mitochondrial replacement therapy

In 2015, the United Kingdom became the first country to legalize a procedure called Mitochondrial Replacement Therapy (MRT), which was used to prevent inheritable health conditions involving the heart, brain, and muscles caused by mitochondrial mutations. This MRT procedure, sometimes called three-person in vitro fertilization (IVF), involves transferring genetic material from the nucleus of the egg or embryo with mitochondrial mutations to a different healthy donor egg with its genetic materials previously removed, allowing the child produced to have three parents.

Eight years later, the Human Fertilization and Embryology Authority (HFEA) of the United Kingdom confirmed that at least one UK child had been born using the procedure as of April 2023. Although this is the first successful case of a fully legalized MRT procedure, it has previously been done successfully unregulated as well. A US doctor used MRT successfully to prevent mitochondrial disease in a baby in Mexico in 2016. Another US doctor, John Zhang, and his team successfully performed IVF on an embryo at New Hope Fertility Center in New York City in 2016. Greece and Ukraine have also conducted MRT to treat infertility. Despite many successes and new countries such as Australia approving MRT in 2022, MRT remains restricted in most areas, including the United States. The extent of IVF’s effectiveness is still to be tested. When, inevitably, a small number of mitochondria are transferred into the donor egg or embryo, it’s unclear whether or not very low levels of mutation-bearing mitochondria cause health problems. Additionally, scientists estimate a 1 in 50 chance of a mismatch in mitochondrial DNA and nuclear DNA could result in mitochondria problems. In some cases, a phenomenon known as reversal, where the carried-over mitochondria can increase markedly over time, replacing donor mitochondria in cells and bringing back the mutation. From scientist Wells’ observation in Greece, of the 6 children born with MRT, 1 child experienced reversal, though the reversal seems to have had no effect on the child’s health. The reason for this phenomenon is not clear, but scientists hypothesize that, due to efficiency reasons, matching donor and recipient on their mitochondrial DNA or freezing the mother’s eggs before transferring the nuclear genetic material into fresh donor eggs could prevent reversal. The process of Mitochondrial Replacement Therapy (MRT) is related to our understanding of mitochondria. From what we’ve learned, mitochondria are passed down only by females and mothers, as a significant amount of mitochondrial DNA exists inside eggs from mothers, whereas no mitochondrial DNA exists in the sperm of males, and all mitochondria are lost during fertilization. This leaves the mitochondrial DNA of the embryo and child originating solely from the mother’s egg. This explains why it is not possible to be treated with simple medicine, as the mutations are passed down genetically, requiring this procedure. Although I think the other side of natural selection should be considered by scientists before widely spreading the use of this procedure, the fact that MRT is life-saving and allows families to be formed outweighs the natural philosophies, and it should be widely used one day. If you needed MRT to give birth to a healthy child, would you do it?

Mitochondria is often nicknamed the powerhouse of cells. It consists of a double membrane, DNA, ribosomes, inner membrane surface area fold called cristae, an inner fluid-filled space called the matrix. Mitochondria can self reproduce and can move around cells and change shape. It is also the site of cell respiration.

Structure of Mitochondrion

Mitochondrial DNA makes up only 0.1% of the human genome and is passed down exclusively from mother to child. There are around 1,000 copies of mitochondrial DNA in each cell. A cell is heteroplasmic if it contains a mixture of healthy and faulty mitochondrial DNA. If a cell has no healthy mitochondrial DNA, it is homoplasmic.

Mistakes in mitochondrial DNA affect how well the mitochondria work. Often more than 60% of the mitochondria in a cell will need to be damaged or mutated for mitochondrial diseases like mitochondrial diabetes to emerge. These diseases are often severe and, in some cases, fatal. They affect around every 1 in 5,000 people. These diseases are incurable and largely untreatable. Well until now….

The MRC Mitochondrial Biology Unit at the University of Cambridge found a possible answer in 2018. They used an experimental gene therapy treatment in mice. There they discovered that in heteroplasmic cells, they were successful in targeting and eliminating faulty mitochondrial DNA. Dr. Michal Minczuk shares that this new research does come with a catch, “It would only work in cells with enough healthy mitochondrial DNA to copy themselves and replace the faulty ones that had been removed. It would not work in cells whose entire mitochondria had faulty DNA.”

Pedro Silva-Pinheiro tells us, “This is the first time that anyone has been able to change DNA base pairs in mitochondria in a live animal. It shows that, in principle, we can go in and correct spelling mistakes in defective mitochondrial DNA, producing healthy mitochondria that allow the cells to function properly.” He, along with Dr. Minczuk and their other colleagues, have also used a biological tool known as a mitochondrial base editor. They use this to edit the mitochondrial DNA of live mice. The treatment works by it being delivered into the mouse’s bloodstream using a modified virus. It is then taken in by its cells. The editor looks for unique combinations of the A, C, G, and T molecules that make up DNA. Next changes the DNA base, changing a C to a T. Mitochondrial base editor can correct inevitable ‘spelling mistakes’ that cause the mitochondria to malfunction.

A recent example of how this research had been used is mitochondrial replacement therapy, or other known as three-person IVF. Mitochondrial replacement therapy replaces a mother’s defective mitochondria with a healthy donor’s. However, this process is extraordinarily complex and happens in fewer than one in three cycles in standard IVF.

BioQuakes

AP Biology class blog for discussing current research in Biology

Tag: mitochondrial replacement therapy

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