Two recently published studies are raising new concerns that the breakthrough CRISPR-Cas9 gene editing system could potentially trigger an increased cancer risk in cells edited using the technique. With human trials using the gene-editing technique set to commence this year, the scientists behind these new studies urge researchers to be aware of this newly discovered and dangerous cancer-driving mechanism. It has been less than a decade since the revolutionary CRISPR-Cas9 gene-editing technique was discovered, allowing scientists an unprecedented way to accurately edit DNA. For the most part, the technique has proved promising, safe and effective. Last year, a controversial study was published claiming the technique could introduce unintended, off-target mutations, but after a flurry of criticism attacking the veracity of the work it was ultimately retracted.
These two new studies raise entirely new concerns regarding the technique’s potential for triggering cancer in edited cells. One study comes from a collaboration between the University of Cambridge and the Karolinska Institutet, while the other is led by a team of researchers at pharmaceutical company Novartis. Both studies illustrate a problematic connection between the efficacy of the CRISPR process and the presence of a cancer-preventing protein known as p53. The research grew from an observation showing that, while CRISPR worked quite effectively in editing cancer cells, it was remarkably inefficient when targeting healthy cells. “When we looked at this further, we found that cutting the genome with CRISPR-Cas9 induced the activation of a protein known as p53, which acts like a cell’s alarm system, signalling that DNA is damaged, and opens the cellular ‘first aid kit’ that repairs damage to the DNA,” explains Emma Haapaniemi, first author on the Karolinska study. “The triggering of this system makes editing much more difficult.” The problem this research raises is that an absence pf p53 in cells may, on the one hand, result in the CRISPR process being more effective, but it also makes a cell much more likely to become cancerous. Mutations or deficiencies in the p53 gene have been found in almost every type of cancer, and the gene is now often referred to as a tumour suppressor gene.
The new research suggests that when scientists are developing CRISPR treatments, they may be inadvertently favouring cells with inactive p53 pathways as they could be the ones demonstrating the greatest editing efficacy. This means that the process could ultimately administer cells into a patient that are much more vulnerable to becoming cancerous in the long-term. “We don’t want to sound alarmist, and are not saying that CRISPR-Cas9 is bad or dangerous,” says Jussi Taipale, lead researcher on the Karolinska study. “This is going to be a major tool for use in medicine, so it’s important to pay attention to potential safety concerns. Like with any medical treatment, there are always side effects or potential harm, and this should be balanced against the benefits of the treatment.” This new research by no means suggests CRISPR gene-editing is fundamentally flawed, but rather it highlights an extra degree of oversight that should be necessary for future work that utilises the technique. The study suggests CRISPR-edited cells should be analysed before clinical use to make sure p53 pathways are not disrupted.
Some scientists, commenting on the new research, suggest it is too soon to claim this discovery could affect all cell types edited using CRISPR. The discovery was only found, so far, in one specific cell line in laboratory conditions. Robin Lovell-Badge, from the Francis Crick Institute, suggests since prior animal research with CRISPR has not shown an increased incidence of cancers, this new research may only signal that certain cell lines are more prone to this p53 disruption. “Indeed there are many papers published using genome editing methods like CRISPR/Cas9 in cells or early embryos from mice, other animals, and humans, including making whole animals with highly efficient rates of genome editing – sometimes approaching 100 per cent,” says Lovell-Badge. “Such high rates would not be apparent if p53 had to be mutated to allow cells to survive. It would be fairly obvious, especially in animals, if p53 or one of its critical downstream target genes had been mutated – they would be prone to developing tumours.”
It is also important to note that this new research is limited to CRISPR-editing using the Cas9 enzyme and primarily seen in one kind of gene-editing technique. The studies show the major p53 disruption when CRISPR is used to make double-strand breaks in DNA. Other forms of CRISPR-editing should not be so disruptive to p53 pathways. However, these two studies do highlight a new and little-understood mechanism that should be incredibly important for researchers developing new CRISPR-based treatments to be aware of. The Karolinska/Cambridge study was published in the journal Nature Medicine, while the Novartis study was published in the journal Nature Medicine.
Source: University of Cambridge
Credit: Rich Haridy for New Atlas, 12 June 2018.