Eight years after the United Kingdom became the first country to regulate the reproductive technique known as mitochondrial replacement, there is news that children have been born using the procedure.
The Human Fertilization and Embryology Authority (HFEA), the UK’s fertility regulator, confirmed that fewer than five UK children had been born using the procedure by April 2023. The confirmation came in response to a request for freedom of information by the Guardian newspaper. The HFEA gave no further information about the procedure or the children.
“It’s exciting news, but at the same time it tells us nothing about whether the method really worked,” said Dagan Wells, a reproductive geneticist at the University of Oxford, UK. “There are open questions and we need to get answers as soon as possible.”
Mitochondrial replacement therapy (MRT), which was legalized in the UK in 2015, aims to prevent the inheritance of serious health problems caused by mutations in mitochondria, the energy-producing organelles of cells; such mutations often affect the heart, brain and muscles.
The procedure – also called triple in vitro fertilization (IVF) – involves moving nuclear genetic material from an egg or single cell embryo with disease-causing mitochondria to a donor egg or embryo that has had the nuclear genetic material removed.
Gray regulations
The procedure has been performed in other countries, where its use is not regulated. In 2016, an American doctor announced that he had successfully used MRT to prevent mitochondrial disease in a baby, in a procedure performed in Mexico. Children have also been born via mitochondrial transfers performed in Greece and Ukraine to treat infertility. Last year, Australia became the second country to adopt MRT. But the method stays limited in many other countries, including the United States.
The mitochondrial transfers discovered by The protector were done at Newcastle Fertility Centre, the only UK clinic licensed to perform MRT. According to current regulations, the HFEA must approve each use on a case-by-case basis.
Researchers are eager to learn more about the procedures in the UK as they begin to conduct their own investigations. “If there are negative things to consider, we need to know about them as soon as possible,” says Wells.
Knowing how well the procedures worked and whether the babies are free of mitochondrial disease is critical, said Robin Lovell-Badge, a developmental biologist at the Francis Crick Institute in London, who issued a statement to the UK Science Media Centre. Lovell-Badge also wants to know “whether there is a risk of them having problems later in life or, if they are female, whether their offspring are at risk of getting the disease.”
This risk can arise during the procedure – when a small number of mitochondria are inevitably transferred to the donor egg or embryo. Wells wants to know the extent of this ‘transfer’ in the UK cases and whether or not very low levels of mutation-carrying mitochondria are causing health problems.
Mutant mitochondria
Scientists also want to know if the levels of mutated mitochondria that are transferred remain stable over time. Animal and cell studies have shown that in some cases transferred mitochondria can significantly increase over time, replacing donor mitochondria in cells – a phenomenon known as reversal1.
And this can happen in humans. This year, Wells and colleagues saw a turnaround from using MRT to treat infertility in a trial of 25 couples in Greece. Of the 6 children born, 5 had mitochondrial DNA that came almost entirely from the donor in cells from blood, umbilical cord and other tissue that was sampled. However, one child’s cells had high levels of mitochondria inherited from the mother – 30-60% of the total. When the embryo was implanted, less than 1% of its mitochondria were transferred from the maternal egg2.
The reversal appears to have had no effect on the child’s health. “If we had followed the same procedure to prevent a mitochondrial DNA disorder, then this could be a cause for concern,” says Wells. “So that’s a big question we have: Has any reversal been observed in any of these kids?”
It is not clear why the proportion of potentially disease-causing mitochondria can increase so dramatically after mitochondrial transfer and during development. One possibility is that genetic factors allow the maternal mitochondrial lineage to replicate more efficiently than mitochondria in the donor egg or embryo, Wells says. If so, it may be worth matching donor and recipient based on similarities in their mitochondrial DNA, he adds; this would potentially reduce one lineage’s ability to out-compete another.
There may be other ways to prevent reversal, says Shoukhrat Mitalipov, a reproductive biologist at Oregon Health & Science University in Portland who was part of the infertility trial. In the five children who received almost all of their mitochondria from a donor, the researchers had frozen the mother’s eggs before transferring the nuclear genetic material into fresh donor eggs. Both eggs were fresh during the transfer creating the child in which the reversal occurred. “We’re still wondering if freezing the mother’s egg is really beneficial,” he says.
MRT’s first UK births also provide an opportunity to take stock of the country’s cautious approach to allowing the procedure.
“It gives the general public some reassurance that these types of sophisticated procedures — which push scientific but also ethical boundaries — are conducted with appropriate oversight,” says Wells. But the fact that only one UK clinic can perform MRT has likely created a treatment bottleneck, he adds. “There are pluses and minuses.”
This article is reproduced with permission and was first print on May 10, 2023.
