Fixing faulty DNA to create children free from inherited genetic disease is one step closer. The first published results from efforts to use gene editing in viable human embryos have found the technique works better than we thought – but they have also confirmed a major problem. 

Previous tests found that the CRISPR technique wasn’t very effective at making genetic changes in human embryos, but the latest work fixed mutations in half of the six embryos it was tried on. “It is encouraging,” says Robin Lovell-Badge of the Francis Crick Institute in London, though he warns the numbers are too small to draw strong conclusions. 

The idea of changing genes to prevent hereditary diseases has been around for awhile, but until recently, we didn’t have the tools to do it. Then came CRISPR – a revolutionary method that makes it possible to cheaply and easily edit DNA inside cells.

There have been two big obstacles to using the technique, however. The first is safety. As well as correcting a bad mutation, the CRISPR machinery can also make unwanted changes elsewhere in an embryo’s genome, which may lead to cancer. However, this is becoming less of a concern. The technique has been refined to make such “off-target” changes extremely rare, plus there are ways to check embryos for unwanted changes before implanting them into the womb. 

The second obstacle has been efficiency – the proportion of embryos fixed. While CRISPR is very efficient at disabling genes, it is less good at repairing faulty ones – a more useful application when it comes to embryos. IVF produces only a few embryos, and even fewer live births, so CRISPR must work most of the time if it is to be used during IVF. 

The first two attempts to fix genes in human embryos repaired very few embryos. However, these embryos were genetically abnormal, formed from the fertilization of an egg with two sperm, and would never have been able to give rise to a child. 

Now a team at the Third Affiliated Hospital of Guangzhou Medical University in China has tried the technique in viable embryos (Molecular Genetics and Genomics, doi.org/b35x). They used unwanted immature eggs donated by people undergoing IVF, matured them, and fertilized them with sperm from men with genetic diseases.

Mosaic of cells

The team managed to correct mutations in three out of six embryos, suggesting CRISPR repair is more efficient in viable embryos. “It does look more promising than previous papers,” says Fredrik Lanner of the Karolinska Institute in Sweden.

However, the study highlights a further roadblock to using gene editing to create healthy babies. Two of the edited embryos were mosaics – mixtures of edited and unedited cells. The team injected the CRISPR machinery when the embryos were just single cells, but it seems that, in these two embryos, it didn’t make repairs until after they had replicated their DNA. So when they divided, some cells inherited unrepaired DNA. 

This is a big problem, as it means a child could still develop the disease that gene editing was supposed to prevent. Testing wouldn’t be able to tell for sure whether the mutation has been fixed. Similarly, tests to ensure there aren’t any unwanted or dangerous mutations elsewhere in the genome wouldn’t be reliable. “This would need to be solved before the methods could be used clinically to correct a disease,” says Lovell-Badge. 

There are possible solutions. Injecting the CRISPR machinery into an embryo as soon as possible after fertilization and then destroying it a few hours later should ensure repairs only take place before the DNA replicates. This approach has already reduced mosaicism in monkey embryos. An alternative would be to fix the DNA inside stem cells from would-be parents, and then use these to generate egg or sperm cells with repaired DNA. 

Even if it does become possible to safely edit our children’s DNA, that doesn’t necessarily mean we should. A recent report by the US National Academy of Sciences concluded that trials of this kind of gene editing should be allowed only if they meet a number of criteria, the first being “the absence of reasonable alternatives”. 

Yet almost all inherited diseases can be prevented for most couples by existing forms of screening, such as testing IVF embryos before implantation, without any need for CRISPR.