TL;DR: Rice University researchers reported on Oct. 13, 2026 that they engineered a heat-tolerant Cas13a enzyme to detect viral RNA with 100-fold higher sensitivity without losing stability.

Rice Team Rebuilds a Heat-Tolerant CRISPR Enzyme for Sharper Viral RNA Detection

Researchers at Rice University in Houston, Texas, have developed an engineered version of the RNA-targeting CRISPR enzyme Cas13a that combines heat tolerance with sharply improved sensitivity, and they validated it in a laboratory detection assay using a synthetic, noninfectious HIV sample, according to Rice News. The work was published online on Oct. 13, 2026 in Cell Chemical Biology under the title “Structural basis and rational engineering of a thermophilic Cas13a for robust RNA detection,” according to Cell Chemical Biology. The engineered variant showed a 100-fold increase in both target RNA sensitivity and collateral activity relative to the wild-type enzyme while retaining programmability, mismatch discrimination and stability across diverse biological matrices, according to Cell Chemical Biology.

A CRISPR tool built for detection, not DNA editing

Scientists have long used CRISPR for precise changes to DNA, but Cas13a targets RNA, the genetic material found in viruses such as HIV, according to Rice News. The Rice team focused on a thermostable Cas13a ortholog from Thermoclostridium caenicola, termed TccCas13a, according to Cell Chemical Biology. That starting point was chosen because it could withstand harsh conditions while still performing its job, although it was not able to detect very small amounts of target RNA, according to Rice News.

CRISPR-Cas-based diagnostics have emerged as a powerful complementary alternative to polymerase chain reaction, or PCR, for rapid and sensitive nucleic acid detection, particularly in settings requiring simplified workflows and faster turnaround times, according to Cell Chemical Biology. Among these systems, CRISPR-Cas13a-based detection platforms have gained prominence due to programmable RNA targeting, collateral RNase activity and compatibility with diverse sensitivity-enhancing platforms that enable signal amplification in detection assays, according to Cell Chemical Biology.

In a detection assay, an enzyme like Cas13a binds to its target, such as a strand of RNA from HIV or SARS-CoV-2, and produces a signal, like a colored light or color change, that can be read by a human or machine, according to Rice News. In most assays, the path to producing a signal requires harsh conditions, according to Rice News. The authors report that the widely used mesophilic LwaCas13a and LbuCas13a orthologs exhibit limited stability, poor activation against structured target RNAs and reduced performance in complex biological matrices, thereby constraining their utility in point-of-care settings, according to Cell Chemical Biology.

Why stability and sensitivity must work together

“Any enzyme used in an assay needs to be both sensitive and stable,” said Yang Gao, an associate professor of biosciences at Rice and the corresponding author on the paper, according to Rice News. Gao said the enzyme needs to detect very small amounts of RNA while enduring harsh conditions, like high temperatures, and that the team took a stable Cas13a and engineered it to have the desired sensitivity, according to Rice News.

The target sensitivity goal was described in concrete terms by first author Seye Oladeji, a graduate student at Rice, according to Rice News. Ideally, a detection assay will tell whether there is as little as one strand of RNA per microliter of liquid — around a drop of blood, according to Rice News. The stable Cas13a variant the team started with was just not sensitive enough, a gap Oladeji described as a problem for an engineering approach, according to Rice News.

The recently identified thermostable TccCas13a overcomes limitations in stability and structured RNA targeting through compatibility with elevated temperatures, but its inherent low target sensitivity and collateral activity constrain diagnostic utility and underscore the need for engineering, according to Cell Chemical Biology. Compatibility with elevated reaction temperatures further supports detection of structured RNA targets, which can be difficult for mesophilic Cas13a enzymes, according to Cell Chemical Biology.

Who conducted the study and when it was published

The paper lists Seye J. Oladeji as first author and Yang Gao of the Department of BioSciences at Rice University in Houston as lead contact, according to Cell Chemical Biology. Additional authors include Diego H. Gonzalez, Xiangyu Deng, Zheng You, Yuxuan Zhang, Devin A. Golla, Jamie Smith, Yi Zhang, Xue Gao and Peter B. Lillehoj, according to Cell Chemical Biology. Contributing departments and institutions include Rice BioSciences, Rice Bioengineering, Rice Chemical and Biomolecular Engineering, Rice Mechanical Engineering, the University of Connecticut Department of Biomedical Engineering and Institute of Materials Science, and University of Pennsylvania departments spanning Chemical and Biomolecular Engineering, Bioengineering and the Center for Precision Engineering for Health, according to Cell Chemical Biology.

The publication history lists receipt on March 19, 2026, revision on June 19, 2026, acceptance on Sept. 16, 2026 and online publication on Oct. 13, 2026, according to Cell Chemical Biology. The article carries DOI 10.1016/j.chembiol.2026.09.012, according to Rice News reporting that also references the journal record. The Rice announcement was dated Oct. 13, 2026 and described the work as a new enzyme optimized for RNA detection assays, according to Rice News.

The work was funded by the National Science Foundation under awards CBET-2431018, CBET-2431019 and CBET-2431020, the Welch Foundation under C-2033-20200401, the National Institutes of Health under R61AI167037 and the Diana McSherry and Patrick Poe Research Award for AY-23-24, according to Rice News.

