Clinical OMICS

JUL-AUG 2019

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com July/August 2019 Clinical OMICs 11 became the most well-known in the Cas family, Doudna and Zhang's labs identified subsequent Cas enzymes in other bacterial species with slightly different properties—includ- ing Cas12a, Cas13, and Cas14. In 2015, Zhang and co-authors from the Broad, NIH, and Wageningen University in the Netherlands identified Cas12a as a new CRISPR system for recognizing and edit- ing double-stranded DNA. Zhang and his colleagues then characterized Cas13 in June 2016. A few months later, in the journal Nature, Doudna and her team described the use of Cas13 collateral cleavage activity for RNA detection. "We realized that Cas13 has a somewhat strange property in that it cleaves RNA that are recognized by the guide RNA, but it can also cleave other RNA molecules at the same time. That's what we call collateral activity," Zhang told Clinical OMICS in an interview. Once Cas13 recognizes and cuts its intended target, it releases a burst of energy and continues to cut other RNA nearby. "Rather than recognizing one molecule and cleaving that molecule and stopping there, Cas13 recognizes one molecule and cleaves many, many more molecules. That cleav- age is the amplification," Zhang said. Cas12a also performs this collateral cleavage when it binds to a target, but it cuts DNA rather than RNA. This CRISPR system is then attached to a reporter mol- ecule. When Cas12a or Cas13 hits its target, the enzyme breaks apart the reporter molecule and gives off a color. "With CRISPR, you have this enzyme that's basically spell-checking the base pairing," said Trevor Martin, Ph.D., co-founder and CEO of Mammoth Biosciences. "You can get this really exquisite specificity and also high sensitivity from the collateral cleavage." More recently, Doudna's lab identified another enzyme— Cas14—that can bind to single-stranded DNA. It's just one- third the size of Cas9, making it the smallest CRISPR system found to date. In March, Mammoth Biosciences licensed the new tool from UC Berkeley. Infectious disease detection Unlike most molecular diagnostic tests, Mammoth and Sher- lock are developing paper-based diagnostics without the need for PCR or next-generation sequencing. Instead, these CRISPR-based tests would be portable, as well as cheap to produce and buy. The paper strip is dipped into a patient sample of blood, spit, or urine, and a line appears to indi- cate whether the target genetic sequence was detected or not. The tests could be performed in virtually any setting by anyone. For these reasons, both companies see huge poten- tial to use these diagnostics for infectious disease testing. (continued on next page) Because CRISPR diagnostics can be developed using a paper strip that changes color, at-home testing could use a mobile app to upload the strip and get results within 30 minutes. Rahul Dhanda, co-founder, president, and CEO of Sherlock Biosciences

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