What Three-Parent Babies are NOT — A word of caution
By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He can be contacted through The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu, and David Albertini, PhD, Visiting Senior Scientist at the CHR and Editor-in-Chief of the Journal for Assisted Reproduction and Genetics (JARG). He can be contacted through The Reproductive Times or dalbertini@thechr.com.
The births of 8 so-called three-parent babies (TPBs) in the UK and a still ongoing 9th pregnancy have recently made headlines in the medical/scientific literature as well as in traditional and social media. Though, for several reasons, the reported case series is really a remarkable medical as well as scientific accomplishment, the substantial attention the paper received, in our opinion, still has been missing important and very relevant information. This article is an attempt to fill in some of this missing information.
Infertility practice, once again, has made headlines! Only too bad that this usually only happens when something truly sensational occurs and—even better—if the news also elicits some controversy. And can anybody think about a more interesting and provocative headline than the birth of 8 three-parent babies (TPBs) born in the UK and a ninth on the way (1)?
So, let’s dig into the subject, trying not to be too repetitive of what others have already said about this publication (1). And voices as well as opinions came from everywhere, with Nature magazine calling the paper a landmark study (2), Science magazine being a little more reserved noting that babies born from “three-parent” IVF look healthy so far (3) (we here welcome the caution in clearly stating “so-far”); and the NPR headline probably being most explanatory but least correct by noting how a third parent’s DNA can prevent an inherited disease (more on this later; but nothing in this paper so-far demonstrated that this procedure can really prevent an inherited disease in the long-term). The Free Press—usually not trending toward exaggeration—considered it a “heroic effort” in the prevention of disease transmission from mother to child and suggested that, as a consequence, “the future is already here” (4).
What are mitochondria, and what do they do?
Facts are, however, somewhat different: Let’s start with an explanation of what the concept of TPBs really entails and why and when this concept may make sense. It all starts with mitochondria, membrane-bound organelles in every cell of our bodies that play an essential role in what is called cellular respiration (i.e., the process that converts nutrients into energy). Chemical energy produced by mitochondria is stored in a small molecule called adenosine triphosphate (ATP) (5). Mitochondria, therefore, are frequently also called the powerhouses or batteries of our cells. In addition, they play other important roles in cell signaling, cell death, and—for that and other reasons—are widely implicated in the aging process (a very important point we will return to a little later when it comes to ovarian aging).
Now to the location of mitochondria within every cell in our body, a crucially important point to the concept of TPBs: Mitochondria are distributed in a cell’s cytoplasm, which is the area of the cell surrounding the nucleus of the cell, in which also reside the many other kinds of cell organelles (see the Figure below).
The figure on the left depicts the intracytoplasmic distribution of mitochondria, while the right outtake depicts a single mitochondrion.
Mitochondria have another highly unique feature that no other subcellular structure in our bodies has - they contain their small circular genome with just a small number of genes (i.e., they have their DNA). In other words, all of our DNA (i.e., our genetic inheritance) is in principle contained in the nuclei of our cells, that is except for a tiny fraction of less than 1% of all DNA known as mitochondrial DNA (mtDNA) located inside mitochondria. And then there is yet a second very unique feature to this mtDNA: It is only passed on into the next generation through the mother. This, of course, stands in strong contrast to our nuclear DNA (nDNA), which is passed on in exactly equal 50/50 amounts (half from mom, half from dad). If one, therefore, considers both DNAs together—a detail of genetic inheritance not widely appreciated—every baby really inherits a tiny amount more DNA from mother than father due to the egg’s contribution of mitochondria and its mtDNA.
Mitochondrial diseases
Which brings us to the concept of mitochondrial diseases, which are a small group of diseases mostly inherited through only the mother, when the mother’s mitochondria are dysfunctional due to a mutation in the mother’s mtDNA. But it’s not all about mtDNA! Turns out those few mitochondrial genes from mom are not enough and, rather, have to conspire with genes in nDNA to get the job done. Thus, mitochondrial diseases can also originate in principle from both parents if caused by a mutation in nDNA that, secondarily, affects mitochondrial function. And, finally, mitochondrial mutations can also occur de-novo (i.e., out of the blue and at random—an extremely rare occurrence in contrast to the other two inheritance patterns).
Mitochondrial diseases can affect different organs, especially those with high energy demands (i.e., for example, the brain), can be quite variable in terms of the organs or tissues they affect, and are often seriously debilitating or deadly. The most common symptoms are neurological (seizures, strokes, developmental delays, vision and hearing loss, and cognitive problems) and muscular (pain, exercise intolerance, weakness, and fatigue). They can affect the heart, liver, kidneys, and the gastrointestinal tract, and the diseases can also cause diabetes.
