Executive Summary

Synthetic cells represent a rapidly advancing frontier in engineering biology. Building on progress across multiple scientific and engineering disciplines, and potentially enabled by technologies such as artificial intelligence and automation, synthetic cell research offers new opportunities to investigate fundamental principles of life and to engineer biological functions in more predictable and modular ways. Although still in early development, synthetic cells could advance applications in health and medicine, environmental monitoring and remediation, sustainable manufacturing, agriculture and food production, education, and future space-related applications, with the potential to deliver substantial societal and economic benefits.

At the same time, the wide range of possible synthetic cell designs, functions, and applications introduces uncertainty about how risks and benefits may emerge and whether existing governance systems can address these diverse systems consistently, proportionately, and adaptively. Synthetic cells span a broad spectrum of complexity, from simple, non-replicating biochemical assemblies used to study basic cellular behaviors, to more complex, genome-containing constructs capable of growth and self-replication for applications such as targeted nutrient delivery to crops or removal of harmful chemicals from soil. This wide spectrum of technical configurations and intended uses complicates efforts to apply uniform governance approaches.

Synthetic cells may also incorporate non-traditional biochemistries, hybrid architectures, or synthetic or redesigned genomes. As a result, some synthetic cells occupy a conceptual space between chemical systems and living organisms, complicating the application of established governance approaches and risk-benefit assessment methods. These challenges are particularly salient for synthetic cells intended for uses beyond traditional laboratory containment, including limited- or open-release applications. In addition, some synthetic cells could include features that allow them to evolve, adapt, or acquire new functions by incorporating capabilities like those of biological cells,

such as mutation via errors in DNA replication combined with selection mechanisms, or mechanisms for horizontal gene transfer. The possibility of such dynamic behaviors reinforces the importance of iterative risk assessment, ongoing monitoring, and governance systems capable of responding to emerging evidence.

As synthetic cell research and development (R&D) continues to advance, decision makers will require clear guidance and practical tools to support effective governance. While the committee’s statement of task emphasizes biosafety, biosecurity, and environmental risks, the committee considered potential benefits alongside risks, recognizing that judgements about acceptable risk depend in part on anticipated value. This study examines synthetic cell R&D from scientific, analytical, and governance perspectives. It establishes a flexible conceptual foundation for understanding how different synthetic cell features, levels of complexity, and intended uses shape governance needs; reviews current approaches for assessing risks, benefits, and uncertainty; evaluates how existing biosafety, biosecurity, chemical, and environmental oversight frameworks and regulations apply across research and potential deployment contexts; and outlines elements of a coordinated governance strategy to support responsible and societally aligned innovation.

Across this analysis, the study finds that synthetic cells do not generally introduce fundamentally new categories of biosafety, biosecurity, or environmental risk. Rather, they introduce uncertainty through novel combinations of features, boundary-blurring system architectures that fall between chemical systems and living organisms, and emerging deployment contexts that can complicate the application of existing analytic tools and governance approaches. These characteristics can create ambiguity about how current oversight mechanisms apply and may strain existing approaches to risk-benefit assessment and regulatory coordination. Together, these findings underscore the need for proportionate, adaptive, and evidence-based governance approaches that build on established biotechnology oversight while remaining responsive to the distinctive features and evolving trajectories of synthetic cell research.

DEFINING SYNTHETIC CELLS: A CONTINUUM-BASED CONCEPTUAL FOUNDATION

Broadly speaking, synthetic cells are constructed, encapsulated systems built from biomolecular components, and they emulate one or more life-like processes such as metabolism, information processing, and self-organization. In practice, the term “synthetic cell” is applied to a wide range of systems, from simple, non-replicating biochemical assemblies to more complex, genome-containing systems capable of self-replication. These systems may incorporate non-traditional biochemistries, hybrid architectures, and synthetic or redesigned genomes. No single, universally accepted definition exists, and this ambiguity complicates communication, funding decisions, oversight, and public engagement.

Rather than proposing a rigid definition, the committee adopted a continuum-based conceptual framework for understanding synthetic cells according to their structural and functional attributes (Figure S-1). This framework recognizes “synthetic cell” as

an umbrella term encompassing multiple categories of constructs that vary in complexity and resemblance to natural systems. By situating specific constructs along this continuum, more consistent, decision-relevant distinctions can be made for purposes of research evaluation, funding, and oversight, while preserving flexibility to accommodate future innovations.

