CRISPR is often described as one of nature’s most precise genetic tools. But scientists have now discovered an ancient RNA-guided system that appears to have been using a very different way of finding DNA long before modern CRISPR systems evolved.
Researchers from the Innovative Genomics Institute at UC Berkeley, led by Nobel laureate Jennifer Doudna, discovered a viral system called VIPR, or Viral Interference Programmable Repeat. The system appears to be an ancient relative of the molecular machinery behind CRISPR and uses a previously unknown “gapped” code to recognize DNA. The discovery not only offers a new clue about the origins of CRISPR, it could eventually provide scientists with another way to control genes.
The discovery began with a difficult question: where did some of the ancient proteins associated with CRISPR systems originally come from?
Rather than searching only for similar DNA or protein sequences, they used AI-assisted structural analysis. They screened roughly 2.3 million protein structures, looking for proteins whose three-dimensional shapes resembled components of ancient CRISPR systems even when their sequences had become too different to recognize easily. Among the candidates was a protein that looked remarkably similar to proteins associated with ancient CRISPR machinery. But there was a problem. It was paired with an unfamiliar RNA that did not resemble a conventional CRISPR guide RNA. That mystery eventually led to VIPR. A genetic code with gaps Typical RNA-guided systems recognize a target by using a sequence that is complementary to the target nucleic acid. In simple terms, the letters in the guide line up with the letters in the target. VIPR does something much stranger.
Its RNA contains repeating GGY and NN motifs, where the variable NN sequences carry information about the target. Instead of matching every position continuously, the system effectively skips every third nucleotide. The result is a recognition system with gaps in the RNA-DNA pairing. Researchers described this as a noncontiguous code, a targeting strategy that had not previously been observed in this context. This unusual arrangement may also explain why the system escaped detection by conventional searches for so long. Instead of cutting DNA, VIPR wraps around it. VIPR is also structurally different from familiar CRISPR systems.
Using cryo-electron microscopy, it was found that multiple VIPR proteins assemble along the RNA to form a helical structure. When the system encounters its target DNA, the RNA does not simply pull apart the DNA strands. Instead, the RNA-DNA structure wraps around the DNA’s nontarget strand, creating an unusual three-stranded structure called a triplex. This interaction allows VIPR to interfere with gene activity. In laboratory experiments, they were able to reprogram the system to target specific DNA sequences and silence gene expression through transcriptional repression. They also redirected the system to defend against bacteriophages, demonstrating that its targeting mechanism can be programmed.
Did viruses invent the ancestor of CRISPR?
Perhaps the most surprising part of the discovery is where VIPR was found. The system appears mainly in viruses and viral genetic material, particularly bacteriophages, viruses that infect bacteria. Analysis of naturally occurring VIPR targets suggests that these systems may have been used by viruses to interfere with competing viruses. That creates an intriguing evolutionary possibility. Instead of CRISPR-like adaptive immunity beginning entirely within bacteria, an ancient viral system may have provided some of the molecular machinery that bacteria later adapted for their own defense against viruses. In this scenario, bacteria may have effectively taken a weapon from viral competition and turned it against their attackers. The finding does not prove every step of this evolutionary history, but it provides an important new clue about how RNA-guided immunity may have emerged.
Could VIPR become the next gene-editing tool?
VIPR is very small compared with many modern genome – engineering systems. Smaller molecular tools can be easier to package and deliver into cells, an important challenge for gene-editing applications. The system also appears capable of recognizing DNA without relying on the same type of nearby sequence requirement that restricts where some CRISPR enzymes can operate. That could potentially expand the range of genomic locations that can be targeted.
They have demonstrated programmable targeting and transcriptional repression in laboratory experiments, not a clinical gene-editing therapy. Much more work is needed to understand its accuracy, efficiency, safety and ability to function inside human cells. For now, VIPR may be most valuable for something even more fundamental: showing scientists that nature has been experimenting with RNA-guided DNA recognition in far more ways than previously imagined. A strange piece of viral RNA, a protein found through structural searches and a genetic code with deliberate gaps have together opened another chapter in the story of CRISPR. And sometimes, understanding the future of gene editing begins by discovering how nature built its oldest tools.
