Several research teams in the United States and the United Kingdom are currently requesting regulatory approval for techniques that would create an embryo with genetic material from three different people and result in inheritable genetic modification (changes that would be passed on to future generations). These techniques have been referred to with several terms, including "mitochondria replacement," "mitochondrial manipulation," "oocyte modification," "three-person embryos," "three-parent babies," and "nuclear genome transfer" (the most technically accurate).
Alert Update - The UK has now legalized use of these techniques, while the US has set up a committee to investigate possible implications prior to committing to any trial (see below)
United States. On January 27 2015, a newly appointed committee of the Institute of Medicine (IOM) held the first in a series of meetings to fulfill the FDA’s request to consider the ethical and social policy issues raised by “genetic modification of eggs and zygotes to prevent transmission of mitochondrial disease.” The meeting was the first public event in an FDA-sponsored study that will take place over approximately the next 14 months.
The US Food and Drug Administration held a public meeting
on February 25 and 26, 2014 that included discussion of "mitochondrial
manipulation techniques." Webcasts of both days of the meeting are now
available here. For an overview of what happened, see here.
United Kingdom. On February 24, 2015, the House of Lords approved regulations, also approved by the UK House of Commons earlier in the month, that carve out an exception to the prohibition on human inheritable genetic modification in the UK. This will allow "3-person IVF" techniques directly into fertility clinics without human clinical trials, and with no required follow up of any resulting children. The regulations go into effect October 29, 2015.
The UK House of Commons Science and Technology Committee held an evidence hearing on “mitochondrial donation” October 22, 2014 and published all of the correspondence they received here.
In July 2014, the UK Department of Health published results here of its three month open consultation on draft regulations to permit the use of "mitochondrial donation."
The UK Human Fertilisation and Embryology Authority (HFEA) released a published report of their third update on safety and efficacy of these techniques on June 3, 2014. See CGS's press statement here.
3-person IVF would be used to attempt allowing a small number of women with a rare kind of severe mitochondrial disease to have a healthy and mostly genetically related child. The techniques work by removing the nucleus of an affected woman's extracted egg and putting it into the enucleated egg of another woman, which contains her mitochondria. The child would thus be genetically related to three people, which is why the media often refers to "three-parent babies" or "three-parent in vitro fertilization."
Critical questions about safety and efficacy have not been answered, and these techniques raise profoundly important social and ethical questions. A strong and long-standing international consensus against inheritable genetic modification currently exists, along with explicit prohibitions in dozens of countries, due to profound ethical and human rights concerns regarding human biological experimentation. No country has ever given regulatory approval for inheritable genetic modification, and yet both the United States and the United Kingdom are contemplating that right now. If approval is given the bright line established by this international consensus will have been crossed for the first time. Furthermore, in the absence of regulatory controls, advances in precision gene editing could open the door to more and different kinds of inheritable genetic modifications in the future.
To quickly get up-to-date, please see:
Frequently Asked Questions
Why is this being explored?
Mitochondria are tiny organelles found in the cytoplasm of all living
cells possessing cell membranes, including all animal and plant cells.
They play important roles in helping regulate cellular energy use and
cell growth. Mitochondria are of special interest because they possess
their own genome, independent of the main cellular genome housed in the
Mitochondria are responsible for producing more than 90% of the energy
needed in our bodies; failures of this system through inherited or
spontaneous mutations of mitochondrial DNA (mtDNA) or nuclear DNA (nDNA)
can cause damage to the brain, liver, heart, skeletal muscles, kidney,
and the endocrine and respiratory systems. Because mitochondria play
such a complex role in our bodies, performing different functions in
different tissues, there are hundreds of different mitochondrial
diseases. Mitochondrial disease often affects children, but is also common in adults due to deteriorating mitochondrial
function with age. Mitochondrial disease is known to affect around 1 in 5,000–10,000
So-called "mitochondria replacement" is a new approach that is being
researched with the goal of allowing a woman who has mutations in her
mtDNA to lessen the risk of passing on inherited mitochondrial disease
to her child. The techniques being developed are variations on combining the nuclear DNA from an egg of an affected woman with the mtDNA of an unaffected woman's egg. A resulting child would possess genes from three adults, and this altered genome would be passed on to succeeding generations.
