Eight healthy babies born in U.K. using ‘three-parent IVF’

LONDON — Ten years ago, U.K. policymakers gave the green light to a pioneering reproductive technology meant to spare children from being born with types of rare but sometimes fatal diseases caused by genetic mutations in the powerplants of cells. The method involved combining not just the genes of a mother and father to produce an embryo, but a bit of DNA from a third person as well. 

On Wednesday, the team in England that has been performing the technique reported that eight healthy babies have been born so far, highlighting that the approach reduced the risk of children inheriting disease-causing mutations in the pieces of DNA contained in our mitochondria. The results, published in a pair of papers in the New England Journal of Medicine, have been long awaited as the first large test of the approach, which is known as mitochondrial replacement therapy or mitochondrial donation. 

“All the children are well and continue to meet developmental milestones,” Bobby McFarland, a professor of pediatric mitochondrial medicine at Newcastle University and one of the experts behind the research, told reporters at a press conference in London Wednesday. 

While doctors will continue tracking the children for several years for any sign of mitochondrial diseases, McFarland added, “we’re cautiously optimistic about these results, and I think that we can provide that reassurance” to potential parents at risk of having children with these diseases that mitochondrial replacement therapy, or MRT, could be an option for them. 

The children described in the papers now range from just a few months old to more than 2 years old. Another pregnancy is underway. 

In an editorial also published Wednesday, Robin Lovell-Badge, a developmental biologist at the Francis Crick Institute who was not involved in the research, wrote that “the articles, which were hotly anticipated, show a (cautiously) good outcome and are well worth the wait.”

The results, other outside experts said, bolster the case that MRT can lower the likelihood of a mother passing along disease-causing genetic variants to her child. The positive outcomes could also stoke the debate about the ethics of the technology, which is explicitly allowed in only the U.K. and Australia and is outlawed in the U.S. because it involves altering the DNA of embryos in ways that can be inherited. 

“This will be really helpful in moving the field forward,” said Paula Amato, a reproductive endocrinologist at Oregon Health & Science University, where much of the pioneering mitochondrial replacement work has been conducted, led by a researcher named Shoukhrat Mitalipov. “It’s super influential that they’re publishing the first results. We were all sort of wondering. We’d heard rumors there were babies born. We were all waiting for them to have enough patients and enough data to put out a publication.” 

While the vast majority of our genes are housed in our cells’ nuclei, there are satellite stretches of DNA that reside outside the nucleus, in the mitochondria that drift around cells and, as your middle school science textbook drilled into you, help power our cells. We inherit our mitochondrial DNA — 37 genes in total — directly from our mothers.

Just like other genes, the mitochondrial DNA can pick up disease-causing mutations. Some children born with these mutations die soon after birth, while others live with severe neurodevelopmental deficits. The idea behind mitochondrial replacement is to allow mothers who carry these pathogenic variants to have biological children without the risk of passing along mitochondrial diseases, which are as yet untreatable. One in 5,000 children has a disorder tied to mitochondrial mutations. 

There are various ways scientists can go about performing mitochondrial replacement, but the method the Newcastle team used — called pronuclear transfer — involves first fertilizing the mother’s egg (which contains healthy nuclear DNA but mitochondria with pathogenic DNA) with the father’s sperm via in vitro fertilization. In the early stages of fertilization, before the genetic material combines to form one nucleus, there are two so-called pronuclei, one containing maternal DNA and the other paternal DNA. At this point, an embryologist plucks out the two pronuclei from the mother’s egg cell and deposits them into an egg cell provided by a donor that has had its own nucleus removed. That egg cell has healthy mitochondria left over floating in its cytoplasm, the goo that fills the cell. 

The result: a fertilized egg with nuclear DNA inherited from mom and dad, and mitochondria provided by the donor. 

“As parents, all we ever wanted was to give our child a healthy start in life,” said the mother of one of the babies born with the help of the technology, in a statement issued by Newcastle University. (Her name was not provided.) “Mitochondrial donation IVF made that possible. After years of uncertainty this treatment gave us hope — and then it gave us a baby.” 

Despite its potential to help families afflicted by mitochondrial diseases, the technology is not without controversy. The U.S., for example, has banned the procedure since 2015, in the form of an amendment to bills that fund the Food and Drug Administration. This rider blocks the FDA from reviewing applications for clinical trials involving technologies that alter the genomes of human embryos in ways that would pass those changes on to future generations. Debates around the approach have led to headlines about “three-parent babies,” a term that most scientists bristle at as sensationalistic.

