Revolutionary Discovery: Ancient Enzyme Rebirth Could Uplift Gene Editing to New Heights!

In a groundbreaking discovery that has the potential to transform the field of genetic engineering, researchers have resurrected an ancient enzyme that could expand the capabilities of the widely-used CRISPR technology. Since its discovery in 2012 as a bacteria-derived immune system, CRISPR has revolutionized gene editing by utilizing a guide RNA and a nuclease. The RNA directs the nuclease to specific locations in the genome, where it cuts DNA, thus allowing for gene disruption or sequence replacement.

However, a notable limitation of existing CRISPR systems is their dependence on a short nearby sequence known as the protospacer adjacent motif (PAM). This PAM-checking mechanism prevents the system from inadvertently targeting the bacteria's own DNA, but it can impede the treatment of genetic diseases if a PAM sequence isn't present near the mutation. "If you want to target a genetic disease, but you don't find the PAM next to the target sequence, you cannot treat that mutation," stated Ylenia Jabalera Ruz, a postdoctoral researcher involved in the study.

While various CRISPR enzymes such as Cas9 and Cas12 offer some flexibility with different PAM sequences, the quest for a PAM-less CRISPR system continues. The research team, led by Jabalera, took an innovative approach by leveraging ancestral sequence reconstruction (ASR) to selectively resurrect an ancient enzyme. This method allowed them to rewind the evolutionary clock, yielding an enzyme capable of editing a broader range of genomic sequences.

The newly engineered protein, known as ReChb, is modeled after what Cas12a might have looked like in the common ancestor of modern hydrobacteria around three billion years ago. Tests revealed that ReChb performs differently and, intriguingly, more effectively in certain contexts than its modern counterparts. In experiments alongside an advanced Cas12a variant designed by Benjamin Kleinstiver's group at Massachusetts General Hospital, ReChb demonstrated comparable editing efficiency while successfully targeting PAM sequences that were previously unrecognized. Impressively, it handled both double-stranded DNA and single-stranded RNA with equal prowess, showcasing its versatility.

Benjamin Kleinstiver commented on the findings, praising ReChb's ability to target specific sites in human cells that were previously considered inaccessible. While this initial study focused on a limited set of gene editing sites, the potential of ReChb to fill editing blind spots in the genome is drawing attention.

Looking ahead, the researchers hope to implement their ancestral reconstruction strategy across various gene editing systems, including pioneering approaches to base editing—a method that acts like a genetic spell-checker. The quest does not end here; the team aims to explore the enzyme's potential for correcting mutations associated with rare diseases such as Amyotrophic Lateral Sclerosis (ALS). However, before ReChb can be utilized in clinical settings, rigorous safety evaluations are indispensable to mitigate the risk of unintended off-target edits.

"This could ultimately broaden the horizons for gene editing tools already making waves in genomics," said Raúl Pérez-Jiménez, Jabalera’s group leader and senior author of the study. "Our mission is clear: to reach the unreachable."

As the race for transformative genetic therapies continues, ReChb stands to be a pivotal player in unlocking new possibilities for treating genetic maladies and advancing personalized medicine. Keep your eyes on this developing story—science may be just on the verge of its next big breakthrough!