This article is part of DNA/IDK , a semi-regular column exploring how genetic modification is shaping the future. Follow along here .
When CRISPR was first revealed to the world in 2013, the peril and promise of the revolutionary new gene-editing technology seemed boundless. CRISPR could end hereditary diseases like Huntington’s and cystic fibrosis, but also raised fears of a designer baby boom or another cold war. Yet if one thing was certain, it was that CRISPR worked and was only getting better: In 2014, researchers used CRISPR to cure a disease in an adult animal for the first time, and since then the technology has been used to modify the genetic material in a human embryo, eliminate HIV in mice, improve agriculture, and enhance its delivery mechanism by using nanoparticles instead of viruses.
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In the past few weeks, however, several studies discovered serious problems with CRISPR and cast the therapeutic potential of the gene-editing tech in doubt. In June, two studies published in Nature Medicine demonstrated that cells altered with CRISPR may be missing key anti-cancer mechanisms, increasing the risk that those cells will initiate tumors.
On Monday, research published in Nature Biotechnology added to these concerns by showing that CRISPR can mess up a cell’s genetic material even worse than previously thought.
“We found that changes in the DNA have been seriously underestimated before now,” said Allan Bradley, a researcher at the UK-based Wellcome Sanger Institute. “It is important that anyone thinking of using this technology for gene therapy proceeds with caution, and looks very carefully to check for possible harmful effects.”
Read More: What is CRISPR/Cas9 and Why Is it Suddenly Everywhere?
CRISPR uses an enzyme called Cas9 to excise small portions of DNA and introduce genetic changes at that location. The core element of the CRISPR system is a small piece of RNA that binds to a specific DNA sequence in a genome and the Cas9 enzyme. Once the RNA is bound to the DNA sequence, Cas9 cuts the DNA at the targeted location and the cell’s natural DNA repair mechanisms work to repair the DNA sequence.
Yet as Bradley and his colleagues discovered through a systematic study of human and mouse cells modified by CRISPR, this cellular repair process introduces a lot of errors—deletions and the scrambling of genetic code—to the DNA during the repair process. The reason that these extensive mutations had been overlooked in previous CRISPR research is because the errors often occur far from the site that was edited by CRISPR.
“Once we realized the extent of the genetic rearrangements we studied it systematically, looking at different genes and different therapeutically relevant cell lines and showed that the CRISPR-Cas9 effects held true,” said Michael Kosicki, a Wellcome Sanger Institute researcher and lead author of the study.
Read More: CRISPR Is Not Accurate Enough To Save Us Yet
These mutations can cause important genes to be turned on or off, such as genetic anti-cancer mechanisms. This poses serious problems for CRISPR as a therapy, which has already been used on 86 people in China and is under consideration for humans in the US. Moreover, because these mutations occur so far away from the gene editing site, they are difficult to detect with standard genotyping methods used to determine whether a CRISPR edit was successful.
For now, the researchers expect that their new study will slow the adoption of CRISPR as a clinical tool and reinvigorate the search for alternative gene-editing technologies.