The following are examples of mitochondrial diseases:
- Leber’s hereditary optic neuropathy (LHON): Causes progressive vision loss in young adults.
- Kearns-Sayre syndrome (KSS): Characterized by ophthalmoplegia (weakness of eye muscles), retinitis
pigmentosa, and heart conduction defects.
- MERRF syndrome: Progressive myoclonic epilepsy.
- Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Involves gastrointestinal
problems, neuropathy, and other neurological issues.
- Alpers-Huttenlocher syndrome: A severe condition with early-onset seizures, developmental
regression, and liver dysfunction.
- Mitochondrial myopathies: Primarily affect muscles, causing weakness and fatigue.
- Mitochondrial encephalomyopathies: Affect both muscles and the brain.
The idea behind TPBs
Now, imagine that a female carries a known mutation in her mtDNA, which she automatically passes on to her offspring. In other words, because during fertilization the male’s spermatozoa enters the environment of the egg (i.e. the eggs cytoplasm), the resulting embryo in an in vitro fertilization (IVF) cycle would have inherited the mutation from the genetically affected egg and, with it, the mitochondrial disease caused by an mtDNA mutation in mitochondria in the cytoplasm of this egg.
Consequently, if this inheritance is to be avoided, something in this fertilization must be done to prevent the diseased maternal mitochondria from becoming part of the newly formed embryo. The question that, therefore, arises is, how can this be done, while still achieving a normal fertilization that combines both partners’ nDNA?
The answer is, indeed, quite simple: because mitochondria are too small to get rid of and replace individually. The best solution, therefore, is to eliminate the egg’s mitochondria-rich cytoplasm and substitute it with the cytoplasm (and its healthy mitochondria) of a young egg donor.
Easily said, but how to do this?
But this–seemingly–magical manipulation can be relatively easily accomplished, with embryos which result from this process, if successful in implanting in the uterus, producing TPBs. In this process, the third parent (i.e., a young and healthy egg donor) comes into play with her mtDNA, with her donated cytoplasm.
Practically, this is done within the embryology laboratory by “simply” enucleating (taking out the nucleus with a pipette) the mother’s egg and placing it into the donor’s egg, which, before, was equally enucleated from the egg’s cytoplasm (this is, of course, where 99+% of the maternal DNA is). The resulting “new” egg now has the nucleus of the affected mother and the cytoplasm of the young egg donor and, with it, all of her young and totally healthy mitochondria (and everything else that the donor’s egg’s cytoplasm contained!). In short, this newly constructed egg has 99+% maternal nDNA and a small fraction of 1% of egg donor mtDNA, can now be fertilized with the father’s sperm, and—voila—we have the embryo of a TPB (a great graphic can be viewed at https://www.youtube.com/shorts/KrHGgIpKZoQ).
What we have been told
British colleagues have now published a previously noted paper in which we are told that for the first time, eight TPBs were born in attempts to prevent the inheritance of often fatal mitochondrial diseases (1). Contrary to media reported, this paper—for several reasons—did not come as a surprise to the IVF field: First, our British colleagues already publicly announced the study several years ago after receiving government permission (yes, the issue even went before Parliament, while in the U.S. the process is still prohibited by the FDA). Second, at least one case of allegedly successful TPB has been reported before in the U.S (6,7)—though unfortunately without the absolutely required follow-up (more on that below). It at the time attracted enormous media attention, but also considerable ill will from the FDA (8). We also would not be surprised if other cases have, simply, not been reported publicly since TPBs have, of course, remained ethically, legally, and politically controversial (9).
All of this, of course, is not meant to take anything away from the achievement of our British colleagues in establishing this case series. Considering the extensive preparation this study required and the rarity of mitochondrial diseases in the general population, the paper, indeed, represents a remarkable accomplishment. We, however, beg to differ a little bit with the interpretation of the results of this study.
Moreover, we have considerable concern that these results may now, without proper studies, be used to argue for the use of this kind of cytoplasm exchange for other medical indications, especially in association with IVF in older females (more on that below).
John Zhang, MD, PhD, from New York’s New Hope Fertility Clinic, holding the first TBS in his arms / Photo Courtesy of New Hope Fertility Clinic
According to the paper in the New England Journal of Medicine (1), women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children received mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT). Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer.