Central to this framework is a two-layer evaluative logic designed to support governance decisions (Box S-1). The first layer focuses on whether a synthetic cell contains genetic material and whether it can replicate itself (with or without genetic material), providing an initial basis for distinguishing systems that may align more closely with chemical safety frameworks (those that do not contain genetic material or replicate) from those that fall within biological governance pathways (those that contain genetic material and may or may not replicate). A second layer of contextual questions addresses intended use, deployment environment, persistence, interactions with living systems, and considerations related to possible misuse. Together, these questions provide a practical structure for assessing risks and benefits in a manner proportionate to system characteristics, application, and deployment setting. For instance, a synthetic cell orally consumed by humans to produce antibiotics at the site of infection in the gut (see Chapter 5, Case 4) will likely require different considerations to a similarly designed system that produces fertilizer at the site of specific crop roots in the field (see Chapter 5, Case 5). Likewise, a genome-containing, replicating synthetic cell used in contained laboratory research to explore fundamental questions of life may raise very different oversight considerations than a similarly designed system intended to be used at-scale for biomanufacturing in an industrial setting.

The continuum framing also clarifies what falls outside the definition of synthetic cells, including purely chemical systems without cellular characteristics, conventional genetically engineered organisms (e.g., genetically modified organisms), and cells containing synthetic genomes that are otherwise identical to natural organisms. At the same time, it acknowledges gray areas and adjacent research domains, such as virus-like synthetic constructs, synthetic genomics, and mirror biochemistry, that may intersect with synthetic cell research or raise related governance considerations.

By emphasizing functionality, structure, and context rather than fixed definitions, this conceptual foundation provides a flexible and durable basis for evaluating synthetic cell research. It establishes a common language for subsequent analysis in the report and serves as a bridge for examining how risks, benefits, oversight mechanisms, regulation, and governance challenges vary across the synthetic cell continuum. The continuum is described in more detail in Chapter 2, which also describes the history and outlook of synthetic cell R&D.

ASSESSING RISKS, BENEFITS, AND UNCERTAINTIES

Many of the risk pathways and endpoints associated with synthetic cells parallel those for chemicals, conventional genetically engineered organisms, and naturally occurring cells. As a result, established analytical approaches, including human health and environmental risk assessment, benefit-cost analysis, and life cycle–based

approaches, could be applied to synthetic cells when sufficient information exists to support key assumptions about hazards, exposure pathways, and system behavior.

At the same time, the applicability of these approaches is conditional and context dependent. Synthetic cells that incorporate non-traditional biochemistries, alternative genetic codes, or hybrid biological-chemical architectures may challenge existing detection and monitoring methods, empirical benchmarks, and modeling assumptions. For synthetic cells that may persist, replicate, or interact dynamically with environmental systems, time-dependent and context-specific approaches, such as quantitative microbial risk assessment, may be required.

Because most synthetic cell research remains at early stages of development, uncertainty (known unknowns), and in some cases ignorance (unknown unknowns), can limit

the reliability of traditional quantitative analyses. Unknowns can emerge from a wide range of sources and circumstances, vary in their degree, and differ in terms of how effectively data and experience can reduce them. Recognizing these distinctions can help decision makers calibrate oversight to the strength of available evidence and the nature of remaining uncertainty. Under these conditions, effective evaluation depends on complementary decision-support approaches, including decision trees, structured expert judgment, multicriteria decision analysis, robust decision making, precautionary reasoning, design for flexibility, and adaptive risk management. Examples of how these different decision support tools could apply to different synthetic cell cases are provided in Chapter 3. These approaches support transparent, proportionate decision making when evidence is incomplete or evolving.

Much of synthetic cell research, consistent with broader traditions in engineering biology, proceeds with the expectation that biological functions can be modularized, characterized, and recombined in ways that support increasingly predictable design. While this engineering vision has enabled substantial progress, biological systems may also exhibit context dependence, emergent behavior, and levels of complexity that challenge strictly modular or reductionist assumptions. If synthetic cell development requires new ways of understanding and engineering complex biological systems, governance frameworks must be sufficiently agile and learning-oriented to respond effectively. The adaptive, proportionate approach outlined in this report is designed to accommodate both anticipated and unanticipated forms of complexity as the field evolves.

