RT-PCR has been the main technology used to detect SARS-CoV-2. However, its widespread use is limited by its reliance on PCR machines and the reliability of hydrolysis probes used. To address this issue, researchers from the University of Connecticut Health Center explored CRISPR-Cas as a detection method to identify nucleic acids that indicate the presence of COVID-19 in a sample. Although current CRISPR systems in use, (DETECTR and SHERLOCK) are effective, they require multiple steps. The researchers modified this by creating the digital warm-start CRISPR assay (dWS-CRISPR), a one-pot quantitative test. As one of its key features, the “warm-start” assay requires temperatures above 50°C to start—so that amplification cannot begin before the desired time frame. It is prepared by combining RT-DAMP primers, Cas RNA complexes, and other components and then coating the solution onto a digital chip. When incubated with a positive COVID-19 sample, quantifiable fluorescence will visibly appear due to reaction with the target RNA and thus confirm detection of SARS-CoV-2 nucleic acids. The researchers also compared two Cas12a nucleases and determined that the A.s. Cas12a nuclease was the best choice for the assay due to its greater cleavage activity at the lower Mg2+ concentrations needed to boost amplification. Additionally, the dWS-CRISPR assay is an improvement upon the non-digital WS-CRISPR assay, and was shown to be more effective due its use of a chip that is typically only used for digital PCR tests. The dWS-CRISPR’s high sensitivity and visible fluorescence allows for relatively simple sample reading, can be effectively used with saliva samples, and can be optimized for broader use by medical professionals.