Securing Cell-Free Biomanufacturing as a Strategic National Capability
Cell-free expression (CFE) is a biomanufacturing platform capable of producing diverse biomolecules, including proteins, enzymes, and mRNA, outside of (or “without needing”) living cells. Because CFE extracts can be freeze-dried, stored at room temperature, and reactivated on demand, they enable rapid, portable, and decentralized production of diagnostics, vaccines, and therapeutics with minimal infrastructure. These properties make CFE a powerful tool for preparedness, point-of-need healthcare, and defense applications. The same properties, however, also create an underappreciated biosecurity risk. Commercially available CFE kits already support the production of toxins, bacteriophages, and virus-like particles, with no oversight of who is purchasing them or why. As CFE becomes more sophisticated and accessible, DNA synthesis and export controls remain the primary regulatory safeguards against de novo production of harmful biological agents, yet governance frameworks lack the situational awareness and enforcement capacity to keep pace with rapidly falling technical barriers.
The United States (U.S.) faces a dual imperative: invest in CFE to secure strategic leadership in next-generation biomanufacturing, and close the governance gap to prevent misuse and to ultimately enable American innovation to advance even more rapidly. We recommend two coordinated actions:
- A tiered oversight framework that includes know-your-customer measures for all CFE vendors and biosafety-level grading for extracts with different capabilities.
- Federal investment to improve CFE yield, reliability, purification, and portable GMP-compatible manufacturing.
Acting now, while norms are still forming, gives the U.S. the opportunity to lead both in the technology and in its governance.
Challenge and Opportunity
CFE enables new production methods that outpace traditional cell-based and chemical synthesis by minimizing the need for specialized infrastructure such as sterile culture systems, bioreactors, and technical expertise to maintain living cells. This makes it the preferred method of production for malicious actors, particularly lone-wolfs or small groups that may be under-resourced.
In parallel, CFE technology is rapidly moving from the research lab into the real world, with improvements in yield being further accelerated by AI, yet U.S. policy has not kept pace on multiple fronts.
Biomanufacturing is a strategic national asset
The challenge is compounded by intensifying international competition in advanced biomanufacturing. Nations that move first to translate CFE into deployable bioproduction infrastructure will gain durable advantages across pharmaceutical supply chains, emergency response capacity, and industrial biotechnology. China, in particular, has moved aggressively to secure intellectual property and scale capabilities in cell-free systems, signaling that CFE is viewed not merely as a scientific tool but as a strategic national asset in China’s race to close the gap with the United States. Absent timely policy engagement, the U.S. risks ceding leadership in a foundational biomanufacturing modality while simultaneously inheriting its downstream security risks. In this context, reactive governance is doubly damaging: it increases both strategic vulnerability and potential biosecurity risks.
The core policy problem is therefore twofold: first, to prevent the unintended security consequences of increasingly accessible synthesis technologies; and second, to do so in a way that enables the innovation needed to maintain U.S. leadership. Addressing only one side of this problem, through either permissiveness or restriction, would undermine the other.
CFE changes the threat landscape
Historically, biological attacks have been rare, in part because the technical and economic barriers to producing dangerous agents were high, and in part because biosecurity itself occupied a relatively narrow space in public consciousness. Lone actors who pursued biological harm tended to default to comparatively crude options, such as ricin, precisely because more sophisticated agents required infrastructure, expertise, and resources that placed them out of reach. This historical pattern has shaped policymakers’ intuitions about biorisk, but it is increasingly a poor guide to the present threat landscape.
Commercially available CFE kits, which are enabling researchers to massively accelerate the design of protein-based therapeutics, can already be used to produce toxins, bacteriophages, and virus-like particles, with no requirement to verify who is purchasing them and why. CFE has also been demonstrated to support the production of non-enveloped mammalian viruses such as polio. This ease of use and commercial access lies in contrast to traditional bioproduction, which requires sterile culture systems, bioreactors, and transfection reagents. In fact, CFE is an increasingly common component of high school and undergraduate biology education. Increased access to such kits eliminates the specialized equipment and expertise that historically served as barriers to entry into biological engineering. To ensure that the U.S.’ industry and education systems can fully capitalize on the promise offered by CFE, biosecurity frameworks need to be reviewed and updated to establish proper guardrails to prevent acquisition by malicious actors.
