When it comes to gene editing, nothing has looked more promising than CRISPR. Over the past few years, CRISPR has made massive leaps forward in what may be possible through editing our DNA. But in amongst all the possibilities and excitement, serious concerns have been raised. The field of gene editing needs to be researched extremely carefully to prevent unintended consequences, and whilst our genes are still being understood, human editing is extremely risky. Whilst accurate to a degree, genetic editing can be directed to the wrong areas by similar sequences that exist elsewhere in the DNA.

In the latest studies on CRISPR by the Francis Crick Institute, Columbia University, and Oregon Health and Science University, it has been found that the technology may have large-scale consequences on the region of DNA that it is aimed at.

CRISPR-Cas9 and ‘designer babies’

CRISPR is a small piece of genetic material that works together with a protein called ‘Cas9’ to target and change a gene of interest. In this two-part system, the CRISPR part acts as a homing beacon to where the researchers want to change, locking on and showing Cas9 where to attack. Once Cas9 has been guided there, it breaks the DNA, forcing the host’s own machinery to fix the break. It is at this point that the researcher can introduce what they want, changing the gene, and potentially stopping a disease caused by it.

In 2018, controversially, a scientist in China genetically modified embryos to try and prevent the babies from being infected with HIV. This was quickly condemned by the genetic community, due to both the fact that genetically engineered babies are illegal, and our lack of understanding of off-target effects makes the experiments unethical. Whilst the scientist is now serving a 3-year term in prison, the babies appeared to be in good health and didn’t suffer any immediate consequences.

This case was the first of its kind and raised serious ethical concerns about the possibilities of CRISPR and the future of "designer babies". Alongside that, we don’t know how the children are affected to this day. But it may not just be a lack of understanding that blocks the way to full genetic editing – CRISPR may actually do more harm than good.

Wreaking havoc in chromosomes

Three studies have now come out that demonstrate large deletions and rearrangements in the DNA sequences of areas around the genes targeted by CRISPR. This has already been shown in mice before, but never in human embryos. In these studies, attempts at correcting mutations in genes resulted in large deletions in a significant number of the embryos, with some even losing the entire chromosome in which the target gene lies. The third study found signs of unitended editing and loss of entire regions around their target gene. All three studies are currently in preprint and have not been peer-reviewed yet. 

The unwanted DNA changes are likely due to the repair mechanisms that close the break in DNA made by Cas9 being prone to error, and so the effects of CRISPR can be unpredictable. CRISPR is established to sometimes edit the wrong DNA far away from the target, but it’s usually hard to see what’s happening close by. These findings demonstrate it may be worse than we thought.

These studies cast doubt over how viable CRISPR-Cas9 really is for accurate gene editing. With how easy it is to cause damaging effects by just a small DNA change, it is all too possible that the unintended effects of CRISPR may cause more problems than being solved. As a result, we will need a much clearer understanding of our genes and the repair mechanisms before this technology can be properly used for safe and accurate editing.

[H/T: Nature]