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    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.

    Recommended: Using time-lapse photography with ART

    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.

    Adam S Levine, MD, JD
    Dr Levine is Adjunct Professor of Law, Stetson University College of Law, Gulfport, Florida, and Adjunct Professor of Law, Western ...

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