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bioRxiv · 10.64898/2026.03.04.709671

The Limits of Sequence-Based Biosecurity Screening Tools in the Age of AI-Assisted Protein Design

Wittmann, B. J.·Wheeler, N. E.·Murphey, S. T.·Mitchell, T.·Magalis, B.·Gemler, B.·Flyangolts, K.·Diggans, J.·Clore, A.·Beal, J.·Bartling, C.·Alexanian, T.·Horvitz, E.
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Abstract

Rapid advancements in AI have enabled significant progress in protein and nucleic acid design, but they also pose biosecurity challenges. We examine the vulnerabilities of biosecurity screening software (BSS) to AI-reformulated synthetic homologs of proteins of concern (POCs) that have been fragmented into smaller segments. We evaluate four BSS tools that were recently patched to enhance their AI resiliency. Without any further modification, we found that two of the four tools were capable of robustly detecting fragments as short as 50 nucleotides, demonstrating screening capabilities that exceed those requested in the U.S. Framework for Nucleic Acid Synthesis. Upgraded versions of the other two tools improved performance. Although our findings confirm the effectiveness of the tested BSS tools, at the same time, they emphasize the urgency of developing alternate BSS approaches to counter evolving AI-enabled biosecurity risks.

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Wittmann, B. J., Wheeler, N. E., Murphey, S. T., Mitchell, T., Magalis, B., Gemler, B., Flyangolts, K., Diggans, J., Clore, A., Beal, J., Bartling, C., Alexanian, T., Horvitz, E.. 2026-03-05. The Limits of Sequence-Based Biosecurity Screening Tools in the Age of AI-Assisted Protein Design. https://doi.org/10.64898/2026.03.04.709671

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