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Unknown risks: Mitochondrial replacement therapy is built on principles borrowed from IVF (above) and cloning

A bit like "Nazi", the E-word, eugenics, is prone to febrile over-use in discussions and debates; and it can be a reliable indicator that the user is losing his grip and the argument. But a report last spring from the Human Fertilisation and Embryology Authority (HFEA) has triggered a rash of worldwide criticism and an outbreak of the E-word — all directed at the HFEA and the British government. 

The report concerned the complex processes of mitochondrial genetic medicine, and it concluded: "Our advice to Government, set out in this report, is that there is general support for permitting mitochondria replacement in the UK." And not just the usual Luddite suspects, pro-life ideologues and Christian fundamentalists, but mainstream, progressive scientific journals, clinical academics and the lay media have all lined up to stress the dangers of the HFEA's recommendations. 

What's going on? In summary, it's a strikingly combustible combination we've seen often before in the UK: some quite brilliant medical science, ethical boundaries stretched or broken, and some quite shocking misinformation.

Every cell in the body contains tiny elements (organelles) called mitochondria. They are responsible for generating energy in the cell: necessary for viability itself, and for the execution of any specialised function-forceful contraction, if the mitochondria are in a muscle cell, electrical impulse generation in a nerve cell, and so on. Surprisingly, and uniquely among the different types of organelle within cells, mitochondria contain not just the enzymes and other molecules necessary for their energy-producing function, but also a certain number of genes. There are only a few dozen mitochondrial genes (compared to around 20,000 in the nucleus) but, just like nuclear genes, defects in them can cause devastating (though rare) diseases. 

Trying to fix or repair gene mutations in "ordinary" nuclear genes presents enormous technical difficulties, but the specific circumstances of mitochondrial genes open up their associated diseases to therapeutic possibilities. During reproduction, half of the new person's nuclear genes come from the mother (in the egg), and half from the father. But the egg also contains all of the new individual's mitochondrial genetic material; none derives from the sperm. So it is impossible to inherit a mitochondrial genetic disease from a father: these disorders may only be maternally transmitted. Modern medicine's technical ability to manipulate and control human fertilisation in the laboratory — in vitro fertilisation (IVF) — presents tantalising therapeutic avenues in relation to mitochondrial gene disorders. 

So-called mitochondrial replacement therapy is built on principles borrowed from IVF techniques combined with those used to make Dolly, the famous cloned sheep. Technical variations are possible, but the principle is that, in a family known to harbour inheritable mitochondrial disease, the nucleus (with its DNA) from an egg from the mother but not the faulty mitochondria in that egg, plus mitochondria (with their DNA) from an egg of an unrelated healthy donor, are united with sperm from the father (and its nuclear DNA) to create an individual who has the vast majority of his or her genetic material (i.e. the 20,000 or so nuclear genes) from his or her "regular" parents, but normal mitochondria, with their several dozen genes, from the healthy female donor. Hence the term "three-parent baby". Pioneering clinical scientists from the UK, in Newcastle, and from the US in Oregon, have brought this technology to within a hair's-breadth of clinical testing.

So why the fuss and where's the misinformation? A horrid disease, a remarkable treatment approach, scientific elegance, and ground-breaking British and American scientists leading the world. And, the HFEA tells us, its extensive public consultation proves there is majority public support. Why spoil the party? 

Simply because we are in fact here considering the first small and tentative steps in altering our genetic constitution, and in a manner that, if successful, will affect the new individual's offspring, and their offspring: a germline modification. The aim may be noble — eradication of a devastating disease — but the means is the generation of unique and artificial genetic constructs of a wholly uncertain nature. And it is presumably the realisation of the awesomeness of this step that has led advocates to be so, well, inventive, in their use of language to calm, to encourage and to mislead. So we have, for example: 

Think of mitochondria as batteries for the cell. This technique would be like changing the battery on a laptop. The energy supply now works properly, but none of the information on the hard drive has been changed.  

There is a certain amount of truth in this: mitochondria are responsible for energy production and so the battery analogy has some rationale. It's the "just replacing" bit that plays fast and loose with real science. For mitochondria cannot remotely really behave like a battery, churning out energy at a fixed rate regardless of the cell's specialised function or situation. They must constantly respond to the cellular environment; they must be subject to control by molecular mechanisms within the cell, and in turn be involved in exercising control over other cellular processes. More than this there are profoundly important and constant interactions and communications between the mitochondria and the nucleus that are vital for the normal health of the cell, and therefore of the organism. 

Mitochondria may only contain a few dozen genes, but no serious scientist could suggest that you measure the importance of genes by their number. Mitochondrial genes and their products appear to influence nuclear genes; normal mitochondrial function both depends on and seems to be required for normal nuclear functioning. When mitochondrial genes go wrong, the diseases that follow can involve muscle weakness or paralysis, blindness, kidney disease, diabetes, brain abnormalities, heart problems, and more. Since this is what happens with rare and major genetic problems, then it is more than likely that common and minor variations in mitochondrial genes (which we call polymorphisms, or collectively the mitochondrial haplotype) might well influence the way all of these organs — including the brain — function. This is an area of active current medical research. There is, for example, increasing interest in the possibility that relatively minor changes in mitochondrial genes may play an important role in psychiatric diseases. 

