A new generation of CRISPR-based genetic tools is capable of inserting entire genes into human DNA — a breakthrough that could transform gene therapies and treatments involving genetically engineered immune cells against cancer.
Until now, large DNA sequences were typically delivered using modified viruses, which insert genetic material at random positions, risking harmful mutations. The original CRISPR system, awarded the Nobel Prize in Chemistry in 2020, improved precision by acting as a molecular scissor, cutting DNA at exact locations. But these cuts still relied on the cell’s imperfect repair mechanisms.
Now, scientists at Harvard and MIT have improved on this with CAST (CRISPR-associated transposase), an advanced system that bypasses DNA cutting altogether. Inspired by enzymes from bacterial “selfish genes” called transposons, CAST allows controlled insertion of large genetic sequences without triggering DNA damage.
In a study published in Science, researchers used directed evolution to refine these bacterial enzymes. Thousands of enzyme variants were tested in bacteria, and the most efficient versions were selected. The final CAST enzymes successfully inserted full genes in 30% of cases — a 400x improvement over natural systems.
Meanwhile, another team at Harvard reported a similar tool based on transposons found in birds. And biotech firm Metagenomi recently unveiled a simplified version of CAST using smaller bacterial enzymes.
Despite promising results, challenges remain: occasional misplacements of the gene, and the complexity of delivering these tools into human cells. But researchers believe CAST could eventually lead to one-time treatments that don’t introduce new mutations.
“It’s a major step toward safer and more flexible genetic therapies,” said researchers involved in the studies. The race is now on to make these tools clinically viable.