Freezing motion to see the enzyme’s structure

To engineer the stable Cas13a into a more sensitive version, Oladeji first had to understand how it worked, which required resolving the structure of the protein, or collecting enough information to accurately draw out the enzyme’s building blocks and how they fold together, according to Rice News. Cas13a is a protein that moves a lot as it binds, making it hard to capture in the crisp detail needed for resolution, according to Rice News. Oladeji designed a way to hold the CRISPR/Cas13a and its target RNA in place while collecting information on its structure, according to Rice News.

The team reports comprehensive biochemical characterization and structure-guided engineering of TccCas13a, including analyses of intrinsic thermostability, nucleotide substrate preferences and tolerance to structured target RNA substrates, according to Cell Chemical Biology. Rational engineering of the spacer-target RNA binding channel improved target engagement and enabled determination of a 3.13-angstrom cryo-electron microscopy ternary structure, according to Cell Chemical Biology. The journal summary describes the structure as the cryo-EM ternary structure of TccCas13a, according to Cell Chemical Biology.

The new-articles listing for Cell Chemical Biology states that Oladeji and colleagues determined the cryo-EM structure of the TccCas13a ternary complex and leveraged structural insights to engineer a thermophilic Cas13a variant with 100-fold enhanced sensitivity, according to Cell Chemical Biology. The engineered nuclease retains programmability and thermostability, enabling highly sensitive RNA detection in different biological matrices, according to Cell Chemical Biology.

Two regions tested, one kept for the final design

Once the structure was resolved, the team identified regions of the enzyme believed to increase sensitivity, selected two regions to engineer and tested the results in the laboratory, according to Rice News. When both regions were altered, the enzyme was a little too sensitive and would signal even if the RNA target was not present, according to Rice News. When just one region was altered, sensitivity went up 100-fold without any loss of stability, according to Rice News.

The journal paper describes extensive structure-guided engineering of active site-proximal regions, which yielded a variant with over approximately 100-fold enhanced target sensitivity and collateral activity across diverse biological matrices, according to Cell Chemical Biology. The analyses establish TccCas13a as a platform for next-generation RNA diagnostics and provide mechanistic insights from structural information used to tune Cas13a enzymes for diagnostic applications, according to Cell Chemical Biology.

“We tested the sensitive — but not too sensitive — engineered Cas13a against a synthetic, noninfectious HIV sample and found that it worked in our detection assay with a 100-fold performance improvement,” Oladeji said, according to Rice News. The test used a synthetic, noninfectious HIV sample, not a patient sample or live virus, according to Rice News. The team described the result as a reminder to be careful not to overengineer a protein, according to Rice News.

Tested on HIV, designed for many RNA viruses

While the team’s laboratory test detected HIV, the benefit of using a CRISPR system is flexibility, because the Cas13a enzyme is paired with a guide that is programmed to target a specific sequence of RNA, according to Rice News. It is easy to change the programmed guide, and the team noted the same Cas13a enzyme could be reprogrammed with a different guide to detect SARS-CoV-2, influenza virus, Ebola virus, Zika virus, respiratory syncytial virus or hepatitis C virus instead of HIV, according to Rice News.

The researchers said the improved Cas13a could make it easier to detect HIV and other RNA viruses in blood and environmental samples, according to Rice News. The journal account emphasizes that the engineered variant maintained programmability and mismatch discrimination alongside stability across diverse biological matrices, according to Cell Chemical Biology. Intrinsic thermostability, nucleotide substrate preferences and tolerance to structured target RNA substrates were part of the reported biochemical characterization, according to Cell Chemical Biology.

Gao said the guide is easy to program, so the critical part of the system is having an enzyme compatible with assays, and described the Rice version of Cas13a as optimized for sensitive and stable RNA detection assays with potential use in commercial assays like RT-qPCR and lateral flow, according to Rice News. That potential commercial use was framed as a possibility, not as an established product or completed deployment, according to Rice News. The overall findings demonstrate how structural information can be used to tune Cas13a enzymes for diagnostic applications, according to Cell Chemical Biology.

What the advance changes for assay developers

For developers, the advance centers on an enzyme that tolerates elevated temperatures, engages structured RNA targets and still delivers stronger collateral signaling once the target is present, according to Cell Chemical Biology. Collateral activity is attractive for nucleic acid detection because robust collateral activity supports signal generation after target recognition, according to Cell Chemical Biology. There has recently been a surge in discovery and engineering of thermostable Cas13a proteins for nucleic acid detection, and the Rice work addresses the relatively low native target sensitivity and collateral activity that required optimization for molecular diagnostic applications, according to Cell Chemical Biology.

The Rice announcement positions the result as an improved version of Cas13a that could simplify detection of HIV and other RNA viruses in blood and environmental samples, according to Rice News. The study’s laboratory demonstration used a detection assay with a 100-fold performance improvement against the synthetic HIV control when the single-region engineered enzyme was used, according to Rice News. The dual-region alteration was not carried forward as the preferred design because it produced signaling even without the RNA target present, according to Rice News.

Together, the reported 3.13-angstrom structure, the single-region engineering choice and the retained stability point to TccCas13a as a starting platform for further diagnostic assay work, according to Cell Chemical Biology. The paper’s significance statement says the findings show how structural information can tune Cas13a enzymes for diagnostic use while preserving compatibility with elevated reaction temperatures that help with structured RNA targets, according to Cell Chemical Biology.

Sources referenced