OVERSIGHT AND GOVERNANCE: FRAGMENTATION, GAPS, AND THE NEED FOR ADAPTATION

Synthetic cell research operates within an interconnected ecosystem of oversight frameworks for biosafety, biosecurity, chemical safety, and environmental protection, described in Chapter 4. Institutional mechanisms, such as institutional biosafety committees (IBCs), provide important safeguards for contained laboratory research, while federal agencies exercise authority across multiple stages of research, development, and application. Together, these frameworks form a foundation for biotechnology governance. However, they were developed for earlier generations of biological and chemical technologies, and whether and how they apply to different synthetic cell cases is not always immediately clear.

The central governance challenge for synthetic cells does not stem from the absence of oversight, but from fragmentation, shifting jurisdictional boundaries, and scientific assumptions and uncertainties embedded in existing frameworks. Oversight responsibilities are distributed across institutions and agencies, with applicability varying by research setting, system characteristics, and stage of development. As a result, two synthetic cell systems with similar functions may be subject to different oversight or regulatory pathways depending on whether genetic material is present, whether replication is possible, or whether they are contained within the laboratory or deployed beyond it. Factors as subtle as how components of the system were produced can also affect

these paths. Information generated to inform decisions in one context also may not be systematically shared or incorporated into oversight or regulatory decisions elsewhere.

Several scientific and technical gaps contribute to these challenges. Existing oversight frameworks consider factors such as human pathogenic risk, presence or absence of genetic content, and replication capacity, but many synthetic cell systems raise uncertainty through other mechanisms, such as functional activity without replication, persistence of components in environmental matrices, or interactions (intended or not) with ecological systems. Detection and monitoring tools may not be well suited for systems that incorporate non-traditional biochemistries or hybrid chemical-biological architectures, limiting confidence in exposure assessment, containment verification, and post-deployment monitoring. In addition, empirical data on environmental behavior, persistence, and ecological interaction remain limited for many synthetic cell designs, constraining evidence-based classification and management.

At the same time, governance gaps and overlaps arise from reliance on categorical triggers that do not always align with synthetic cell characteristics. Frameworks designed for recombinant DNA, conventional genetically engineered organisms, or chemical substances may not map cleanly onto non-living or hybrid systems, particularly those intended for environmental, industrial, or consumer-facing contexts. As synthetic cells progress from foundational research toward translational development and deployment, oversight and regulatory responsibilities shift across actors and governance domains, sometimes without clear handoffs or shared expectations. Early-stage laboratory research may rely primarily on institutional biosafety review, while later environmental, industrial, or clinical applications may require coordination across multiple federal agencies and long-term monitoring mechanisms. This can create uncertainty about which authorities apply, when additional review is warranted, and how risks and benefits should be evaluated consistently over the technology life cycle.

These challenges underscore the need for governance approaches that emphasize coordination across agencies and institutions, clearer alignment of oversight responsibilities, and mechanisms for iterative learning. Effective oversight will depend on integrating scientific evidence as it emerges, improving communication and data sharing across governance domains, and adopting flexible approaches that can adapt as synthetic cell designs, applications, and societal expectations evolve. Governance gaps, overlaps, and potential approaches for addressing them are discussed further in Chapter 4.

CASES ACROSS THE CONTINUUM: HOW DESIGN AND CONTEXT SHAPE RISK AND GOVERNANCE

The implications of synthetic cell design choices, intended applications, and deployment settings become most evident when examined through concrete examples. To explore how biosafety, biosecurity, and environmental considerations surface in practice, Chapter 5 presents a set of illustrative cases spanning the synthetic cell continuum, ranging from simple, non-replicating biochemical assemblies used in basic research to genome-containing, replicating systems intended for industrial, agricultural, or environmental use, as well as forward-looking cases that are fictional or remain technically hypothetical (Table S-1).

TABLE S-1 Synthetic Cell Cases Across the Continuum¹

¹ Table summarizes illustrative cases spanning a continuum of synthetic cell designs and representing a range of applications and containment or deployment contexts. The cases are used to examine how biosafety, biosecurity, and environmental considerations and governance needs vary with system characteristics, intended use, and context.

