Maternal mitochondria that “three-parent IVF” was intended to replace have been found in some children, prompting debate over whether to suspend its use for mitochondrial disease or test it first for infertility

Maternal mitochondria that “three-parent IVF” was intended to replace have been found in some children, prompting debate over whether to suspend its use for mitochondrial disease or test it first for infertility

On November 3, STAT brought together data on children born in Greece, the United Kingdom and Ukraine.

Mitochondria have their own DNA, which children inherit from their mothers. Mutations in this DNA can cause severe disease. In “three-parent IVF,” the nucleus of a donor cell containing healthy mitochondria is replaced with the nucleus from the mother’s egg or a newly fertilized egg. The child inherits nuclear DNA from both parents and mitochondrial DNA from the donor.

A small number of maternal mitochondria are transferred along with the nucleus. In 2016, biologist Shoukhrat Mitalipov’s group showed that although donor DNA accounted for more than 99% of mitochondrial DNA in embryos after replacement, maternal mitochondrial DNA gradually displaced it in some stem cell lines derived from those embryos. The group called this reversion and proposed that some mitochondrial DNA variants replicate more efficiently than others.

In a Greek infertility trial, the proportion of maternal mitochondria in one of six children rose from less than 1% in the embryo to 30–60% at birth. In Newcastle, in the United Kingdom, where the technique is used for mitochondrial disease, maternal mitochondria carrying a mutation accounted for 5, 12 and 16% of mitochondria in the blood of three of eight children. Ukraine’s Nadiya clinic provided STAT with unpublished data: reversion was found in two of six children tested, with maternal mitochondria reaching 12% and 72%.

Nadiya used the technique for infertility, and no disease-causing mutations were found in the mothers. Embryologist Jacques Cohen therefore considers reversion less concerning in these cases, given the known risks. In mitochondrial disease, the mutation returns along with the maternal mitochondria. According to STAT’s assessment, even a small proportion of maternal mitochondria could compromise the technique’s effectiveness. Cohen supports a moratorium on its use for mitochondrial disease until researchers can reduce the risk of reversion. Bioethicist Guido Pennings of Ghent University proposes another approach: first test the technique in couples with infertility who do not carry the mutation, so that reversion can be studied without the known disease risk.

A STAT investigation found that clinics sell the technique to older women with infertility, claiming that younger mitochondria will help embryos develop. Nadiya embryologist Pavel Mazur transferred nuclei from the embryos of 19 women aged 36–44 into eggs from young donors. Only one woman produced an embryo with a normal chromosome count. When he transferred nuclei from young donors into eggs from some of the patients, however, 40% of the embryos were suitable for transfer, and 70% of those had a normal chromosome count. He concluded that most women in this group had damaged nuclear DNA, which transfer into a younger cell does not repair.

In Ghent, reproductive medicine specialist Dominic Stoop’s group sought permission to test the technique in three groups of seven patients each. Belgian authorities approved two groups: patients with mitochondrial disease and patients whose eggs or embryos had stopped developing. The third group consisted of older women. Stoop said of the first group:

The patient group that the ethics committee sees as the least problematic is, in my view, the one at greatest risk.

Mary Herbert of Monash University, who previously led the Newcastle group, cites that group’s clinical data. She says transmission of disease-causing mutations fell by 75–100%, and when reversion occurred, the proportion of mutant mitochondria remained below 50%, the threshold above which symptoms are expected. Her group is preparing an application for an Australian trial to assess whether this proportion remains stable over time and across different organs.