Mitochondrial donation

Mitochondrial donation (sometimes called mitochondrial manipulation technology or MMT) is a special form of in vitro fertilisation in which the future baby's mitochondrial DNA comes from a third party.[1][2][3] This technique is used in cases when mothers carry genetic mitochondrial diseases, and conventional in vitro fertilization techniques do not work. Mitochondrial diseases often involve energy production issues, and ultimately muscular issues down the road for people affected.[4]

The two most common techniques in mitochondrial donation are pronuclear transfer and maternal spindle transfer. What this implies is that a baby is being produced with the DNA of both parents, as well as some DNA from a healthy donor of mitochondrial contents. Due to the uncharted nature of producing a child with 3 sources of DNA, this subject is currently quite contentious in the field of bioethics, as is the case with many other gene therapies. Currently, mitochondrial donation techniques are legal in the United Kingdom.[5][6] In February 2016, a report was issued by the U.S. Food and Drug administration declaring that further research into mitochondrial donation is ethically permissible. There are many active debates on the matter, as of 2016.[7]

Background of mitochondrial disease

Genetic faults in the mitochondria cause Mitochondrial disease and affect parts of children's bodies that use a lot of energy causing problems such as loss of muscle coordination, heart disease, liver disease, neurological problems, diabetes mellitus and deafness and dementia. About 1 out of every 1,000 children in the United States are born with disease and most die from it before reaching adulthood.[8]

History of mitochondral donation

In the United States in 1996 embryologist Jacques Cohen and others at the The Institute for Reproductive Medicine and Science, Saint Barnabas Medical Center in Livingston, New Jersey discovered an early technique called cytoplasmic transfer in which the cytoplasm of an egg from a healthy donor were injected into the egg of the mother who had undergone unsuccessful attempts of in vitro fertilisation and had genetic disorders of the mitochondria.[9] The resulting egg was then fertilized with sperm and placed in the womb of the mother.[10] In 2015, cytoplasmic transfer was not regarded as mitochondrial donation, the latter term being used for procedures where all of the mother's faulty cytoplasm was changed.[11]

In 1997 the first successful baby was born using this procedure (Emma Ott). in In 2001 Cohen and others reported that 10 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.[12] twins in Naples, Italy[13] and a twins in India.[14] In total, 30-50 children worldwide have been reported to have been born using cytoplasmic transfer.[8]

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.[8] The FDA informed clinics that they considered that the cytoplasmic transfer technique was a new treatment that 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[15] and the cytoplasmic transfer procedure fell out of favour.[16] A limited follow up took place in 2016 with 12 (out of the 13) parents of children born using cytoplasmic transfer at the Saint Barnabas Center replying to an on-line questionnaire. No major problems were reported on the children whose ages then were 13-18.[17]

In the United Kingdom, following animal experiments and the recommendations of a government commissioned expert committee,[18] the Human Fertilisation and Embryology (Research Purposes) Regulations were passed in 2001 regulating and allowing research into human embryos. In 2004, the Newcastle University applied for a licence to develop pronuclear transfer to avoid the transmission of mitochondrial diseases which was granted in 2005. Following further research by Newcastle and the Wellcome Foundation,[19] [20] scientific review,[21] public consultations and debate, the UK government passed the Human Fertilisation and Embryology (Mitochondrial Donation) Regulations in February 2015, and which came into force on 29 October 2015 making human mitochondrial donation legal in the UK. The Human Fertilisation and Embryology Authority was authorised to licence and regulate medical centres which wanted to use human mitochondrial donation.[22][23] Professor Douglass Turnbull, the driving force behind mitochondrial research at Newcastle University, was awarded a knighthood in 2016.[24][25]

In 2016, John Zhang and his team at New Hope Fertility Center in New York, USA, used the spindle transfer mitochondrial donation technique to help a Jordanian woman to give birth to a baby boy in Mexico where there was no law against using such a technique. The mother had Leigh disease and already had four miscarriages and two children who had died of the disease.[26] Ukrainian doctors also reported that they had used the pronuclear transfer method of mitichondrial donation to help two previously infertile women become pregnant. The doctors first got approval from an ethical review board of the Ukrainian Association of Reproductive Medicine but there was no law in the Ukraine against mitochondrial donation. [27]

