12 Startups Applying AI to Gene Editing: From Custom CRISPR to Zinc-Finger Revivals

While the CHOP–Penn therapy was built on established molecular and delivery technologies, it highlighted the pace that targeted interventions can now reach. For many, the next question is how such approaches might scale beyond bespoke development. One path involves increasing reliance on computational tools to guide design and reduce iteration time. Reflecting on that broader possibility in late 2024, CRISPR co-inventor Jennifer Doudna noted:

“It’s still early days, but the potential to appropriately harness the joint power of AI and CRISPR, arguably the two most profound technologies of our time, is clear and exciting—and it’s already started.”

In this article: The Cradle of Gene Editing—CRISPR Arrives—Life after CRISPR—AI-Powered Applications—Startups Applying AI—DNA Cleavage Layer—DNA-Base Editing — RNA Editing—Epigenetic Rewiring—CRISPR-Customising Layer—Policy, Funding, and the Future

The Cradle of Gene Editing

Genetic engineering began in 1974 with an experiment in mice, where Rudolf Jaenisch and Beatrice Mintz injected viral DNA into early embryos and showed it had integrated into the animals’ germline. In 1980, Jon Gordon and Frank Ruddle advanced the method by microinjecting foreign DNA into fertilized eggs, producing mice that passed the genetic changes to their offspring. The term “transgenic” was introduced a year later to describe these genetically altered animals.

“Important as transgenic mice are, they are really the tip of the iceberg when compared with what we are going to see in the next few years.”—Janet Rossant (National Research Council, 1994)

In 1981, two groups—Martin Evans with Matthew Kaufman, and independently Gail Martin—isolated pluripotent embryonic stem (ES) cells from mouse blastocysts. This made way for targeted gene deactivation using homologous recombination (a method that replaces a stretch of DNA with an engineered copy by using the cell’s own repair machinery) in ES cells. In the late 1980s, Oliver Smithies and Mario Capecchi independently applied that technique, and together with Evans, shared the 2007 Nobel Prize in Physiology or Medicine.

Shortly after, the Cre-lox system, originally derived from a bacteriophage, introduced temporal and spatial control to genetic alteration (pioneered by Nat Sternberg, and later adapted for mammals by Brian Sauer and Nancy Henderson).

A marked advance came when researchers showed, first with the yeast-derived meganuclease, that introducing a site-specific double-strand break (DSB) in mammalian DNA massively increases the cell’s uptake of foreign sequences.

These nucleases (enzymes that cut DNA) trigger the cell’s repair machinery, which can act in two ways:

• Error-prone non-homologous end joining (NHEJ), leaving random insertions and deletions (INDELs).
• High-fidelity homology-directed repair (HDR) when a suitable donor template is present, enabling precise sequence replacement or gene insertion.

Although meganucleases such as I-SceI showed the concept works, each one cuts only a single 20–30-bp DNA sequence, so scientists had to scrupulously redesign the enzyme for every new target, making it clear we needed nucleases that can be retargeted far more easily.

In 1996, scientists built zinc-finger nucleases (ZFNs) by attaching a customizable DNA-binding module (“handle”) to Fok1, a nuclease derived from a marine bacterium. By 2005, this breakthrough had sparked the phrase “genome editing”, as ZFNs let researchers tweak genes with pinpoint accuracy, even turning off specific genes in animals like rats.

In 2010, the discovery of transcription activator–like effector nucleases (TALENs) offered more flexible DNA-binding modules in comparison to ZFN further simplifying genome editing. Together, these three—meganucleases, ZFNs, and TALENs—laid the groundwork for today’s advanced gene-editing.

CRISPR Arrives

Imagine a nuclease merging the precision-binding prowess of ZFNs and TALENs, but sidestepping all the painstaking protein engineering, because nature had already perfected the mechanism.

In the late 1980s, curious genetic patterns were discovered in E. coli genomes: clusters of short DNA repeats, each separated by unique sequences that didn’t repeat. The purpose of these alternating repeat–spacer patterns was unknown at the time.By the early 2000s, scientists realized these arrays, now called Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), were consistently present with Cas genes across bacteria and archaea.

By 2007, Horvath’s group uncovered CRISPR/Cas as microbial adaptive immunity, a molecular memory bank storing viral genetic snippets (spacers) to guide precision-strike nucleases that recognize and cut matching viral sequences during future infections. Central to this system is the CRISPR RNA (crRNA), directing the nuclease, and the protospacer-adjacent motif (PAM), specifying the exact genomic target.

CRISPR/Cas9 structure. From