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DNA swap and inherited disease

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“Dozens of human embryos with three parents have been created by British scientists,” reported the Daily Mail. Many papers covered the news of an experimental research technique that aims to prevent genetic disorders.

In this study, DNA from the nucleus of one egg was transferred to another egg that contained different mitochondrial DNA. Mitochondria are often referred to as the “batteries” of cells as they produce energy. Mutations in mitochondrial DNA are a common cause of genetic disease. The technique, which has previously been tested in monkeys, results in embryos that have nuclear DNA from both parents and donor mitochondria from another woman.

This technique raises the possibility that women carrying mitochondrial mutations could have children without these mutations. As mitochondrial DNA only makes up a very small part of the overall DNA in the cell and is involved in helping the mitochondria to function, the offspring’s characteristics would still mostly be derived from the nuclear DNA of the mother and father. The embryos generated in this study were only allowed to develop for six to eight days to determine whether they were able to continue development and were then tested for the presence of the donor mitochondrial DNA.

Several newspapers claimed that this technique has similarities with cloning. However, this is not correct and the technique is similar to types of IVF already in use. The technique does involve making genetic changes to unborn children who will have some DNA from two mothers. The ethical issues surrounding this will need to be considered by the Human Embryology and Fertilisation Authority, the UK body that licenses research on embryos. The agency will determine what further studies into the safety of the technique are needed before a human embryo that has undergone the procedure can be allowed to develop fully.

Where did the story come from?

The research was carried out by Dr Lyndsey Craven and colleagues from the Mitochondrial Research Group at the Institute for Ageing and Health in Newcastle University. The study received funding from several sources including the Muscular Dystrophy Campaign, the Wellcome Trust and the Medical Research Council. It was published in the peer-reviewed journal Nature.

The media covered the story in some depth, accurately reporting the technique, with diagrams in some cases, and the related ethical issues. However, some reports may have given readers the impression that the research is at a later stage of development than it is. The researchers estimate that the technique is three years away from being tested in trials for these conditions.

What kind of research was this?

This laboratory study investigated whether pronuclear transfer (transfer of DNA from the nucleus of one egg to another) in human embryos is possible and, if so, what proportion of embryos survive for six to eight days and how much donor mitochondrial DNA is carried over to the new embryo.

The study was appropriately designed to answer these questions. Researchers are currently prohibited from allowing embryos, such as the ones in this study, to develop beyond six to eight days and from implanting them back into the womb. For this technique to progress further, appropriate ethics approval and a change in the law would be necessary.

What did the research involve?

The researchers explain that mutations in mitochondrial DNA are a common cause of genetic disease, responsible for at least 150 hereditary conditions. Mitochondria are present in all cells and are often referred to as the cells’ “batteries” as they produce energy. They are found in the membrane-bound structures that lie outside the nucleus. The nucleus is where most DNA is found, but mitochondria have some DNA of their own.

Mitochondrial DNA mutations can result in neurological, muscular and heart problems and deafness. Some of these conditions are serious and can be fatal at birth. Around 1 child in 6,500 is born with a mitochondrial disease, and at least 1 adult in every 10,000 is affected by disease caused by mutations in their mitochondrial DNA. As each cell has multiple mitochondria, whether or not a person is affected by a mitochondrial disease depends on the proportion of their mitochondria that carry the mutation. Disease occurs in people carrying the mutation in at least 60% of their mitochondria.

The study used abnormally fertilised one-cell embryos (called zygotes), which had been donated by patients having IVF treatment at the Newcastle Fertility Centre. These eggs are usually not used in fertility treatment as they are not normal and typically do not survive. These abnormally fertilised eggs were identified at day one of their development at the Fertility Centre.

The researchers took the nucleus together with some plasma membrane and a small amount of the surrounding cytoplasm out of the cell and transferred it to an empty recipient cell. The recipient cell was also an abnormally fertilised zygote, at the same stage as the donor’s cell. This cell had had its nuclear DNA removed, using a similar process to that used on the donor cell. After the nucleus from the first embryo had been inserted into the recipient cell, it was either cultured for six to eight days to monitor development or cultured for a short period before being analysed for its mitochondrial DNA content.

Accepted genotyping techniques were used to determine the carry-over of mitochondrial DNA from the donor zygote into the recipient cell. This is important because, if the technique were to be used to prevent mitochondrial mutation disease in humans, it would need to be known how much, if any, mutated mitochondrial DNA is transferred along with the nucleus.

What were the basic results?

The researchers report that the transfer of the nucleus was successful. There was minimal carry-over of donor zygote mitochondrial DNA into the recipient cell (less than 2% after improving the procedure). Many of these early embryos contained no detectable donor mitochondrial DNA. The researchers say that this technique would allow onward development to embryo stage.

How did the researchers interpret the results?

The researchers concluded that pronuclear transfer between zygotes has the “potential to prevent the transmission of mitochondrial DNA disease in humans”.

Conclusion

Current treatments, including genetic counselling and pre-implantation genetic diagnosis, can help women who have only low levels of mutations in the mitochondria of their egg cells to have children of their own. This new technique could potentially help women who have more mutations and who may otherwise not be able to have children.

It is important to note that the third parent (the donor of the recipient egg) in the news reports only supplied a small, but essential, part of the genetic code for these embryos. This DNA affects energy production in cells and would probably not affect the offspring’s characteristics in a noticeable way.

There are further ethical and research obstacles to overcome before the technique could be available to affected families. First, an ethical debate about the procedure will need to occur. Second, how the procedure is regulated, if it is approved, will need to be agreed. Long-term safety of the procedure and refinements in the technique would also need be looked at in a research setting.

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