CRISPR proteins developed for use in molecular diagnostics

By Joseph Constance, The Science Advisory Board staff writer

February 11, 2020 -- New CRISPR technology is being developed as a molecular diagnostic tool with the capability of detecting unique disease biomarkers. Eventually, these at-home tests will allow patients to conduct at-home diagnostic tests quickly.

Leveraging Cas14 proteins

One company, Mammoth Biosciences, has received an exclusive license from the University of California, Berkeley to Cas14, and it intends to develop an easy and affordable diagnostic test. The company also was issued two U.S. patents (Nos. 10,253,365 and 10,337,051) that cover comprehensive techniques enabling Mammoth to offer DNA and RNA detection as CRISPR diagnostics.

The CRISPR protein, Cas14, which contains up to 700 amino acids, can detect double-stranded and single-stranded DNA, as well as RNA, and is able to detect a bacteria or virus.

"Similar to the way Google built a search engine for the web, Mammoth Biosciences has used CRISPR to build the search engine for biology," Trevor Martin, PhD, CEO and co-founder of Mammoth Biosciences, explained in an email. "This search engine can be used to find and edit cells for therapeutic uses as is traditionally done, or Mammoth's CRISPR-based platform can also search and find nucleic acids that are indicative of disease in samples ranging from blood to saliva, and report these results back as a diagnostic."

According to Martin, the company's CRISPR-based detection platform can sense any biomarker or disease by detecting DNA or RNA.

"The base functionality of a CRISPR system is created by 'programming' a Cas enzyme to bind to a certain DNA or RNA sequence by designing a guide RNA that is complementary to the sequence you want the enzyme to interact with," he said.

"For diagnostics, we leverage this same 'programming' of the Cas enzyme through a guide RNA, but instead of sending the protein to a gene we want to edit, we send the protein to find a DNA or RNA sequence that is unique to what we want to detect -- for example, an RNA or DNA molecule that specifically indicates a disease," Martin continued.

"To leverage this binding for diagnostics, we have developed special classes of enzymes that, if they find their target DNA or RNA sequence, actually cut many orders of magnitude more DNA or RNA more broadly in the sample," he added.

The test could be leveraged in all settings -- from the hospital, to the point of care, to the home.

Amplifying CRISPR signals

Meanwhile, another startup that is also applying CRISPR to diagnostics was launched in March 2019. Sherlock Biosciences in Cambridge, MA, is using CRISPR and synthetic biology, which involves engineering biological systems to have new capabilities.

Sherlock Biosciences was named after one of its foundational platform technologies -- specific high-sensitivity enzymatic reporter unlocking (SHERLOCK) -- which it exclusively licensed from the Eli and Edythe L. Broad Institute, a biomedical and genomic research center that is a part of both the Massachusetts Institute of Technology and Harvard University.

SHERLOCK was developed by a team led by Feng Zhang, PhD, company co-founder and chair of Sherlock's scientific advisory board, who collaborated with co-founder Jim Collins, PhD. It was created as a way to identify specific genetic targets using CRISPR, and SHERLOCK can detect the unique genetic fingerprints of virtually any DNA or RNA sequence in any organism or pathogen, according to the company.

The SHERLOCK platform amplifies genetic sequences and programs a CRISPR molecule to detect the presence of a specific genetic signature in a sample, which can also be quantified. When it finds those signatures, the CRISPR enzyme activates signaling molecules for detection. This signal can be adapted to work on a simple paper-strip test or on laboratory equipment, or it could provide an electrochemical readout that can be read with a mobile phone, explained Rahul Dhanda, Sherlock's co-founder, president, and CEO.

He indicated that Sherlock Biosciences is initially targeting CRISPR diagnostics to infectious diseases. The technology is approximately two years from clinical trials for point-of-care targets and three years from being a commercial test, which would be available first in the U.S. and eventually internationally.


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