Mitochondrial replacement therapy

{{Short description|Special form of in vitro fertilisation}} {{Use American English|date=March 2021}} {{Infobox medical intervention | name = Mitochondrial replacement therapy | image = | caption = | alt = | pronounce = | synonyms = Mitochondrial donation | ICD10 = | ICD9 = | ICD9unlinked = | CPT = | MeshID = D000069321 | LOINC = | other_codes = | MedlinePlus = | eMedicine = }} '''Mitochondrial replacement therapy''' ('''MRT'''), sometimes called '''mitochondrial donation''', is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. MRT originated as a special form of in vitro fertilisation in which some or all of the future baby's mitochondrial DNA (mtDNA) comes from a third party. This technique is used in cases when mothers carry genes for mitochondrial diseases. The therapy is approved for use in the United Kingdom<ref name=NAS2016ethics>{{cite book|last1=Claiborne |first1=A. |last2=English |first2=R. |last3=Kahn |first3=J. |editor1-last=Claiborne|editor1-first=Anne|editor2-last=English|editor2-first=Rebecca|editor3-last=Kahn|editor3-first=Jeffrey|title=Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations|date=2016|publisher=National Academies Press|doi=10.17226/21871 |pmid=27054230 |isbn=978-0-309-38870-2|url=https://www.nap.edu/read/21871/chapter/1}} [http://nationalacademies.org/hmd/reports/2016/Mitochondrial-Replacement-Techniques Index page] {{Webarchive|url=https://web.archive.org/web/20181126135516/http://www.nationalacademies.org/hmd/reports/2016/Mitochondrial-Replacement-Techniques |date=2018-11-26 }} with links to summaries including [http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2016/Mitochondrial%20Replacement%20Techniques/mito%20ethics%20infographic_FINAL.pdf one page summary flyer].</ref><ref name=2015CreeRev>{{cite journal|last1=Cree|first1=L|last2=Loi|first2=P|title=Mitochondrial replacement: from basic research to assisted reproductive technology portfolio tool-technicalities and possible risks.|journal=Molecular Human Reproduction|date=January 2015|volume=21|issue=1|pages=3–10|pmid=25425606|doi=10.1093/molehr/gau082|doi-access=free}} {{open access}}</ref> and Australia.<ref>{{Cite web |last=Cross |first=Liana |date=2022-03-31 |title=Mitochondrial donation now legal in Australia |url=https://www.australiangenomics.org.au/mitochondrial-donation-now-legal-in-australia/ |access-date=2025-07-18 |website=Australian Genomics |language=en-US}}</ref> Eight babies have been born using MRT in the UK as of July 2025.<ref name=":3">{{Cite web |last=Press release |date=2025-07-16 |title=Eight babies born after Mitochondrial donation |url=http://www.ncl.ac.uk/press/articles/latest/2025/07/mitochondrialdonationtreatment/ |access-date=2025-07-18 |website=Newcastle University |language=en}}</ref><ref name=":2">{{Cite journal |last1=McFarland |first1=Robert |last2=Hyslop |first2=Louise A. |last3=Feeney |first3=Catherine |last4=Pillai |first4=Rekha N. |last5=Blakely |first5=Emma L. |last6=Moody |first6=Eilis |last7=Prior |first7=Matthew |last8=Devlin |first8=Anita |last9=Taylor |first9=Robert W. |last10=Herbert |first10=Mary |last11=Choudhary |first11=Meenakshi |last12=Stewart |first12=Jane A. |last13=Turnbull |first13=Douglass M. |date=2025-07-16 |title=Mitochondrial Donation in a Reproductive Care Pathway for mtDNA Disease |journal=New England Journal of Medicine |volume=393 |issue=5 |article-number=NEJMoa2503658 |language=en |doi=10.1056/NEJMoa2503658 |pmid=40689593 |issn=0028-4793|pmc=7617939 }}</ref><ref name=":4">{{Cite journal |last1=Hyslop |first1=Louise A. |last2=Blakely |first2=Emma L. |last3=Aushev |first3=Magomet |last4=Marley |first4=Jordan |last5=Takeda |first5=Yuko |last6=Pyle |first6=Angela |last7=Moody |first7=Eilis |last8=Feeney |first8=Catherine |last9=Dutton |first9=Jan |last10=Shaw |first10=Carol |last11=Smith |first11=Sarah J. |last12=Craig |first12=Kate |last13=Alston |first13=Charlotte L. |last14=Lister |first14=Lisa |last15=Endacott |first15=Karina |title=Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease |journal=New England Journal of Medicine |date=2025 |issue=5 |article-number=NEJMoa2415539 |volume=393 |doi=10.1056/NEJMoa2415539 |pmid=40673696 |issn=0028-4793|pmc=7617940 }}</ref> A second application is to use autologous mitochondria to replace mitochondria in damaged tissue to restore the tissue to a functional state. This has been used in clinical research in the United States to treat cardiac-compromised newborns.<ref name=NYT2018>{{Cite news|url=https://www.nytimes.com/2018/07/10/health/mitochondria-transplant-heart-attack.html|title=Dying Organs Restored to Life in Novel Experiments|last=Kolata|first=Gina|work=The New York Times |date=10 July 2018|access-date=2018-07-12|language=en}}</ref>

==Medical uses==

=== ''In vitro'' fertilisation === Mitochondrial replacement therapy has been used to prevent the transmission of mitochondrial diseases from mother to child. In the UK it could only be performed in clinics licensed by the Human Fertilisation and Embryology Authority (HFEA), only for people individually approved by the HFEA, for whom preimplantation genetic diagnosis is unlikely to be helpful, and only with informed consent {{en dash}} given that the risks and benefits are not well understood.<ref name=HFEA2016regs>{{cite web|title=33. Mitochondrial donation|url=http://www.hfea.gov.uk/9931.html|publisher=Human Fertilisation and Embryology Authority|access-date=2016-12-20|archive-date=2016-10-12|archive-url=https://web.archive.org/web/20161012060509/http://www.hfea.gov.uk/9931.html|url-status=dead}} Linked in HFEA [http://www.hfea.gov.uk/10563.html announcement] {{Webarchive|url=https://web.archive.org/web/20161217204034/http://www.hfea.gov.uk/10563.html |date=2016-12-17 }} of the regulations issued 15 December 2016.</ref>

