The importance of accurate and efficient diagnoses for dealing with illness is apparent to anyone who has struggled against an unidentified ailment, making it no surprise that diagnostic tools occupy the front lines in the global fight against infectious disease. Laboratories with diagnostic capabilities are few and far between in developing regions, which already experience heightened vulnerability to infectious disease at the hands of “weak and poorly resourced healthcare systems.” The development of “novel [diagnostic] devices” for use beyond the bounds of the laboratory and directly within disease epicenters could greatly improve the prognosis for both patients and health care systems in the developing world by equipping patients and doctors with knowledge of disease-causing antagonists faster and more reliably.

Imagine a tool that could condense the work of identifying genetically distinct agents like tumors and pathogenic viruses, previously allocated to resource-heavy laboratories, into a thin strip of paper.

Imagine a tool that could condense the work of identifying genetically distinct agents like tumors and pathogenic viruses, previously allocated to resource-heavy laboratories, into a thin strip of paper. Developed by researchers at the Broad Institute of MIT and Harvard partnered with multiple departments at MIT, a technology known as SHERLOCK (Specific High Sensitivity Enzymatic Reporter Locking version 2) harnesses the power of CRISPR to do just that, detecting anything with a unique genetic pattern in concentrations on the attomolar scale. Attomolar translates to 10-18 molar, a level of specificity allowing for the detection of agents present in amounts analogous to under 10 grains of sand out of all the sand in the entire world. Aligning with the tendency of innovation to converge towards smaller and better devices, the newest version of SHERLOCK reflects a variety of remarkable improvements at an impressively small scale.

 
CRISPR, or Clustered Regularly Interspaced Short Repeats, emerged as a component of bacterial defense systems, constituting a group of DNA sequences which allow for the detection and intracellular targeting of specific genetic motifs like those of pesky viruses. Perhaps most well-known for the gene-editing capabilities it confers, a specific type of CRISPR system known as CRISPR/Cas9 unleashed a storm of thought-provoking gene-editing possibilities, many of which may be on the near horizon since the system’s discovery.

However, SHERLOCK is distinct from this system in both its purpose and its construction, trading Cas9 for Cas13a to cut specific genetic slices of interest in RNA as well as DNA, allowing for the detection of a wide variety of agents. Researchers applied fluorescent labels to detect these slices, visible on SHERLOCK strips upon their Cas13a-mediated release. The researchers behind SHERLOCK successfully tested it on inputs derived from the Dengue and Zika viruses, genetic prototypes for a family of devastating viruses including West Nile virus and Yellow Fever, indicating that the technology may successfully map to target some of the most pernicious diseases putting populations at risk around the world.

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While other CRISPR-based tools have used Cas9, a CRISPR protein that aids in cutting DNA, SHERLOCK employs Cas13 (diagram above), which instead cuts RNA.

Graphic courtesy of the Broad Institute

 
Although the team had published an earlier version of SHERLOCK, the most recent version boasts a combination of significant advances, including 3.5 times the sensitivity attained by allying Cas13a with Csm6 – a helper enzyme which activates the cleavage process – as well as the ability to simultaneously run four reactions alongside each other in separate channels and to produce quantitative measurements down to impossibly small (2 attomolar) concentrations. The accuracy and rapidity of SHERLOCK makes it especially suited to quickly and easily address high volumes of diagnostic need even during difficult disease epidemics in regions that may not have access to power or basic diagnostic resources.

 
According to its inventors, although future augmentations, such as readouts that are apparent through color changes in solution, are still waiting to be developed, SHERLOCK is a “field ready for rapid and portable deployment.” Regardless of the fast pace of technological development, public health cannot move forward if technology is not accessible; diseases considered benign in their vulnerability to simple treatments like fluids or antibiotics become deadly when such resources are not available. SHERLOCK’s broad potential availability and use are poised to transform disease detection in economically and socially disadvantaged regions, affording the protection of diagnostic certainty through the mighty authority of thin, paper slips.

About The Author

Leslie Chan