Apr 29, 2022 8:00 AM

Australia Moves Ahead Cautiously With '3-Parent IVF'

The nation follows the UK in permitting mitochondrial donation, which aims to prevent the transmission of rare but often fatal conditions.

Australia has become the second country after the United Kingdom to legalize a fertility procedure that mixes genetic material from three people. The technique is meant to prevent couples from having children with certain debilitating disorders caused by faulty mitochondria, the energy-generating structures in our cells. But it’s controversial because it involves a genetic change that can be passed to future generations, so its rollout in Australia will be extremely cautious.

On March 30, the Australian Senate passed the Mitochondrial Donation Law Reform Bill, also known as Maeve’s Law, named after a 6-year-old Australian girl with a mitochondrial disorder called Leigh syndrome. The disease causes a loss of mental abilities and motor skills over time, and those born with it typically do not survive beyond childhood.

Mitochondria have their own DNA, which is passed to children from their mother’s egg. If a mother carries mutations in her mitochondrial DNA for disorders like Leigh syndrome, she could have a child with one of these diseases. These disorders are rare but often fatal, and treatments are extremely limited.

Mitochondrial donation, also known as mitochondrial replacement therapy, was developed as a way to let the mother pass along almost all of her genetic material—but not the mitochondrial DNA. The procedure takes advantage of the fact that the vast majority of our DNA resides in the nucleus of our cells, while the mitochondria float around in the gelatinous fluid outside the nucleus.

It works like this: The nucleus from a donor egg is replaced with the nucleus from the mother’s egg, leaving the donor’s healthy mitochondria intact while keeping nearly all of the mother’s DNA. The combined egg is then fertilized with sperm through in-vitro fertilization and transferred to the uterus of the mother so she can carry the pregnancy. The procedure is often referred to as “three-parent IVF,” because the baby has DNA from three biological parents, though the contribution from the egg donor is tiny.

Patient advocates in Australia and elsewhere see the new law as a win for women who are at risk of passing on these diseases. “This law provides mitochondrial disease patients in Australia with a pathway to having a genetically related child while minimizing the risk of mitochondrial disease transmission from mother to child, which is a significant unmet medical need,” says Philip Yeske, science and alliance officer at the United Mitochondrial Disease Foundation, a nonprofit based in Pennsylvania.

Yet the procedure raises thorny ethical questions. It is banned in the United States because of a legal provision prohibiting the creation of human embryos that involve a heritable genetic change. While some see it as an extension of IVF, others have argued that it could open the door to the gene editing of embryos, including for human enhancement.

Both the Australian and UK laws passed after years of public debate and input. One point of contention during the legislative process in Australia was whether to allow prospective parents to choose only male embryos for mitochondrial donation. Since female embryos transmit mitochondria—and thus mitochondrial diseases—some have argued that it should be possible to select only male embryos to limit the risk of transmitting these diseases to future generations. However, Australia doesn’t allow sex selection for IVF, so legislators removed a provision in the bill that would have permitted that distinction.

Australia’s cautious approach is similar to that of the UK, where Parliament voted to legalize mitochondrial donation in 2015. There, only one clinic, Newcastle Fertility Centre, is licensed to perform the procedure. It must appeal to the UK's fertility agency, the Human Fertilisation and Embryology Authority, to approve patients on a case-by-case basis.

Under the new Australian law, mitochondrial donation will initially be offered at just one fertility clinic as part of a clinical trial. The trial likely won’t begin for another year or two, and once underway it is expected to last 10 to 12 years. Families interested in joining the trial will need to attend counseling to discuss potential risks involved in mitochondrial donation, and participants will ultimately need to be approved by a board of experts.

The law requires researchers to track participants' pregnancies and birth outcomes, including any miscarriages, premature births, birth defects, or instances of mitochondrial disease among babies born from these pregnancies. Investigators will also monitor the ongoing health and development of children born as a result of the trial.