The procedure has been done in a few other countries where there are no laws that prohibit it, first in Mexico in 2016 by an American doctor working with a Jordanian family that had already lost two children to a mitochondrial disease called Leigh syndrome. 

More recently, clinics in Greece, Ukraine, and Cyprus have begun using mitochondrial donation as a way to treat infertility, despite limited evidence that it leads to higher birth rates compared with traditional IVF. “It’s problematic,” said Amato. “People are probably paying a lot of money to do this for an unproven technology that carries risks that we don’t even know yet what they are.” 

So far, only one study of mitochondrial donation for overcoming infertility has been published — a pilot study involving 25 patients in Greece. It produced six children who showed normal development in two-year follow-ups, demonstrating that the technique can help some people with a history of failed IVF attempts to safely conceive and carry healthy pregnancies. But the study was too small to determine the efficacy of the approach, Amato stressed. “We need more research,” she said. 

The U.K. was the first country to specifically authorize mitochondrial donation in 2015, after a lengthy public engagement process, with Newcastle University winning a license for the work in 2017. Australia legalized MRT in 2022, and researchers there hope to start performing the procedure next year. In both cases, the technique may only be used to prevent serious mitochondrial disease.

In the new research, the Newcastle team only offered mitochondrial donation to parents who likely couldn’t have healthy children via other reproductive technologies. 

Women who carry pathogenic mitochondrial variants produce eggs with varying levels of those disease-causing mutations. Some will have such low levels that the resulting baby won’t be at risk for developing disease. Clinicians can analyze which IVF embryos have those low mutation levels via a technology called preimplantation genetic testing, and then start a pregnancy only with those “with low enough mutation loads not to have disease,” said Mary Herbert, a longtime reproductive biologist at Newcastle and an author of the new papers, who is now at Australia’s Monash University. 

(This helps explain why a woman who is healthy enough to live into adulthood and have children, despite carrying these mutations, can have a baby who is more severely or even fatally affected by the mutations — the baby’s mitochondria have higher levels of the pathogenic variants than its mother’s mitochondria.)

Some women, however, produce eggs with pathogenic variants in all copies of their mitochondrial DNA. It was these women who were offered pronuclear transfer. 

Ultimately, eight women got pregnant with embryos made via mitochondrial donation, resulting in four baby boys, four baby girls, and one ongoing pregnancy (there was one set of twins).

The researchers framed the results as showing the technology was a successful risk reduction strategy, but cautioned that it didn’t eliminate the risk of passing on pathogenic DNA variants. The reason is that when embryologists remove the pronuclei from the mother’s egg, some amount of cytoplasm — and the mitochondria it contains — comes along for the ride, like a bit of the white sticking to the yolk when separating an egg. “The cytoplasm is just jam-packed full of mitochondria,” Herbert said, meaning some are going to come along as hangers-on. 

Indeed, while five of the eight children had no detectable pathogenic variants in their mitochondrial DNA based on blood tests, the other three did — one in 5% of mitochondrial DNA copies, and the other two at 12% and 16%, levels that the researchers acknowledged were higher than anticipated. 

The scientists said it was not clear how that had occurred. One hypothesis, they said, is that the mitochondria that were carried over with the pronuclei to the donor egg cell didn’t spread evenly throughout the cell as it began dividing, and got amplified in the cells that went on to form the fetus as opposed to the placenta. But while they acknowledged the carryover of some mitochondrial DNA was a limitation of the procedure, they stressed that the levels of pathogenic variants would need to reach perhaps 80% for it to be a disease concern — far higher than was seen in the babies.

The research team will continue to follow the children until they are 5 and has been tracking every health issue that has arisen to assess if it might be a result of any disease-causing mitochondrial DNA still around. That will help the field, but doesn’t go as far as some ethicists would prefer.

“Collecting long-term data, including ideally in the future, multi-generational data, is really important here,” said I. Glenn Cohen, a Harvard Law School professor of health law and bioethics. Such monitoring would be required to detect effects that might appear later in life or in any offspring born to these children many decades down the line. 

So far, the children in the Newcastle study remain healthy — an outcome that years of work by the research team, dating back to the lab and animal studies underlying the technique, laid the groundwork for. 

“During the preclinical research, there were times when we thought we could take it no further,” such as when they struggled to reliably generate embryos with the procedure, Herbert said. “To go from there to having babies is really, I think, fair to say, rewarding for all of us.”