Introduction to the Special Feature,Part 2: Enabling and Implementing Threat Agnostic Approaches to Biodefense and Public Health

This is the Second of a 2-part special feature that focuses on threat agnostic approaches for the early detection of naturally occurring or humanmade biological threats, which are critical for a robust biodefense and public health response. ¹

The impetus for the threat agnostic special feature grew out of an internally funded strategic capability development effort at Pacific Northwest National Laboratory. The selection of threat agnostic biodefense was driven by the observed limitations of existing biothreat detection, diagnostic, and countermeasure capabilities when confronted by a novel pathogen. The 2018 National Academies of Sciences Engineering, and Medicine report, Biodefense in the Age of Synthetic Biology, states that “an overreliance on the Select Agent list is a systemic weakness affecting many aspects of the United States' current biodefense mitigation capability.” ² Ultimately, we defined threat agnostic biodefense as actions to counter biological threats, reduce risks, and prepare for, respond to, and recover from biological incidents, regardless of whether the pathogens or toxins involved are known in advance.

The questions we sought to answer included: How might biodefense be transformed to be more agile and to more effectively address unknown pathogens? What are the basic/fundamental science gaps that need to be addressed to enable this approach? What are the data collection and analysis gaps?

Based on existing strengths and capabilities, we identified the following 3 research pillars: 1.

Signatures of infection and disease – determining function and phenotype from genomic data; identifying physiological response markers for infection and disease in a host

However, research and development strategies are limited in their impact without efforts to operationalize the discoveries that are made. The 7 commentaries featured in Part 2 of this special feature address some of the ways a threat agnostic approach to biodefense and public health could be implemented and identify potential barriers to adoption. Downie et al present 2 review articles—a literature review of clinical specimen testing using threat agnostic methods ³ and a review of US government agency activities using threat agnostic methods ⁴ —and observe that coordination among agencies and the development of a sentinel surveillance system using metagenomics and other threat agnostic approaches is needed. The elements of a standardized, national threat agnostic biosurveillance system are detailed by Rubin et al, ⁵ including the development of standardized definitions, tools, and metrics to aid in operationalizing and evaluating the system. Lim and Popescu ⁶ propose a combined list-based and threat agnostic approach to biodefense that addresses potential threats across the detect, prevent, and prepare spectrum. Srikrishna ⁷ describes the use of spike-triggered virtualization and artificial intelligence (AI) to reduce the cost of daily metagenomic screening of air samples to no longer be cost-prohibitive. Eisenkraft ⁸ combines AI with continuous patient monitoring to generate faster outbreak identification, improved situational awareness, and more informed decisionmaking and resource allocation. Although some barriers still remain, Lin et al ⁹ outline the advances in computational and systems biology that are bringing the biodefense community closer to the development of threat agnostic biological signatures.