challenged by Darnovsky and the CGS) qualify as 'advice'? The sine qua non for ethical approval is surely not support in principle, but whether it works... safely. That such 'ethical concerns' – where ethics properly means 'do no harm', and not 'do not offend sensibilities' – are outweighed by permissive arguments suggests those concerns are trivial. But they're not, are they?

More reassuringly on page 29:

6.75          The Authority advises that mechanisms be put in place to allow for further consideration of the safety and efficacy of the techniques, in light of further research suggested by the expert scientific panel (outlined in its report at Annex viii), in conjunction with HFEA consideration of a licence application. The techniques should only be carried out in clinical practice once experts advise the HFEA that these results are reassuring.

Yes. But results from what? The group seeking the go-ahead says:

'... we now wish to determine the safety and efficacy of different techniques in normally fertilised human oocytes by exploring embryo development and assessing human ES cell lines.'

But mitochondrial replacement is not just an IVF procedure; it is also a nuclear transfer technique, the ultimate desired outcome of which cannot be fully evaluated in vitro (can it?). Granted, it is not concerned with the more complex re-programming of an adult cell nucleus following transfer to an enucleated egg, implantation of which is prohibited by law. Transfer before programmed development is likely to be far less problematic and more reliable... suggesting the likelihood of safety. But full determination of that safety necessitates effecting change in the law... for this particular application. That, says Darnovsky, is the slope. Whether or not one agrees with her on that (and I think the invoking of eugenics, which is about state coercion, is not justified), she is justified in raising concerns about safety, what determining that safety entails, and of the apparent scope and conclusions of the HFEA consultation.

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