Journal article
Beyond sequence similarity: toward function-based screening of nucleic acid synthesis
Frontiers in bioengineering and biotechnology, Vol.14, 1832724
05/01/2026
DOI: 10.3389/fbioe.2026.1832724
Abstract
Synthetic nucleic acids are a key input to modern biotechnology, yet they represent dual-use materials that require robust screening to mitigate biosecurity risks. The prevailing screening paradigm, which identifies sequences of concern (SoCs) through sequence similarity to controlled pathogens and toxins, may not fully capture risks posed by AI tools that can decouple biomolecular function from reliance on known sequences. Rapidly advancing biodesign capabilities enable the generation of genes and proteins that might evade sequence-based detection. We highlight the critical need for function-based screening approaches that can detect sequences capable of hazardous biological functions, regardless of similarity to known SoCs. We examine the feasibility of function-based screening with an initial focus on proteins, arguing that, while protein sequence space is vast, biologically functional proteins are significantly constrained by biophysical and biochemical requirements that can be learned and modeled. We propose a concrete implementation framework organized along a continuum of complexity, starting with toxins as the most tractable targets before expanding to more complex pathogenic functions. We then discuss open challenges and describe a research and development strategy to address them.
Details
- Title: Subtitle
- Beyond sequence similarity: toward function-based screening of nucleic acid synthesis
- Creators
- Gary Abel JrTessa Alexanian - Alliance Bioversity International - CIATCraig Bartling - BattelleJacob BealSamuel Curtis - American National Standards InstituteKevin FlyangoltsLeonard Foner - SecurAcath (United States)Samuel ryGene Godbold - Signature Research (United States)Eric Horvitz - Office of the Chief ScientistBin Hu - Los Alamos National LaboratoryCorey Hudson - Align Technology (United States)Caitlin JaglaRassin Lababidi - Alliance Bioversity International - CIATSheng Lin-Gibson - National Institute of Standards and TechnologyBrittany Rife Magalis - University of LouisvilleJaspreet Pannu - Johns Hopkins UniversitySebastian Rivera - Molecular Biology ConsortiumDavid Ross - National Institute of Standards and TechnologyBruce Wittmann - Office of the Chief ScientistJames Diggans - Twist Bioscience (United States)
- Resource Type
- Journal article
- Publication Details
- Frontiers in bioengineering and biotechnology, Vol.14, 1832724
- DOI
- 10.3389/fbioe.2026.1832724
- ISSN
- 2296-4185
- eISSN
- 2296-4185
- Publisher
- Frontiers Media SA
- Grant note
- Center for National Security and International Studies at Los Alamos National Laboratory
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by funding from Sentinel Bio. BH acknowledges the Center for National Security and International Studies at Los Alamos National Laboratory for its support of this work.
- Language
- English
- Date published
- 05/01/2026
- Academic Unit
- Electrical and Computer Engineering
- Record Identifier
- 9985164080802771
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