At the simplest end of the synthetic cell continuum, cases involving genome-free, non-replicating systems demonstrate that cell-like behaviors can emerge from minimal biochemical assemblies (Case 1). These systems generally pose little direct risk to the health of humans, animals, plants, or the environment, yet they highlight a recurring governance challenge: Constructs that are not living organisms but exhibit biological functions may fall ambiguously between chemical and biological oversight systems. As a result, similar constructs may be reviewed differently across institutions, depending on whether oversight is triggered by the presence of genetic material, the use of recombinant components during construction, or the novelty of the behavior exhibited by the synthetic cell itself. These boundary situations illustrate how oversight outcomes can vary even when intrinsic hazards are low.

Moving toward greater functional and structural complexity, mid-continuum cases introduce genetic material and programmed biological activity while remaining intentionally non-replicating (Cases 2–4). Examples include synthetic cells designed for consumer hazard detection, targeted therapeutic delivery, or environmental bioremediation. These cases show how relatively small design choices, such as whether DNA is present and whether the cell can replicate, can substantially influence oversight pathways. Systems designed to be safer alternatives to conventional genetically engineered organisms may reduce some risks, such as uncontrolled replication, while introducing new considerations related to exposure pathways, environmental fate, chemical transformation products, and the persistence of genetic components. In these cases, governance challenges often arise not from novelty alone, but from how existing frameworks assign responsibility across biosafety, chemical safety, environmental protection, and product oversight.

Environmental considerations become more prominent in synthetic cell systems that involve replication, persistence, and sustained interaction with living systems (Cases 5–8). Agricultural and environmental applications involving replicating synthetic cells raise questions about spread, long-term persistence, interactions with native life (microbiota, flora, and fauna), and effects on ecosystem processes. While such systems may still pose minimal direct pathogenic risk to humans and therefore fall within low risk group classifications (see Chapter 4, Table 4-3), they can generate ecological uncertainties that are not well addressed by human health-centered biosafety frameworks. These cases highlight the absence of systematic approaches for evaluating environmental risks posed by non-traditional or hybrid biological systems intended for settings outside of the laboratory.

Highly engineered synthetic cells designed for industrial biomanufacturing illustrate a different set of governance issues (Case 6). Although intended for use under contained conditions, extensive genome redesign and non-standard genetic codes challenge assumptions embedded in existing oversight frameworks regarding detectability, containment reliability, and classification. These cases underscore that containment alone does not reduce governance complexity, particularly when systems are scaled up.

Finally, forward-looking cases, such as bottom-up construction of a fully synthetic replicating cell (Case 7) or the hypothetical development of mirror life (Case 8), highlight the importance of anticipatory governance. Even where technical feasibility

remains uncertain, these cases raise questions about detectability, control, ecological interaction, and international coordination that existing governance frameworks are not yet designed to address. They illustrate why governance discussions may need to begin before technologies are realized, rather than after deployment pathways are established.

Taken together, the cases reinforce several overarching insights. Synthetic cells do not constitute a single class of technologies and do not present uniform risks, benefits, uncertainties, or governance needs. Instead, risks and oversight requirements depend on combinations of design features, intended use, and exposure context. Across the continuum, the most significant governance challenges arise not from the absence of oversight, but from variability in how existing frameworks apply, gaps in environmental assessment, and limited mechanisms for coordination and shared learning. The cases therefore underscore the value of function- and context-based evaluation, supported by adaptive governance approaches that can evolve as synthetic cell technologies and applications continue to develop.

A NATIONAL BIOTECHNOLOGY GOVERNANCE STRATEGY SUPPORTING RESPONSIBLE SYNTHETIC CELL INNOVATION

The scientific, analytical, and governance challenges identified across the synthetic cell continuum point to the need for a coordinated governance strategy to support responsible innovation while managing uncertainty and risk. Many governance challenges associated with synthetic cells, including rapid innovation cycles, convergence across disciplines, dual use considerations, and gaps between research and regulatory frameworks, are shared across engineering biology and biotechnology more broadly. At the same time, the distinctive properties of synthetic cells, including non-living or hybrid architectures, non-traditional biochemistries, and diverse deployment contexts, warrant focused and explicit attention. Accordingly, this report situates synthetic cells as a priority sub-area within a broader national biotechnology governance framework (Figure S-2). This approach recognizes that no single governance mechanism can address the full diversity of synthetic cell designs and applications. Effective oversight instead depends on coordination across existing authorities, shared principles for decision making, and adaptive governance systems that evolve alongside scientific understanding and technological capability.

