A nick instead of a cut
Standard CRISPR-Cas9 editing works by cutting both strands of a DNA double helix at a chosen location and then relying on the cell’s own repair machinery, which is often imprecise and prone to introducing unwanted small insertions or deletions at the cut site. Prime editing, disclosed in October 2019 by David Liu’s laboratory at the Broad Institute, with Andrew Anzalone and Luke Koblan as lead authors, takes a different approach designed to avoid that imprecision. It uses a modified version of Cas9, altered so that it nicks only one strand of the DNA rather than cutting through both, fused via a protein linker to a reverse transcriptase enzyme, the kind of enzyme that builds DNA from an RNA template.
A guide RNA that carries its own template
The system is directed by an extended guide RNA, called a prime editing guide RNA, that does two jobs at once: it locates the intended target sequence the way an ordinary CRISPR guide RNA does, but it also carries a template encoding the exact replacement sequence the researchers want installed. Once the Cas9 nickase cuts one strand, that cut exposes a free end that primes the reverse transcriptase to begin synthesising new DNA directly from the guide RNA’s template, producing an edited strand that the cell then incorporates, with the unedited flap of DNA trimmed away and the cell’s mismatch repair system resolving the remaining differences between strands. The result is a way of installing a precise, pre-specified edit without ever creating the kind of double-strand break that drives much of standard CRISPR’s imprecision.
Writing DNA rather than relying on repair
The method’s versatility has held up as a genuine advance over both standard CRISPR-Cas9 and the base editors Liu’s own lab had developed earlier: prime editing can carry out all twelve possible single-letter DNA changes, along with insertions of up to 44 base pairs and deletions of up to 80 base pairs, a considerably broader range of edit types than base editors, which are limited to specific chemical conversions between certain letter pairs. Since the original 2019 disclosure, successive engineered versions, moving through a series labelled PE1 through later variants including PEmax, have progressively improved editing efficiency, with reported gains of roughly seven to thirteen-fold from optimising the reverse transcriptase and other components, addressing what was initially a real efficiency shortfall relative to simpler editing methods.
A wider range of edits
The method still has real limits. Efficiency varies considerably depending on the cell type being edited and the specific location in the genome targeted, meaning results that work well in one context do not automatically transfer to another. Larger genetic alterations remain difficult for prime editing to achieve reliably, and the prime editing guide RNA itself is vulnerable to degradation inside cells, which has required additional engineering, including protective structural elements, to keep enough of it intact long enough to complete an edit. In plant systems specifically, editing efficiency has so far remained low, in some cases only a few percent, indicating the technique’s maturity varies substantially by application rather than being uniformly ready across every organism it has been tested in.
Seven generations of improvement
The clinical stakes of these limitations becoming solved rather than remaining theoretical became concrete in 2024, when a prime editor-based therapy named PM359 entered human clinical trials aimed at chronic granulomatous disease, a genetic immune disorder. By December 2025, the company developing the therapy reported that two patients treated with PM359 had been effectively cured of the condition, a result that, if it holds up under further scrutiny and longer follow-up, would represent one of the fastest journeys from a foundational genome-editing technique’s publication to an applied human therapy on record, spanning roughly five years from the original 2019 paper.
From lab bench to two treated patients
This is well worth understanding in its own right, separate from CRISPR-Cas9 generally, because the specific mechanical innovation, writing new DNA in directly via a nick and a template-carrying guide RNA rather than cutting and hoping repair goes well, is what explains both the method’s precision and its remaining efficiency challenges. The reported clinical outcome for chronic granulomatous disease gives the technology a concrete stake in the ground, though it is worth treating as an early, company-reported result rather than a fully settled scientific consensus at this stage. For anyone trying to keep track of where gene editing has actually gotten to, rather than where the original CRISPR story left off, this is time well spent.