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Objective: DNA synthesis companies screen orders to detect controlled sequences with misuse risks. Assessing screening accuracy is challenging owing to the breadth of biological risks and ambiguities in risk definitions. Here, we detail an International Gene Synthesis Consortium working group's rationale and process to develop a prototype DNA synthesis screening test dataset, aiming to establish a baseline of screening system accuracy to compare with various screening approaches. Methodology: Construction of the prototype test dataset involved four tool developers screening nucleic acid sequences from three taxonomic clusters of controlled organisms (Orbivirus, Francisella tularensis, and Coccidioides). Results were mapped onto predefined, comparable categories, checking for consensus or conflicts. Conflicts were grouped based on gene annotation and resolved through discussion. Results: The process highlighted several long-standing challenges in DNA synthesis screening, including the qualitative differences in approaches taken by screening tools. Our findings highlight the lack of clarity in assessing pathogen sequences with respect to regulatory control language, compounded by scientific uncertainty. We illustrate the current degree of consensus and existing challenges using classification statistics and specific examples. Conclusions and Next Steps: This prototype underscores the necessity of expert-regulator coordination in assessing gene-associated risks, offering a template for creating test sets across all taxonomic groups on international control lists. Expanding the working group would enrich dataset comprehensiveness, enabling a transition from species-focused to function-focused regulatory controls. This sets the foundation for quality control, certification, and improved risk assessment in DNA synthesis screening. [ABSTRACT FROM AUTHOR]

Introduction: Nucleic acid synthesis is a powerful tool that has revolutionized the life sciences. However, the misuse of synthetic nucleic acids could pose a serious threat to public health and safety. There is a need for international standards for nucleic acid synthesis screening to help prevent the misuse of this technology. Methods: We outline current barriers to the adoption of screening, which include the cost of developing screening tools and resources, adapting to existing commercial practices, internationalizing screening, and adapting screening to benchtop nucleic acid synthesis devices. To address these challenges, we then introduce the Common Mechanism for DNA Synthesis Screening, which was developed in consultation with a technical consortium of experts in DNA synthesis, synthetic biology, biosecurity, and policy, with the aim of addressing current barriers. The Common Mechanism software uses a variety of methods to identify sequences of concern, identify taxonomic best matches to regulated pathogens, and identify benign genes that can be cleared for synthesis. Finally, we describe outstanding challenges in the development of screening practices. Results: The Common Mechanism is a step toward ensuring the safe and responsible use of synthetic nucleic acids. It provides a baseline capability that overcomes challenges to nucleic acid synthesis screening and provides a solution for broader international adoption of screening practices. Conclusion: The Common Mechanism is a valuable tool for preventing the misuse of synthetic nucleic acids. It is a critical step toward ensuring the safe and responsible use of this powerful technology. [ABSTRACT FROM AUTHOR]