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Three-parent baby, human offspring produced from the genetic material of one man and two women through the use of assisted reproductive technologies, specifically mitochondrial manipulation (or replacement) technologies and three-person in vitro fertilization (IVF). In general, the reproductive technologies used to produce three-parent babies focus on replacing or otherwise reducing the effects of mutations that occur in the DNA of cellular organelles known as mitochondria, which reside in the cell cytoplasm. The various approaches could help women to overcome infertility and could prevent the transmission to their offspring of potentially debilitating mitochondrial diseases. The first three-parent babies were born in the 1990s and early 2000s, the products of a then-novel IVF-based technique known as ooplasmic transfer (cytoplasmic transfer). The success of the technique was seen as miraculous, but its use was controversial. It prompted scientists to develop improved techniques and caused regulatory agencies to restrict the use of three-parent IVF. Much was unknown about the safety of various three-parent IVF techniques, and their use to generate human babies raised ethical and social concerns, among them the possible impacts on health and heredity. Mitochondrial manipulation technologies Ooplasmic transfer entails the injection of a small amount of cytoplasm from an egg cell (ovum) donated by a healthy woman into the mother’s egg, which is then fertilized by the father’s sperm and implanted into the mother’s uterus using IVF. Because ooplasmic transfer involves the mixing of cytoplasm from maternal and donor eggs—the health and hereditary risks of which could be significant—interest in its potential use to overcome infertility or mitochondrial disease has declined. Furthermore, other techniques have supplanted ooplasmic transfer, the two most significant of which are maternal spindle transfer and pronuclear transfer. In maternal spindle transfer, the nucleus is removed from a donor egg, leaving behind the cytoplasm. The nucleus from the mother’s egg cell is then inserted into the donor egg. The egg is fertilized with the father’s sperm and then transferred to the mother’s uterus for normal gestation, similar to other IVF procedures. In pronuclear transfer, the mother’s egg is first fertilized with the father’s sperm, producing a zygote. The pronuclei of the egg and sperm are then removed from the zygote and inserted into a donor egg that has been fertilized and has had its own nucleus removed (a pronucleus is the nucleus of the egg or sperm at the stage of fertilization prior to nucleus fusion). The zygote derived from the donor egg is then implanted into the mother’s uterus. The biological basis of mitochondrial manipulation Normally, a zygote possesses a nucleus that houses a genome comprising nuclear DNA from both the father and the mother and mitochondria that house a distinct genome, which is solely composed of mitochondrial DNA (mtDNA) from the mother (paternal mitochondria in the sperm are destroyed by the egg). Maternally inherited mtDNA accounts for only a very small percentage of the total DNA in cells (less than 1 percent in mammals, by most estimates), yet the ability of an egg to be fertilized successfully is thought to be associated with the health of a woman’s mitochondria and in particular her mtDNA. Correlations have been identified, for example, between reduced mtDNA quantity and infertility, as well as between mtDNA mutations and fertilization rates. Mutations in mtDNA are a cause of mitochondrial disease, a heterogeneous group of diseases that can lead to premature death, sometimes in infancy or childhood. Most mitochondrial diseases lack specific treatments, and women who carry the causative mutations are at high risk of transmitting the diseases to their offspring. Risk of transmission is greatest for women with high heteroplasmy—women whose total mtDNA content in affected cells or tissues is made up of between 60 and 90 percent mutated mtDNA, the threshold at which mitochondrial disease becomes apparent clinically. However, even women with low heteroplasmy and who are therefore asymptomatic are at risk of passing on mitochondrial disease to their offspring. In such women, heteroplasmy levels can be increased by phenomena such as selective replication of mtDNA and mitochondrial bottleneck, in which only a select number of mtDNA molecules are transferred to eggs at the time of egg maturation. Both maternal spindle transfer and pronuclear transfer attempt to minimize heteroplasmy by replacing the mother’s mitochondria with healthy donor mitochondria. Ooplasmic transfer, on the other hand, may contribute to heteroplasmy, thereby possibly diluting the effects of mutations in maternal mtDNA and enabling embryo survival. The precise mechanisms by which any of the three techniques could potentially treat infertility or prevent inherited mitochondrial disease are not fully known. #3