Several techniques are currently being developed by researchers who have announced some success in animals and in human zygotes, but have not yet transferred genetically altered embryos into a woman.
The techniques being investigated could only be attempted in a minority of the cases of mitochondrial disease. They would not be applicable to mitochondrial disease that is caused by nuclear DNA, which makes up the majority of cases, nor would they prevent mitochondrial disease that arises due to spontaneous mutations or deterioration with age.
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What are the different techniques?
Pronuclear transfer (PNT)
(See diagram here)
Pronuclear transfer begins with an embryo created via in vitro fertilization, using the intended parents’ sperm and eggs. Simultaneously, a second embryo is created using a donor egg with healthy mitochondria and the father’s (or donor) sperm. When the embryos are one day old, still at the single-cell stage, the pronuclei are removed from the first embryo. The majority of the mother’s mutated mitochondria are left behind in the enucleated embryo, which is discarded. Meanwhile, the pronuclei of the second embryo are removed and discarded. The parents’ pronuclei are then placed into the second embryo, which has maintained the healthy mitochondria from the donor’s egg. This constructed embryo can continue to develop and then be transferred into the mother.
Researchers at Newcastle University, where PNT is being developed, acknowledge that the technique is not ready to go to clinical trial (1, 2, 3, 4). They plan to undertake follow-up work that was requested by the HFEA, but the center where they will do so opened in September 2012 and no results have yet been reported. There have been no published results of using PNT in non-human primates, nor of human embryos produced with PNT developing past an early stage.
Maternal Spindle Transfer (MST)
(See diagram here)
In this technique, nuclear DNA is removed from the intended mother’s egg; the rest of the egg is discarded, including the unhealthy mtDNA. The nuclear DNA of an egg from a woman with healthy mitochondria is removed at the same time, leaving her healthy mitochondria in the cytoplasm. The mother’s nuclear DNA is placed into the enucleated donor egg, which can then be fertilized with sperm from the father. The resulting embryo can then be transferred into the mother.
Researchers at Oregon Health and Science University have created rhesus macaque monkeys using maternal spindle transfer, but their published report of this study failed to consider several key aspects of safety. The monkeys were followed for only three years, not long enough to generate useful data since mitochondrial disease often develops late in life. And because the genetic alterations would be passed to subsequent generations, multi-generational safety data are needed.
In addition, a worrying difference has been noted between the study of MST on the rhesus macaques and the trials so far on human zygotes: More than half of the human MST zygotes had abnormalities that were not observed in the monkeys. Some experts believe that human oocytes are more sensitive to spindle manipulations than monkey oocytes, a significant variation that requires further study before MST is used in humans.
MST can also involve other kinds of errors. Genetic material can be lost during transfer; small amounts of mtDNA from the unhealthy egg can be transferred; a mismatch between foreign mtDNA and nuclear DNA can occur; and the segregation of mutated mtDNA to specific tissues may lead to a significant accumulation of the mutant load. Negative effects caused by any of these would not be reversible.
Nuclear Genome Transfer (NGT)
(See full report [pdf])
Nuclear genome transfer is essentially the same as MST. Scientists at Columbia University in New York, working with human eggs, developed a technique that avoided premature oocyte activation and thus increased success rates. (They did not fertilize the eggs, but did activate them via parthenogenesis.) NGT research is still in preliminary stages, and the researchers working on it recognize the need for studies on a larger number of samples, and on animal models. They also realize the need to publicly discuss patient needs, ethical considerations, and appropriate guidelines for the use of this procedure in assisted reproduction, if it were to be approved for human clinical trial.
Polar Body Genome Transfer (PBT)
(See full report here)
Polar body transfer is a new and more experimental technique than the others. It
involves transferring polar body genomes instead of the pro-nucleus or
maternal spindle. It is hypothesized that
this would reduce carryover mutant mitochondria since polar bodies
contain few mitochondria, but have the same genomic information as the
oocyte. Normally, polar bodies can't survive since they don't have
mitochondria, but the theory is that they would get it from the
donor egg in this case.