Four core values guide this strategy: responsibility, balance, coordination, and adaptability. These values are operationalized through objectives that emphasize responsible innovation; navigation of benefits, risks, and uncertainty; strengthened coordination and accountability; and governance systems capable of learning and adjustment over time. Grounding governance in enduring values, rather than rigid rules, allows oversight to remain proportionate and responsive as synthetic cell research progresses from foundational science toward real-world applications.

Conclusion 7-1: Existing oversight frameworks for biosafety, biosecurity, chemical safety, and environmental risk are distributed across multiple agencies and were not explicitly designed to address the diversity of synthetic cell architectures, including non-living constructs, hybrid systems, and designs employing novel features, such as non-traditional biochemistries. Fragmentation across institutions, agencies, and stages of development limits coordination, consistency, and shared learning, constraining the nation’s ability to evaluate risks and benefits in an integrated and adaptive manner. Coordinated governance that aligns federal efforts under a shared vision of responsible innovation is essential to ensure that synthetic cell technologies advance safely, transparently, and in ways that maximize societal benefit.

Recommendation 7-1: The White House Office of Science and Technology Policy (OSTP), in coordination with the National Security Council (NSC), should lead the development of a national strategy for biotechnology governance, within which synthetic cells are explicitly designated as a priority subarea requiring tailored coordination, standards, and oversight approaches.

This strategy should:

• Define a shared federal vision grounded in the core values of responsibility, balance, coordination, and adaptability, providing a common framework to guide agency actions across research, oversight, and security domains.
• Establish an interagency Synthetic Cell Working Group, nested within a broader biotechnology coordination structure, to clarify roles, share data and expertise, coordinate oversight approaches, and identify gaps and overlaps in authorities relevant to synthetic cell R&D and applications.
• Include mechanisms for transparency, public engagement, and regular evaluation to ensure that governance approaches remain responsive to scientific advances and societal values, including periodic assessment of whether synthetic cell developments create new oversight needs within the broader biotechnology governance landscape.
• Assess whether existing regulatory authorities, jurisdictional boundaries, oversight mechanisms, and risk-benefit trade-offs are appropriate for emerging biotechnology capabilities, including synthetic cells, and identify issues that may require statutory reform to be addressed.

Congress should provide statutory continuity, resources, and accountability for this interagency effort through periodic progress reviews and, as necessary, utilize additional Congressional actions to enable better biotechnology governance.

An interagency Synthetic Cell Working Group should bring together agencies with relevant research, oversight, standards, security, and application mandates, including the National Science Foundation (NSF) and the National Institutes of Health (NIH);¹

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¹ NIH is within the Department of Health and Human Services.

the Food and Drug Administration (FDA); the Environmental Protection Agency (EPA) and the United States Department of Agriculture (USDA); the U.S. Fish and Wildlife Service (USFWS);² the National Marine Fisheries Service (NMFS);³ the Occupational Safety and Health Administration (OSHA);⁴ the National Institute of Standards and Technology (NIST);⁵ the National Aeronautics and Space Administration (NASA) and the Department of Energy (DOE); the Department of Defense/War (DoD/DoW); and the Department of Homeland Security (DHS). Additional participation from the Department of Commerce Bureau of Industry and Security, the Department of State (DOS), and the Department of the Treasury would address export controls, international coordination, and investment-related biosecurity considerations.

Effective governance also depends on a stronger empirical foundation. Although many risk pathways for synthetic cells parallel those for chemicals or conventional genetically engineered organisms, systems incorporating non-traditional biochemistries, hybrid components, or synthetic genomes may strain existing detection methods, modeling assumptions, and empirical benchmarks. Limited data on persistence, survivability, ecological interaction, and detectability constrain the precision and confidence of current risk-benefit analyses. Targeted investment by federal research funders in empirical research and data infrastructure, including comparative benchmarking and development of detection and monitoring tools that extend beyond standard molecular assays, is therefore a key component of effective synthetic cell governance.

Conclusion 7-2: Empirical data on synthetic cell persistence, survivability, ecological interaction, and detectability remain limited, constraining the precision and confidence of current risk-benefit analyses. Synthetic cells employing non-traditional biochemistries, hybrid components, or synthetic genomes may elude standard detection and modeling approaches developed for conventional chemical or biological systems, hindering effective evaluation and monitoring. Robust, shared data infrastructure and standardized methodologies would enable proportionate oversight, analytic rigor, and informed policy making.

