Researchers have been exploring a novel but controversial field called mitochondrial replacement therapy. In this procedure, embryos are made by combining sperm from dad, a cell nucleus from mom, and the egg of a female donor. The approach is supposed to eliminate the risk of inheriting sometimes deadly mutations in mitochondrial DNA. However a new study reported on May 19th in Cell Stem Cell corroborates what have long been speculated, that the undesirable DNA still manages to sneak into the donor egg during the procedure, and mitochondria containing it could even grow to outnumber the power plants with healthy DNA. Although researchers working in this field were aware of this potential risk, this is the first direct evidence that demonstrates that this risk is real.
Mitochondrial replacement technique have only been attempted in animals thus far. But last year, the United Kingdom passed legislation approving the procedure for mothers with known mitochondrial DNA mutations. That same year, an expert panel at the U.S. National Academies of Sciences, Engineering, and Medicine endorsed clinical testing, pending a green light from the U.S. Food and Drug Administration. Nonetheless, some find the concept ethically troubling.
The delicate procedure involves sucking the microscopic DNA-containing nucleus from a mother’s cell into a tiny glass straw and transferring it to a nucleus-free donor egg. Trace amount of mitochondria, potentially containing the disease-causing flaw, can get into the donor egg. Although they’re vastly outnumbered by the hundreds of thousands of copies of native mitochondrial DNA, those proportions can change unpredictably as mitochondria replicate. Animal testing of mitochondrial replacement has already revealed some potential risk. Monkey embryos that developed from the procedure, for example, seemed to retain the hitchhiking mitochondrial DNA in some of their cells. But in human cells, it wasn’t known whether this DNA would disappear, or if it could make a home for itself long-term.
In the new study, stem cell biologists from the New York Stem Cell Foundation tracked proportions of carryover mitochondrial DNA in human stem cells created through two different types of nuclear transfer. One by moving nuclei from one egg cell to another and letting the egg develop into a clump of cells known as a blastocyst. Another by moving somatic nuclei to embryos grown from human eggs. Although the large majority of the cell lines received some foreign mitochondrial DNA in the transfer, most also seemed to stamp it out, leaving no trace of it after several divisions. But three of the lines—one from the blastocyst and two from the somatic cell transfer—managed to swing the other direction: After dividing and being cultured dozens of times, they produced colonies that contained only the carryover DNA. Cells from these lines developed into cardiac muscle and connective tissue, which also showed fluctuating levels of the foreign DNA in their mitochondria, sometimes reaching 100%.
The author noted that It might not be possible to screen out these embattled cells in favor of more stable ones, because the key mitochondrial replications occur only after the embryo is implanted in the uterus. Instead, reducing the risk will mean reducing this carryover before the battle can start. Juan Carlos Izpisua Belmonte, a developmental biologist of the Salk Institute for Biological Sciences in San Diego, California, says his lab is working on a way to target and destroy undesirable mitochondrial DNA in eggs or embryos using targeted DNA-cutting enzymes.
Read more: “Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes”, Cell Stem Cell, May 2016, DOI: http://dx.doi.org/10.1016/j.stem.2016.04.001
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