Researchers at Oregon Health and Sciences University, who are developing techniques to replace defective mitochondrial DNA in human egg cells to prevent congenital mitochondrial disease, have drawn some criticism for pursuing germ line therapies that make genetic changes which are passed on to future generations. The group published a study in Nature this week where they showed they could produce normal embryos from human egg cells whose chromosomes had been replaced with those from a donor egg.
Congenital disorders caused by defects in mitochondria, the compartments in cells that convert oxygen to energy, affect about 1 in a 10000 children. Unlike most specialized compartments in cells, however, mitochondria contain a small bit of DNA that lets them make some of their own proteins. This is the DNA defective in mitochondria diseases, and this DNA only transfers from mother to child with the mitochondria in the mother's egg.
The vast majority of DNA in the cells is the genomic DNA which is wrapped up on the chromosomes, usually in the nucleus of the cell. However, human eggs in the ovary arrest in the maturation process just before division, and they don't actually finish this division until after fertilization. As a result, the chromosomes are not in the nucleus but part of a structure called the spindle fiber. It is the DNA on the chromosomes on this structure that mix with the sperm's chromosomes during fertilization.
The researchers harvested 106 eggs from seven volunteers. If the mitochondria were defective in these cells, correcting the problem would require replacing them with healthy mitochondria. However, the actual approach is somewhat reversed. This technique extracts the chromosomes on the spindle fibers from the donor eggs and puts them into a different egg cell whose own chromosomes were previously removed. Basically, the new egg receives all the maternal DNA except the little bit in the mitochondria which is left behind with the rest of the old donor egg.
In the study, the researchers did this chromosome transfer with 65 of the eggs they harvested, keeping the others as controls. After transferring the chromosomes into the new egg cells, they tested them to ensure they would be fertilized and would development into embryos. They also isolated and characterized the stem cells from the embryos.
There did appear to be some problems with fertilization of some of the chromosome-transferred eggs. This was a surprise since they had not seen this discrepancy in previous studies using monkeys. However, the researchers attributed the lower fertilization frequency to the egg cell line used to receive the chromosomes. These cells normally have a small chromosome abnormality that the researchers were unaware of initially.
Aside from the lower successful fertilization frequency, though, the eggs that appeared normal after fertilization developed normally into embryos. In analyzing the cells, they found that none of the maternal mitochondrial DNA carried over into the chromosome-transferred eggs.
The study has generated some controversy, as mentioned in this NPR piece. The issue is that this type of treatment involve manipulation of the heritable DNA in eggs.
Gene therapy involving germ line cells--eggs and sperm--is controversial because the changes are heritable. Genetic changes in these cells affect untold future generations so the impact of any mistake can be catastrophic.
However, on the other hand, this sort of approach does have the ability to permanently eliminate a hereditary disease. Also, this study is trying a unique form of gene therapy that does not directly alter the chromosomal or mitochondrial DNA. The researchers are simply pairing up a donor's chromosomes with new mitochondrial DNA, so it might be considered less risky than changing part of the one of the chromosomes, for example. Perhaps this is a reasonable first approach to the cautious development of this sort of treatment.
You can read more about the general ethical issues with this sort of technique in What is the Concern over Germ Line Gene Therapy?.