Redefining normality? Mitochondrial disease and replacement

By Philippa Brice

3 September 2014


Mitochondrial diseases are a complex and incompletely understood group of conditions arising from genetic defects that impair the function of the mitochondria, the cellular energy-producing structures. These include mutations in the small amounts of extra-nuclear mitochondrial DNA (mtDNA).

Mitochondrial mutations in healthy individuals

A new paper published in the journal PNAS reports on heteroplasmy, the presence of different mtDNA variants within a single human cell. Using data from over 1000 individuals, researchers showed that over 90% displayed heteroplasmy; more significantly, at least 20% were found to have a mtDNA variant associated with mitochondrial disease. They observed that the proportion of abnormal mitochondria fell of sharply above a level of around 60%.

This was proposed to be a functional threshold for disease, and at which the body may bring into play active mechanisms to exclude or inactivate these abnormal mitochondria. Focusing on this finding as their NHGRI Genome Advance of the Month, the US National Human Genome Research Institute observe that understanding such mechanisms could ultimately help the development of therapeutic interventions to treat mitochondrial disease.

The authors of the paper conclude that the ‘prevalence of mitochondrial heteroplasmy with high pathogenic potential in healthy individuals’ underlines the importance of managing mitochondrial heteroplasmy to prevent disease progression.

Defining genetic modification for mitochondrial replacement

Meanwhile, efforts in the UK to make mitochondrial replacement therapy (MRT) legal for the benefit of women who carry pathogenic mtDNA mutations continue, with an evidence session on mitochondrial donation held by the House of Commons Science and Technology Committee. The MRT procedure involves the use of the mother’s egg cell and a healthy donor egg cell, as well as the father’s sperm cell, to create a composite embryo. As this involves creating a heritable (germ-line) genetic change, albeit confined to the mtDNA only, it is currently prohibited.

However, the UK Government has proposed a legal definition of ‘genetic modification’ as being the ‘germ-line modification of nuclear DNA’, which excludes mitochondrial replacement. They emphasise that gene therapy and tissue donation are not considered to be genetic modification either – although this is possibly because these procedures do not involve heritable (germ-line) genetic changes. Some, including supporters of mitochondrial replacement therapy (MRT), argue that the government’s definition is flawed and even dishonest.

Many researchers and clinicians (not forgetting patients) do strongly favour legalisation and introduction of the technique, and they in turn express considerable frustration with the way in which it is generally referred to as ‘three-person’ or ‘three-parent’ IVF, which, whilst technically accurate,  is in many respects misleading, since the genetic contribution of the egg donor is very small.

Keep calm and carry on

So, who is right in this ongoing debate? It is difficult to make a dispassionate decision when some of those involved resort to emotive arguments. Chief Medical Officer Prof Dame Sally Davies has called MRT ‘life-saving’ and likened it to changing a car battery; analogies of this kind combined with the tragic stories of families who have lost children to mitochondrial disease make opting to legalise the technique seem a no-brainer; certainly public consultation on the issue has suggested little general concern. However, who could fail to be worried by opposing arguments not merely of safety issues but also that Britain could become the world’s ‘rogue state’ in bioethical terms by redefining the law, or that MRT could ultimately lead to the creation of humans for the ‘sole purpose of harvesting their useful parts’? 

Ultimately, the application of emerging science and technology to address medical problems must go hand in glove with social acceptability. This is often a difficult thing to achieve in public policy terms when the scientific and clinical issues involved are highly complex and simultaneously pose potential ethical concerns. Rational evidence-based approaches do not necessarily win over emotive counter-arguments, as demonstrated by the massive public opposition to genetically modified food when first proposed. Nor is finding a balanced and appropriate way forward easy to do in a fair manner when stakeholders have different drivers and potentially opposing views. However, utilising a robust and responsive regulatory system that seeks to minimise risks and include transparent public and governmental consultation and debate is the right way forward – irrespective of the decisions reached via that process.

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