Eight of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively, established a clinical pregnancy. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy in the blood of the 8 newborn infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Maternal pathogenic mtDNA variants were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%.
Based on these findings, the authors concluded the following: (i) Mitochondrial donation through pronuclear transfer was (in principle) compatible with human embryo viability. (ii) An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants.
But these are, of course, very general and almost uninformative conclusions. What does this study, therefore, really mean?
How we see it
Considering abundant prior animal model research, there really was never any doubt that pronuclear transfer could and would be compatible with human embryo viability. And—for the same reason—there was also never any doubt that this procedure would be able to reduce the generational transmission of pathogenic mtDNA variants from mother to embryo and newborn child.
But where the real questions lie is in how much and for how long these benefits are achieved? There is especially good reason to be concerned about what happens in offspring over time, even if, after birth, they demonstrate no or only very little mutated mtDNA. The reason is what Dieter Egli’s laboratory already reported in 2016: One usually observes a significant genetic drift following mitochondrial replacement therapy via pronuclear transfer in human oocytes (10). A genetic drift is a fancy term for steady growth in the percentage of mutated mtDNA in individuals over time.
In practical terms, this means that these 8 and other future TPBs will have to be followed for years to determine their real degree of heteroplasmy. And only after such follow-up will it be known how successful cytoplasmic replacement really can be as a treatment of selected and typically rare mitochondrial diseases.
What, however, for the IVF field may be an even more important issue
Mitochondrial diseases are, fortunately, rare. A recent review article suggested a prevalence of ca. 1/5,000 to 1/8,000 live births (11). In practical terms, it likely means a very small commercial market opportunity for genetic testing and IVF industries, and—forgive the suspicion—an immediate search by industry for other diagnostic targets that may benefit from this kind of treatment in IVF.
Our real concern surrounding all of the excessive publicity over this paper in the New England Journal of Medicine (1), therefore, reaches into very different directions; The cure of mitochondrial diseases is by no means the only proposed application of cytoplasm exchange between a patient and a young cytoplasm donor. The idea behind this concept was already explored almost 25 years ago when Jacque Cohen, PhD, and co-workers experimented with at least partial cytoplasm exchange in mostly older women (12) and were stopped in this research by the FDA in 2001 (13).
With the advent of nuclear and/or spindle transfer, the concept has been officially resurrected in a collaborative effort by Spanish and Greek investigators in Greece (in Spain the procedure is—like in the U.S.—not permitted) (14), has been reported from the Czech Republic (15), and with known routine clinical applications in some other countries (though without official outcome reports). Official and unofficial reports so far have, however, not been very encouraging. Everything that is known from these very limited data—official and unofficial—so far suggests that mitochondrial replacement does not appear to significantly improve IVF outcomes in older women (16) though there exists some dissent (17).
So, what is our concern?
Our concern is that the (also, as noted above, still unconfirmed) success in establishing TPBs who in a majority were free of a major disease-causing mtDNA mutation after birth due to a cytoplasm switch between a young and healthy donor and their carrier mothers, now will be interpreted by the public and regulatory agencies as good enough evidence to release restrictions against this treatment for the additional indication of “advanced female age.”
This does not mean that we oppose properly conducted studies. To the contrary, the just-published UK study should and can, indeed, be an example (1): Cytoplasm exchange is in the UK still forbidden, unless performed under strict study protocols and pre-approved by regulatory authorities. The group of investigators that published the paper has, for a good number of years, remained the only one allowed to conduct cytoplasm exchanges under an approved experimental protocol, and it seems unlikely that this will change anytime soon. But Greece already allows such treatments for advanced female age (14) and so do apparently Ukraine and several other countries.
Current-day IVF practice is already deeply contaminated by useless “add-ons” to IVF, often not only lacking outcome benefits but, actually, adversely affecting IVF outcomes for several subgroups of infertility patients. We don’t need more of such useless treatments!
References
Hyslop LA, et al., N Engl J Med 2025; online ahead of print. DOI: 10.1056/NEJMoa2415539
Callaway E. Nature 2025; https://www.nature.com/articles/d41586-025-02276-5
Inampudi A. Science Adviser. July 17, 2025. https://www.science.org/content/article/babies-born-three-parent-ivf-look-healthy-so-far-new-study-finds
Dugdale LS. The Free Press. July 23, 2025. https://www.thefp.com/p/one-embryo-three-parents-the-future
National Human Genome Research Institute. Updated July 25, 2025. https://www.genome.gov/genetics-glossary/Mitochondria
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