Changing A Cell's Biological Battery

A new method tested in monkeys for replacing mitochondrial DNA could one day prevent devastating diseases.

Mitochondrial diseases, which affect as many as one in 4,000 people, can impair muscles, nerves, even entire organ systems, and have no known cure. Now, in a breakthrough study, Oregon researchers replaced defective mitochondrial DNA with that from a healthy donor. The first subjects, four baby monkeys, are pushing the envelope on the ethical debate that surrounds bioengineering.

Born of science: Spindler, a baby rhesus macaque, is one of only four monkeys born with DNA from three parents. Credit: Nature

Multimedia   Watch how the researchers create a fertile egg.

Mitochondria are often called the cell's power plants--the tiny organelles are responsible for energy production, and there can be hundreds to thousands of them in a single cell. They also contain their own DNA. Unlike nuclear DNA, which is a unique combination of both parents' genomes, mitochondrial DNA (or mtDNA) is passed down through the mother, is derived almost exclusively from her egg, and typically remains unchanged from one generation to the next. Mutations in a woman's mtDNA are inherited by her child, and so far there has been no way to cure these conditions or stop their transmission.

Now, Shoukhrat Mitalipov and his colleagues at Oregon Health & Science University in Beaverton, OR, have found a way to get rid of mutant mtDNA. Using a process similar to cloning, they first harvested a fertile egg. Then, when the egg was undergoing cell division, they removed a set of its chromosomes and inserted them into an egg harvested from another female, one that already had its nucleus removed. In essence, the enucleated egg provided a set of mitochondrial chromosomes, while the transferred nuclear chromosomes provided the main genetic material for development. Other researchers have attempted similar processes, but previous efforts couldn't prevent mutant mitochondria from tagging along to the new egg.

The researchers avoided this problem by carefully isolating chromosomes during a very specific and segregated process of cell division, in which nuclear DNA is tied up into an elliptical spindle. "Our whole technique comes to efficiently separating the two different types of DNA that [mammals] carry, and to separate them very cleanly," Mitalipov says. "We believe this can be used to prevent transmission of mutated mitochondrial DNA...[and] correct for mitochondrial DNA mutations in children even before they're born."

To date, there are 200 to 250 known disease-causing mutations in mitochondrial DNA, and they occur in as many as one in 4,000 people. The syndromes vary in severity, with symptoms ranging from muscle weakness and loss of motor control to diabetes, liver disease, and developmental delays. Many die before ever reaching adulthood. "The patients carrying these types of mutations don't have the same options for genetic counseling," Mitalipov says, since any mutation a woman has will be passed to her egg. "Currently, her only options are using donated eggs or adopting a child."

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"It's an important study, and it's the only approach that I can think by which you could render a family free of risk of their offspring developing a mitochondrial DNA disease," says Douglas Wallace, a mitochondrial DNA researcher at the University of California, Irvine. Because mitochondrial DNA is self-replicating, the technique allows for a way to "swap" healthy versions for mutant ones without genetic alterations.

But therein also lies the rub. Many researchers and ethicists alike balk at the idea of making genetic changes to the germline, ones that fundamentally affect an egg or sperm and will be passed along to the next generation. While swapping out mitochondrial DNA may not qualify as the kind of germline engineering people have in mind when they worry about made-to-order babies--with certain traits like intelligence or eye color specifically engineered--it edges toward that shaky ethical ground.