It’s legal, but is mitochondrial donation ethical and safe?
From the get-go, the patient-led lobby for a radical new in-vitro fertilisation technique had an unlikely champion: a sitting prime minister.
It was the kind of radical reproductive technology that ordinarily might make a conservative Pentecostal politician deeply uncomfortable. But from the get-go the patient-led lobby for a radical new in-vitro fertilisation technique known as mitochondrial donation had an unlikely champion in a sitting prime minister, Scott Morrison.
“This has been a very difficult issue, I know, for many,” said Morrison – a patron of patient group the Mito Foundation – after a bill to legalise mitochondrial donation was passed in the federal parliament. “Indeed these issues, as a person of faith, are difficult for me. I just pray this will give hope to so many Australian families.”
Three and a half years after Morrison corralled his conservative colleagues into supporting mitochondrial donation, shepherding the passage of the bill that amended the nation’s laws governing human cloning and reproduction to enable the creation of human embryos that contained the genetic material of three parents, with heritable changes to the genome, the technology is on the threshold of being trialled in human eggs in Australia.
The science is moving in real time but remains controversial and there are still many unknowns.
Mitochondrial disease is a group of genetic disorders affecting mitochondria, which are the energy powerhouses of cells. When the body cannot efficiently turn sugar and oxygen into energy, cells can malfunction, causing disruption to the organs and potentially leading to organ failure. Mitochondrial disease affects one in 4300 people in Australia and is the most common group of inherited metabolic disorders. About 60 babies a year are born with the condition.
The plight of teenager Kara Crawley, who died at 18 of complications of mitochondrial disease and lived in Morrison’s electorate in Sydney’s Sutherland Shire, was the genesis for the former prime minister’s passionate advocacy for mitochondrial donation.
But three years after the passing of the bill in 2022 that became known as Maeve’s Law after another affected child, Maeve Hood, Kara’s mother, GP Karen Crawley, is not convinced mitochondrial donation is the reproductive panacea many affected families believed it would be.
“I was very excited when I first heard about mitochondrial donation,” Crawley says. “It was always sold on the basis of: ‘This will fix the problem, you never have to worry about the gene in your family again.’ The whole technique was sold as a great solution to having healthy children.
“But I’m probably a little bit deflated at this point in time.”
This week a group of scientists from Newcastle University in Britain reported the births of eight babies as a result of an IVF technique known as pronuclear transfer. Britain was the first country to legalise mitochondrial donation in 2015 and the babies – four girls and four boys, including a set of identical twins – were born during the past two years.
Pronuclear transfer means the nuclear DNA material is transplanted from two parents, in which the mother is affected by mitochondrial mutations, into a fertilised healthy donor egg. The resulting embryo inherits its parents’ DNA but the mitochondrial DNA is inherited primarily from the egg donor, substantially reducing the risk of the transmission of mitochondrial disease.
“These findings give grounds for optimism,” says Mary Herbert, who worked with the Newcastle team and is now professor of reproductive biology at Monash University in Melbourne. “As a reproductive biologist, I find it enormously gratifying that a new assisted reproductive technology can be used successfully to enable women with very high levels of disease-causing mitochondrial DNA to have children with a greatly reduced risk of developing the disease.”
While providing hope to many families, the British births have confirmed what was already becoming clear in preclinical studies: mitochondrial donation does result in some level of carryover of diseased mitochondria in babies born as a result of the technique. In most babies the carryover is likely to be very low, but in a minority it’s higher – and may increase across time.
The findings have supported the fears of cautious scientists and clinicians who held concerns from the start that laws legalising mitochondrial donation were passed too hastily, with a near-total absence of safety data and amid unacceptable uncertainty as to the long-term ramifications of the technology.
“I am less satisfied than ever,” says Paul Komesaroff, an endocrinologist who is one of Australia’s leading medical ethicists, in the wake of the announcement of the British births. “The broad and far-reaching concerns about the entire mitochondrial donation project are in no way attenuated by these British outcomes. The absolute and overwhelming concern is that of safety, of which only a part is the question of degrees of carryover.