Relevant mutations are found in about 0.5% of the population. Disease affects a much smaller proportion of the population {{en dash}} around one in 5000 individuals, 0.02% {{en dash}} because cells contain many mitochondria and only some carry mutations. The proportion of the cell's mitochondria affected needs to reach a threshold in order to affect the entire cell; and many cells need to be affected for the person to show disease.<ref name=2015CreeRev/>

The average number of births per year among women at risk for transmitting mtDNA disease is estimated as approximately 150 in the United Kingdom and 800 in the United States.<ref name="GormanGrady2015">{{cite journal|last1=Gorman|first1=Gráinne S.|last2=Grady|first2=John P.|last3=Ng|first3=Yi|last4=Schaefer|first4=Andrew M.|last5=McNally|first5=Richard J.|last6=Chinnery|first6=Patrick F.|last7=Yu-Wai-Man|first7=Patrick|last8=Herbert|first8=Mary|last9=Taylor|first9=Robert W.|last10=McFarland|first10=Robert|last11=Turnbull|first11=Doug M.|author-link11=Douglass Turnbull|title=Mitochondrial Donation — How Many Women Could Benefit?|journal=New England Journal of Medicine|year=2015|pages=885–887|issn=0028-4793|doi=10.1056/NEJMc1500960|pmid=25629662|volume=372|issue=9|pmc=4481295}}</ref>

Where both legal and feasible, MRT provides a fourth reproductive option for women who are at risk for transmitting mtDNA disease and who want to prevent transmission. The other three are using an egg from another woman, adoption, or childlessness.<ref name=NAS2016ethics/>{{rp|45}}

=== Tissue function === Autologous mitochondria extracted from healthy tissue and supplied to damaged tissue has been used to treat cardiac-compromised newborns. Alternatives to the approach include use of an extracorporeal membrane oxygenator (ECMO) or tissue or organ transplantation.<ref name=NYT2018/>

==Techniques== ''In vitro'' fertilization involves removing eggs from a woman, collecting sperm from a man, fertilizing the egg with the sperm, allowing the fertilized egg to form a blastocyst, and then transferring the blastocyst into the uterus. MRT involves an additional egg from a third person, and manipulation of both the recipient egg and the donor egg.<ref name="NAS2016ethics" />

As of 2016 there were three MRT techniques in use: maternal spindle transfer (MST); pronuclear transfer (PNT); and the newest technique, polar body transfer (PBT). The original technique, cytoplastic transfer, in which mitochondria-containing cytoplasm taken from a donor egg is simply injected into the recipient egg, is no longer used.<ref name=NAS2016ethics/>{{rp|46–47}} The UK Parliament only approved the use of two techniques -maternal spindle transfer and pronuclear transfer - for mitichondrial replacement in 2015.<ref>{{Cite web |title=HFEA: UK fertility regulator |url=https://www.hfea.gov.uk/treatments/embryo-testing-and-treatments-for-disease/mitochondrial-donation-treatment/ |access-date=2025-07-19 |website=Human Fertilisation & Embryology Authority (HFEA) |language=en-GB}}</ref><ref name=":5">{{Cite web |title=The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 |url=https://www.legislation.gov.uk/uksi/2015/572/contents/made |archive-url=https://web.archive.org/web/20250717071929/https://www.legislation.gov.uk/uksi/2015/572/contents/made |archive-date=2025-07-17 |access-date=2025-07-19 |website=www.legislation.gov.uk |language=en |url-status=live }}</ref>

=== Maternal spindle transfer === thumb|Diagram of the meiotic phases, showing how the chromosomes look in metaphase II In maternal spindle transfer, an oocyte is removed from the recipient, and when it is in the metaphase II stage of cell division, the spindle-chromosome complex is removed; some of the cytoplasm comes with it, so some mitochondria are likely to be included. The spindle-chromosome complex is inserted into a donor oocyte from which the nucleus has already been removed. This egg is fertilized with sperm and allowed to form a blastocyst, which can then be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations, prior to being implanted in the recipient's uterus.<ref name=NAS2016ethics/>{{rp|47–48}}

=== Pronuclear transfer === In pronuclear transfer, an oocyte is removed from the recipient and fertilized with sperm. The donor oocyte is fertilized with sperm from the same person. The male and female pronuclei are removed from each fertilized egg prior to their fusing, and the pronuclei from the recipient's fertilized egg are inserted into the fertilized egg from the donor. As with MST, a small amount of cytoplasm from the recipient egg may be transferred, and as with MST, the fertilized egg is allowed to form a blastocyst, which can then be investigated with preimplantation genetic diagnosis to check for mitochondrial mutations before being implanted in the recipient's uterus.<ref name="NAS2016ethics" />{{rp|50}}

=== Polar body transfer === thumb|The process of fertilization in the ovum of a mouse, showing pronuclei.

In polar body transfer, a polar body (a small cell with very little cytoplasm that is created when an egg cell divides) from the recipient is used in its entirety, instead of using nuclear material extracted from the recipient's normal egg; this can be used in either MST or PNT. This technique was first published in 2014 and as of 2015 it had not been consistently replicated, but is considered promising as there is a greatly reduced chance for transmitting mitochondria from the recipient because polar bodies contain very few mitochondria, and it does not involve extracting material from the recipient's egg.<ref name=2015Wolf>{{cite journal|last1=Wolf|first1=DP|last2=Mitalipov|first2=N|last3=Mitalipov|first3=S|title=Mitochondrial replacement therapy in reproductive medicine.|journal=Trends in Molecular Medicine|date=February 2015|volume=21|issue=2|pages=68–76|pmid=25573721|pmc=4377089|doi=10.1016/j.molmed.2014.12.001}}</ref> thumb|left|Diagram showing the creation of polar bodies.

