Molecules set to work to eliminate mutated DNA from mitochondria (yellow) in an egg (Image: Salk Institute)
Gene-editing has been used to remove faulty mitochondria in mouse egg cells, leaving mostly healthy ones to be passed to the next generation. The technique could be used to stop mothers from passing on some harmful diseases to their children.
It is the first time gene editing has been used to manipulate mammal mitochondria that can be inherited, says Juan Carlos Izpisua Belmonte of the Salk Institute for Biological Studies in La Jolla, California, who was part of the team that carried out the work.
The study follows the news that researchers in China have already begun testing genome editing techniques in human embryos, a scientific and ethical milestone that many are unhappy about. Belmonte’s team is now gearing up to try its own technique on human eggs.
Mitochondria are the cellular components that generate energy in our cells. They have their own set of DNA, which differs from that in the cell nucleus. Unlike nuclear DNA, which is inherited from both parents, mitochondrial DNA is passed down only from the mother via her egg.
Harmful mutations in mitochondrial DNA can cause a range of severe diseases for which there are currently no treatments. Earlier this year, this prompted the UK parliament to greenlight the donation of healthy mitochondria from someone other than the parents, essentially creating embryos with DNA from three parents.
Belmonte says his technique could offer a simpler alternative to such mitochondrial replacement therapy, which some believe carries genetic risks, while others are uncomfortable about the ethics of “three-parent” babies.
Shifting the balance
Belmonte’s team worked with mouse egg cells that contain two different types of mitochondria, each with a different genome, a state known as heteroplasmy, which is a common phenomenon in mitochondrial disease.
They injected a short set of genetic instructions into each egg cell, which cut the DNA at a specific site in only one of the mitochondria types. These ones are then destroyed. This meant there was more of one of the types of mitochondria in the cell than the other. The technique is called TALENs.
Because most women at risk of passing on faulty mitochondria to their children carry some healthy and some mutated mitochondria, this technique offers a way to potentially increase the number of healthy mitochondria and lower the number of harmful mitochondria in their eggs.
A certain percentage of mutated mitochondria is needed to have a noticeable effect, so reducing the proportion of faulty DNA in this way may be enough to prevent disease in their child.
To show that the technique could be used to prevent the inheritance of human disease, Belmonte’s team created hybrid cells from mouse egg cells and cells taken from people carrying one of two serious disease mutations: one resulting in Leber’s hereditary optic atrophy, which causes blindness, and the other causing nerve, balance and sight problems.
In both cases, they reduced the proportion of mitochondria carrying the harmful mutation in the hybrid. “Although our technique does not allow the total elimination of mutated mitochondrial DNA, we aim to reduce levels below the percentage needed for the disease to manifest,” says Belmonte.
Ethical sticking point
“This study demonstrates that genome editing can be used in an animal to reduce the transmission of mitochondrial genes associated with certain diseases,” says David Liu of Harvard University.
Because it involves simply injecting a genetic sequence into an egg cell, Belmonte believes this method is simpler than mitochondrial replacement therapy, which requires the nucleus of a fertilised egg cell to be removed and then transplanted to a donor egg cell.
The technique also avoids creating embryos that have genetic material from three parents. But the ethics of gene editing in human embryos is also hotly debated, with leading researchers calling for a moratorium on such research last month.
This hasn’t stopped researchers pushing ahead. The first study testing these techniques in human embryos was published last week by a group in China. Only four of the 86 embryos edited were modified in the desired way and there was also a high number of unwanted mutations, possibly caused by the technique.
That work involved a different editing system, called CRISPR/Cas9, which is easier to use than the TALENs technique, but also causes more unintended mutations.
Not there yet
However, mitochondrial gene editing is not without risk, says Robert Lightowlers at Newcastle University, UK. For example, it remains unclear whether the numbers of lost mitochondria will have a long-term effect, he says, or whether cells will be able to compensate. And while the study found that TALENs editing seemed to target only the mitochondria, it could potentially be harmful if even a very low amount of the TALENs genetic instructions found their way into the cell’s nuclear genome.
Next, Belmonte’s team will collaborate with IVF clinics to test the method in unneeded human egg cells that have been donated for research by people with mitochondrial disease. But, he says, more basic research is needed before gene editing techniques can be used to create healthy embryos for parents with faulty mitochondria. “An open dialogue between scientists, physicians, legislators and society at large is urgently needed,” he says.
By: Penny Sarchet