Securing Commercial Nucleic Acid Synthesis

The increasing availability and decreasing cost of custom synthetic nucleic acids presents a risk of misuse. Made-to-order synthetic nucleic acids could be used to reconstruct an existing but hard-to-obtain pathogen or to engineer a novel or more-virulent pathogen, leading to the construction of a biological weapon. Securing nucleic acid synthesis is a policy priority for the U.S. government and the synthetic biology industry. Executive Order 14110 tasks the White House Office of Science and Technology Policy with establishing a framework “to encourage providers of synthetic nucleic acid sequences to implement comprehensive, scalable, and verifiable synthetic nucleic acid procurement screening mechanisms, including standards and recommended incentives” (Executive Order 14110, 2023, p. 75201). Executive Order 14110 further requires agencies to restrict federal funding only to entities that obtain nucleic acid synthesis services from providers that adhere to the screening framework.

There is currently no legal requirement that gene synthesis providers screen their customers or their orders to ensure that the requested synthetic DNA and RNA constructs are not used for harmful purposes, although many providers screen orders voluntarily. The International Gene Synthesis Consortium (IGSC), a consortium of industry gene synthesis companies, requires members to adhere to requirements in its Harmonized Screening Protocol. In 2010, Office of the Secretary of the U.S. Department of Health and Human Services (HHS) issued voluntary guidance on ordering and customer screening for providers of synthetic nucleic acids. This voluntary guidance was updated in 2023 by the Administration for Strategic Preparedness and Response, also within HHS. But there is currently no universally accepted standard for screening customers or orders. Not all companies screen their orders, and companies that do screen orders may follow different protocols or have different criteria for rejecting or reporting suspicious orders.

In this study, we review government screening guidelines, industry consortium requirements, legislative proposals, and the scientific literature to assess the current state of commercial gene synthesis screening; summarize proposals for strengthening screening; and contribute recommendations for implementing comprehensive screening policies to secure commercial nucleic acid synthesis. These recommendations expand on and strengthen government communications, such as the HHS guidance, industry consortium rules and best practices (such as those developed by IGSC) and proposals developed by researchers and provider organizations. Our recommendations also go beyond the Framework for Nucleic Acid Synthesis Screening (Fast Track Action Committee on Synthetic Nucleic Acid Procurement Screening, 2024) in describing specific steps and decision criteria in the screening workflow, along with the conformity assessment tools providers should use in designing screening procedures to comply with the framework.

The recommendations in this study address the following components of Executive Order 14110 (2023):

• 4.4(b)(i)(B) “determine standardized methodologies and tools for conducting and verifying the performance of sequence synthesis procurement screening, including customer screening approaches to support due diligence with respect to managing security risks posed by purchasers of biological sequences . . . and processes for the reporting of concerning activity to enforcement entities” (p. 75201)
• 4.4(b)(ii)(A and D) “develop and refine for possible use by synthetic nucleic acid sequence providers: (A) specifications for effective nucleic acid synthesis procurement screening; . . . and (D) conformity-assessment best practices and mechanisms” (p. 75202)
• 4.4(b)(iv)(A) “develop a framework to conduct structured evaluation and stress testing of nucleic acid synthesis procurement screening” (p. 75202).

The recommendations also complement proposals for international mechanisms to secure nucleic acid synthesis.

Key Findings

Our review of government nucleic acid synthesis screening guidelines, industry consortium requirements, legislative proposals, and the scientific literature yielded the following findings:

• Commercial gene synthesis presents a serious risk of misuse or accident.
• Screening protocols vary across providers.
• Providers currently have no way to share information about suspicious customers or orders.
• Strengthening customer screening and verification is a promising way to help secure gene synthesis.
• Clearer standards for reporting suspicious orders to authorities would streamline follow-up screening and improve enforcement.
• The U.S. government currently has no mechanism for assessing the conformity of providers' screening systems with guidelines or policies.

Recommendations

We recommend that the U.S. government take the following actions to address the components of Executive Order 14110 described above. The first recommendation proposes the overall screening workflow to be implemented by providers. Subsequent recommendations describe in more detail several steps in this workflow, including customer screening, checking a database for evidence of split orders, and communicating with law enforcement about suspicious orders. The final recommendation covers assessment of providers' conformity with the proposed screening framework.

• Revise the 2023 Administration for Strategic Preparedness and Response guidelines to include specific information to be collected and decision criteria for each step of the screening pipeline.
• Establish a third-party database to log information about synthetic nucleic acid orders and periodically check those records for evidence of suspicious activity.
• Establish customer screening requirements, including identity verification measures.
• Establish criteria and data requirements for sharing information about suspicious orders with law enforcement agencies.
• Implement procedures and standards for assessing the conformity of providers' screening practices with requirements.