SHERLOCK vs. DETECTR: How Cas13 and Cas12a Power Two Different CRISPR Diagnostics

SHERLOCK and DETECTR are foundational CRISPR-based diagnostic platforms that differ in their core molecular machinery: SHERLOCK uses Cas13 for RNA detection, while DETECTR uses Cas12a for DNA detection. Both platforms employ collateral cleavage for signal generation, and understanding their specific enzyme, target, and readout differences is crucial for selecting the right tool for pathogen detection.

Maria Flores

October 22, 2026 · 5 min read

SHERLOCK and DETECTR are two foundational CRISPR-based diagnostic platforms that differ at their core molecular machinery: SHERLOCK uses the enzyme Cas13, which natively targets RNA, while DETECTR uses Cas12a, which natively targets DNA. Both convert a pathogen's genetic material into a visible signal through the same clever trick—collateral cleavage of reporter molecules—but they differ in the enzyme, the target nucleic acid, and the reporter chemistry that produces the readout. Understanding those differences is the key to choosing the right platform for a given pathogen detection application.

**Sherlock: Detecting disease with CRISPR**To visually explain the SHERLOCK system's mechanism and its application in disease detection, providing a dynamic complement to the textual explanation.Watch on YouTube

The SHERLOCK System: Cas13 and RNA Detection

SHERLOCK—short for Specific High Sensitivity Enzymatic Reporter UnLOCKING—was developed in the lab of Feng Zhang at the Broad Institute and MIT. Its engine is Cas13, an enzyme first identified in 2016 as an RNA-guided RNase, as described by Addgene's scientific blog. A single CRISPR RNA (crRNA) guides Cas13 to a complementary RNA sequence; once the enzyme finds and binds its matching target, it activates a promiscuous RNase activity that cleaves not only the target but any nearby single-stranded RNA molecules.

The platform exploits that promiscuity. Researchers introduce synthetic RNA reporters into the reaction; when Cas13 locks onto its target, it shreds these bystander RNA reporters, releasing a measurable signal. According to a tabulated review of CRISPR-Cas diagnostic tools, the original SHERLOCK assay pairs the LwCas13a enzyme with recombinase polymerase amplification (RPA) and fluorescence detection, targeting viruses and bacteria with single-nucleotide specificity and a reported sensitivity of roughly 2 × 10⁻¹⁸ molar, in a process taking two to five hours.

The Zhang lab later refined the tool for field use. As reported by the Association for Diagnostics & Laboratory Medicine, the team adapted the readout to a paper strip resembling a pregnancy test: users dip the strip into a processed sample and watch for a line to appear. "The new paper readout for SHERLOCK lets you see whether your target was present in the sample, without instrumentation," said co-first author Jonathan Gootenberg. A later version combined multiple Cas13 enzymes with Cas12a to sense several targets—such as dengue and Zika virus—in a single reaction, and paired Cas13 with the enzyme Csm6 to boost sensitivity threefold.

Core mechanistic and operational differences between the SHERLOCK and DETECTR platforms
Characteristic	SHERLOCK System	DETECTR System
Primary Cas enzyme	Cas13 (e.g., LwCas13a), an RNA-guided RNase	Cas12a (e.g., LbCas12a), an RNA-guided DNA endonuclease
Target nucleic acid	RNA (viruses, bacteria listed as targets)	DNA (demonstrated with HPV 16/18)
Collateral cleavage target	Bystander single-stranded RNA reporters	Bystander single-stranded DNA reporters
Amplification method	RPA (isothermal)	RPA (isothermal)
Reported readout	Fluorescence; later paper-strip lateral flow	Fluorescence
Reported sensitivity	2 × 10⁻¹⁸ M (original assay)	10⁻¹⁸ M
Reported time	2–5 hours (original assay)	2 hours

Choosing the Right Platform for Pathogen Detection

For a specific application, the first question is the nature of the pathogen's genome. A DNA virus or a bacterium whose diagnostic signature is genomic DNA aligns naturally with DETECTR's Cas12a machinery, as demonstrated in the HPV work. RNA targets align naturally with SHERLOCK's Cas13. This distinction is based on the native target preference of the Cas enzymes, though the platforms' developers have extended each tool's reach—the SHERLOCK team, for instance, demonstrated detection of cancer mutations in cell-free DNA from saliva samples.

Secondary considerations follow from the published performance characteristics. The tabulated review reports comparable sensitivity for the foundational assays, with DETECTR's two-hour workflow at the faster end of SHERLOCK's two-to-five-hour range, and SHERLOCK offering single-nucleotide specificity against DETECTR's roughly six-nucleotide resolution. SHERLOCK's paper-strip readout, requiring no instrumentation, is a meaningful advantage in outbreak and resource-limited settings, while DETECTR's single-reaction format was designed from the outset for point-of-care DNA detection. These metrics come from published studies and may vary in real-world clinical use.

Two caveats bound this guidance. This comparison addresses the foundational SHERLOCK and DETECTR technologies, not every commercial product or later "version 2.0" iteration, such as the multi-enzyme SHERLOCKv2 that added Cas12a and Csm6 to the original Cas13 core. And neither platform is endorsed here for any specific medical diagnosis—the choice of a clinical diagnostic requires validation and regulatory review beyond a mechanistic match.