Recommendation 7-2: Federal research funders (e.g., NSF, NIH, USDA, DOE, and DoD/DoW) should invest in systematic studies and data infrastructure to fill empirical gaps supporting synthetic cell risk and benefit assessment.

Priority areas include:

• Persistence and survivability beyond conventional containment, including in limited- and open-release contexts;
• Effectiveness of means to control persistence and survivability beyond conventional containment, such as genetically encoded elements that limit growth;

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² USFWS is within the Department of the Interior.

³ NMFS is an office of the National Oceanic and Atmospheric Administration within the Department of Commerce.

⁴ OSHA is within the Department of Labor.

⁵ NIST is within the Department of Commerce.

• Ecological and interspecies interactions and horizontal gene transfer, including comparative studies across environmental conditions;
• Benchmarking synthetic cells against engineered microbes, traditional genetically modified organisms, and relevant chemical alternatives to support evidence-based comparison of risks and benefits; and
• Detection and monitoring tools for non-traditional biochemistries, hybrid components, and synthetic genomes that fall outside of standard molecular assays.

Standards development and measurement science play a central role in making this evidence base usable across agencies and sectors. Coordinated standards for measurement, traceability, and data sharing improve reproducibility, comparability, and confidence in oversight and regulatory decisions while enabling collaboration across academia, industry, and government. NIST is already engaged in advancing measurement science and standards for engineering biology, providing a strong foundation for efforts relevant to synthetic cell research and applications.

Recommendation 7-3: NIST should coordinate standards development for measurement, traceability, and data sharing across agencies and sectors to support synthetic cell characterization, detection, and monitoring. Congress should authorize and fund NIST to expand its existing engineering biology and measurement science activities to explicitly address synthetic cell research and applications.

Because synthetic cells exist along a continuum of designs and applications, governance approaches must be flexible enough to accommodate this diversity. An adaptive framework that considers key structural and functional characteristics, including genetic content, replication capacity, and contextual factors such as intended use, deployment environment, persistence, and interaction with living systems, provides a practical basis for proportionate oversight. Structured decision-support tools, including risk-tier matrices, technology-readiness–linked checklists, and multicriteria analyses, can help align funding decisions, oversight expectations, and regulatory review with system characteristics and evolving evidence.

Conclusion 7-3: Synthetic cells span a continuum from non-replicating biochemical assemblies to genome-based, potentially self-replicating entities, across many possible applications. An approach that considers replication, genetic content, intended use, and environmental context is necessary for proportionate, evidence-based oversight.

Implementing this adaptive oversight approach will require coordination across the federal agencies that fund, regulate, and provide oversight for synthetic cell research and development. Because responsibilities are distributed across multiple governance domains, mechanisms for information sharing, consistent interpretation of oversight

responsibilities, and iterative learning will be essential. An interagency Synthetic Cell Working Group could provide this coordination by strengthening communication and shared situational awareness across agencies, while complementing, rather than replacing, existing statutory authorities. By supporting coordination and proportionate risk management across diverse research and deployment contexts, the working group would provide connective architecture across the federal governance landscape.

Recommendation 7-4: An interagency working group focused on synthetic cells should develop and pilot a decision-support toolkit to guide proportionate classification and oversight of synthetic cell research and applications. This group should include key federal agencies that fund, regulate, and provide oversight for synthetic cell research and development, such as NSF, NIH, FDA, EPA, USDA, USFWS, NMFS, OSHA, NIST, NASA, DOE, DoD/DoW, and DHS.

The tools should:

• Distinguish different synthetic cells by key biological features (e.g., replication, genetic content);
• Incorporate contextual factors (intended use, environment, persistence, potential interactions); and
• Enable adaptation as research and development advance.

Decision-support tools, such as risk-tier matrices, uncertainty assessments, technology-readiness checklists, and multicriteria decision analyses, should be used to operationalize this framework and be tested across public and private research and development.

