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| 날짜 : | 2015-01-22 |
|---|---|
| 관련 링크 : | http://www.geneticsandsociety.org/article.php?id=6527 |
| 기관 / 기타정보 : | Center for Genetics and Society |
3-Person IVF | ||
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 House of Commons Science and Technology Committee held anevidence 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 apublished report of their third update on safety and efficacy of these techniques on June 3, 2014. See CGS's press statement here. 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. Overview 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."
Resources
Frequently Asked Questions 1. 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 cell nucleus.  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 people. 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. 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. 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. 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. 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. Where is the research taking place? 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 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-standingposition against funding research that results in modification of the human germline. Columbia University, New York 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:
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.
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. 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. 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 [back to top] [back to top] 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:
[back to top] It is misleading to draw ethical, social or medical comparisons between "mitochondria donation" and organ donation.
How has the media covered the issue?
[back to top] 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" ismuch 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. 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. Last modified November 14, 2014 |
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 (
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
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---------------------------------------------------
http://www.biopoliticaltimes.org/article.php?id=8331
Key Questions About the Social and Ethical Implications of Nuclear Genome Transfer or “3-Person IVF” Techniques
Posted by Jessica Cussins on January 22nd, 2015
Nuclear genome transfer for preventing the transmission of mitochondrial disease – also known as “3-person IVF” – is a form of inheritable human genetic modification, which has long been considered off limits. More than 40 countries have adopted laws to prohibit it (and human reproductive cloning), citing deep and enduring concerns about safety, human dignity, and societal consequence.
Extreme biological procedures such as inheritable genetic modification and reproductive cloning pose enormous safety issues. They also raise profound social and ethical challenges. Here we show eight questions that should be considered in assessing nuclear genome transfer or “3-person IVF” techniques. For more detail, see our resource pagehere.
Key questions
- What are the likely policy consequences of permitting nuclear genome transfer? If we allow inheritable genetic modification for preventing the transmission of mitochondrial diseases, won’t it increase pressure to allow it for other diseases? If a new line is to be drawn, where would it be? Or will people simply design their children as they wish as soon as technology allows? If so, how could a “genetics arms-race,” leading to new and increasing social disparities, be prevented?
- How will women affected by mitochondrial disease be informed of alternative options for having healthy children, which include IVF with genetic screening to choose a healthy embryo, prenatal genetic testing, using third-party eggs with IVF, and adoption?
- How will women considering using these techniques be fully informed of the risks they pose and the controversies they raise? Would physician-researchers unduly pressure women who are candidates for the procedures, consciously or unconsciously, because of their eagerness for a technical “breakthrough?” Would women in this position be especially vulnerable to persuasion because of their illness?
- Increasing evidence highlights the impact of mitochondria not only on energy production, but on other traits. How will any resulting children feel to know they have been the subjects of biological experimentation, and have inherited traits from three different people? Will they be told? Will they be permitted to know the woman who provided the second egg leading to their conception? (Proposed regulations in the UK claim a child will have no right to this information, and that the child will have no relation to this woman.)
- How will any resulting children be followed up to know if the techniques work or are safe? Mitochondrial disorders often manifest late in life; are long-term studies plausible? Since these altered genomes will be passed on to future generations, will the children’s children also be followed up? (Proposed regulations in the UK currently do not require any follow-up; they also don’t require parents to inform children of the means of their conception.)
- How will the non-parenting women who provide their eggs be recruited? How will they be compensated? How will they be followed up to monitor the long-term impact of egg retrieval on their health?
- Who will fund this work? Who will profit from it? Who will oversee it? Who will be at fault if anything goes wrong?
- How can we ensure that people who are already alive and suffering from mitochondrial diseases receive the treatment and care that they need right now?
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