Over the past decades CRISPR, short for “clustered regularly interspaced short palindromic repeats”, has become somewhat of a household name, holding the promise of directly addressing genetic mutations by effectively removing, silencing, or even fixing them. Yet the original purpose of CRISPR is slightly less cute and cuddly: the evolutionary origin of these DNA sequences is that of a core component of the prokaryotic immune system.

In most medical applications today we only try to use CRISPR to detect sequences and then apply enzymes such as the well-known Cas9 to cut DNA at specific locations in the process of gene-editing. In a recent study (paywalled, bioRxiv pre-print) by Jingkun Zheng et al. in Nature such benign enzymes are dropped for Cas12a2, which turns a detection event into the release of a DNA-destroy enzyme as the molecular equivalent of a guided missile.

The pitched use case here is the detection of cancer-cell specific mutations in the DNA, following which the tumor cells will be instantly shredded from the inside. This could theoretically provide a cure for many cancer types, but should we expect to see this kind of therapy approved any time soon?

The Original CRISPR

CRISPR-based immunity overview. (Credit: Guido4, Wikimedia)

What we call CRISPR is quite literally what the name says: clustered occurrences of repeats with spacers made of genetic code fragments in the prokaryotic DNA. These can be considered to be the memory of the prokaryotic immune system, with genetic sequences from e.g. invasive viruses and bacteriophages embedded in the organism’s own DNA as these spacers.

In prokaryotic organisms like bacteria these CRISPR arrays are accompanied by multiple CRISPR-associated systems (CAS, or Cas): genes that are translated into proteins which are associated with these CRISPR arrays. Of these, CRISPR-associated protein 9 (Cas9) is a protein that that performs double-strand DNA cutting action when provided with a transcribed RNA copy (crRNA) of the CRISPR spacer in question after it has been attached to a protospacer adjacent motif (PAM). This PAM ensures that the original sequence in the CRISPR locus is not attacked.

Directly attacking the genetic material of an intruder in this manner is somewhat more aggressive than the comparable system eukaryotes called RNA interference. This merely silences target mRNA genes, which incidentally is a problem with mRNA-based vaccines and thus require a special coating of the mRNA particles.

Cas12a2

Although we could conceivably use Cas9 for an anti-cancer therapy as well by damaging the DNA with a double-strand DNA break and pray it’s enough, the Cas12a protein lineage offers us an even more suitable protein, since it’s less complex and yet much more versatile than Cas9. The first step remains the same, with a transcription of the target RNA fragment containing the mutated gene’s signature with PAM used to track down any affected cells in the patient’s body.

Abortive infection strategy compared with uncontained infection in bacterial colony. (Credit: Lopatina et al. Annu Rev Virol. 2020) — Abortive infection strategy compared with uncontained infection in bacterial colony. (Credit: Lopatina et al., Annu Rev Virol. 2020)

The variant of Cas12a that has received a lot of attention lately is Cas12a2, which as Oleg Dmytrenko et al. reported in 2023 induces cell death. This effectively means that the infected bacteria commits suicide if it detects via Cas12a2 that it has become infected, destroying itself before it can be used by e.g. a bacteriophage to replicate itself and infect the rest of the colony.

How Cas12a2 exactly achieves the shredding of the host cell’s DNA is elucidated in a 2026 study by Paul Scholz et al. in Nature. The simple version is that rather than performing a targeted cut of double-stranded DNA (dsDNA), Cas12a2 continues making cuts to the host’s dsDNA and chromatin until said cell enters apoptosis.

Crucial here in the context of using Cas12a2 for cancer treatments is that it accurately recognizes the crRNA sequence and does not have a high off-target ac...

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