There has been no public discussion of this third technique, and indeed very few people seem to know anything about it. It was not considered in the FDA's meeting, nor was it considered throughout the process in the UK until the Government asked the HFEA in July 2014 to assess the technique's safety and efficacy, which it did in an addendum to its third safety review on 14 October 2014. The addendum admits, "compared with both PNT and MST, it is clear that PBT is at an earlier stage of development, with little or no human data publicly available for the methods."
When the UK Department of Health held its consultation on draft regulations, there was not a word about it, but the regulations that are now about to move into law suddenly have a lot of language about "polar bodies". Presumably this last-minute "refining [of] the definition" is intended to allow this brand-new technique with entirely different cellular manipulations into fertility clinics, despite the lack of evidence.
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Where is the research taking place?
Newcastle University, UK
Researchers at Newcastle University have focused on pronuclear transfer in mice. The UK currently prohibits any modifications of the human germline, but the Newcastle researchers are asking that PNT clinical trials be made legal (1, 2, 3), arguing that the technique could help those who suffer from mitochondrial disease.
In 2008, the HFEA issued a report outlining additional tests the researchers would have to undertake before this could be considered. The university received a grant of over 4 million pounds from the Wellcome Trust to build a new Centre for Mitochondrial Research to continue PNT research, including testing on primates, but none has been completed to date.
The HFEA held a public consultation on mitochondria replacement at the end of 2012, largely motivated by Newcastle’s research, that has now been passed on to the UK Secretary of State for Health. He will draft regulations to be reviewed by Parliament that will determine whether or not the Newcastle researchers may proceed to human clinical trials, and if so under what conditions. The Newcastle researchers do not currently refer to their work as creating “three-parent babies” or as constituting inheritable genetic modification, although the HFEA is aware of these concerns and references them in its consultation.
Oregon Health and Science University
Researchers at Oregon Health and Science University (OHSU) have focused on maternal spindle transfer. They have created "three-parent blastocysts" and used them to generate embryonic stem cells, as a demonstration that the blastocysts could create a viable embryo and child. Three years ago, they used the same process in rhesus macaques, producing four live offspring, which appear to be healthy and developing normally.
The OHSU researchers are explicit about the fact that if this technique were used in humans, it would irreversibly alter the human germline. The FDA has in effect banned this kind of modification since 2001, when it ordered an end to unauthorized efforts using earlier mitochondria replacement techniques. The OHSU researchers have been privately funded to date. They are now asking the FDA to lift its restrictions, and to break from its long-standing position against funding research that results in modification of the human germline.
Columbia University, New York
In December 2012, Columbia University scientists, in conjunction with the New York Stem Cell Foundation, published a paper in Nature describing their results with what they refer to as “nuclear genome transfer.” Their technique represents a variation of MST, which they present as an improvement over PNT. Their paper, unlike the one by OHSU researchers, does not acknowledge that mitochondria replacement would constitute germline modification.
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What concerns does 3-person IVF raise?
The critical question of whether 3-person IVF is safe has not yet been resolved. Some remaining concerns include:
- Epigenetic harm caused by nuclear transfer (See here and here)
- Mito-nuclear mismatch (Reinhardt, et al.)
- Impact of mitochondria on traits i.e. not just metabolic function (Dowling, also New Scientist here and here)
- Preferential replication of even tiny amounts of carryover mutated mtDNA (Burgstaller et al.)
These issues could cause immediate problems for any child born from these techniques, but could also cause problems later in life. Any problems that arise would additionally be passed on to future generations.
Changing the human germline:
3-person IVF would result in inheritable genetic modification. Altering the human germline is considered to be the most objectionable of genetic technologies and has constituted a bright line not to be crossed. Many bioethicists, scholars, and advocates from around the world have argued that "mitochondria replacement" does not justify crossing this line.
The 1966 United Nations International Covenant on Civil and Political Rights, which the US has signed and ratified (with some reservations), states in Article 7 that, "No one shall be subjected without his free consent to medical or scientific experimentation."
The 2004 European Union treaty establishing the European Constitution states in Article 63:
1. Everyone has the right to respect for his or her physical and mental integrity.
2. In the fields of medicine and biology, the following must be respected in particular: (a) the free and informed consent of the person concerned, according to the procedures laid down by law;
(b) the prohibition of eugenic practices, in particular those aiming at the selection of persons;
(c) the prohibition on making the human body and its parts as such a source of financial gain;
(d) the prohibition of the reproductive cloning of human beings.
