Francisco Mojica was not the first to see CRISPR, but he was probably the first to be smitten by it. He remembers the day in 1992 when he got his first glimpse of the microbial immune system that would launch a biotechnology revolution. He was reviewing genome-sequence data from the salt-loving microbe Haloferax mediterranei and noticed 14 unusual DNA sequences, each 30 bases long. They read roughly the same backwards and forwards, and they repeated every 35 bases or so. Soon, he saw more of them. Mojica was entranced, and made the repeats a focus of his research at the University of Alicante in Spain.
It wasn’t a popular decision. His lab went years without funding. At meetings, Mojica would grab the biggest bigwigs he could find and ask what they thought of the strange little repeats. “Don’t care about repeats so much,” he says that they would warn him. “There are many repeats in many organisms — we’ve known about them for years and still don’t know how many of them work.”
Today, much more is known about the clustered, regularly interspaced short palindromic repeats that give CRISPR its name and help the CRISPR–Cas microbial immune system to destroy invading viruses. But although most in biomedicine have come to revere the mechanics of the system — particularly of a version called CRISPR–Cas9 — for the ways in which it can be harnessed to edit genes, Mojica and other microbiologists are still puzzling over some basic questions about the system and how it works. How did it evolve, and how did it shape microbial evolution? Why do some microbes use it, whereas others don’t? And might it have other, yet-to-be-appreciated roles in their basic biology?