“Of greater concern are all of the other risks, including those related to our very limited knowledge about the functions of the mitochondrion in the regulation of the nucleus and other cellular functions. The lack of a strategy for establishing safety – which does not appear to have even been an endpoint in the British program – is alarming. There has been very extensive discussion about the ethical problems associated with scientific practices that aim to alter the germline, but somehow this has just been bypassed in this case without further public debate. Why this has been allowed to happen is puzzling.”
In 2023, Monash University was granted $15m from the Medical Research Future Fund to carry out a clinical trial in Australia that is set to serve as a pilot for the clinical introduction of mitochondrial donation in this country. When applications for the grant were called for, Komesaroff joined one of Australia’s leading experts on the interaction of nuclear and mitochondrial genomes during development, University of Adelaide professor Jus St John, in pitching for the grant. The team, which also included fellow Adelaide University professor Raymond Rodgers, took a cautious approach and proposed conducting preclinical safety studies for the first four years of the grant, moving to mitochondrial transfer in human embryos only in the fifth year.
“We looked very carefully into what had happened with the Human Fertilisation and Embryology Authority in England and we were a bit astounded to find that there really had not been any safety testing, not just there but anywhere, and that for some reason they had legalised the procedure in general terms,” Komesaroff says. “They were legalising clinical applications rather than a research-based process, which would require careful applications and assessment by ethics committees as well as public accountability.
“And so we were completely amazed by that, and looked through the literature, and as far as we could tell at that time, there had only ever been one baby born, in Mexico, and that occurred in questionable circumstances, outside the law, and there were no data about the consequences.”
In an editorial published in the Internal Medicine Journal in 2022 before the Monash grant being awarded, Komesaroff outlined several reasons for caution.
The issue of carryover of diseased mitochondria from the mother to the baby was only one issue. The possibility of mitochondrial DNA haplotype mismatch was another concern, as well as questions over how the mother’s nucleus would interact with the population of mitochondrial DNA in the donor egg. Mitochondrial DNA haplotypes are specific sets of inherited genetic variations within the mitochondrial genome. A substantial mismatch of mitochondrial DNA haplotypes in the donor and recipient could result in a process in the biology of a baby born from mitochondrial donation in which pathogenic mitochondria are given a selective advantage, resulting in disease.
“Rapidly expanding recent knowledge about the functions of mitochondria have highlighted their broad scope and complexity,” the editorial stated. “Whereas it was once thought that mitochondria were relatively simple structures controlled by a modest number of genes, it is now recognised that they interact dynamically with all other cellular organelles and nuclei, and contribute to an extensive array of cellular and bodily processes. In the context of this rapidly developing complexity, it has become recognised that it is impossible to predict with certainty the effects of disruptive interventions of the kind introduced by (mitochondrial donation techniques).
“If the technology were to turn out to be unsafe, profoundly harmful consequences could result, such as the transmission of the very conditions that were sought to be averted, the creation of new, previously unknown diseases and the introduction of novel forms of mitochondrial dysfunction with effects impossible to predict. The implications for this entire field of research could be disastrous.”
St John’s research across decades into the behaviour of transplanted mitochondria in animal embryos gives him grounds for caution as to mitochondrial donation in humans. His studies have pointed to potential epigenetic effects on gene expression that are thought to have a potential downstream effect on development, as well as differences in biochemical markers.
“I don’t know that we actually have any solid evidence that the technology is safe,” St John says. “As far as I’m aware no children born with this technique have reached adulthood so they haven’t been through the full developmental process, which would tell us that from the age of zero through to, say, 18 or 21 there have been no abnormalities reported or that they failed any developmental milestones.”
Two years since the awarding of the MRFF grant, the Monash clinical trial has yet to be granted a research licence even to begin practising the technique of pronuclear transfer on human embryos. Concerns surrounding ethics and clinical practice – particularly the degree of informed consent required by those who donate spare IVF embryos to research – has held up approval by the National Health and Medical Research Council’s Embryo Research Licensing Committee.
