A team at the University of Illinois have invented a brand-new type of CRISPR gene-editing technique. Unlike the classic version, which effectively snips out DNA fragments and pastes in bespoke ones, this one does something a little different: instead of breaking strands of DNA, it changes individual points within a sequence.
Known as CRISPR-SKIP, there’s a chance that it could lead to gene-editing with a lower likelihood of dangerous genetic mutations.
It’s putting it crudely to say that CRISPR acts as scissors when it cuts apart double-stranded segments of DNA, but that’s essentially how it works. This is famously precise compared to plenty of other pre-existing gene-editing techniques, but it’s not without its problems. Those double-strand breaks, or DSBs, are what makes CRISPR work, but these genetic wounds can trigger unpredictable mutations to occur.
While the revolutionary gene-editing technique is already beginning to change the biomedical world, there’s much we still don’t know about CRISPR, and a handful of recent studies suggest that in some specific situations, it can inadvertently increase cancer risk via these DSBs.
While DSBs are being closely investigated, alternatives to this DNA cutting are being looked into. CRISPR-STOP, for example, uses stop codons – organic molecules with genetic information that tells cells to stop making proteins – to alter DNA without doing any snipping.
In our and other mammals’ cells genes are subdivided into components called exons. These exons are scattered within regions of DNA, named introns, that don’t seem to do anything in particular.
When a cell transcribes a gene into RNA and preps it to be translated into a protein, the DNA sequence lights up, so to speak. This lets researchers see what parts are useful exons and what parts aren’t. Only the portion of the DNA that is needed by the cell, the exons, are transcribed into RNA before being sewed together.
That’s useful, because knowing where those exons are mean that you can hack the gene sequences as it does its transcribing. No snipping required: just alter a single base just ahead of an exon, and the cell might think it’s a useless intron.
This exon is ignored and not transcribed, meaning that action-inducing proteins appear without them. Unlike other gene-editing techniques that use the same principle, these changes aren’t temporary, but permanent.
It’s a bit like turning a few lines of code invisible before the whole thing is copied and pasted elsewhere, leaving that bit of code behind. Sure, the eventual proteins are missing a few of their building blocks – the amino acids – but the authors note that the proteins remain partially or entirely functional.
Using human and mice cells, both healthy and cancerous, the team found that CRISPR-SKIP is both precise and efficient at engendering such changes. The implications, beyond boosting our genetic comprehension, are wide-ranging.
The authors emphasize that SKIP-like tech has shown promise in treating a range of conditions, from cancer and rheumatoid arthritis to Huntington’s disease and Duchenne muscular dystrophy (DMD). “Exon skipping is especially exciting for the treatment of DMD,” the paper explains, as targeting just one of two exons in this way could provide a significant benefit to the patient.
The data suggests “that CRISPR-SKIP can produce exon skipping at therapeutically significant levels,” but the team can’t say for sure at present, as live animals have yet to be targeted. It may be early days, but it’s safe to say that classic CRISPR isn’t the only genetic magician in town.