Case of Emma Ott

Maureen Ott, a mechanical engineer living in Pittsburgh, Pennsylvania was the first mother to become pregnant using the cytoplasmic transfer procedure in August 1996. She had tried unsuccessfully for almost seven years to become pregnant using in vitro fertilisation. In May 1997, she gave birth to a baby girl Emma Ott. In 2014, Emma, then 17, was reported to playing varsity sports, getting A marks for her studies and to be treasurer of her senior class at school.[28] Tests on Emma have shown she only has the DNA from her mother and father and no DNA from her third donor.[28]

Case of Alana Saarinen

Alana Saarinen (born 2000) is a girl from West Bloomfield, Michigan, US conceived through cytoplasmic transfer and the daughter of Sharon and Paul Saarinen, and a third donor.[8]

Before Saarinen's birth, her parents had gone through four attempts to have a baby through numerous IVF procedures without success. The fifth attempt using cytoplasmic transfer succeeded when her mother was 36. The treatment involved the transfer of a third donor's cytoplasm, containing healthy mitochondria, to Sharon Saarinen's egg with unhealthy mitochondria. The egg was then fertilized with Paul Saarinen's sperm. During the process of transferring DNA, some DNA from the donor was in the embryo. Ninety-nine percent of Saarinen's genetic material is from her parents, and one percent is from the third donor.[29]

According to her mother, Saarinen is healthy and has a normal life as a teenager such as playing golf and the piano, listening to music and hanging out with friends.[30]

Availability

As of February 2016 in the US there were no regulations governing mitochondrial donation in the US, and Congress had barred the FDA from evaluating any applications that involve implanting modified embryos into a woman.[31] China prohibited it after a woman tried to undergo the procedure.[32][33] Some research is also taking place in the United States.

The United Kingdom[4] became the first country to legalize the procedure (for women whose eggs have mitochondrial abnormalities) after the Parliament and House of Lords approved The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations[34] in February 2015. This act came into force in October 2015.[34][35][36][37]

Technique

In 2016, there were several processes that could be used for mitochondrial transfer.[11][32] One, called maternal spindle transfer involved taking the nucleus (or spindle of chromosomes) out of the mother's egg and discarding the rest of the mother's egg with the unhealthy mitochondrial DNA (mtDNA). The nucleus of an egg from a donor female was removed leaving an egg with healthy mtDNA. The nucleus of the mother was then inserted into the second egg and fertilized with the sperm of the father. The egg was then placed in the womb of the mother.[38]

A second method, called pronuclear transfer, started with the mother's egg which was fertilized with the father's sperm. The nucleus from a female donor's egg was fertilized, extracted and discarded. The fertilized nucleus from the mother was extracted from her egg and the rest of the mother's egg with the unhealthy mtDNA discarded. The fertilised nucleus was transferred to the donor egg with the healthy mtDNA and the egg placed in the mother's womb.[19][20][39]

Nuclear genome transfer was similar to maternal spindle transfer but the eggs were not initially fertilized and were then activated using parthenogenesis. This was a newer procedure but held promise of better success rates.[40]

Polar body genome transfer involved the transfer of polar body genomes from the nucleus and was at a very early stage of development.[41]

Cytoplasmic transfer used by Cohen and others in 1996-2001 was not regarded as mitochondrial transfer in 2015.[11]

Although the donor egg is said to contribute only 1% to the genetic make up of the child, when examining the genetic material of these children there are still three identifiable genetic parents.[42] This is due to the fact that the donor egg usually comes from a non-maternal relative. For a child having undergone this procedure to have only two identifiable genetic parents, the donor egg must have come from a maternal relative (this is because mitochondrial DNA mtDNA is inherited maternally; thus maternal relatives will have identical mitochondrial DNA, barring random mutations). Maternal relative egg donation is not commonly used, because if the female egg has a mitochondrial disease then it is highly likely that the maternal relatives inherited the disease as well.

Ethics

Despite the promising outcomes of the two techniques, pronuclear transfer and spindle transfer, mitochondrial gene replacement raises ethical and social concerns.

Mitochondrial donation involves modification of the germline, and hence such modifications would be passed on to subsequent generations.[43] This could also lead down a slippery slope towards genetically modified and designer babies, whereby certain traits are "fixed" or "changed". Using human embryos in vitro research is also controversial, as embryos are created specifically for research and the financial compensation of egg donors.[44]

Implications for identity is another ethical concern that has psychological and emotional impacts on a child's life regarding of a person's sense of identity. It debates whether the genetic make-up of children born as a result of mitochondrial replacement affect their emotional well-being when they are aware that they are different from other healthy children conceived from two parents.[45] Safety and efficacy of mitochondrial DNA replacement are still unanswered[46] (although mice from mitochondrial DNA replacement lived 20% longer than control mice in one experiment[47]).