The diversity of synthetic cell systems highlights the need to update and modernize biosafety and biosecurity oversight. Current U.S. biosafety oversight is largely based on the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, which have served as a foundation for institutional and federal oversight for decades but were developed primarily for recombinant and synthetic nucleic acid research. As synthetic cell systems increasingly blur distinctions among biological, chemical, and engineered systems, existing frameworks do not fully address non-living or hybrid constructs or applications beyond contained laboratory research. Clearer, more coordinated guidance can articulate how biosafety, biosecurity, environmental, and chemical considerations should be evaluated together, including when alternative containment, monitoring, or stewardship approaches may be more appropriate than traditional laboratory controls.

Conclusion 7-4: Existing biosafety and related institutional oversight frameworks were not designed for the full diversity of synthetic cell systems, particularly non-living or hybrid constructs and applications beyond contained laboratory research. While biosecurity policies address risks of deliberate misuse, they do not by themselves provide comprehensive guidance for managing synthetic cell research that combines biological, chemical, and engineered features. The absence

of integrated, explicit guidance leaves researchers and institutional review bodies uncertain about appropriate classification, containment, monitoring, and reporting practices, especially for environmental, industrial, or other limited- or open-release applications.

Recommendation 7-5: Research institutions and funders should support the development or adaptation of institutional review mechanisms that integrate assessments of biosafety, biosecurity, environmental, and relevant chemical risks for synthetic cell-related research, particularly at the early stages of development. These mechanisms complement, rather than replace, existing institutional safety committees and compliance systems.

At the federal level, ongoing policy developments create an important opportunity to modernize biosafety and biosecurity oversight more broadly. NIH’s Biosafety Modernization Initiative reflects recognition that biosafety policy must evolve to keep pace with scientific and technological advances, and the May 2025 Executive Order on Improving the Safety and Security of Biological Research signals broader federal interest in strengthened, coordinated oversight of high-risk biological research, including certain research conducted outside federally funded settings. Because NIH’s mission is primarily focused on human health research, coordination with other agencies, including USDA and EPA, is needed to ensure appropriate oversight of research involving agricultural systems, environmental release, and non-human organisms.

Recommendation 7-6: Leveraging its Biosafety Modernization Initiative, NIH should work with USDA, EPA, and other federal entities that fund or oversee biological research, as appropriate, to update and, where necessary, replace current biosafety guidelines, including the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. This effort should more holistically address biosafety and biosecurity risks arising from rapidly advancing engineering biology and other emerging biotechnologies, and ensure that oversight provides comprehensive coverage of research involving humans, animals, plants, and microbes.

The update should:

• Address governance gaps identified in this report and ensure coordinated, comprehensive oversight of synthetic cell research across sectors, including health, agriculture, materials, and the environment.
• Provide illustrative case studies linking engineering biology design features, including for synthetic cells, to appropriate biosafety and biosecurity measures, such as containment and monitoring approaches, and clarify where traditional risk group or biosafety level frameworks may not fully apply.
• Promote consistent oversight practices across publicly and privately

• funded research, including encouraging institutional review mechanisms (e.g., IBC-equivalent structures) in industry.

Beyond technical oversight, effective governance depends on social legitimacy and public trust. Responsible innovation requires transparency, ethical foresight, and sustained two-way engagement so that societal values shape research trajectories and governance decisions. Embedding social science, communication, and engagement throughout the research and governance landscape supports informed decision making and public confidence.

Conclusion 7-5: Public confidence in biotechnology depends on transparency and active involvement. Because synthetic cells may provide distinct and context-dependent benefits, governance should include ongoing bidirectional communication, ethical foresight, and social science integration. Responsible innovation frameworks can help ensure that societal values shape the trajectory of research and deployment toward public benefit.

Recommendation 7-7: Federal agencies, research institutions, and industry partners should embed principles of responsible innovation and two-way public engagement throughout the synthetic cell research and governance landscape.

Actions should include:

• Integrating responsible innovation, stakeholder engagement, and communication training into funding programs and laboratory practice;
• Establishing advisory panels and feedback mechanisms that incorporate end-user and community perspectives; and
• Communicating benefits, risks, and uncertainties transparently, in plain language, to a breadth of audiences.

Implementing this governance strategy also requires institutional and human capacity. A skilled, interdisciplinary workforce is essential for integrating technical, ethical, and societal considerations into oversight and practice. Current gaps in biosafety, biosecurity, communication, and policy analysis highlight the need for targeted investments in training and infrastructure.

