CRISPR’s rise from obscure bacterial defense system to molecular scalpel has always hinged on one small component: the guide RNA. For years, that guide RNA—meticulously designed, modified, and optimized in countless labs—has been treated as an immutable feature of the system. CRISPR cuts where the RNA tells it to cut. That’s the central dogma of the system. But a new approach suggests the system is more flexible than anyone expected. The study, published in Nature Biotechnology, is titled “DNA-guided CRISPR–Cas12 for cellular RNA targeting.” Researchers at the University of Florida (UF) have developed the first CRISPR system that uses DNA, rather than RNA, to direct Cas enzymes to RNA targets. The platform, called ΨDNA, reprograms Cas12 nucleases to recognize and act on RNA using a DNA-based guide scaffold. The result is a fundamentally different way of controlling RNA inside cells—one “that extends Cas12 systems beyond genome editing and diagnostics to enable precise, programmable control of cellular transcriptomes and their epitranscriptomic marks,” according to the authors. The concept is rooted in a simple biological distinction. DNA stores the cell’s long-term instructions, but RNA carries the working copies. “Those RNA copies are like Xerox copies of the original manual, and sometimes those copies have errors,” said Piyush Jain, PhD, associate professor of chemical engineering at UF and lead author of the study. Errors in those working copies can drive disease, and targeting RNA offers a way to intervene without altering the underlying genome. But RNA‑guided CRISPR systems, such as Cas13, can suffer…