The genetic modification of human embryos would violate these provisions.
Another concern with allowing germline modification, even in a limited form, is that it can create a "slippery slope"; if researchers are allowed to use it to limit the transmission of even a few specified diseases, why shouldn't its use be allowed to limit any disease? And if it is allowed to increase well-being by treating disease, why not allow it to increase well-being by "enhancing" non-disease traits? MtDNA plays a critical role in cellular energy production and it is conceivable that if 3-person embryos were made legal that some would propose their creation in order to increase the athletic ability, decrease the risk of obesity, or increase the longevity, for example, of their children.
For much more information on inheritable genetic modification, see here.
Implications for identity
Sharing mitochondrial DNA is certainly less of a genetic contribution than an entire egg or sperm, but it is likely to nonetheless have a very profound impact on a child’s phenotype. Such increasing evidence asserts that mitochondria act as much more than "batteries" and do in fact influence the traits that make us who we are.
Of course, identity is also influenced by more than one's phenotype. If successful, this donation will allow a child to live free of otherwise debilitating diseases. It is easy to imagine the human curiosity, gratitude, and connection one would feel to the woman that made this possible. If the procedure is unsuccessful, the emotions and relationship between the child and parents, as well as the donor, could be particularly fraught. In either scenario, the current recommendation that donors remain anonymous could be hard for resulting children.
Furthermore, a child resulting from this technique could feel burdened with the knowledge that his or her genetic make-up is different from that of children conceived from two parents. Some children may feel uncomfortable with the fact that their creation was experimental and that they will be encouraged to participate in follow-up studies throughout their life. Finally, girls will likely be made aware of the possibility that genetic anomalies will be passed on to their own children, and they may feel uncomfortable with the recommendation that they undergo IVF and carry out PGD to ensure this is not the case.
Risks of egg extraction
Egg extraction poses under-studied risks to women, including memory loss, bone ache, seizures, and Ovarian Hyperstimulation Syndrome. Nuclear genome transfer research in the U.S. and U.K. has already required hundreds of eggs from women. Economically disadvantaged women are often specifically targeted as potential egg donors, while the risk to their bodies is routinely downplayed and follow-up care tends to be minimal. Many are concerned that the great need for eggs in order to carry out these techniques will lead to increased exploitation of egg donors. These concerns need to be taken into account when considering the advisability of producing 3-person embryos.
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How many people would use this technology?
The techniques that are being considered here will be of potential benefit to only a small number of people. Inherited disease caused by mitochondrial DNA of all kinds, including those not relevant to the proposed procedures, affects 1 in 5,000–10,000 people. Women who have inheritable mitochondrial disease and who want to have children have four other options to avoid passing on mutated mtDNA: adoption, egg donation, prenatal genetic diagnosis, and preimplantation genetic diagnosis. Only a very small number of women who have particularly complicated mutations would have reason to consider using one of the mtDNA techniques now being proposed. In the United Kingdom, for example, it has been estimated that this would number not more than ten to twenty families per year. Although the desire of these families to have a genetically related child is understandable, it needs to be balanced against the implications of opening the door to a new era in which human beings have become artifacts of genetic modification.
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Can people use PGD to have a genetically related healthy child?
Women who have mitochondrial disorders can produce eggs that have varying degrees of mutated mitochondria. And it has been shown that an embryo with less than 18% of mutated mtDNA has a 95% or greater chance of being unaffected by mitochondrial disease. Therefore, the use of Preimplantation Genetic Diagnosis (PGD) to choose an embryo with a low level of mitochondrial mutations is a valuable option for women who wish to have a fully genetically related child who is healthy.
The complexity of mitochondrial disorders may mean that PGD is never able to completely eliminate the risk of transmission, but there is increasing evidence that it can drastically reduce the risk for most people.
This method has the additional benefit of being able to screen against mitochondrial disorders caused by nuclear DNA, which account for the majority of cases, so it is of potential use to many more women than "mitochondrial transfer." Although there is still more to learn about this option, numerous clinics now offer it to women with mitochondrial diseases.
