A mother's gift, minus mitochondria

At least one in 10,000 people in the UK are affected by diseases caused by mutations in their mitochondrial DNA (mtDNA). A new study in human embryos provides a potential route to prevent transmission of such diseases to the offspring of affected women, via nuclear transfer techniques. Lyndsey Craven et al.¹ fused a donor zygote from an affected mother with an enucleated zygote from a healthy recipient. The resulting embryos were able to develop to the blastocyst stage. The embryos, on average, contained only two percent donor mtDNA, and many contained none. We asked the experts about the potential applicability of the technique and the associated safety and legal concerns.

Zev Rosenwaks

Pronuclear transfer into a healthy recipient zygote: a new way to eliminate unwanted mitochondria? Credit: Douglass M. Turnbull

The nuclear transfer technique reported by Craven et al.¹ achieved similar results as one developed previously². In the new study, however, the most fundamental of outcome measures—survival—was drastically reduced in the manipulated group. The new approach offers an alternative method for transferring maternal nuclear material with limited mitochondrial contamination. But whether these approaches are associated with other risks, such as epigenetic changes, is not known. Such issues must be carefully addressed before the pronuclear transfer technique can be considered safe.

Director, the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, New York Presbyterian Hospital–Weill Cornell Medical College, New York, New York, USA.

Carlos Simón

This technique, as well as one previously developed, called metaphase II spindle transfer, suffers from technical, safety and legal issues. As a result, it will be difficult to apply these techniques to prevent human mtDNA diseases.

Both the presence of carry-over mutated mtDNA and the mixture with the recipient mtDNA must not be underestimated in light of new evidence showing a role for mitochondria in regulating epigenetic modification in the nucleus. Moreover, only 8.3% of reconstructed zygotes developed into blastocysts in this study, and no chromosomal analysis was performed to assure normalcy. Using the same human model³, 41% of resulting blastocysts were euploid after removal of one pronucleus from triploid zygotes (both studies^1,3 used such abnormally fertilized zygotes). This suggests that the embryos obtained in this work were chromosomally abnormal, not only because of the model but also as a result of the technique.

Legal troubles could arise in the future, because a recipient zygote must be either donated from another couple or created specifically for this purpose. Finally, producing a genetically 'mosaic' or 'manipulated' embryo, such as with these techniques, is not legal, even under the most advanced assisted reproductive laws in Europe.

Professor of Obstetrics and Gynecology at Valencia University and Scientific Director of Instituto Valenciano de Infertilidad, Valencia, Spain.

Douglas C. Wallace

Each cell contains thousands of mtDNAs. Individuals who harbor severe mutations have mitochondrial heteroplasmy—mixtures of mutant and normal mtDNAs—and the greater the percentage of mutant mtDNAs, the more devastating the disease. This percentage can fluctuate within tissues, clouding results from prenatal testing.

The new approach from Craven et al.¹ offers hope for women carrying a high mutant mtDNA percentage, who are likely to transmit the mutations and are confronted with the terrible choice of either not having children or playing genetic roulette. Regrettably, the result of reproduction has often been fetal or early childhood death. Zygote nuclear transfer could avoid this dilemma, as the large amount of normal mtDNAs within the recipient egg should dilute out the small numbers of mutant mtDNAs carried over with the zygote pronuclei.

There is a caveat, however, and that is that mixing two very different mtDNAs might also adversely affect the development of the child through incompatibility between the genes of the two mtDNAs. It might be advisable to use a recipient egg with similar mtDNA to the mother, such as an egg donated by a maternal relative. In this case, the child would be genetically identical to the original zygote, lacking only the pathogenic mtDNA.

Although promising, human embryo manipulation and germline gene therapy are currently discouraged by the US government on philosophical grounds, making it unlikely that nuclear transplantation will become an option for avoiding mtDNA disease for families in the US.

Director of Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, California, USA.