===Cytoplasmic transfer=== Cytoplasmic transfer was originally developed in the 1980s in the course of basic research conducted with mice to study the role that parts of the cell outside of the nucleus played in embryonic development.<ref name=2015CreeRev/> In this technique, cytoplasm, including proteins, messenger RNA (mRNA), mitochondria and other organelles, is taken from a donor egg and injected into the recipient egg, resulting in a mixture of mitochondrial genetic material.<ref name=2015CreeRev/> This technique started to be used in the late 1990s to "boost" the eggs of older women who were having problems conceiving and led to the birth of about 30 babies.<ref name=2015CreeRev/> Concerns were raised that the mixture of genetic material and proteins could cause problems with respect to epigenetic clashes, or differences in the ability of the recipient and donor materials to effect the development process, or due to the injection of the donor material.<ref name=2015CreeRev/> After three children born through the technique were found to have developmental disorders (two cases of Turner's syndrome and one case of pervasive developmental disorder (an autism spectrum disorder), the FDA banned the procedure until a clinical trial could prove its safety.<ref name=2015CreeRev/> As of 2015 that study had not been conducted, but the procedure was in use in other countries.<ref name=2015CreeRev/>

A related approach uses autologous mitochondria taken from healthy tissue to replace the mitochondria in damaged tissue. Transfer techniques include direct injection into damaged tissue and injection into vessels that supply blood to the tissue.<ref name=NYT2018/>

==Risks== Assisted reproduction via MRT involves preimplantation genetic screening of the mother, preimplantation genetic diagnosis after the egg is fertilized, and in vitro fertilization. It has all the risks of those procedures.<ref name=NAS2016ethics/>{{rp|60}}

In addition, both procedures used in MRT entail their own risks. On one level, the procedures physically disrupt two oocytes, removing nuclear genetic material from the recipient egg or fertilized egg and inserting the nuclear genetic material into the donor unfertilized or fertilized egg; the manipulations for both procedures may cause various forms of damage that were not well understood as of 2016.<ref name=HFEA4th/>{{rp|23}}

Maternal mitochondria will be carried over to the donor egg; as of 2016 it was estimated that using techniques current in the UK, maternal mitochondria will comprise only around 2% or less of mitochondria in the resulting egg, a level that was considered safe by the HFEA and within the limits of mitochondrial variation that most people have.<ref name=HFEA4th/>{{rp|23–24}}

Because MRT procedures involve actions at precise times during egg development and fertilization, and involves manipulating eggs, there is a risk that eggs may mature abnormally or that fertilization may happen abnormally; as of 2016 the HFEA judged that laboratory techniques in the UK had been well enough developed to manage these risks to proceed cautiously with making MRT available.<ref name=HFEA4th/>{{rp|33–34}}

Because mitochondria in the final egg will come from a third party, different from the two parties whose DNA is in the nucleus, and because nuclear DNA encodes genes that make some of the proteins and mRNA used by mitochondria, there is a theoretical risk of adverse "mito–nuclear" interactions. While this theoretical risk could possibly be managed by attempting to match the haplotype of the donor and the recipient, as of 2016 there was no evidence that this is an actual risk.<ref name=HFEA4th/>{{rp|34–37}}

Because MRT is a relatively new technology, there are concerns that it is not yet safe for public use as there have been limited studies that used MRT in large animal models.<ref>{{cite news | url=https://www.abc.net.au/news/science/2022-03-31/maeves-law-passes-senate-mitochondrial-donation/100954484 | title='Maeve's Law' to legalise mitochondrial donation through IVF passes Senate | newspaper=ABC News | date=31 March 2022 }}</ref>

Finally, there is a risk of epigenetic modification to DNA in the nucleus and mitochondria, caused by the procedure itself or by mito–nuclear interactions. As of 2016 these risks appeared to be minimal but were being monitored by long-term study of children born from the procedure.<ref name=HFEA4th/>{{rp|38}}

==History== In the United States in 1996 embryologist Jacques Cohen and others at the Institute for Reproductive Medicine and Science, Saint Barnabas Medical Center in Livingston, New Jersey first used cytoplasmic transfer in a human assisted reproduction procedure.<ref>Kim Tingley for the New York Times. June 27, 2014 [https://www.nytimes.com/2014/06/29/magazine/the-brave-new-world-of-three-parent-ivf.html The Brave New World of Three-Parent I.V.F.]</ref> In 1997 the first baby was born using this procedure. In 2001, Cohen and others reported that ten single babies, twins, and a quadruplet at his New Jersey clinic and a further six children in Israel had been born using his technique. Using modifications of his procedure, a baby had been born at Eastern Virginia Medical School, five children at the Lee Women's Hospital Infertility Clinic in Taichung, Taiwan.<ref name="HRU">{{cite journal|last1=Cohen|first1=Jacques|title=Cytoplasmic transfer in assisted reproduction|journal=Human Reproduction Update|date=6 April 2001|volume=7|issue=4|pages=428–435|doi=10.1093/humupd/7.4.428|display-authors=etal|pmid=11476356|doi-access=free}}</ref> twins in Naples, Italy<ref>{{Cite journal|last1=Dale|first1=Brian|last2=Wilding|first2=Martin|last3=Botta|first3=Giuseppe|last4=Rasile|first4=Marianna|last5=Marino|first5=Marcella|last6=Matteo|first6=Loredana Di|last7=Placido|first7=Giuseppe De|last8=Izzo|first8=Alfredo|date=2001-07-01|title=Pregnancy after cytoplasmic transfer in a couple suffering from idiopathic infertility Case report|journal=Human Reproduction|language=en|volume=16|issue=7|pages=1469–1472|doi=10.1093/humrep/16.7.1469|pmid=11425831|issn=0268-1161|doi-access=free}}</ref> and a twins in India.<ref>{{Cite web|url=http://news.webindia123.com/news/articles/India/20111121/1876130.html|title=Woman conceives through cytoplasmic transfer technology|date=2011-11-21|website=News|publisher=Web India 123|access-date=2016-10-27|archive-date=2016-10-28|archive-url=https://web.archive.org/web/20161028152045/http://news.webindia123.com/news/articles/India/20111121/1876130.html|url-status=dead}}</ref> In total as of 2016, 30–50 children worldwide had been reported to have been born using cytoplasmic transfer.<ref name="Shane">{{cite news|last1=Kula|first1=Shane|title=Three-Parent Children Are Already Here|url=http://www.slate.com/articles/technology/future_tense/2016/02/three_parent_babies_have_been_here_since_the_late_90s.html|work=Slate|date=18 February 2016}}</ref>

