Reproductive technologies and the new math: When it takes three parents to make an embryo

Almost 37 years after Steptoe and Edwards made history by announcing the birth of the world’s first “test tube baby,” Louise Brown,¹ reproductive technology in the United Kingdom again took center stage when members of Parliament voted to allow for the creation of babies from 3 distinct genetic sources.² Similar to children born without assisted reproductive technologies (ART), through Mendelian genetics Louise Brown inherited half her father’s nuclear DNA, half her mother’s nuclear DNA, and likely all of her mother’s mitochondrial DNA (mtDNA).

And until these new reproductive technologies were developed, the prevention of genetic disorders relied upon the post-fertilization, pre-implantation genetic diagnosis (PGD) of ART derived embryos and the selective transfer, or cryopreservation, of embryos without markers for genetic disorders. However, because embryos likely inherit only oocyte-derived mtDNA,³ PGD’s utility was limited primarily to the prevention of nuclear derived DNA genetic disorders.

But it is now becoming known that mtDNA defects are responsible for a wide variety of inherited disorders⁴ that affect virtually all organ and bodily systems.³ And recent data suggest a significant role for mtDNA-inherited disorders in many widespread, multi-factorial disorders such as diabetes.⁵ Although the epidemiology of mtDNA remains unsettled, it appears that the prevalence of mtDNA disease is at least 1 in 5000.⁵ As a result, evolving reproductive technologies were developed to allow for the substitution of an oocyte’s mtDNA. Reproductive technologies such as maternal spindle transfer (MST) and pronuclear transfer (PNT) allow for the creation of an embryo with nuclear DNA arising from two distinct gametes and mtDNA from a source other than the maternal nuclear DNA donor.

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MST occurs before fertilization when the spindle is physically removed from a donor oocyte and replaced with a spindle from an oocyte at risk of passing on an mtDNA disorder. The spindle contains the maternal nuclear DNA that will ultimately join with the paternal nuclear DNA from the sperm after fertilization. After fertilization, the resulting embryo will contain the nuclear DNA from both gametes and a third person’s mtDNA.

PNT occurs after fertilization when both the oocyte donor and the oocyte at risk of an mtDNA disorder are fertilized and the donor’s pronucleus is replaced by the at risk donor’s pronucleus. The resulting embryo will contain the nuclear DNA from both gametes and a third person’s mtDNA. Importantly, although it may sound similar, PNT actually differs from cloning because the nuclear DNA in PNT is derived from two distinct gametes while the nuclear DNA for cloning arises from a single, mature somatic cell.

Thus, in both MST and PNT, using mtDNA from a healthy donor may prevent mtDNA disorders. Critical to understanding these new technologies is a basic knowledge of human genetics because the difference between nuclear DNA and mtDNA is vast. Nuclear DNA likely codes for between 20,000 and 25,000 genes⁶ while mtDNA only codes for 13 genes.⁷ Because mtDNA primarily functions within the energy processing functions of mitochondria, and because mtDNA only codes 13 genes, it is not likely that mtDNA would play a role in an individual’s identity or identifying characteristics.

NEXT: A look at the legal complexities.

Like ART, MST and PNT are controversial because in addition to potentially placing us on the proverbial ethical slippery slope to creating genetically modified children, these new technologies definitely add to the ever-enlarging number of parents a single child may have, including the genetic father who contributes half the nuclear DNA; the birth father who raises and claims the child as his own; the genetic nuclear DNA mother who contributes half the nuclear DNA; the genetic mtDNA mother who contributes all the mtDNA, the gestational carrier or birth mother who carries the pregnancy, allows it to come to term, and delivers the baby; and the mother who raises and claims the child as her own.

Regulation of ART in the United States differs significantly from that in the United Kingdom. Federal ART regulation in the United States is limited to the 1992 Fertility Clinic Success Rate and Certification Act⁸ that requires ART clinics to report their results to a central registry. And various disparate state regulations either ban human cloning for reproductive or research purposes, require insurance coverage of ART, or regulate or prohibit surrogacy agreements.⁸

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In contrast, in addition to prohibiting cloning, the United Kingdom regulates ART to a much greater extent than in the United States through the 1990 Human Embryology and Fertilization Act and the 1985 Surrogacy Arrangement Act.⁸ And it is important to note that neither MST nor PNT involve human cloning, because the nuclear DNA comes from gametes and not mature somatic cells. However, because our understanding of pathology related to mtDNA disorders continues to evolve, the true utility and role for MST and PNT in ART remain to be determined. Finally, although Parliament approved the use of MST and PNT, further approval by the House of Lords is required before the United Kingdom’s reproductive regulatory agency will consider permitting human trials of MST and/or PNT.

References

1.    British Broadcasting Company. On this Day 25 July 1978: First ‘test tube baby’ born. Available at: http://news.bbc.co.uk/onthisday/hi/dates/stories/july/25/newsid_2499000/2499411.stm. Accessed February 26, 2015.

2.    British Broadcasting Company. MPs say yes to three person babies. Available at http://www.bbc.com/news/health-31069173. Accessed February 26, 2015.

3.    Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005;6(5):389-402.

4.    Schapira AH. Mitochondrial disease. Lancet. 2006;368(9529):70-82.

5.    Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders--past, present and future. Biochim Biophys Acta. 2004;1659(2-3):115-20.

6.    Human Genome Project Information Archive. The science behind the Human Genome Project, understanding the basics. Available at: http://web.ornl.gov/sci/techresources/Human_Genome/project/info.shtml. Accessed February 26, 2015.

7.    Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981;290: 457-465.

8.    The Center for Bioethics and Human Dignity. G12 country regulations of assisted reproductive technologies. Available at https://cbhd.org/content/g12-country-regulations-assisted-reproductive-technologies. Accessed February 26, 2015.

Dr Levine is Adjunct Professor of Law at Stetson University College of Law in DeLand, Florida and Adjunct Professor of Law at Western Michigan University Cooley School of Law in Kalamazoo. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.