Opponents argue that scientists are "playing God" and that children with three genetic parents may suffer both psychological and physical damage.[48] These critics include Alison Cook of Great Britain's Human Fertilisation and Embryology Authority, who argues that bans were "written to protect the welfare of the embryo and the child."[32]

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.[32]

On February 3, 2016, a report was issued by the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine (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 is 'ethically permissible' to continue clinical investigations of MRT, so long as certain conditions are met.[7] They recommended that initially it should only be used for male embryos giving rise to newspaper headlines like "no girls allowed."[49] The purpose of using solely male embryos in clinical trials is to ensure that DNA with mitochondrial disease won't be passed on. [50]

References

  1. ↑ Keim, Brandon, Three-Parent Children: Reality or Technicality?, Feb 5, 2008.
  2. ↑ Alleyne, Richard.'Three parent babies' take a step closer to reality, The Telegraph, Nov. 12, 2009.
  3. ↑ Randerson, James. Scientists seek to create 'three-parent' babies The New Scientist Oct. 19. 2004
  4. 1 2 Three-Parent IVF Set to Go Ahead in Britain, Discover Magazine, June 28, 2013
  5. ↑ "UK approves three-person babies". BBC News. BBC. 24 February 2015. Retrieved 24 February 2015.
  6. ↑ "Britain votes to allow world's first 'three-parent' IVF babies". Reuters. 3 February 2015. Retrieved 3 February 2015.
  7. 1 2 "Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations - Institute of Medicine". iom.nationalacademies.org. Retrieved 2016-02-27.
  8. 1 2 3 4 Kula, Shane (18 February 2016). "Three-Parent Children Are Already Here". Retrieved 2 March 2016.
  9. ↑ Potter, DFDaniel; et al. (11 May 2005). What to Do When You Can't Get Pregnant. Da Capo Press. p. 228. ISBN 9781569243718.
  10. ↑ Kim Tingley for the New York Times. June 27, 2014 The Brave New World of Three-Parent I.V.F.
  11. 1 2 3 "3 Person IVF". Centre for Genetics and Society. 9 March 2015. Retrieved 2 March 2016.
  12. ↑ Cohen, Jacques; et al. (6 April 2001). "Cytoplasmic transfer in assisted reproduction". Human Reproduction Update. 7 (4): 428–435. doi:10.1093/humupd/7.4.428.
  13. ↑ Dale, Brian; Wilding, Martin; Botta, Giuseppe; Rasile, Marianna; Marino, Marcella; Matteo, Loredana Di; Placido, Giuseppe De; Izzo, Alfredo (2001-07-01). "Pregnancy after cytoplasmic transfer in a couple suffering from idiopathic infertility Case report". Human Reproduction. 16 (7): 1469–1472. doi:10.1093/humrep/16.7.1469. ISSN 0268-1161.
  14. ↑ "Woman conceives through cytoplasmic transfer technology". News. Web India 123. 2011-11-21. Retrieved 2016-10-27.
  15. ↑ Connor, Steve (25 August 2015). "Three-parent babies: 'As long as she's healthy, I don't care', says mother of IVF child". The Independent. Retrieved 2 March 2016.
  16. ↑ Hamzelou, Jessica (2016-09-28). "Everything you wanted to know about '3-parent' babies". The New Scientist. Retrieved 2016-10-01.
  17. ↑ Chen, Serena H.; Pascale, Claudia; Jackson, Maria; Szvetecz, Mary Ann; Cohen, Jacques. "A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre". Reproductive BioMedicine Online. doi:10.1016/j.rbmo.2016.10.003.
  18. ↑ Donaldson, Liam (16 August 2000). "Stem cell research: medical progress with responsibility" (PDF). UK National Archives. UK Department of Health. Retrieved 24 March 2016.
  19. 1 2 Boseley, Sarah (2010-04-14). "Scientists reveal gene-swapping technique to thwart inherited diseases". London: Guardian.
  20. 1 2 Craven, Lyndsey; Tuppen, Helen A.; Greggains, Gareth D.; Harbottle, Stephen J.; Murphy, Julie L.; Cree, Lynsey M.; Murdoch, Alison P.; Chinnery, Patrick F.; Taylor, Robert W.; Lightowlers, Robert N.; Herbert, Mary; Turnbull, Douglass M. (2010). "Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease". Nature. 465 (7294): 82–85. doi:10.1038/nature08958. PMC 2875160Freely accessible. PMID 20393463.