In 2002, the US Food and Drug Administration (FDA) asked a Biological Response Modifiers Advisory Committee Meeting to advise on the technique of cytoplasmic transfer to treat infertility. This committee felt that there were risks at the time of inadvertent transfer of chromosomes and enhanced survival of abnormal embryos.<ref name="Shane"/> The FDA informed clinics that they considered the cytoplasmic transfer technique as a new treatment, and, as such, it would require an Investigational New Drug (IND) application. Cohen's clinic started the pre-IND application, but the clinic then went private, funding for the application dried up, the application was abandoned, the research team disbanded,<ref name="Connor">{{cite news|last1=Connor|first1=Steve|title=Three-parent babies: 'As long as she's healthy, I don't care', says mother of IVF child|url=https://www.independent.co.uk/news/science/three-child-babies-the-mothers-view-as-long-as-she-s-healthy-i-don-t-care-9690059.html |archive-url=https://ghostarchive.org/archive/20220515/https://www.independent.co.uk/news/science/three-child-babies-the-mothers-view-as-long-as-she-s-healthy-i-don-t-care-9690059.html |archive-date=2022-05-15 |url-access=subscription |url-status=live|access-date=2 March 2016|work=The Independent|date=25 August 2015}}</ref> and the cytoplasmic transfer procedure fell out of favor.<ref name = NewScientist2016>{{Cite web|url=https://www.newscientist.com/article/2107451-everything-you-wanted-to-know-about-3-parent-babies/|title=Everything you wanted to know about '3-parent' babies|last=Hamzelou|first=Jessica|date=2016-09-28|publisher=The New Scientist|language=en-US|access-date=2016-10-01}}</ref> In 2016, 12 (out of the 13) parents of children born using cytoplasmic transfer at the Saint Barnabas Center participated in a limited follow-up inquiry via online questionnaire. Children whose ages then were 13–18 reported no major problems.<ref>{{Cite journal|last1=Chen|first1=Serena H.|last2=Pascale|first2=Claudia|last3=Jackson|first3=Maria|last4=Szvetecz|first4=Mary Ann|last5=Cohen|first5=Jacques|title=A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre|journal=Reproductive BioMedicine Online|doi=10.1016/j.rbmo.2016.10.003|pmid=27789184|volume=33|issue=6|pages=737–744|date=December 2016|doi-access=free}}</ref>

In 2009, a team in Japan published studies of mitochondrial donation.<ref>{{cite news|last1=Alleyne|first1=Richard|title='Three parent babies' take a step closer to reality|url=https://www.telegraph.co.uk/news/health/news/6546448/Three-parent-babies-take-a-step-closer-to-reality.html|work=Telegraph|date=12 November 2009}}</ref> In the same year, a team led by scientists at Oregon Health & Science University published results of mitochondrial donation in monkeys; that team published an update reporting on the health of the monkeys born with the technique, as well as further work it had done on human embryos.<ref>{{cite web|last=Naik|first=Gautam|title=DNA Switch Shows Promise Against Genetic Disease|url=https://www.wsj.com/articles/SB10001424052970204076204578076530392342640|publisher=Wall Street Journal|date=27 November 2012}}</ref>

Human trials in 2010 by a team in Newcastle University and Newcastle Fertility Centre were successful in reducing transmission of mtDNA. The results of the study found the mean mtDNA carried over was on average under 2% in the experimental embryos. This was true for both the MI-SCC and PN transfer methods of MTR. This research did not extend past the blastocyst stage because of ethical concerns, and there are still concerns about whether results retrieved from the blastocyst stage are viable representations of whole embryos. Because of these speculations and to further the viability of MTR as a safe and effective technique, further research and clinical trials would need to be initiated to test the efficacy of MTR in the long term in human patients.<ref>{{Cite journal|title=CRISPR/Cas9 and mitochondrial gene replacement therapy: promising techniques and ethical considerations|last=Fogleman|first=Sarah|date=2016-09-20|journal=The American Journal of Stem Cells|language=en-US|pmc=5043096|pmid=27725916|volume=5|issue=2|pages=39–52}}</ref>

