In a twist on how gene editing technology might be applied in the future, DARPA’s newest biotechnology funding opportunity aims to incorporate gene editors into detectors for distributed health biosurveillance and rapid, point-of-need diagnostics for endemic, emerging, and engineered pathogenic threats. The “Detect It with Gene Editing Technologies” (DIGET) program could help the Department of Defense maintain force readiness by informing rapid medical response and increasing the standard of care for troops, and preserve geopolitical stability by preventing the spread of infectious disease from becoming a driver of conflict. DARPA is hosting a Proposers Day meeting on December 11, 2019, in Atlanta to provide interested researchers with additional details: https://go.usa.gov/xpkce.
The overarching goal of DIGET is to provide comprehensive, specific, and trusted information about health threats to medical decision-makers within minutes, even in far-flung regions of the globe, to prevent the spread of disease, enable timely deployment of countermeasures, and improve the standard of care after diagnosis. The DIGET vision incorporates two devices: a handheld, disposable point-of-need device that screens samples for at least 10 pathogens or host biomarkers at once, combined with a massively multiplexed detection platform capable of screening clinical and environmental samples for more than 1,000 targets simultaneously. Both pieces of the system could be quickly reconfigured to adapt to changing needs.
“DARPA is pursuing the capability to detect and characterize any pathogen, regardless of when or where it emerges,” said Renee Wegrzyn, the DIGET program manager. “There are three primary reasons that we think gene editing systems can help us realize that vision, and they boil down to speed, accuracy, and precision. First, they’re programmable, which means we can easily adapt assays as needed to account for previously unknown threats. Second, their extreme sensitivity means they can identify pathogenic targets even when those targets are present in very low abundance. And third, they can be both broad and specific, meaning a user might, for instance, confirm the presence of influenza generally or identify a specific flu strain along with its characteristics.”
While DARPA seeks a variety of approaches, DIGET technologies could work by introducing an inactive gene editor paired with a programmable guide into a biological sample to identify a target protein. Upon detection, the gene editing enzymes would be activated, triggering them to cut the RNA or DNA at the exact target location. The activated enzyme would remain active and continue to cleave reporter molecules in close proximity to the reaction, providing an easily observed indication of a positive match. That boosting of the reporter signal removes the need to amplify targets prior to testing, simplifying the process and reducing time to result.
The distributed, effectively continuous detection capability DARPA is pursuing with DIGET does not currently exist. At present, biosurveillance relies on periodic shipping of samples from across broad geographic areas for analysis at centralized laboratories. The timeline for shipping, testing, and reporting results delays the return of actionable information anywhere from hours to days. If a central laboratory detects a threat, the finding may lead to distributed laboratories coming online to better track the spread of disease, but often that new surveillance capacity comes too late to halt an outbreak before its natural peak. With DIGET technology on the other hand, it could become possible to begin with a distributed biosurveillance model, then use the results from that network to inform the rapid creation and distribution of single-use diagnostics to accurately measure the spread of infection.
“Two hypothetical, but realistic scenarios reveal the potential impact of these tools and the unambiguous results they’d provide,” explained Wegrzyn. “First, consider the case of a service member presenting with flu-like symptoms. With DIGET, we think it will be possible to not only confirm that he or she has influenza, but also to determine the strain, the origin, and whether the strain is drug resistant. In addition, DIGET tools could assess the severity of disease to guide how the patient is triaged and treated. Second, think about an Ebola triage center in a low-resource country. If you’re screening someone for a deadly disease, you know that every minute of potential exposure counts, so you need a fast-acting assay. You also need absolute certainty in the diagnosis, because if a test comes back with a false positive, you risk that the patient will contract the disease based on proximity to actual infected individuals during treatment. If a test returns a false negative, the individual is released back into the community to unintentionally spread the virus. These are life and death scenarios that DARPA believes DIGET technology can resolve.”
DIGET researchers will face a range of challenges that will demand expertise in gene editing, synthetic biology, assay development, nucleic acid technologies, bioinformatics, and diagnostic device engineering and development. In the computational design space, research teams will need to identify a minimal set of targets from a robust bioinformatics pipeline. These targets will inform the design of programmable probes and guides for broad target sequences present across a number of strains, as well as for more specific target sequences that identify subtypes of pathogens, rare mutations, and even co-infections. In the gene editing space, researchers will need to design assays, enzymes, and reporters for identification and signaling of positive results. And in the engineering space, teams will need to integrate their detection and reporting capabilities into user-friendly, field-ready prototype systems that go from sample to answer in under 15 minutes and provide unambiguous results. Scheduled capability demonstrations and planned independent validation and verification will test researchers’ prototype systems, assess their ability to screen clinical and environment samples, and gauge the speed with which the systems can be reconfigured.
If the DIGET program succeeds, the resulting platforms will provide a wealth of information for global health monitoring and rapid response, and support characterization of circulating pathogens to inform the development of medical countermeasures, including the class of nucleic acid-based countermeasures DARPA is pursuing under its Pandemic Prevention Platform, Nucleic Acids On-Demand Worldwide (NOW), and PReemptive Expression of Protective Alleles and Response Elements (PREPARE) programs. Additionally, although DIGET is focused on biological threats, similar technologies could be applied to chemical and radiological threats by detecting biomarkers of exposure.
“DARPA is already transforming nucleic acid technologies into fast-acting tools for preserving or restoring health, and now we’re extending their value to rapid detection and characterization of health threats to better direct how those prophylactic and therapeutic tools are used,” said Wegrzyn. “DIGET fills in a major piece of the puzzle for DARPA’s vision of defending against any biological threat, anytime, and anywhere.”
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