The biological basis for defining bi-parental or tri-parental origin of offspring from cytoplasmic and spindle transfer

doi:10.1016/j.rbmo.2013.03.008

Reproductive BioMedicine Online

Volume 26, Issue 6, June 2013, Pages 535-537

https://doi.org/10.1016/j.rbmo.2013.03.008 Get rights and content

Abstract

The bi-parental genetic state is not a given after assisted reproduction. This is based on a biological definition of parentage that concerns generational inheritance of genetic material. Often three or more individuals may participate in artificial reproduction. Only cytoplasmic and spindle transfer can result in the genetic tri-parental state. All other forms involving three or more assisting persons with no heritable genetic contribution must be considered differently. Can a cytoplasmic donor be a biological parent based on a potential contribution of mitochondrial DNA to the offspring? – only if the mitochondrial DNA sequence can be traced back to the donor, a phenomenon which may not be very common. When considering spindle transfer for avoiding transmission of mitochondrial disease, all offspring is likely to be tri-parental.

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In 2015, the United Kingdom became the first country to legalize novel reproductive technologies known as mitochondrial donation or mitochondrial replacement therapy, enabling women with mitochondrial disease to have healthy, genetically related children. This chapter explores the situation in the UK and the review process that preceded legalization amid global concerns about human genetic modification. As the technique uses part of a donated egg to replace disease causing faulty mitochondria, the child (and future generations) would inherit DNA from a “third person”—the mitochondrial donor. The chapter explores the process of legalization in the UK and the social and ethical issues raised, including whether the donor is a “parent” and the implications for identity, genetic modification, and the “slippery slope,” and the potential risks for the donor. The chapter concludes by explaining why mitochondrial disease presents challenges for genetic counseling and considers alternatives to mitochondrial donation and future technologies.
Ethics of mitochondrial gene replacement therapy
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In 2015, the United Kingdom became the first country to legalize novel reproductive technologies known as mitochondrial donation or mitochondrial replacement therapy, enabling women with mitochondrial disease to have healthy, genetically related children. This chapter explores the situation in the United Kingdom and the extensive review process that preceded legalization amid global concerns about human genetic modification. As the technique uses part of a donated egg to replace disease causing faulty mitochondria, the child would inherit DNA from a “third person”—the mitochondrial donor—whose genes could be inherited by a future generation. The chapter considers ethical issues: whether the donor is a “parent” and the implications for identity, genetic modification, and the “slippery slope,” the potential risks for the donor, and differences between the two techniques: maternal spindle transfer and pronuclear transfer. The chapter concludes by explaining why mitochondrial disease presents challenges for genetic counseling and considers alternatives to mitochondrial donation.
Setting the record straight
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A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre
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Citation Excerpt :
Mitochondrial DNA, unlike nuclear DNA, does not determine phenotypic characteristics like eye colour, skin colour or height. As a third person (the egg donor), however, was involved in the assisted reproduction process, the popular press referred to these children as ‘three parent babies’, a provocative but inaccurate reference (Cohen and Alikani, 2013). The publication of the finding that two of the eight tested children retained some mtDNA from the egg donors generated further controversy and concern in the scientific community.
Experimental ooplasmic transplantation from donor to recipient oocyte took place between 1996 and 2001 at Saint Barnabas Medical Center, USA. Indication for 33 patients was repeated implantation failure. Thirteen couples had 17 babies. One patient delivered twins from mixed ooplasmic and donor egg embryos. A limited survey-based follow-up study on the children is reported: 12 out of 13 parents completed a questionnaire on pregnancy, birth, health, academic performance and disclosure. Parents of a quadruplet did not participate. Prenatal development and delivery were uneventful. School grades ranged from good to excellent. Children were of good health. Body mass index (BMI) was normal in 12 out of 13 children. One child had chronic migraine headaches, two mild asthma, three minor vision and three minor skin problems. One boy from a boy/girl twin was diagnosed with borderline pervasive developmental disorder – not otherwise specified at age 18 months, but with no later symptoms. One couple disclosed the use of egg donor to their child. One reported intention to disclose; six were undecided and four reported they would not disclose. This limited follow-up strategy presents a high risk of bias. Parents may not assent to standardized clinical analysis owing to lack of disclosure to their children.
Cytoplasmic, rather than nuclear-DNA, insufficiencies as the major cause of poor competence of vitrified oocytes
2015, Reproductive BioMedicine Online
Citation Excerpt :
This is compatible with the crucial role of mammalian ooplasm to support fertilization and early embryonic development (Sirard, 2012). Recently, karyoplast exchange has been investigated as a salvage tool to overcome oocytes insufficiencies often resulting from ageing or inheritable mitochondrial problems (Cohen and Alikani, 2013). Given the indispensable crucial importance of oocyte cryopreservation in current and future repertories of assisted reproductive techniques, karyoplast transplantation may also have far-reaching clinical applications to rescue cytoplasmic insufficiencies of vitrified oocytes.
To unravel the differential contributions of nuclear-DNA and cytoplasm to the poor ‘competence’ of oocytes after cryopreservation, reciprocal exchange of metaphase II-spindle chromosomal complex (karyoplast) between vitrified and fresh oocytes was carried out in an ovine animal model. Karyoplast exchange per se was accomplished with high efficiency and in-vitro development of oocytes reconstituted with fresh-karyoplast and vitrified-cytoplast (FK/VC) showed no improvement over VK/VC and control-vitrification oocytes. Blastocyst development of oocytes that were reconstituted with vitrified-karyoplast and fresh-cytoplast (VK/FC) approached that of fresh-controls, however, and was significantly higher than FK/VC, VK/VC, and control-vitrification (all P ≤ 0.05). These results point toward ‘cytoplasmic insufficiencies’ as the main cause of poor ‘competence’ of matured oocytes after vitrification.
Potential impact of human mitochondrial replacement on global policy regarding germline gene modification
2014, Reproductive BioMedicine Online
Previous discussions regarding human germline gene modification led to a global consensus that no germline should undergo genetic modification. However, the UK Human Fertilisation and Embryology Authority, having conducted at the UK Government’s request a scientific review and a wide public consultation, provided advice to the Government on the pros and cons of Parliament’s lifting a ban on altering mitochondrial DNA content of human oocytes and embryos, so as to permit the prevention of maternal transmission of mitochondrial diseases. In this commentary, relevant ethical and biomedical issues are examined and requirements for proceeding with this novel procedure are suggested. Additionally, potentially significant impacts of the UK legalization on global policy concerning germline gene modification are discussed in the context of recent advances in genome-editing technology. It is concluded that international harmonization is needed, as well as further ethical and practical consideration, prior to the legalization of human mitochondrial replacement.

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CommentaryThe biological basis for defining bi-parental or tri-parental origin of offspring from cytoplasmic and spindle transfer

Abstract

Reprod. Biomed. Online

Reprod. Biomed. Online

Reprod. Biomed. Online

Neutral mitochondrial heteroplasmy alters physiological function in mice

Biol. Reprod.

Sequence and organization of the human mitochondrial genome

Nature

Mitochondrial DNA rearrangements in human oocytes and embryos

Mol. Hum. Reprod.

Mitochondria in human offspring derived from ooplasmic transplantation

Hum. Reprod.

Commentary
The biological basis for defining bi-parental or tri-parental origin of offspring from cytoplasmic and spindle transfer