=== Developments in the United Kingdom using MRT to prevent transmission of mitochondrial disease === In the United Kingdom, following animal experiments and the recommendations of a government commissioned expert committee,<ref name="DoH">{{cite web|last1=Donaldson|first1=Liam|title=Stem cell research: medical progress with responsibility|url=http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_4065085.pdf|archive-url=http://webarchive.nationalarchives.gov.uk/20130107105354/http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_4065085.pdf|url-status=dead|archive-date=7 January 2013|website=UK National Archives|publisher=UK Department of Health|access-date=24 March 2016|date=16 August 2000}}</ref> the Human Fertilisation and Embryology (Research Purposes) Regulations were passed in 2001 regulating and allowing research into human embryos. In 2004, Newcastle University applied for a license to develop pronuclear transfer to avoid the transmission of mitochondrial diseases,<ref>{{cite news|last1=Randerson|first1=James|title=Scientists seek to create 'three-parent' babies|url=https://www.newscientist.com/article/dn6547-scientists-seek-to-create-three-parent-babies/|work=New Scientist|date=19 October 2004}}</ref> and was granted the license in 2005. Following further research by Newcastle and the Wellcome Trust,<ref name =Boseley>{{cite news |last=Boseley |first=Sarah |title=Scientists reveal gene-swapping technique to thwart inherited diseases |publisher=Guardian |date=2010-04-14 |url=https://www.theguardian.com/science/2010/apr/14/scientists-gene-swap-technique-disease |location=London}}</ref><ref name=CravenTuppen2010>{{cite journal|last1=Craven|first1=Lyndsey|last2=Tuppen|first2=Helen A.|last3=Greggains|first3=Gareth D.|last4=Harbottle|first4=Stephen J.|last5=Murphy|first5=Julie L.|last6=Cree|first6=Lynsey M.|last7=Murdoch|first7=Alison P.|last8=Chinnery|first8=Patrick F.|last9=Taylor|first9=Robert W.|last10=Lightowlers|first10=Robert N.|last11=Herbert|first11=Mary|last12=Turnbull|first12=Douglass M.|author-link12=Douglass Turnbull|title=Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease|journal=Nature|volume=465|issue=7294|year=2010|pages=82–85|pmid=20393463|pmc=2875160|doi=10.1038/nature08958|bibcode=2010Natur.465...82C}} {{open access}}</ref> scientific review,<ref name="HFEAReview">{{cite book|editor1-last=Greenfield|editor1-first=Andy|title=Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2014 update|date=June 2014|publisher=Human Fertilisation and Embryology Authority|location=UK|url=http://www.hfea.gov.uk/docs/Third_Mitochondrial_replacement_scientific_review.pdf|access-date=2 March 2016|archive-date=3 February 2016|archive-url=https://web.archive.org/web/20160203100323/http://www.hfea.gov.uk/docs/Third_Mitochondrial_replacement_scientific_review.pdf|url-status=dead}}</ref> public consultations, and debate, the UK government recommended that mitochondrial donation be legalized in 2013.<ref name=2013CMO>{{cite news|last1=Connor|first1=Steve|title=UK becomes first country in world to approve IVF using genes of three|url=https://www.independent.co.uk/news/science/uk-becomes-first-country-in-world-to-approve-ivf-using-genes-of-three-parents-8677595.html |archive-url=https://ghostarchive.org/archive/20220515/https://www.independent.co.uk/news/science/uk-becomes-first-country-in-world-to-approve-ivf-using-genes-of-three-parents-8677595.html |archive-date=2022-05-15 |url-access=subscription |url-status=live|work=The Independent|date=28 June 2013}}</ref> In 2015 parliament passed the Human Fertilisation and Embryology (Mitochondrial Donation) Regulations, which came into force on 29 October 2015, making human mitochondrial donation legal in the UK.<ref name=":5" /> The Human Fertilisation and Embryology Authority (HFEA) was authorized to license and regulate medical centers which wanted to use human mitochondrial donation.<ref name="StemCells">{{cite journal|last1=Craven|first1=Lindsay|title=Research into Policy: A Brief History of Mitochondrial Donation|journal=Stem Cells|date=29 September 2015|volume=34|issue=2|pages=265–267|doi=10.1002/stem.2221|display-authors=etal|pmid=26418557|pmc=4855617}}</ref><ref name="BBC2016regs" /> In February 2016, the US National Academy of Sciences issued a report describing technologies then current and the surrounding ethical issues.<ref name="NAS2016ethics" />

The HFEA Safety Committee issued its fourth report in November 2016 recommending procedures under which HFEA should authorize MRT,<ref name="HFEA4th">{{cite web|last1=Greenfield|first1=Andy|title=Scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2016 update|url=http://www.hfea.gov.uk/docs/Fourth_scientific_review_mitochondria_2016.PDF|publisher=Human Fertilisation and Embryology Authority|date=30 November 2016|access-date=20 December 2016|archive-date=3 June 2017|archive-url=https://web.archive.org/web/20170603102446/http://www.hfea.gov.uk/docs/Fourth_scientific_review_mitochondria_2016.PDF|url-status=dead}} linked from accompanying [http://www.hfea.gov.uk/10557.html press release] {{Webarchive|url=https://web.archive.org/web/20170331185540/http://www.hfea.gov.uk/10557.html |date=2017-03-31 }}</ref> the HFEA issued their regulations in December 2016<ref name="BBC2016regs" /><ref name="HFEA2016regs" /> and granted their first license (to Newcastle Fertility Centre; Newcastle upon Tyne Hospital NHS Foundation Trust led by Dr Jane Stewart as Person Responsible to the HFEA) in March 2017.<ref>{{Cite news|url=https://www.bbc.co.uk/news/health-39292381|title=Three-person baby licence granted|last=Gallagher|first=James|date=2017-03-16|work=BBC News|access-date=2017-03-16|language=en-GB}}</ref> Between August 2017 and January 2019, the HFEA received 15 requests from women to undergo MRT, of which 14 were granted.<ref>{{Cite news|url=https://www.theguardian.com/science/2018/feb/01/permission-given-to-create-britains-first-three-person-babies|title=UK doctors select first women to have 'three-person babies'|date=2018-02-02|work=The Guardian|language=en-GB}}</ref><ref>{{Cite web|last=Doyle-Price|first=Jackie|date=2019-04-05|title=Embryos - Question for Department of Health and Social Care|url=https://questions-statements.parliament.uk/written-questions/detail/2019-04-05/241389|access-date=2020-12-16|website=UK Parliament|language=en}}</ref>

In July 2025 it was announced that 22 patients had taken part in a mitichondrial replacement trial in the UK. Eight babies (including one set of identical twins<ref name=":3" />) had been born using the pronuclear transfer procedure with one pregnancy still ongoing. The babies showed little or no signs of mitochondrial disease which would otherwise have been passed down from their mothers.<ref name=":1">{{Cite web |last=Lanese |first=Nicoletta |date=2025-07-16 |title=8 babies spared from potentially deadly inherited diseases through new IVF 'mitochondrial donation' trial |url=https://www.livescience.com/health/genetics/8-babies-spared-from-potentially-deadly-inherited-diseases-through-new-mitochondrial-donation-trial |access-date=2025-07-18 |website=Live Science |language=en}}</ref><ref name=":2" /><ref name=":4" />

Professor Douglass Turnbull, the driving force behind mitochondrial research at Newcastle University, was awarded a knighthood in 2016<ref name="sirdoug">{{London Gazette | issue = 61608 | date = 2016-06-11 | page = B2 | supp = y }}</ref><ref>{{Cite web |date=2016-06-10 |title=Birthday honours: Mitochondrial disease doctor recognised |url=https://www.bbc.co.uk/news/health-36499807 |access-date=2016-06-10 |website=BBC News}}</ref> and the Buchanan Medal by the Royal Society in 2020.<ref>{{Cite web |title=Royal Society announces 2020 winners of prestigious medals and awards {{!}} Royal Society |url=https://royalsociety.org/news/2020/08/medals-and-awards-winners-2020/ |access-date=2025-07-19 |website=royalsociety.org |language=en}}</ref>

