Functional Genomic and Computational Assessment of Threats (Fun GCAT)

The Functional Genomic and Computational Assessment of Threats (Fun GCAT) program is substituting current simplistic look-up table-based methods to flag dangerous DNA sequences with smart, AI-driven threat screening software that considers DNA function, can process short or highly engineered sequences, and does not require follow-up analysis by an expert. Fun GCAT is also uncovering the cellular and molecular roles of DNA, sequence by sequence, using new experimental pipelines. One pipeline is testing virus genes for the ability to disrupt the immune system hardwired within each of our cells.

Raytheon BBN Technologies applies new DNA screening software to accelerate the development of better SARS-CoV-2 diagnostics
June 25, 2020: Raytheon BBN Technologies is applying its FAST-NA software, funded under the IARPA Fun GCAT program, to rapidly screen for DNA sequences unique to the SARS-CoV-2 virus. The goal is a low-cost, point-of-care diagnostic test that will use saliva and a paper strip to deliver test results for SARS-CoV-2 in less than an hour. FAST-NA was originally developed for screening commercial DNA synthesis orders by defining and flagging unique DNA signatures of pathogenicity. The software identifies the specific DNA sequences associated with SARS-CoV-2 for the diagnostic assay to detect the virus, with confidence, in human saliva. The SARS-CoV-2 diagnostic test development is a collaboration with Purdue University, PortaScience Inc., Coretex Design Inc., and LaDica LLC.

Summary statistics of distinguishing amino acid sequences for SARS-CoV-2 compared to all other Coronaviridae genomes isolated using the FAST-NA software.  For each open reading frame (ORF) indicated on the x-axis, the fraction of the ORF judged to be unique and the total number of amino acids in unique sequences is presented. As an example, the large 1ab polyprotein, QHO60603.1, has many unique residues, though the fraction is not large. In contrast, the surface glycoprotein, QHO60594.1, has both a large amount and large fraction of unique material. The unique region of the surface glycoprotein, identified in January, has since been determined to be a critical region of the spike protein tied to the infectiousness of COVID-19. The same technology is now being used to identify stable diagnostic targets. Image Credit: Jacob Beal, Thomas Mitchell, Daniel Wyschogrod, Jeff Manthey, and Adam Clore (doi: https://doi.org/10.1101/2020.01.31.929497)

The Fun GCAT Program and Harvard University are exploring how SARS-CoV-2 evades and disrupts the human immune system
February 2020: Researchers at Harvard University led by Professor Pamela Silver recently developed an experimental pipeline for the evaluation of viral genes that disrupt the human immune response as part of IARPA’s Functional Genomic and Computational Assessment of Threats program. This pipeline is specifically tailored to the rapid analysis of novel viruses during the early stages of an outbreak from engineered cell lines (Fig 1A). With the outbreak of COVID-19, the Harvard team has shifted priorities to analyze and compare a first set of 120 genes from SARS-CoV-2, the virus that causes COVID-19, and six closely related coronaviruses (e.g., SARS, MERS, and more common circulating variants) to reveal how SARS-CoV-2 disrupts our immune system and what genetic features make the virus particularly pathogenic (Fig 1B). An improved understanding of coronavirus immune evasion mechanisms is essential for the development of future vaccines and therapeutics. While these types of investigations can take months of dedicated work, the Fun GCAT team at Harvard has developed rapid analysis approaches that take only days from sequence receipt to answer, significantly accelerating our capabilities.

Figure 1: High-throughput testing of many coronavirus genes reveals that the NSP1 gene of the SARS-CoV-2 virus is the most powerful of the genes tested at inhibiting protein synthesis and the antiviral response of the infected cell. Credit: Timothy Chang, Erika Olson, Jeffrey Way, and Pamela Silver. (Figure used with permission)

Research Highlights

• Cybersecurity tool may help unlock rapid COVID-19 tests