Mitochondrial Replacement Therapy (MRT) is a specialized form of in vitro fertilization (IVF) designed to prevent the inheritance of severe mitochondrial diseases from a mother to her child. The procedure replaces a mother’s defective mitochondria with healthy mitochondria from a donor egg. Mitochondria function as the powerhouses within nearly every cell, generating the necessary energy for the body. Unlike the majority of genetic material stored in the cell’s nucleus, mitochondria possess a small, separate genome called mitochondrial DNA (mtDNA). The goal of MRT is to ensure the resulting embryo inherits the parents’ nuclear DNA while receiving healthy mtDNA from a third-party donor.
Why Mitochondrial Replacement Therapy Is Necessary
Mitochondrial diseases arise from mutations in the mitochondrial DNA, causing cellular powerhouses to fail and leading to an energy production crisis. Organs with high energy demands, such as the brain, heart, eyes, and muscles, are disproportionately affected by this dysfunction. The resulting conditions are often devastating, causing multi-system failure, severe neurological disorders, and a significantly shortened lifespan.
Mitochondrial genetics are unique because mtDNA is passed down exclusively from the mother’s egg cell. This maternal-only transmission means a woman carrying pathogenic mtDNA mutations risks passing the disease to all her children. Traditional genetic screening is often ineffective because a mother’s egg may contain a mixture of healthy and mutated mitochondria, making disease severity difficult to predict. MRT offers a direct intervention to break this cycle of maternal inheritance.
The Mechanics of Mitochondrial Replacement Therapy
MRT is accomplished using highly precise micromanipulation techniques in an IVF setting. It primarily uses two distinct methods: Maternal Spindle Transfer (MST) and Pronuclear Transfer (PNT). Both approaches combine the nuclear DNA of the intended parents with the healthy mitochondria of a donor. The procedure requires eggs from the intended mother, a healthy donor, and sperm from the intended father.
Maternal Spindle Transfer (MST)
MST is performed before fertilization of the egg. The first step involves removing the spindle-chromosome complex, which contains the mother’s nuclear DNA, from her unfertilized egg. Simultaneously, the nucleus is removed from the donor’s egg, leaving behind its healthy cytoplasm and mitochondria. The mother’s nuclear DNA is then transferred into the enucleated donor egg. This reconstructed egg is then fertilized with the father’s sperm.
Pronuclear Transfer (PNT)
PNT is performed after the eggs have been fertilized. The intended parents’ egg is fertilized with the father’s sperm, creating a zygote with two pronuclei. A donor egg is also fertilized with the father’s sperm. The pronuclei are removed from the parents’ fertilized egg and transferred into the donor’s fertilized egg after its own pronuclei have been removed. In both MST and PNT, the resulting embryo has nuclear DNA from the two parents and mitochondrial DNA from the donor, leading to the term “three-person baby.”
Ethical and Regulatory Status
The development of MRT has sparked significant global discussion due to its unique ethical implications. A primary concern is that MRT involves germline modification, meaning the genetic change is heritable and passed on to all subsequent generations. This permanent change to the human genome raises questions about unforeseen long-term effects on the child and their descendants.
The resulting child has genetic material from three individuals: nuclear DNA from the two parents and mtDNA from the donor. This combination challenges traditional notions of genetic parenthood. Regulatory responses vary dramatically across the world.
The United Kingdom became the first country to legally authorize MRT in 2015, following extensive public consultation and scientific review. The technique is permitted under strict license and regulatory oversight by the Human Fertilisation and Embryology Authority (HFEA) for women at high risk of transmitting severe mitochondrial disease.
Conversely, the use of MRT in the United States remains effectively prohibited in a clinical setting. A rider attached to the 2016 Congressional Appropriations Act prevents the Food and Drug Administration (FDA) from reviewing any application for clinical trials that would result in a heritable genetic modification of a human embryo. This regulatory barrier has halted all federally funded research and clinical application of MRT in the US.