“I have patients that have signed up for the mitoHOPE program who are waiting to be informed about what’s happening,” says Carolyn Sue, one of Australia’s leading researchers in mitochondrial disease. “And I have patients that don’t want to sign up to the mitoHOPE program and are looking at other reproductive options. I just feel very disappointed for the patients who are not actually getting what they thought they had fought for, because the clinical trial is nowhere near ready.”
The Monash team is confident that the progress of the clinical program in Britain will provide reassurance to regulators in Australia that it is appropriate to proceed with the Melbourne trial. They hope to recruit couples to their clinical trial midway through 2026 to begin creating three-parent pregnancies.
“What this paper will do will provide an evidence base in which the decision-making about regulation can be made,” says John Carroll, director of Monash’s Biomedicine Discovery Institute and head of mitoHOPE. “I think, like the introduction of any new clinical procedure, and particularly in this case where manipulations are happening to the fertilised egg, you really have to have a long-term view on this and to build a body of knowledge around it.
“We don’t really know what the situation will be in the babies that are born. But I think the British births are a really exciting announcement. It provides a whole lot of reassurance, a lot of hope and a demonstration that mitochondrial donation can be a really effective way of avoiding mitochondrial genetic disease in the future.”
In Yowie Bay on the Port Hacking river in Sydney’s leafy south, Karen Crawley is discussing the ramifications of the British research with her 19-year-old daughter, Samantha. The genetic disorder known as MELAS runs through the Crawley family. Samantha Crawley is unaffected at this stage but her 25-year-old brother Braden is experiencing significant symptoms of mitochondrial disease. In future years, Samantha may face difficult choices if she wants to have her own children.
“I know mitochondrial donation isn’t a cure but at least it could help reduce the risk,” Samantha Crawley says. “So this really provides hope for me, even if it doesn’t 100 per cent cure mitochondrial disease, at least it may provide the possibility that I could reduce the risk of passing it on and have children of my own.”
Other reproductive options for people with mitochondrial disease – which is inherited only through the mother – include embryo screening or using a donor egg.
Karen Crawley says her initial hope that mitochondrial donation would eliminate the transmission of diseased mitochondria does not seem likely. The procedure now is being described as risk reduction. Though that risk reduction may be very substantial, she is fearful about her daughter rolling the dice.
“I think all options need to be weighed, and weighed against,” Karen Crawley says. “Are you going through a whole cycle to just reduce the risk a little bit? Are you reducing it a lot? What other options are there? How important is it to have your own genetic child?
“It is Samantha’s choice to make, but I’d probably lean her away from having a genetically related child.”
Since the MRFF grant was awarded in 2023, the clinical partner in the mitoHOPE trial, Monash IVF, has endured several scandals. In 2024, the company settled for $56m a class-action lawsuit taken by more than 700 patients who received genetic testing on their live embryos who were not informed of the risks of false positive abnormal readings and who discarded embryos that could have led to successful pregnancies. This year, Monash IVF revealed to the Australian Securities Exchange that it had twice mixed up embryos, in one case leading to a woman giving birth to a child who was biologically not her own.
Komesaroff is concerned that IVF companies are operating in a cutthroat commercial environment in which big profits are at stake and are pushing the boundaries of careful science.
“The entire commercial environment of reproductive technology is just out of control, and the commercial imperatives impose obvious perverse incentives and are just alarmingly dangerous,” he says. “And whatever has happened with Monash IVF is clearly a result of the commercialisation of the field, and I’m concerned that they could be more interested in profits than they are in just taking their time to ensure safety.
“I guess the cluster of questions related to mitochondrial donation is what is really driving the whole thing.”
There is already at least one international IVF provider, operating outside regulatory controls, that is offering mitochondrial donation as an add-on IVF technique for older mothers. One of the main reasons older women fail to become pregnant as a result of IVF is because the health of the mitochondria degrades across time. If mitochondrial donation could dramatically increase the chances of a viable pregnancy, it could open up a new lucrative market for IVF providers.
“The question we need to ask here is whether there’s actually been a process whereby commercial interests have managed to redirect or to suborn the thinking and values of parliamentarians in legalising this technology, and whether, in fact, what we need to do is actually stop what’s being done and go back to the beginning again and rethink it before it’s too late,” Komesaroff says.
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