Germline genetic engineering and ‘mitochondrial transfer’ Prof. Donna Dickenson

Enhancement and germline genetic engineering If it were possible to select genes for intelligence and other supposed enhancements, would we want to do so for present only, or for future generations too? If for future generations too, we would be talking about germline genetic engineering, in which DNA is changed and that change remains inheritable ‘Mitochondrial transfer’: timely case study in (non-)regulation of this enhancement technology

Evidence base Previous evidence base for successful germline genetic engineering was limited to one study in marmosets, in which foreign DNA (gene coding for fluorescent protein) was transmitted through viral vector But attrition rate in these experiments would be unacceptable in humans, requiring 120 unsuccessful pregnancies to achieve one success Carcinogenic genes led scientists to conclude that it would be ‘unwarranted and unwise’ to apply transgenic techniques in humans

A new development New alternative form of germline genetic engineering: ‘mitochondrial transfer’ Might allow women with mitochondrial disease to have genetically related children who would not be at risk (disease passes through maternal line) If it were possible to eliminate mitochondrial disease in future generations, wouldn’t this be a straightforward benefit?– more than enhancement ‘It is only right that we look to introduce this life- saving treatment as soon as we can’ (Sally Davies, Chief Medical Officer for England)

But… The technique doesn’t save lives or cure mitochondrial disease At best it might lower the incidence of such disease in future But there are other ways to do that (PGD in some cases) that don’t require donor women to undergo risky processes of ovarian stimulation and retrieval

Chronology October 2012: Oregon scientists (Mitalipov et al.) publish key Nature paper on MR in 5 macaques, followed by UK research (Herbert et al.) June 2013: UK government proposes regulatory changes to allow MR, although HFEA consultation finds majority of public opposed. Expert panel says no evidence techniques unsafe. February 2014: US FDA hearings, however, conclude that ‘the full spectrum of risks has yet to be identified’ and that both basic and clinical science not far enough advanced to legalise MR

Chronology continued March 2014: MPs of both parties speak against proposals. Government repeats that it intends to allow MR and will only allow debate on how trials will be regulated, but later has to modify position to allow conscience vote in Parliament. Another poll undermines official claim that public in favour. HFEA opens final scientific evidence call on safety; allows only two weeks for submissions. June 2014: HFEA expert panel concludes techniques ‘not unsafe’ July 2014: DoH announces intention to proceed pending Parliamentary vote in autumn

What precisely is ‘mitochondrial replacement’? Term is actually inaccurate, masking contribution of egg donor and egg’s role in programming DNA What is being transferred is not the 37 genes in mitochondria, but somatic cell (with some 20,000 genes) from a woman affected with mitochondrial disease to another woman’s healthy egg, from which nucleus has been removed; really ‘nuclear transplantation’ Preliminary research (Mitalipov et al.) used 106 eggs from 7 women, one of whom donated 28 eggs, indicating possible ovarian hyperstimulation

A paradox, or at least a contradiction Proponents of mitochondrial transfer often claim the mitochondrial genes are too few to matter, compared to those in the nucleus: too few to justify calling this development ‘three-parent IVF’ Yet they also insist that those genes are absolutely crucial, because they determine the incidence of mitochondrial disease

More on mitochondrial disease Mitochondria sometimes described as the energy ‘batteries’ of the cell One in 200 babies born with some mitochondrial disorder, but majority are healthy. Better estimate for severe disease is about one in Can cause muscle weakness, heart, kidney and liver disease, and neurological disorders Expected number of treatments: only 10 cases p.a., depending on cost (probably around £80,000)

So why this controversy over such a small number of cases? UK proposals fly in face of international agreement against germline genetic modification (e.g. Oviedo Convention) The fact that the US regulator has come out against the technology hasn’t been publicised in UK; indeed, the HFEA expert panel report wrongly claimed the US hadn’t decided, when it’s actually decided not to proceed Opponents are being portrayed as either pro- Catholic, anti-science, or both, although many scientists are sceptical

Scientific evidence base FDA: Apart from risks to egg donor and recipient, possible mutations from incompatibility between DNA of somatic cell donor and egg donor Because only one study to date has used human eggs or embryos containing abnormal mitochondria, too early to judge effectiveness. Other studies showed abnormalities in human zygotes not found in monkeys. Unclear whether‘bad’ mitochondria might reappear in later generations

Ethical concerns: 1. Altering DNA of future generations Consultation document acknowledges that ‘the treatment techniques are akin to germline therapy to the extent that mitochondrial donation may have implications not only for the children born as a result of the procedure but for their descendants’ Although this might seem a change for the better, too little is known about disruption of complex interactions between mitochondrial genes and those in cell nucleus

2. Risks for recipients US professor David Keefe has written to HFEA in these terms: ‘Displays of technical virtuosity should not blind us to potential hazards…Our own group moved away from this research because PGD (preimplantation genetic diagnosis) provides a relatively safe alternative to MR for the majority of patients and because vexing concerns linger about the safety of MR.’ In any case, women with severe mitochondrial disease might be too ill to endure pregnancy (FDA patient witnesses came out against technique)

Will it even work? FDA: Only one study to date has used human eggs or embryos containing abnormal mitochondria ‘It is not clear whether these data provide any support for potential effectiveness in humans’ UK proposals don’t legally mandate clinical trials or follow-up of next generation

3. For donors: parentage, consent and exploitation Three or even four parents, if surrogate required because recipient too ill: questions downplayed in UK as sensationalistic Donor’s contribution of labour and risk-taking is being ignored. ‘Lady vanishes’: common phenomenon in stem cell research as well Is altruism of donors being exploited? Can’t give truly informed consent in absence of long-term information about risks of technique

Country comparisons Neo-liberal, science-led approval process for trials now being pushed through in UK contrasts with cautious findings of US FDA hearings Consultation only concerns ‘the detail of the regulations that would put into effect the Government’s intention to allow it’ (s. 2.4 of document). Fait accompli?

En somme… Consultation document, annex C: ‘The intended effects of the proposal are: A. To enable safe and effective treatment for mitochondrial disease But neither safety nor efficacy is yet established, and this is not treatment: at most prevention.

B. Second aim B. ‘To ensure that only those mothers with a significant risk of having children with severe mitochondrial disease would be eligible for treatment’ But these might well be the very severely affected women for whom the risks of pregnancy would be too great

C. The heart of the matter ‘To signal the UK’s desire to be at the forefront of cutting edge of medical techniques’ But as any aficionado of spaghetti westerns knows, the frontier can be a lonely and dangerous place