Mitochondrial donation: a triumph of scientific innovation – and so much more

Mitochondria are the energy-producing organelles of the body's cells. They contain mitochondrial DNA (mtDNA), and as such, are prone to changes to that DNA (mutations) that can disrupt mitochondrial function and cause disease.

Two new research papers from a team at Newcastle (see BioNews 1298) describe the first UK clinical use of mitochondrial donation, which aims to reduce the risk of transmitting a class of mitochondrial diseases from mother to child. This is an often devastating and life-limiting group of diseases, for which no curative treatments exist. The specific mitochondrial donation technique described, based on IVF, is pronuclear transfer (PNT). This is one of two mitochondrial donation techniques that were made lawful in the UK in 2015 (see BioNews 826).

The last preclinical review of the safety and efficacy of mitochondrial donation, commissioned by the Human Fertilisation and Embryology Authority (HFEA) and published in 2016, recommended the clinical use of mitochondrial donation as a risk reduction strategy – to be used only in those women for whom preimplantation genetic testing (PGT), followed by selection of an embryo with low levels of pathogenic mtDNA for transfer, was unlikely to be a successful strategy (see BioNews 882). In other words, mitochondrial donation was recommended for use only in women with high levels of pathogenic mtDNA (elevated heteroplasmy), or exclusively pathogenic mtDNA (homoplasmy), in all of their eggs.

This cautious approach is at the heart of these new reports, which assess mitochondrial donation alongside PGT in an integrated programme at Newcastle Fertility Centre, under a regulatory framework developed by the HFEA. While PGT for mtDNA is an established procedure that acts as a useful comparator, the attention here will – quite rightly – be focused on the mitochondrial donation clinical data.

Thirty-two women received HFEA approval for treatment with PNT, and the eggs of 19 of these women were used for PNT, resulting in eight live births plus one ongoing pregnancy. This headline result alone is highly significant – PNT is compatible with embryo viability in humans.

Levels of pathogenic mtDNA varied from undetectably low to 16 percent in blood and 20 percent in urine. The last figure hints at a degree of reversion to the maternal mtDNA type, but is also sufficiently low to conclude that PNT has successfully reduced the risk of mitochondrial disease in all children born. The amount of maternal mtDNA could, however, vary from tissue to tissue, and so follow-up of these children is vitally important. One of the two papers reports that none of the children has any health condition that could be attributed straightforwardly to the presence of maternal mtDNA. As the authors note, there are reasons to be optimistic about the outcome of this first mitochondrial donation treatment in the UK.

The data reported are the culmination of decades of work, from the earliest investigations in mice (aimed at understanding the impacts of nuclear transfer) through to targeted experiments in human embryos (to provide preclinical evidence of safety and effectiveness). But this is to focus only on some of the scientific/technical challenges that have been overcome. There were parallel activities over a similar time frame concerning ethical inquiry, public and patient engagement, lawmaking, drafting of regulations, and execution of those regulations by committees.

Last, but not least, there was the careful establishment of a clinical pathway along which mothers and infants could be cared for, and their health could be monitored. All of this represents a vast amount of work by a large number of people over a long period.

The other paper is a treasure trove of data, which will likely be the starting point for new avenues of research and opportunities for refinement. What is the explanation for the somewhat elevated maternal mtDNA levels (still beneath the clinical threshold for disease) detected in two babies born following PNT? Further studies of mtDNA replication, segregation and interaction with the nuclear DNA may provide clues.

The reduction in normally fertilised eggs in the PNT group also requires explanation, and may indicate that some mtDNA pathogenic variants can compromise fertilisation of the egg, which is an energy-demanding process. This observation opens up a whole area of research concerning the role played by mitochondria in fertility. Of course, numbers analysed here are still low, and a larger and more diverse cohort will be required in order to draw firm conclusions about efficacy and safety of mitochondrial donation at a population level.

We can also look forward to future assessments of maternal spindle transfer, the other mitochondrial donation technique permitted in the UK. We might even anticipate the use of targeted, enzymatic degradation of pathogenic mtDNA to eliminate the risk of carryover and reversion.

How do we summarise what all of this means? It is a triumph of scientific innovation in the IVF clinic. It is a world-first that shows that the UK is an excellent environment in which to push boundaries in IVF. It is a tour de force by the embryologists, who painstakingly developed and optimised the micromanipulation methods. It is an example of the value of clinical expertise, developed over decades of working with children and adults suffering from these devastating diseases, being used to support a new intervention and subsequent follow-up – potentially for many years.

It is also so much more, depending on whether one's perspective is that of an historian, sociologist, ethicist or philosopher. It is tempting to suggest that these papers mark the end of a process, but it is actually the beginning of a new era in which technologies that change how we think about human reproduction are introduced into a tightly regulated environment, which is the only way in which they should be introduced.

In time, there will no doubt be retrospective studies and assessments of how all this was done (some of them critical), and there will be much to learn. It is hoped that other papers will follow, detailing different aspects of the process by which these first UK children were born. This whole exercise has been a steep learning curve for all involved, and future progress relies on such learning being shared. Safety assessment should be at the heart of all these and future reports.

Some may wonder about the time taken for these reports to see the light of day, but that would be to underestimate what is required to transition from preclinical research activities in an academic setting to offering a bona fide clinical service on the NHS (with the spanner of COVID-19 thrown into the works for good measure). Others will wonder whether supporting the desire to have biological children merits all this time and effort, when unmet clinical need is the focus and budgetary constraints are the norm. But this evaluation unnecessarily attempts to marginalise a human activity – 'having children' – that is actually central to the health and wellbeing of a significant proportion of the population, and those ordinary resemblances that parents and children often share also matter to them.

Of course, the results of clinical follow-up of the children born following PNT will be a major determinant of the future prospects for mitochondrial donation in the IVF clinic, as these papers acknowledge. There will be many responses to this work, but I see these reports – despite their matter-of-fact understatement – as an extraordinary reminder of what well-intentioned science, collaborating with medicine, can do to improve the lives of human beings.

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Mitochondrial donation pioneers Professor Sir Doug Turnbull and Professor Mary Herbert will discuss their work at the free-to-attend online event Mitochondrial Donation: Does It Work? What Next?, taking place on Wednesday 8 October 2025.

This will be a joint UK/Australian event. Find out more and register here.