The only time PGD may not be an option is if close to 100 percent of a
woman’s mitochondrial DNA is mutated (homoplasmy.) However in such rare
cases, that woman is likely to be suffering from debilitating illness
and pregnancy could pose serious risks to her and her child.
Multiple recent studies have shown the promise of PGD for the prevention of mitochondrial disease:
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Is "mitochondrial donation" similar to other kinds of donation?
The "donation of mitochondria" is a misleading way to discuss this technique, which actually removes the nucleus from one woman's egg and puts it into another woman's egg. This procedure is markedly different from organ donation because it alters every part of a person’s existence as it is in continuous interaction with the rest of their DNA; it can have unforeseen complications later in life; and because it forever changes one’s genetic inheritance. It is also not a decision made for oneself as with using a donated organ. The resulting child would never be able to give free and informed consent for the procedure.
It is misleading to draw ethical, social or medical comparisons between "mitochondria donation" and organ donation.
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How has the media covered the issue?
Many articles have entirely neglected the fact that this technique is inheritable genetic modification. Additionally, there has been misleading information regarding the current uses, safety, and ramifications of nuclear genome transfer. See here for common misconceptions that have proliferated in the media; see here for information about an article that continues to confuse readers because it is undated; and see here for coverage of a live debate that took place, in which one debater misleadingly used "mitochondria replacement" as an example of why we should oppose a ban on the genetic engineering of babies.
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children already born years ago following cytoplasmic transfer (ooplasmic transfer), a similar
germline modification technique? What happened with that?
A technique known as cytoplasmic transfer or ooplasmic transfer was used by several fertility clinics between the late 1990s and 2001 to establish as many as 30 pregnancies. It was offered as a way to help
infertile women have a child, but was done without any evidence of safety or efficacy, and with no understanding of what "defect" the technique might be correcting.
The FDA reported that of "30 fertilizations achieved after ooplasm transfer...13 pregnancies were reported," and of these, "[t]wo fetuses were karyotypically 45, XO (Turner’s syndrome). One of these fetuses aborted spontaneously and the other pregnancy was terminated."
The FDA intervened in 2001, citing concerns about safety and "de facto germline gene transfer." The agency told the fertility clinics offering the procedure that they needed to submit a request for approval before treating additional patients. Apparently no submission was ever made, and the techniques seem to have been abandoned.
A couple of the families who had babies after using the technique have recently spoken to the BBC and The New York Times, saying that their child is perfectly normal. But there has been no long-term follow up of the children's health, or any investigation into the amount of third-party genetic material any of them might have.
Recently, the researcher who oversaw these procedures told BBC that one
of the babies who seemed fine at birth went on to develop "early signs
of pervasive early developmental disorder which is a range of cognitive
diseases which also includes autism."
While cytoplasmic transfer does involve a second woman's genes, it is quite different from "mitochondrial transfer." Cytoplasmic transfer involves the injection of a second woman's youthful mitochondria into an infertile woman's egg. Any resulting child will still inherit all of their mother's mitochondrial DNA (mtDNA), but potentially also some mtDNA from the other woman."Mitochondrial transfer" on the other hand involves the complete enucleation and transfer of a nucleus from one egg or embryo into another. The goal is for the child to have as close to 100% of the second woman's mtDNA as possible. Therefore, there is reason to believe "mitochondrial transfer" is much riskier, because it could impede with critical fine-tuned mito-nuclear interactions, and because the process of enucleation is quite traumatic and more likely to cause epigenetic harm.
While it is reassuring to hear that at least some of the small number of children born following cytoplasmic transfer are healthy at this point, it is of limited relevance to the safety of "mitochondrial transfer," and is of no relevance to the efficacy of the latter technique in being able to prevent the transmission of mitochondrial diseases.
An undated Daily Mail article that is actually over a decade old has unfortunately led to a great deal of confusion about the current state of this technique, and of genetically modified humans in general.
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How can I get involved?
Please contact CGS at info[AT]geneticsandsociety[DOT]org to find out more about 3-person IVF, and about how you can make your voice heard in the growing policy debate.
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Last modified February 27, 2015