Conclusion 7-6: Effective implementation of responsible synthetic cell governance requires a skilled, interdisciplinary workforce capable of integrating technical, ethical, and societal considerations. Current capacity gaps exist in biosafety, biosecurity, communication, and policy analysis, in addition to gaps in regulatory risk assessment. Federal and institutional investments are needed to strengthen both human and technical infrastructure supporting safe and responsible innovation.

Recommendation 7-8: Federal funders of synthetic cell research, including

NIH, NSF, NASA, USDA, DOE, DoD/DoW, and other federal and institutional partners should strengthen the workforce and infrastructure required for responsible synthetic cell governance.

Key priorities include:

• Identify and define measurable core competencies and skills in synthetic cell research and development, and incorporate these competencies into funding announcements, training grants, and evaluation criteria;
• Support the development and implementation of educational and training programs, designed in collaboration with synthetic cell researchers, social scientists, and biosafety and biosecurity experts, that prepare trainees to critically assess and responsibly advance emerging technologies;
• Develop and fund interdisciplinary training programs in biosafety, biosecurity, ethics, and risk assessment and communication related to synthetic cells and engineering biology more broadly;
• Incentivize team-science approaches that integrate biological, social, ethical, and policy expertise across the research life cycle; and
• Establish and assess biosecurity competencies across different types and stages of training, ensuring that programs emphasize practical, scenario-based learning and comprehensive understanding of dual use and misuse considerations in synthetic cell research.

Finally, synthetic cell research operates within a global scientific ecosystem. No comprehensive international framework yet addresses biotechnologies that blur the line between living and non-living systems. International collaboration can harmonize principles, standards, and practices; reduce regulatory fragmentation; and support responsible innovation across borders.

Conclusion 7-7: Synthetic cell research and its implications cross national and sovereign boundaries. No international framework yet addresses biotechnologies that blur the line between living and non-living systems. Without proactive collaboration, regulatory fragmentation could impede innovation and safety. International dialogue can help harmonize standards, manage transboundary risks, support and accelerate responsible biotechnology innovation, and strengthen international scientific partnerships.

Recommendation 7-9: OSTP, in partnership with relevant departments and agencies, should pursue international collaboration to harmonize principles, standards, and practices for synthetic cell research and oversight. U.S. expert networks at departments and agencies including DOS, DOE, USDA, EPA, FDA, NIH, NSF, and NIST should engage with international bodies, such as the Organization for Economic Co-operation and Development (OECD), North Atlantic Treaty Organization (NATO), World Health Organization (WHO), United Nations Educational, Scientific and Cultural Organization (UNESCO),

International Gene Synthesis Consortium (IGSC), and treaty organizations such as the Convention on Biological Diversity (CBD), Biological Weapons Convention, and Chemical Weapons Convention, to prioritize:

• Shared registries and reporting templates;
• Standards for transboundary movement, environmental release, and space applications; and
• Dialogue on emerging domains such as non-traditional biochemistries, including mirror biology.

Taken together, the conclusions and recommendations summarized in Table S-2 describe how synthetic cell governance can be implemented within a broader national biotechnology governance strategy, enabling the potential benefits of synthetic cell innovation to be realized while managing associated risks. By aligning scientific advancement with transparent, adaptive governance grounded in shared societal values, this strategy provides a forward-looking pathway for supporting innovation that is safe, secure, and responsive to public priorities.

TABLE S-2 Crosswalk of Themes Underlying Conclusions and Recommendations for Supporting Responsible Synthetic Cell Innovation

NOTE: OSTP: Office of Science and Technology Policy; NSC: National Security Council; NSF: National Science Foundation; NIH: National Institutes of Health; USDA: United States Department of Agriculture; DOE: Department of Energy; DoD: Department of Defense; DoW: Department of War; NIST: National Institute of Standards and Technology; FDA: Food and Drug Administration; EPA: Environmental Protection Agency; USFWS: U.S. Fish and Wildlife Service; NMFS: National Marine Fisheries Service; OSHA: Occupational Safety and Health Administration; NASA: National Aeronautics and Space Administration; DHS: Department of Homeland Security; IBCs: institutional biosafety committees; DOS: Department of State; OECD: Organization for Economic Co-operation and Development; NATO: North Atlantic Treaty Organization; WHO: World Health Organization; UNESCO: United Nations Educational, Scientific, and Cultural Organization; IGSC: International Gene Synthesis Consortium.