A technique may one day prevent something that is currently unpreventable -- the transmission of mitochondrial diseases from mother to child, according to a proof-of-concept paper published online today (April 14) in Nature.

Blastocyst on day 5 after fertilization Image: Wikimedia commons, Ekem

The authors swapped the nuclei from one fertilized human egg with the nuclei from another, creating an embryo with nuclear DNA from the donor egg, but mitochondrial DNA primarily from the recipient. They suggest the technique could ultimately prevent the transmission of mitochondrial diseases if doctors moved nuclei from a fertilized egg carrying the disease to another egg with disease-free mitochondria.

The results come with major caveats, however. The resulting embryo would carry DNA from three parents, and to prove the technique could work in the clinic, scientists would have to try the technique in healthy human embryos -- a task that would be "impossible" due to the associated ethical issues, Jun-Ichi Hayashi of the University of Tsukuba in Japan, who was not involved in the research, told The Scientist.

Nonetheless, the results are "very promising," said neurogeneticist Carolyn Sue of the Kolling Institute of Medical Research at the University of Sydney in Australia, who was also not directly involved in the research. "It's moving towards [a] treatment to prevent transmission of mitochondrial disease."

Mitochondria, the cell's energy-making organelles, carry their own set of DNA -- 13 genes that encode the construction and function of new mitochondria. Pathogenic mutations in mitochondrial DNA (mtDNA) are found in about 1 in 250 live births, and can cause a variety of neuromuscular ailments. Currently, there are no specific treatments for mitochondrial diseases.

Because mitochondrial are maternally inherited, women carrying mtDNA mutations pass them on to their children. To prevent the transmission of disease, an embryo must receive a whole new set of mitochondria.

To achieve this goal, clinical scientist Doug Turnbull and his colleagues at Newcastle University in the UK transplanted the nuclei from one human oocyte (termed pronuclei) into an oocyte whose pronuclei had been removed. The resulting embryos, which contained predominately mtDNA from the recipient oocyte, were then raised in culture for about a week. About 20 percent showed continued development, some all the way to the blastocyst stage, demonstrating the viability of the manipulated embryos.

"This is definitely showing a proof of concept" that this type of technique, which had previously been applied to primates and other animals, can be applied to human oocytes, Sue said.

However, the embryos still contained some mtDNA from donor egg. The technique, which involves sucking the pronuclei from the donor oocyte with a micro-manipulated pipette, Turnbull explained, can result in the transfer of small amounts of donor cytoplasm containing donor mitochondria, as well. "It's really tricky to" get just the pronuclei, he said.

Refining their technique, the researchers were able to limit the amount of mitochondrial transfer, creating manipulated embryos with less than 2 percent donor mitochondria, "which we felt was a significant breakthrough in this area," Turnbull said.

But even 2 percent "is still not quite acceptable to be translated into clinical practice," Sue said, as "very low levels [of mutated mtDNA] can still result in mitochondrial disease."

Additionally, the safety and efficacy of the treatment must be tested before the therapy can begin to make its way towards clinical development, Turnbull said. The oocytes used in the study were abnormally fertilized embryos generated during in vitro fertilization (IVF) treatments that would have otherwise been discarded, but, to be approved for clinical use, the technique would have be tested in healthy embryos, researchers say.

Indeed, the manipulation itself could increase the risk of epigenetic abnormalities in the offspring, said developmental biologist Josef Fulka, Jr. of the Institute of Animal Science in the Czech Republic. "These risks can not be excluded without using human healthy embryos and testing whether they are healthy throughout their life," Hayashi said in an email, and "it's impossible to carry out these experiments."

Turnbull said that he and his team are currently discussing the next steps with the Human Fertility & Embryology Authority -- a UK regulatory authority -- but could not comment more specifically on any potential future experiments.

Other issues may arise from the fact that the resulting offspring would have three genetic parents -- the mother and father who donated the nuclear material, and a second mother who donated the mitochondria. "The interaction between the nuclear genome and the mitochondrial genome is still unclear," Sue said. "Simply, nobody on the earth ever had three biological parents," Hayashi added.

L. Craven et al., "Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease," Nature, published online April 14, 2010, doi:10.1038/nature08958.


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