Two shifts are eroding the conditions that kept the historical incidence of bioattacks low. First, the rise of large language models and broader public discourse around AI-enabled threats has dramatically raised general awareness of biological weapons as a category of weapon of mass destruction. Even when frontier models decline to provide synthesis instructions, they readily communicate which agents are dangerous and why, effectively lowering the informational barrier to identifying high-consequence targets. Second, and more critically, CFE collapses the economic and infrastructural gap between “crude” and “sophisticated” biological agents. Producing a functional non-enveloped virus using a commercial CFE kit is approaching the same order of magnitude in cost and complexity as producing a classical toxin, while yielding an agent with vastly greater potential for harm and transmissibility. Additionally, directly purchasing the toxin itself is now more expensive than purchasing the CFE and DNA needed to synthesize the same amount of toxin. The historical logic that pushed bad actors toward cheaper, lower-impact agents no longer holds: when the cheapest option is also among the most dangerous, the deterrent effect of cost and complexity disappears.
This is the heart of why CFE warrants near-term policy attention rather than deferred study. Unlike scenarios in which an AI model must walk a malicious actor through a difficult synthesis, CFE provides the production capability directly out of the box.
The need to update regulatory frameworks
Regulating CFE research, however, will require a different approach than that of regulating CFE distribution. Existing biosafety rules, such as BSL designations and previous guidelines regarding dual-use research of concern, govern how scientists work with dangerous material inside institutions. They do not govern what biological templates scientists use with these commercial CFE kits, or whether a given kit can support the synthesis of harmful agents. A researcher using CFE to produce a pathogenic virus might not trigger any regulatory review today, especially if the virus is not on the Select Agents list, and a non-state actor utilizing the same kit could potentially fly completely under the radar.
DNA synthesis screening, the main current safeguard, addresses the template but not the production machinery. This means that in cases where synthesis orders circumvent existing regulatory measures, a malicious actor could still use CFE to rapidly synthesize harmful biological material. While new legislation such as the Biosecurity Modernization and Innovation Act of 2025 introduces important guidelines for DNA synthesis screening that could also protect against misuse of CFE, uneven international standards, AI-driven protein design, and the ability to split orders across multiple vendors mean this protection is insufficient. In the meantime, benchtop and unregulated DNA synthesis capabilities coupled with CFE exacerbate the need for near-term policy.
This gap is also not easily addressable by simply applying expanded DNA synthesis guidelines to a new tool. CFE systems will likely vary in risk profile depending on their composition: mammalian cell extract with intact translation machinery can support the production of pathogens that a minimal reconstituted system optimized for protein product cannot. Addressing this requires a new, capability-based approach to oversight that is proportionate to the actual risk of each type of CFE formulation.
CFE can strengthen biodefense and health security
CFE’s portability and on-demand production capability make it directly relevant to homeland defense, supply chain resiliency, and health security. CFE has been demonstrated as an effective diagnostic platform, and recent work has shown that full-scale production of mRNA vaccines formulated in lipid nanoparticles can be achieved using benchtop microfluidic devices. Additional work has shown the incorporation of CFE into Zika virus detection assays, zinc level quantification, and portable GMP-grade therapeutic production. These capabilities establish that CFE can operate at clinically relevant scales in compact, field-deployable formats — enabling diagnostics, vaccines, and other critical biologics to be produced closer to the point of need. This reduces vulnerability to supply chain disruptions and could dramatically accelerate response timelines in a national security emergency. As costs decline with scale and standardization, CFE becomes increasingly cost-competitive with traditional biomanufacturing for time-sensitive and distributed applications.
Critically, CFE offers a rare opportunity to build security in from the start rather than bolt it on later. Because CFE operates in test tubes rather than inside replicating living organisms, production platforms can be engineered with intrinsic safety features. For example, bioorthogonal genetic systems that use reassigned or non-natural molecular components incompatible with standard biological systems are made possible by CFE. Such systems would make any agent produced within them unable to function in natural biological contexts, providing a built-in containment mechanism. Importantly, these same modifications are already required to push CFE into its most commercially valuable applications, such as producing proteins incorporating non-natural amino acids. This means that investing in safety-by-design CFE simultaneously advances biosecurity and commercial competitiveness: a rare alignment of incentives that policymakers should move quickly to capitalize on.
The window for proactive governance is open, but it will not remain so. CFE capabilities are expanding rapidly, and both the norms and commercial infrastructure around these systems are still being formed. Policymakers must act now to enable the United States to shape those norms, lead in establishing global standards, and position our nation as a leader in responsible next-generation biomanufacturing. The recommendations below outline a two-pronged strategy: tiered regulatory oversight calibrated to actual CFE capabilities, and targeted federal investment to accelerate safe, scalable CFE infrastructure that supports decentralized biomanufacturing.
Plan of Action
CFE enables a new model of biomanufacturing that is faster, more flexible, and less dependent on centralized infrastructure traditionally needed for cell culture. Those same features also introduce novel risks, especially since CFE is currently commercially available and has demonstrated the ability to produce functioning viruses and toxins. Due to the unique technical makeup of the technology, the traditional trade-off between innovation and regulation does not apply, as safety-improving technological measures, such as bioorthogonality, can also boost CFE’s manufacturing capacity. Thus, harmonizing these efforts with other dominant biosecurity measures, DNA synthesis screening, will safely unlock this technology to its full capacity.
