Zhang Feng’s team makes a major breakthrough in Science! Discovers 188 novel CRISPR systems—gene editing poised for a new leap forward.

Thirty years ago, at the University of Alicante in Spain, a doctoral student named Francisco Mojica was studying salt-tolerant archaea collected from local beaches. In the DNA sequence of one archaeon, Mojica noticed a puzzling phenomenon: a 30-base-long segment repeated at regular intervals. After a decade of research, Mojica finally uncovered the function of these repeats: they serve as an ‘immune system’ for archaea and bacteria, enabling them to remember the genetic signatures of bacteriophages and thereby resist subsequent infections. These sequences bear a name now universally familiar: CRISPR. Mojica’s discovery did not gain immediate recognition; his manuscripts were rejected by multiple academic journals before finally appearing in the relatively low-impact Journal of Molecular Evolution. Yet the scientific community soon grasped the immense potential of CRISPR—and what followed is the now-familiar story. In 2012, Professors Emmanuelle Charpentier and Jennifer Doudna published their landmark work on the CRISPR-Cas9 gene-editing system, using the Cas9 endonuclease to achieve precise, site-specific DNA cleavage. Less than a year later, Professor Feng Zhang’s team successfully adapted and applied the CRISPR-Cas9 system to mammalian and human cells for the first time. Today, CRISPR has become a revolutionary tool reshaping biological research and disease therapy. Yet scientists remain unsatisfied—and continue probing deeper into CRISPR’s untapped potential. In the latest issue of Science, Professor Feng Zhang’s team from MIT and the Broad Institute, collaborating with Professor Eugene Koonin of the U.S. National Institutes of Health, leveraged a newly developed algorithm to screen billions of protein sequences—and identified 188 previously unknown CRISPR-associated systems. This discovery may expand the classification of CRISPR systems to seven major classes. It further confirms the extraordinary diversity of CRISPR systems and holds promise for delivering next-generation gene-editing tools. In recent years, computational mining of protein sequence databases has dramatically expanded the CRISPR toolbox. To date, scientists have classified six types of CRISPR systems, designated Types I–VI. The widely used CRISPR-Cas9 system belongs to Type II. We know that CRISPR systems consist of two essential components: a guide RNA that recognizes and binds to phage DNA or RNA, and an enzyme that cuts or otherwise interferes with genetic material at the site specified by the guide RNA. Different CRISPR types employ distinct enzymes—and differ in how they recognize, bind to, and cleave genetic material. But this is not the full picture: many unknown CRISPR systems likely reside in rare bacterial or archaeal species found in nature. The discovery of novel CRISPR systems promises to advance biotechnology further—and aid in developing safer, more effective gene therapies.

Performing ‘surgery’ on DNA—the magical CRISPR-Cas9 technology (Part I)

This process unfolds in three core stages—‘Adaptation,’ ‘Expression,’ and ‘Interference’—like three tightly interlocked gears, forming a complete defense cascade. Stage One: Adaptation—‘Recording’ fragments of invading viral DNA to build a ‘viral sample library’ When a virus first enters a bacterium—for instance, carried in by a bacteriophage—the bacterium initiates its ‘memory archiving’ process—akin to saving important files onto a computer—by integrating characteristic fragments of the invader into its own genome, thus preparing thoroughly for future defensive operations. • Recognition and cleavage: Once viral DNA enters the bacterium, the Cas1 and Cas2 proteins act like elite detectives, identifying specific sequences (typically conserved, mutation-resistant regions within the viral genome) and cutting them into short fragments (~20–40 bases), termed ‘spacers.’ But before cleavage occurs, the Cas1–Cas2 complex must first accomplish two tasks. First, it scans the foreign viral genome for a special PAM sequence (Protospacer Adjacent Motif)—a ‘molecular ID card’ of the invading virus. Second, the Cas1–Cas2 complex rapidly compares the candidate viral DNA fragment against mature crRNA (see below) transcribed from the CRISPR array. If the match is 100% identical, the crRNA and DNA form a stable duplex, signaling to the Cas1–Cas2 complex that this DNA fragment is already stored in the CRISPR array—prompting immediate release of the fragment and initiation of a new scan. This energy-independent step—ensuring swift, decisive ‘breakups’ without lingering entanglement—completes within milliseconds and is termed ‘pre-integration proofreading.’ If the viral DNA fragment fails to match the crRNA perfectly, the complex uses the PAM as a positional anchor to precisely excise the functional fragment from the viral DNA—excluding the PAM sequence itself. • Integration into the CRISPR locus: Next, the Cas1–Cas2 complex inserts the cleaved spacer into the bacterium’s own genome—at the CRISPR locus. The CRISPR locus has a distinctive structure: alternating repeats (endogenous ‘conserved sequences’ from the bacterium) and spacers (exogenous ‘memory fragments’ derived from viruses). The new spacer integrates at the leader-proximal end of the CRISPR array—a ‘most-recent-first’ archival strategy, analogous to placing the newest photos at the front of an album. During integration, the two DNA strands of a repeat are first nicked at both ends; then the double-stranded spacer DNA is ligated—one strand to the upstream end, the other to the downstream end. Finally, cellular DNA repair machinery seals the gaps, restoring the repeat and yielding a fully intact, updated CRISPR array. (See Figure 3. Also Figures 4 and 5, all from ‘An Introduction to CRISPR Systems.’ Grateful acknowledgment to the original source!) • Significance: This step effectively ‘vaccinates’ the bacterium. By preserving fragments of viral DNA, it equips both the host and its progeny to recognize and counteract the same class of invaders.

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