In contrast to the law in the UK, Australian children born from this procedure will be able to access identifying information about the egg donor in the same manner as children born as a result of egg donation.

The number of participants for the trial hasn’t been determined yet, but according to an April 10 funding announcement by the Australian government, the trial must “provide a pathway for impacted families to access the technology.” While about one in 5,000 babies are born in Australia with a severely disabling form of mitochondrial disease, not all women with mitochondrial disease will need access to this technology, says Megan Munsie, a stem cell scientist and professor of emerging technology at the University of Melbourne.

“The reform rightly limits the use of mitochondrial donation to circumstances where this is the only option available to them to reduce the risk of a woman’s child inheriting mitochondrial DNA disease that is likely to result in serious illness,” she says. “Depending on how the disease affects their mitochondria, other assisted reproductive technologies, such as preimplantation genetic testing, will be sufficient.” This type of testing allows prospective parents going through IVF to select only healthy embryos to implant.

Even after Australia’s trial period, it’s not a given that the technology will be made more widely available to women who carry mitochondrial DNA mutations. “It is not yet certain that the technology will be implemented clinically,” says Catherine Mills, director of the Monash Bioethics Centre in Australia. That will depend on the outcome of the clinical trial, which will weigh safety and efficacy.

There are two major safety concerns with the procedure, says David Thorburn, a mitochondrial disease researcher at the Murdoch Children's Research Institute in Melbourne. One is that a small amount of “carryover” mitochondrial DNA from the mother could end up in the baby. “There may be potential for this to increase to a higher amount during development, such that it could result in mitochondrial disease,” he says.

The other is the possibility of incompatibility between the mother’s nuclear DNA and the egg donor’s mitochondrial DNA. However, scientists in both Australia and the UK concluded that the risk of either causing disease was low.

Clinics in Greece and Ukraine are using mitochondrial donation as a way to treat infertility, despite the lack of evidence that it leads to higher birth rates compared with traditional IVF. The clinics claim it has led to several healthy births among these mothers. But only one baby conceived through this method in order to circumvent mitochondrial disease is known to have been born disease-free. The baby, a boy, was born in 2016 to a mother who carried genes for Leigh syndrome. The disease killed her first two children. She underwent the procedure in Mexico, where there are no laws on the books that prohibit it. In a 2017 peer-reviewed paper, her fertility doctor and his team revealed that a small percentage of mutated mitochondrial DNA from the mother unintentionally ended up in the healthy donor egg. But it’s unknown how it has affected the child’s long-term health because his parents refused additional testing and monitoring.

So far, Newcastle Fertility Centre has not released any data on how many mitochondrial donation procedures it has performed or how many births have resulted from it. The Newcastle Fertility Centre did not respond to requests from WIRED for this information. In an email to WIRED, Lauren Snaith, external communications officer HFEA, said that as of January 2022, 27 applications for the procedure had been approved, and 11 patients had been treated. The agency gave the number of live births as being less than five, but was unable to give a specific number and to confirm whether there had been any at all so far.

“There was a lot of excitement when the UK first legalized this several years ago, so it's surprising that there haven't been reports of failures or successes one way or the other,” says I. Glenn Cohen, director of Harvard Law School's Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics, who has been following the international landscape of mitochondrial donation closely.

The Australian trial “will provide much-needed clarity on the effectiveness and safety of mitochondrial techniques,” Munsie says.

In the United States, Democratic members of Congress attempted to revisit the ban on genetically altering embryos for IVF in 2019, but Republicans restored the provision. With both Australia and the UK allowing mitochondrial donation to proceed cautiously, there could be a renewed US efforts to legalize the procedure. “I do think there’s a good chance that there will be more pressure in the United States to revisit this question,” says Cohen.

Update 5-12-2022 5:01 pm ET: This story was updated to add comments from Lauren Snaith of HFEA regarding the number of applications the agency has approved, the number of patients who have been treated, and the number of live births so far.