DNA swap for gene disorders

“Scientists are on the verge of ridding inherited diseases from future generations,” The Independent reported. It said researchers had successfully tested a new technique in monkeys that could be used to swap genes between unfertilised human eggs before implanting them into the womb. The Independent 's article on DNA swapping said that the technique could be used for women at risk of passing on genetic disease, but that there are some ethical concerns.

This technique clearly has potential to reduce the rates of 150 rare but often life-threatening genetic conditions. Whether the technique will be suitable for more common diseases such as diabetes and dementia is unclear as the genetic causes of these diseases are not yet fully understood.

Putting aside the ethical issues of using this sort of treatment in humans, there is scope for further research to determine whether the infant monkeys continue to develop normally and what the long-term implications are for this technique.

Where did the story come from?

This research into swapping DNA was carried out by Dr Tachibana and colleagues from the Oregon National Primate Research Center, the Oregon Stem Cell Center and the Departments of Obstetrics and Gynecology, and Molecular and Medical Genetics at the Oregon Health and Science University. This study was funded by internal funds from the centres, and grants from the National Institutes of Health. It was published in the scientific journal Nature .

What kind of scientific study was this?

This research developed a technique for taking DNA from the nucleus (which contains the majority of a cell's DNA) from one monkey egg cell and transferring it to another egg cell that had had its nucleus removed. In addition to this, cells also have a small amount of DNA in their mitochondria (membranes surrounding the nucleus in the cell). The DNA contained in the mitochondria can contain mutations that cause a range of genetic diseases. The result was an egg that contained the mitochondria from one egg and the nuclear DNA from another. This potentially means that eggs with mutated mitochondria can have their nuclear DNA transplanted into a cell with a healthy mitochondria.

The researchers explain mitochondria and the DNA found in them.

• Mitochondria are found in all cells with a nucleus and contain their own genetic code known as mitochondrial DNA or mtDNA. Unlike the genetic code in the nucleus, half of which comes from the mother and half from the father, the mtDNA in the embryo comes almost exclusively from the mother’s egg.
• Each mitochondrion contains between two and 10 copies of mtDNA, and because cells have numerous mitochondria, a cell may harbour several thousand mtDNA copies.
• Mutations in mtDNA can cause a range of incurable human diseases and disorders, some of which cause muscle weaknesses, blindness or dementia.

The researchers explain the technical obstacles of transferring mtDNA from one egg to another. These include difficulties in finding and separating the mitochondrial chromosomes and the fact that the chromosomes themselves are prone to damage when they are manipulated. To resolve these problems the researchers developed new techniques for DNA staining and for extracting the DNA at exactly the right time in egg development.

The technique, called spindle–chromosomal complex transfer involved transplanting the nuclear DNA attached to the spindle (a structure that organises and separates chromosomes when a cell divides). This complex was taken from one monkey egg cell and transferred into a second egg that had had its spindle-complex removed. The process was designed so that the newly reconstructed egg contained mitochondria only from the second egg cell, without any mitochondria from the original cell. The cell was then used in a standard in vitro fertilisation to produce an embryo for implantation into a monkey. In this case, the researchers used Macaca mulatta monkeys, whose reproduction physiology closely resembles that of humans.

The researchers used cytogenetic analysis to check that the baby monkeys’ cells contained normal rhesus monkey chomosomes (one male 42 XY and one female 42 XX) with no detectable chromosomal anomalies. They also tested the monkeys' offspring to see whether they contained any of the mtDNA from the nuclear DNA donor monkey.

What were the results of the study?

The mitochondrial genetic code was successfully replaced in a mature monkey egg cell by transfer from one egg to another.

The researchers showed that the reconstructed egg cells with the mitochondrial replacement were capable of supporting normal fertilisation, embryo development and producing healthy offspring.

Genetic analysis confirmed that nuclear DNA in the three infants born so far originated from a different mother to the mtDNA donor and that none of the mtDNA from the nuclear donor cells were detected in the offspring. This means that the researchers proved that the DNA in the monkey offspring (DNA and mitochondrial) came from different sources.

What interpretations did the researchers draw from these results?

The researchers say that spindle replacement is shown to be an “efficient protocol replacing the full complement of mitochondria in newly generated embryonic stem cell lines”.

They suggest that the approach may offer a reproductive option to prevent mtDNA disease transmission in affected families.

What does the NHS Knowledge Service make of this study?

This proof of concept study will be welcomed by scientists. The technique clearly has potential if various scientific, ethical and legal issues are addressed. Several of these are mentioned in the newspapers and by the authors:

• As the work was done in monkeys, demonstrating that it can be done safely in humans will require further research. Human embryo research is contentious and strictly controlled by legislation in many countries.
• There are around 150 known disorders directly caused by mitochondrial mutations and these are all rare conditions. The hope that the technique will be suitable for more common diseases such as diabetes and dementia seems more tenuous as the usual forms of these diseases are not yet clearly linked to mitochondrial DNA mutations.
• The fact that the authors were unable to find any mitochondrial DNA that could have contaminated the spindle and been brought over from the defective egg is important as this sort of contamination has been shown when similar experiments were tried on mice using pronuclear transfer.