=== Australian developments on the use of MRT to prevent mitochondrial disease transmission === In June 2018 Australian Senate's Senate Community Affairs References Committee recommended a move towards legalising MRT, and in July 2018 the Australian senate endorsed it.<ref>{{Cite web |last=Pritchard |first=Sarah |date=2018-07-02 |title=Australian Senate endorses mitochondrial donation |url=https://www.bionews.org.uk/page_136808 |access-date=2018-09-11 |website=BioNews |language=en}}</ref> Research and clinical applications of MRT were overseen by laws made by federal and state governments. State laws were, for the most part, consistent with federal law. In all states, legislation prohibited the use of MRT techniques in the clinic, and except for Western Australia, research on a limited range of MRT was permissible up to day 14 of embryo development, subject to a license being granted. In 2010, the Hon. Mark Butler MP, then Federal Minister for Mental Health and Ageing, had appointed an independent committee to review the two relevant acts: the ''Prohibition of Human Cloning for Reproduction Act 2002'' and the ''Research Involving Human Embryos Act 2002''. The committee's report, released in July 2011, recommended the existing legislation remain unchanged.<ref>{{Cite news |title=Mitochondrial Donation |url=https://www.mito.org.au/mitochondrial-donation/ |access-date=2018-07-11 |work=Mito Foundation (formerly AMDF)}}</ref> The Australian National Health and Medical Research Council issued two reports on legalising MRT in June 2020.<ref>{{Cite web |date=5 June 2020 |title=Australian Government CEO Statement: Should Australia introduce mitochondrial donation? |url=https://www.nhmrc.gov.au/sites/default/files/documents/attachments/CEO-statement-mitochondrial.pdf |access-date=16 December 2020 |website=Australian Government}}</ref><ref>{{Cite web |date=November 2019 |title=Mitochondrial Donation |url=https://www.nhmrc.gov.au/health-advice/all-topics/mitochondrial-donation |access-date=16 December 2020 |website=Australian National Health and Medical Research Council}}</ref>

In 2022, Maeve's Law was passed by the Australian Parliament, legalising MRT under a specified mitochondrial donation licence for research and training, and in clinical settings<ref name=":6">{{Cite web |author=Australian Commonwealth Parliament |title=Mitochondrial Donation Law Reform (Maeve's Law) Bill 2021 |url=https://www.aph.gov.au/Parliamentary_Business/Bills_LEGislation/Bills_Search_Results/Result?bId=r6697 |access-date=2022-04-07}}</ref> (Maeve was a Melbourne girl who had severe mitochondrial disease<ref>{{Cite web |last=Osborne |first=Paul |date=2021-03-23 |title=Government acts on DNA donation laws |url=https://7news.com.au/politics/government-acts-on-dna-donation-laws-c-2422517 |access-date=2025-07-18 |website=7NEWS |language=en}}</ref>). In July 2025 it was forecast that the first MRT clinical trial in Australia would start in the second half of 2026.<ref>{{Cite web |title=July 2025 update |url=https://www.monash.edu/medicine/mitohope/news/july-2025-update |access-date=2025-07-18 |website=The MitoHOPE Program |language=en}}</ref> === MRT to help with infertility === In 2016, John Zhang and a mixed team of scientists from Mexico and New York used the spindle transfer technique to help a Jordanian woman to give birth to a baby boy. The mother had Leigh disease and already had four miscarriages and two children who had died of the disease.<ref>{{Cite news|url=https://www.bbc.co.uk/news/health-37485263|title=First 'three person baby' born using new method|last=Roberts|first=Michelle|date=2016-09-27|newspaper=BBC News|language=en-GB|access-date=2016-09-28}}</ref>

In August 2017, in a letter to two clinics, including Zhang's, the FDA warned that the technique should not be marketed in the U.S.<ref>{{cite web |date=9 August 2017 |title='Three parent' technique must not be marketed in US, says FDA |url=https://www.newscientist.com/article/mg23531384-100-three-parent-technique-must-not-be-marketed-in-us-says-fda/ |access-date=10 August 2017 |work=New Scientist}}</ref>

In August and October 2017 the British HFEA authorized MRT for two women who had a genetic mutation in their mitichondria that causes myoclonic epilepsy with ragged red fibers.<ref>{{Cite news |last=Hamzelou |first=Jessica |date=2018-02-02 |title=First UK three-parent babies could be born this year |url=https://www.newscientist.com/article/2160120-first-uk-three-parent-babies-could-be-born-this-year/ |access-date=2018-02-03 |work=New Scientist |language=en-US}}</ref>

In June 2018 Valery Zukin, director of the Nadiya clinic in Kyiv, Ukraine, reported that doctors there had used the pronuclear transfer method of MRT to help four women give birth (three boys and a girl) and three women to become pregnant (one from Sweden). The team had 14 failed attempts.<ref name=":0">{{Cite news|url=https://www.npr.org/sections/health-shots/2018/06/06/615909572/inside-the-ukrainian-clinic-making-3-parent-babies-for-women-who-are-infertile?t=1531299279185|title=Clinic Claims Success In Making Babies With 3 Parents' DNA|last=Stein|first=Rob|date=2018-06-06|work=National Public Radio|access-date=2018-07-11|language=en}}</ref> In January 2019 it was reported that seven babies had been born using MRT.<ref>{{Cite web|url=https://www.eggdonationfriends.com/3-parent-baby-groundbreaking-pronucleus-transfer-interview-with-nadiya-clinic/|title=Three parent baby in Ukraine|last=Walas|first=Dorothy|date=2019-01-05|website=Egg Donation Friends|language=en-GB|access-date=2019-03-09}}</ref> Treatment of infertility was reported as the reason for the Ukrainian procedures, not for preventing inherited mitichondrial disease.<ref>{{Cite news |last=Gallagher |first=James |date=2016-10-12 |title=Three-person baby 'race' dangerous |url=https://www.bbc.com/news/health-37607528 |access-date=2025-07-19 |work=BBC News |language=en-GB}}</ref> The doctors had first gotten approval from an ethical committee and a review board of the Ukrainian Association of Reproductive Medicine<ref>{{cite news|url=http://www.nature.com/news/reports-of-three-parent-babies-multiply-1.20849|title=Reports of 'three-parent babies' multiply|last1=Reardon|first1=Sara|date=20 October 2016|work=Nature News|doi=10.1038/nature.2016.20849}}</ref><ref>{{Cite news|url=https://www.newscientist.com/article/2108549-exclusive-3-parent-baby-method-already-used-for-infertility/|title=Exclusive: '3-parent' baby method already used for infertility|last=Coghlan|first=Andy|date=2016-10-10|work=New Scientist|access-date=2018-07-11|language=en-US}}</ref> and the Ukrainian Postgraduate Medical Academy, under the auspices of the Ukrainian Ministry of Healthcare;<ref name=":0" /> there was no law in Ukraine against MRT. One of the first children, a boy, was born to a 34-year-old woman in January 2017, and genetic test results were reported as normal.<ref>{{Cite news|url=https://www.thetimes.com/uk/healthcare/article/three-parent-baby-born-to-infertile-woman-using-controversial-new-ivf-l5zhpx0qz|title=Three-parent baby born to 'infertile' woman using controversial new IVF|last=Moody|first=Oliver|date=2017-01-18|work=The Times|page=12|language=en|url-access=subscription |access-date=2017-01-18}}</ref><ref>{{Cite news|url=https://www.npr.org/sections/health-shots/2018/06/06/616334508/her-son-is-one-of-the-few-children-to-have-3-parents|title=Her Son Is One Of The Few Children To Have 3 Parents' DNA|last=Stein|first=Rob|date=2018-06-06|work=National Public Radio|access-date=2018-07-11|language=en}}</ref>

