A new study sounds a cautionary note for a controversial procedure used in creating “three-parent babies.”
That procedure replaces defective mitochondria, the energy-generating organelles in cells, with healthy ones. But even a tiny amount of defective mitochondria may replicate and take over the cell, researchers report online May 19 in Cell Stem Cell. Exactly which mitochondria can stage a comeback and when is unpredictable, say stem cell biologist Dieter Egli of the New York Stem Cell Foundation and colleagues.
Mitochondrial replacement therapy is designed to prevent women from passing diseased mitochondria to their children. Mutations in the DNA of mitochondria can impair energy generation, starving some organs, such as the brain and muscles. Scientists designed a work-around in which they could transfer an egg cell nucleus from a would-be mother carrying a mitochondrial disease into the shell of a donor egg containing healthy mitochondria (SN: 11/17/12, p. 5). Fertilization by sperm would create a three-parent baby who gets most of his or her DNA from the mother and father but gets mitochondrial DNA from a donor woman.
Researchers have always known that the therapy could fail if too many of the unhealthy mitochondria were transferred along with the mother’s nucleus. “It was assumed that if the level of carryover was initially very low — on the order of 1 percent — then this ought to be inconsequential,” says mitochondrial biologist Vamsi Mootha of Harvard Medical School. “The current paper demonstrates that even trace levels of carryover can get amplified to alarmingly high levels. This is a real concern.”
In a series of experiments, Egli and colleagues transferred nuclei from eggs of women with healthy mitochondria to eggs of women containing a different variety of healthy mitochondria. The team created cells with different combinations of mitochondrial varieties, with one type in each cell making up 2.2 percent or less of the mitochondrial population of the cell.
In most cases, carrying over a little bit of mitochondria was not a problem. But in a small number of cases, mitochondria could balloon from less than 1 percent to become the only type of mitochondria in the cell. One lineage of cells contained 1.3 percent of a particular mitochondrial DNA variety, called the H1 haplotype, at the beginning. After 36 rounds of growth in lab dishes, the H1 mitochondria made up 53.2 percent of the mitochondrial population. But after 59 rounds of growth, they had dwindled again to 1 percent. Individual cells removed from the dish at various time points and grown as clones in separate dishes contained between 0 and 90 percent H1 mitochondria. Those and other instances of shifting mitochondria happened at random.
It is important to know the risk of failure due to mutant mitochondria reestablishing themselves after replacement therapy, says Philip Yeske, the science officer for the United Mitochondrial Disease Foundation in Pittsburgh. More research is needed to determine how high the risk of resurgence is, he says.
Improved transfer techniques and other advances might reduce the chance of mutant mitochondria staging a coup, says Caltech mitochondrial biologist David Chan. “We should find a way to move forward, but it should be done cautiously.”
Others, including stem cell researcher Paul Knoepfler of the University of California, Davis, hope scientists will hold off on human clinical trials until more data are collected on replacement techniques and mitochondrial function in early human embryos. The technique was approved last year in the United Kingdom, but no three-parent babies have been born yet. In the United States, the Institute of Medicine ruled it would be ethical to produce male embryos using the technique (SN Online: 2/3/16), but federal laws would be need to be changed before researchers could conduct clinical trials.