Abstract
The early 21st century witnessed a revolution in biology, specifically in the realm of synthetic biology that has transformed not only the conduct of life sciences but also has delivered new treatments and cures for countless ailments. Synthetic biology has also provided more environmentally friendly and cost-effective approaches for manufacturing goods across several industrial sectors. This revolution was presaged by the advent of molecular biology in the late 20th century, but modern synthetic biology no longer needs a biological source of materials (in this case DNA) to manipulate. Information uploaded to the internet on the genomes of thousands of microorganisms (pathogenic, harmless, and beneficial), humans, plants (cultivated and wild), and animals (livestock, companions, and wild) can be chemically synthesized and stitched together to create the blueprints for countless enzymes, structural proteins, genetic circuits, and metabolic pathways.
With these advances come risks, and no longer is the control of dangerous microorganisms limited to the control of stocks of existing pathogens. In 2003, Wimmer and colleagues demonstrated that chemically synthesized DNA could be used to rescue an infectious virus and since that time rescue systems have been developed for all the major viral pathogens. Even more simply, on-line information could enable an actor to synthesize the gene for a toxin and produce sufficient quantities of the toxin in a recombinant organism to cause harm.
Early discussions of these risks and the analysis of potential policy approaches to address it included those published by the National Science Advisory Board for Biosecurity, 1 the J. Craig Venter Institute, 2 and Gryphon Scientific. 3 By 2009, the key role of commercial providers of synthetic DNA in reducing this risk came into focus, and the International Gene Synthesis Consortium was formed as a venue for these providers to develop harmonized approaches for screening customers and DNA sequence orders. 4
In 2010, buoyed by the emerging consensus in support of a screening framework and based on requirements and approaches described in the Gryphon Report, HHS released its Screening Framework Guidance, a foundational policy that has been influential not only for US-based nucleic acid synthesis but also throughout the world. This Guidance calls on providers of synthetic nucleic acids to screen customers and sequence orders to reduce the risk that nucleic acids that contain “sequences of concern” from a pathogen or toxin are shipped to a customer without a legitimate use for them.
Over the next few years, as providers of synthetic nucleic acids gained experience in implementing this Guidance, a few key lessons emerged. 5 These included (1) sequence screening that is challenging to implement and ambiguities in sequence screening require time and expertise to resolve, raising barriers to adherence with the Guidance; and (2) determining legitimacy of customers who order sequences of concern is difficult for companies, which have limited insight into research plans and directions.
Moreover, the technological landscape has shifted beneath the foundational policies. To address technical challenges in predicting the function (and therefore understand more about the risk) associated with novel sequences, the Intelligence Advanced Research Projects Agency initiated its Functional Genomic and Computational Assessment of Threats program, or Fun GCAT program, in 2016 and the Finding Engineering-Linked Indicators, or FELIX program in 2017 to develop sequence screening tools in support of these providers.6,7
This issue comes at a time when the US government is demonstrating a renewed commitment to managing risks arising from synthetic genomics. In October 2023, the Screening Framework Guidance was updated to address advances in benchtop DNA synthesis technologies, to broaden nucleic acid sequence screening, and to delineate roles for institutions and users of synthetic nucleic acids in biosecurity screening. 8 Concurrently in October 2023, the Biden Administration's “Executive Order on Safe, Secure, and Trustworthy Artificial Intelligence” called for more stringent standardization of nucleic acid screening practices and requirements for researchers funded by the US government to use providers who adhere to these standards. 9
It is with this background that this Special Issue was envisioned and created. The manuscripts seek to further explore challenges, opportunities, and lessons learned when managing risks arising from synthetic genomics. This collection provides biosafety and biosecurity professionals with a thorough grounding on contemporary thought regarding managing risks that arise from research involving synthetic genomics and practical approaches to explore in their own institutions.
These discussions can help biosafety and biosecurity professionals understand their current and pending responsibilities. For example, Sharkey et al. discuss how the updated US Department of Health and Human Services guidance will shift the burden of screening from being exclusively on providers to a responsibility that is shared by all stakeholders, specifically the principal users, end users, and their institutions.
Several manuscripts illuminate the biorisk management efforts that may (or may not) occur between researchers in their institutions and providers of critical reagents. Parker and Kane give us a snapshot of how screening practices vary among leading providers of synthetic DNA. Given that providers of synthetic DNA are found outside the United States and also that customers for the domestic industry are found overseas, effective risk management approaches must extend beyond political borders. Wheeler et al. describe the tools and a framework to internationalize effective risk management while also fostering collaboration and trust.
Several manuscripts provide a perspective on the scope and nature of the current risks, including approaches to mitigate risks. Walsh et al. describe how barriers to accessing synthetic DNA may be lowered by artificial intelligence systems, and De Haro provides a framework to determine how risk in synthetic biology research may be changed by the advent of systems using artificial intelligence. Guido et al. describe a methodology for evaluating genetic biocontainment technologies for their feasibility and applicability to manage risks arising from synthetic genomics.
Although the research community represented by this Special Issue is broad and extensive, knowledge gaps remain regarding applied biosafety and biosecurity research related to synthetic genomics. For example, how biosafety and biosecurity practitioners are implementing and interpreting new rules and guidelines regarding synthesis screening is largely unexplored. Case studies and research regarding how different institutions (and Institutional Biosafety Committees) are managing risks associated with synthetic genomics have yet to be published. Assessments for how purchasing departments are (or are not) managing synthetic nucleic acid orders remains an open issue. In short, the entire biosafety and biosecurity life cycle of synthetic genomics has yet to be explored. We call upon scientists and experts to consider furthering research and publication in this area of study.
Authors' Contributions
All authors contributed equally to this manuscript.
Authors' Disclosure Statement
No competing financial interests exist.