In January 2019, Embryotools, Barcelona, Spain announced that a 32-year-old Greek woman had become pregnant using the spindle transfer technique. MRT was not legal in Spain so they had performed the trial in Greece where there was no law against MRT. They were helped by the Institute of Life in Athens, Greece and had obtained approval from the Greek National Authority of Assisted Reproduction. The pregnant Greek woman had already had four failed IVF cycles and surgery twice for endometriosis.<ref>{{Cite web|url=https://www.bionews.org.uk/page_141058|title=Birth expected in mitochondrial donation for infertility trial - BioNews|last=Willows|first=Jennifer|date=2019-01-29|website=BioNews, UK|access-date=2019-03-09}}</ref> 25 infertile couples took part in a pilot study at the Greek Institute of Life-IASO IVF Center in 2018 to use the spindle transfer technique to achieve pregnancy. Six babies were born in the study and by 2023 (when they were four years old) they were reported to be healthy. In one child, mitochondria from the mother had expanded to 50% by the time the child was born.The mother did not have mitochondrial disease and so the baby was not affected. But the researchers noted MRT might not be completely successful in preventing passage of mitochondrial disease if this happened again.<ref>{{Cite journal |last1=Costa-Borges |first1=Nuno |last2=Nikitos |first2=Eros |last3=Späth |first3=Katharina |last4=Miguel-Escalada |first4=Irene |last5=Ma |first5=Hong |last6=Rink |first6=Klaus |last7=Coudereau |first7=Clement |last8=Darby |first8=Hayley |last9=Koski |first9=Amy |last10=Van Dyken |first10=Crystal |last11=Mestres |first11=Enric |last12=Papakyriakou |first12=Evmorfia |last13=De Ziegler |first13=Dominique |last14=Kontopoulos |first14=George |last15=Mantzavinos |first15=Themistoklis |date=June 2023 |title=First pilot study of maternal spindle transfer for the treatment of repeated in vitro fertilization failures in couples with idiopathic infertility |journal=Fertility and Sterility |language=en |volume=119 |issue=6 |pages=964–973 |doi=10.1016/j.fertnstert.2023.02.008|pmid=36787873 |doi-access=free }}</ref><ref>{{Cite web |last=Press release |date=2023-03-17 |title=Results from the first clinical pilot study using maternal spindle transfer |url=https://www.iolife.eu/en/results-from-the-first-clinical-pilot-study-using-maternal-spindle-transfer/ |access-date=2025-07-19 |website=Institute of Life |language=en-US}}</ref>

=== Other uses of MRT === In 2018, researchers announced the use of MRT to restore function to heart tissue in cardiac-compromised newborns. The damaged heart cells absorbed mitochondria extracted from healthy tissue and returned to useful activity.<ref name=NYT2018/>

==Society and culture==

===Regulations by Country=== The United Kingdom became the first country to legalize the procedure: the UK's chief medical officer recommended it be legalized in 2013.<ref name="2013CMO" /> Parliament passed The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations in 2015,<ref name="BBC2015law">{{cite news|last1=Gallagher|first1=James|title=UK approves three-person babies|url=https://www.bbc.com/news/health-31594856|work=BBC News|date=24 February 2015}}</ref><ref name="Regulation572">{{Cite web|url=https://www.legislation.gov.uk/uksi/2015/572/contents/made|title=The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015|website=www.legislation.gov.uk}}</ref> and the regulatory authority published regulations in 2016.<ref name="BBC2016regs">{{Cite news|url=https://www.bbc.co.uk/news/health-38328097|title=Babies made from three people approved in UK|last=Gallagher|first=James|date=2016-12-15|newspaper=BBC News|language=en-GB}}</ref>

In 2022, the Australian Parliament passed Maeve’s Law, legalising mitochondrial replacement therapy (MRT) under a specific mitochondrial donation licence for both research and training purposes, as well as in clinical applications.<ref name=":6" />

As of February 2016, the United States had no regulations governing mitochondrial donation, and Congress barred the FDA from evaluating any applications that involve implanting modified embryos into a woman.<ref>{{cite news |last1=Oswald |first1=Kirsty |date=8 February 2016 |title=Panel recommends FDA approval of mitochondrial donation |url=http://www.bionews.org.uk/page_614550.asp |url-status=dead |archive-url=https://web.archive.org/web/20160214063058/http://www.bionews.org.uk/page_614550.asp |archive-date=14 February 2016 |access-date=11 February 2016 |publisher=Bio News}}</ref>

In China, the 2003 Chinese Ministry of Health guidelines essentially prohibit the use of MRT.<ref name=":7">{{Cite journal |last1=Ishii |first1=Tetsuya |last2=Hibino |first2=Yuri |date=April 2018 |title=Mitochondrial manipulation in fertility clinics: Regulation and responsibility |journal=Reproductive Biomedicine & Society Online |language=en |volume=5 |pages=93–109 |doi=10.1016/j.rbms.2018.01.002 |pmid=30094357 |pmc=6076383}}</ref>