  21. ↑ Greenfield, Andy, ed. (June 2014). Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2014 update (PDF). UK: Human Fertilisation and Embryology Authority. Retrieved 2 March 2016.
  22. ↑ Craven, Lindsay; et al. (29 September 2015). "Research into Policy: A Brief History of Mitochondrial Donation". Stem Cells. 34 (2): 265–267. doi:10.1002/stem.2221.
  23. ↑ Walsh, Fergus (2016-06-08). "Three-person babies IVF technique 'safe'". BBC News. Retrieved 2016-10-12.
  24. ↑ The London Gazette: (Supplement) no. 61608. p. B2. 2016-06-11.
  25. ↑ "Birthday honours: Mitochondrial disease doctor recognised". BBC News. 2016-06-10. Retrieved 2016-06-10.
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  27. ↑ Reardon, Sara. "Reports of 'three-parent babies' multiply". Nature. doi:10.1038/nature.2016.20849.
  28. 1 2 Tingley, Kim (27 June 2014). "The Brave New World of Three-Parent I.V.F". The New York Times. Retrieved 2 March 2016.
  29. ↑ "CNN.com - How far will couples go to conceive? - Mar 12, 2004".
  30. ↑ "BBC News - The girl with three biological parents". BBC News.
  31. ↑ Oswald, Kirtsy (8 February 2016). "Panel recommends FDA approval of mitochondrial donation". Bio News. Retrieved 11 February 2016.
  32. 1 2 3 4 Frith, Maxine. Ban on scientists trying to create three-parent baby, The Independent, October 14, 2003
  33. ↑ "Now, a three-parent baby". Rediff. 14 October 2003.
  34. 1 2 The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 No. 572
  35. ↑ Knapton, Sarah (25 February 2015) "Three-Parent babies by next year after Lords change the law", The Daily Telegraph, Page 2; A similar article is available on Internet at , Retrieved 27 February 2015
  36. ↑ Gallagher, James (3 February 2015) MPs say yes to three-person babies BBC News health, Retrieved 3 February 2015
  37. ↑ Howe, Katie (2 November 2015). "UK mitochondrial donation regulations introduced". Bio News. Retrieved 11 February 2016.
  38. ↑ Naik, Gautam (27 November 2012). "DNA Switch Shows Promise Against Genetic Disease". Wall Street Journal. Retrieved 2 March 2016.
  39. ↑ "Background: Maternal spindle transfer". Retrieved 22 April 2014.
  40. ↑ Paull, Daniel; et al. (31 January 2013). "Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants" (PDF). Nature. 493: 632–637. doi:10.1038/nature11800. Retrieved 2 March 2016.
  41. ↑ Wang, T.; et al. (19 June 2014). "Polar body genome transfer for preventing the transmission of inherited mitochondrial disea ses.". Cell. 157 (7): 1591. doi:10.1016/j.cell.2014.04.042. PMID 24949971.
  42. ↑ Françoise Baylis (2013) The ethics of creating children with three genetic parents, Reproductive BioMedicine Online, 26(6): 531-534
  43. ↑ Darnovsky, M. (2013). A slippery slope to human germline modification. Nature, 499(7457), 127
  44. ↑ Amato, P., Tachibana, M., Sparman, M., & Mitalipov, S. (2014). Three-parent in vitro fertilization: Gene replacement for the prevention of inherited mitochondrial diseases. Fertility and Sterility, 101(1), 31-35.
  45. ↑ "CGS : 3-Person IVF".
  46. ↑ http://ac.els-cdn.com/S1043276013001550/1-s2.0-S1043276013001550-main.pdf?_tid=057e4a48-5ae5-11e4-a0e4-00000aab0f6b&acdnat=1414090221_f91d28a4c4ca11ede355aca9305a4797
  47. ↑ "Three's company". The Economist. 420 (8997). London, UK. 2016-07-09. pp. 68–69. ISSN 0013-0613. Retrieved 2016-07-08.
  48. ↑ Check E (November 2005). "Gene study raises fears for three-parent babies". Nature. 438 (7064): 12. doi:10.1038/438012a. PMID 16267521.
  49. ↑ "US experts approve creation of three-parent boys – but no girls allowed". RT. 5 February 2016. Retrieved 1 March 2016.
  50. ↑ "http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2016/Mitochondrial%20Replacement%20Techniques/mito%20ethics%20infographic_FINAL.pdf" (PDF). National Academics. Retrieved 11 October 2016. External link in |title= (help)

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