So the introduction of "third" parent mitochondria into the reproductive equation is not just "changing the battery". Rather, the evidence suggests that many aspects, as yet undefined, of the function and behaviour of the offspring will be significantly influenced. One recent study suggested that mitochondrial replacement "changed the expression of roughly 10 per cent of [nuclear] genes in adult males" — a potentially huge alteration. Admittedly these findings were obtained in studies of the fruit fly, but, like many if not most experiments on the fruit fly the study would not have been performed if scientists did not believe the findings would probably illuminate human biology. Arguably the fruit fly is the right place to make such discovery. 

If you want a laptop analogy, then mitochondria and their genes might more accurately be compared not to batteries, but to one of those rather hidden, small background programmes, taking up maybe less than 0.1 per cent of the disk space, but operating every time our laptop runs and influencing many other programmes. 

And we must hardly forget that this would be a small programme that automatically copies itself onto our next laptop when we upgrade, and to the next one, and so on. Not much like a battery then.

But wouldn't this save lives, babies' lives? It would not. If successful, it would avoid some babies with mitochondrial disease being born. It would have no effect on the condition of any individual, adult or infant, currently living with mitochondrial disorder.  

And the frequency of these serious diseases is not "one in 200 births", as the HFEA claims, but closer to one in 5,000 individuals. Furthermore, in a significant proportion of cases, the mitochondrial mutation appears to have arisen spontaneously, with no preceding family history — in other words, wholly unpredictably. Such cases would therefore never be preventable by this technique.

As Stuart Newman, Professor of Cell Biology and Anatomy at New York Medical College, exquisitely puts it: "One factor in placing these procedures on the social agenda seems to be the conflation of biological modification of people who do not yet exist with medical treatment of actual sick people. The attempt to improve future people is not medicine, however, but a new form of eugenics."

And from the HFEA: "There is general support for permitting mitochondria replacement in the UK," — based on its own surveys. 

The HFEA's survey, and its interpretation of the results, has been publicly criticised. The HFEA indicated that "1,235 responses were made" to the key first question, which was "about the acceptability of the techniques", and there were "approximately equal numbers supporting and opposing their introduction into clinical practice...349 state that they consider [the techniques] acceptable, while 106 agree but with some caveats, but 502 say they are not acceptable". Hardly "general support"; indeed some might, not entirely unreasonably, infer there was more opposition than support. Further criticism concerning the HFEA, its "permissive record" and its claims concerning mitochondrial replacement were offered in July by Marcy Darnovsky, director of the Center for Genetics and Society in Nature, a journal far better known for its support of progressive science than for any rigid ethical conservatism. 

Lord Winston, pioneer of IVF treatment, is likewise no scientific reactionary, but he too has questioned both the technique, and the role — even the competence — of the HFEA. "We know fiddling with mitochondrial DNA may make a massive difference to what happens to nuclear DNA...Abnormal children have been born as result of mitochondrial transfer," he said. "I think, in preventing one genetic disease, you are likely to cause another genetic disease." He has for some while been warning against the resurgence of eugenics, and takes the view that "the regulatory framework that we have in this country is almost completely pointless...I think that the HFEA is not capable of regulating either the commercial aspects of reproductive technologies or the risks that people who undergo these technologies really run."

The UK appears on the verge of "a slippery slope to human germline modification", as the headline to Darnovsky's Nature article put it. "Were the United Kingdom to grant a regulatory go-ahead, it would unilaterally cross a legal and ethical line on this issue that has been observed by the entire international community," she wrote. Article 13 of the Council of Europe's Convention on Human Rights and Biomedicine outlaws such science — "an intervention seeking to modify the human genome may only be undertaken if...its aim is not to introduce any modification in the genome of any descendants". 

As recently as October members of the Parliamentary Assembly of the Council of Europe adopted a Written Declaration affirming that "the creation of children with genetic material from more than two progenitor persons, as is being proposed by the United Kingdom HFEA, is incompatible with human dignity and international law". In support they cited the Unesco Universal Declaration on the Human Genome and Human Rights, the EU Charter of Fundamental Rights, and the European Convention on Human Rights and Biomedicine — all of which prohibit practices which would introduce inheritable changes into the human gene line. And in a cautious and carefully argued article in the journal Science, evolutionary biologists from Germany, Australia and the UK weighed the evidence (concentrating particularly on the importance of the dialogue and interactions between mitochondrial and nuclear DNA), suggested that the risks had been downplayed, and concluded that "it is premature to move this technology into the clinic at this stage".

No matter. The HFEA, curiously to many, appears to see its principal role as cheerleader for controversial new developments in genetic medicine and human embryology, rather than impartial assessor. As the BBC reported, "Professor Lisa Jardine, chairwoman of the HFEA, said the UK was in one of the most advanced positions in the world. 'Other countries are astounded that we're this far on in the discussions'," she said. Quite.

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