Mexico does not have specific federal legislation regulating assisted reproductive technologies. However, mitochondrial donation is allowed under certain conditions to address unresolved infertility. Some Mexican states prohibit the technique based on local laws that protect life from the moment of fertilization.<ref>{{Cite journal |last1=Palacios-González |first1=César |last2=Medina-Arellano |first2=María de Jesús |date=April 2017 |title=Mitochondrial replacement techniques and Mexico's rule of law: on the legality of the first maternal spindle transfer case |url=http://academic.oup.com/jlb/article/4/1/50/3078927/Mitochondrial-replacement-techniques-and-Mexicos |journal=Journal of Law and the Biosciences |language=en |volume=4 |issue=1 |pages=50–69 |doi=10.1093/jlb/lsw065 |pmid=28852557 |pmc=5570699 |issn=2053-9711}}</ref>

Albania’s regulation of mitochondrial donation is unclear. Law 8876/2002 on Reproductive Health governs assisted reproduction but it does not explicitly address the use of mitochondrial donation.<ref name=":7"/>

Northern Cyprus has no regulation on MRT.<ref name=":7" />

Singapore was considering whether to permit the MRT in 2018.<ref>{{Cite journal |last=Ong |first=Sandy |date=2018-06-06 |title=Singapore could become the second country to legalize mitochondrial replacement therapy |url=https://doi.org/10.1126/science.aau3989 |journal=Science |doi=10.1126/science.aau3989 |issn=0036-8075|url-access=subscription }}</ref>

A 2018 article in ''Reproductive Medicine and Society'' concluded that in 12 countries studied (Albania, Canada, Czech Republic, India, Israel, Italy, Japan, Mexico, Spain, Taiwan, Turkey and the United Arab Emirates) the regulations on MRT were 'insufficiently regulated.'<ref name=":7" />

=== Ethics ===

Despite the promising outcomes of the two techniques, pronuclear transfer and spindle transfer, mitochondrial gene replacement raises ethical and social concerns.<ref>{{cite journal|last1=Baylis|first1=F|title=The ethics of creating children with three genetic parents.|journal=Reproductive Biomedicine Online|date=June 2013|volume=26|issue=6|pages=531–4|doi=10.1016/j.rbmo.2013.03.006|pmid=23608245|doi-access=free}}</ref>

Mitochondrial donation involves modification of the germline, and hence such modifications would be passed on to subsequent generations.<ref name="Darnovsky">{{cite journal | author = Darnovsky M | year = 2013 | title = A slippery slope to human germline modification | journal = Nature | volume = 499 | issue = 7457| page = 127 |pmid=23846625| doi=10.1038/499127a| bibcode = 2013Natur.499..127D | doi-access = free }}</ref> Using human embryos for in vitro research is also controversial, as embryos are created specifically for research and egg donors are induced to undergo the procedure by financial compensation.<ref>{{cite journal |author1=Amato P. |author2=Tachibana M. |author3=Sparman M. |author4=Mitalipov S. | year = 2014 | title = Three-parent in vitro fertilization: Gene replacement for the prevention of inherited mitochondrial diseases | journal = Fertility and Sterility | volume = 101 | issue = 1| pages = 31–35 | doi=10.1016/j.fertnstert.2013.11.030 | pmid=24382342 | pmc=4005382}}</ref>

Mitochondrial donation also has the potential for psychological and emotional impacts on an offspring through an effect on the person's sense of identity. Ethicists question whether the genetic make-up of children born as a result of mitochondrial replacement might affect their emotional well-being when they become aware that they are different from other healthy children conceived from two parents.<ref name=CGS>{{cite web|title=CGS : 3-Person IVF: A Resource Page|url=http://www.geneticsandsociety.org/article.php?id=6527#1a|publisher=Center for Genetics and Society|access-date=20 December 2016|date=December 19, 2016}}</ref>

Opponents argue that scientists are "playing God" and that children with three genetic parents may suffer both psychological and physical damage.<ref>{{cite journal |author=Check E |title=Gene study raises fears for three-parent babies |journal=Nature |volume=438 |issue=7064 |pages=12 |date=November 2005 |pmid=16267521 |doi=10.1038/438012a|bibcode=2005Natur.438...12C |doi-access=free }}</ref>

On the other hand, New York University researcher James Grifo, a critic of the American ban, has argued that society "would never have made the advances in treating infertility that we have if these bans had been imposed 10 years" earlier.<ref>{{Cite news|title=Ban on scientists trying to create three-parent baby|last=Maxine|first=Frith|date=2003-10-14|work=The Independent|location=UK}}</ref>

On February 3, 2016, the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine issued a report, commissioned by the U.S. Food and Drug Administration, addressing whether it is ethically permissible for clinical research into mitochondrial replacement techniques (MRT) to continue. The report, titled ''Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations'', analyzes multiple facets of the arguments surrounding MRT and concludes that it is 'ethically permissible' to continue clinical investigations of MRT, so long as certain conditions are met. It recommended that initially the technique should only be used for male embryos to ensure that DNA with potential mitochondrial disease would not be passed on.<ref name=NAS2016ethics/>

In 2018 Carl Zimmer compared the reaction to He Jiankui's human gene editing experiment to the debate over MRT.<ref name="NYT-20181201">{{cite news |last=Zimmer |first=Carl |author-link=Carl Zimmer |title=Genetically Modified People Are Walking Among Us - And, so far, they're just fine. America needs a sober debate about the pros and cons of Crispr instead of a paranoid ban on the technology. |url=https://www.nytimes.com/2018/12/01/sunday-review/crispr-china-babies-gene-editing.html |date=1 December 2018 |work=The New York Times |access-date=2 December 2018 }}</ref>

==See also== * Microchimerism ==References== {{Reflist|33em}}

{{Assisted reproductive technology}} {{parenting}} {{Family}}

Category:Assisted reproductive technology Category:Obstetrics Category:Human pregnancy Category:Human reproduction Category:Human genetics Category:Molecular biology Category:Mitochondrial diseases Category:Gene therapy Category:Transhumanism Category:1996 introductions