Because CFE risk depends not only on the DNA template but also on the CFE system’s functional capabilities, governance should focus on tiering, standards, and capability-based controls. We recommend:
1. a tiered oversight framework anchored by NIST standards, integrated into NIH/CDC biosafety tiering, and linked to export controls and industry know-your-customer measures through a Cell-Free Expression Oversight Consortium modeled after the IGSC.
2. A federal investment strategy to improve CFE yield, reliability, purification, and portable GMP-compatible manufacturing. CFE is unusually well-suited for safety-by-design: the same modifications that improve performance and commercial competitiveness, including the use of biological orthogonalization, can also constrain misuse by reducing compatibility with uncontrolled biological contexts.
Recommendation 1. Enable Safe Scaling of CFE Through Capability-Based Tiering and Export Alignment
Establishing clear, capability-based tiers for CFE systems would not only improve biosecurity but also provide regulatory clarity that enables innovation, commercialization, and responsible scaling. While different types of CFE can share similar material components, characteristics such as yield, the ability to produce modified proteins, and the capacity to support viral production can differ substantially. These differences depend not only on the DNA template but on the properties of the CFE system itself, and those should be taken as a central consideration for classification, especially given the proliferation of benchtop DNA synthesizers. The National Institute of Standards and Technology (NIST) synthetic cell laboratories can support the technical validation and calibration of these tiering frameworks, utilizing the National Agile Biomanufacturing Initiative , enabling standardized evaluation of systems with different functional properties, including those incorporating orthogonal biological components.
- Given that the main biosafety risk CFE poses currently comes from malicious activity from lone wolf actors, the Department of Commerce should convene a Cell-Free Expression Oversight Consortium, modeled on the International Gene Synthesis Consortium, to encourage sellers of CFE mixes to implement know-your-customer measures and harmonize customer screening internationally, implement export controls, and international standards.
- The NIH should be engaged to update dual-use research of concern (DURC) guidelines, ensuring that emerging CFE-based research on mammalian viral synthesis is flagged early for ethical and security review.
- The Department of Commerce’s Bureau of Industry and Security (BIS), in coordination with the Departments of State and Energy, should explicitly classify advanced cell-free expression (CFE) systems under the Export Administration Regulations (EAR), harmonized with the Australia Group control lists, establishing clear export control thresholds based on functional capabilities (such as the ones relevant for the biosafety framework). This classification should enable licensing requirements, end-user verification, and international alignment without impeding benign academic or industrial research.
Recommendation 2. Invest in Safe, Scalable, GMP-Compatible CFE Infrastructure
Congress should establish a National Agile Biomanufacturing Initiative, housed within the Office of Science and Technology Policy (OSTP), with a five-year mandate and an option for renewal, to accelerate the development of distributed, GMP-compatible manufacturing infrastructure. For the initiative to be effective, it will require appropriations of at least 40 million USD annually, with coordinated investment across NASA, the Department of Defense (including DARPA and DEVCOM-CBC), NIST, and NSF. Cell-free expression is a critical enabling technology within this strategy, but the initiative should encompass the full portfolio of agile biomanufacturing modalities for distributed deployment in public health, defense, and emergency-response settings.
- NIST should receive 10 million USD annually to deliver measurements and standards that support quality and performance benchmarks, safety requirements, and compliance metrics for cell-free manufacturing systems (as listed in recommendation 1). This will inform risk and performance tiers for cell-free manufacturing, in alignment with NSCEB recommendation 4.1a (appendix C).
- NSF should expand its Cell-Free Innovations in Research and Engineering (CFIRE) program by doubling its $40 million budget and extending its duration by five years. The expanded program should fund projects that develop and test modular, GMP-compatible CFE units, while incentivizing the integration of safety-constraining design features into federally funded systems. Progress can be tracked through concrete indicators such as improvements in CFE yield and demonstrated advances in safety-by-design bioorthogonalization (e.g., genetic code reassignment, orthogonal ribosomes).
- Congress should direct DARPA, or another suitably equipped laboratory within the DoD research ecosystem, to fund the development of field-deployable, GMP-compliant manufacturing platforms built on CFE technologies. In parallel, NASA should pursue complementary work on cell-free systems for space applications, where its operational environments can serve as a testbed for autonomous, remote biomanufacturing.
Conclusion
CFE represents a unique opportunity to both strengthen American competitiveness and preparedness in bioproduction while anticipating and preventing biorisks posed by lone actors. Targeted government investments in developing CFE could position the US as a global leader in next-generation biomanufacturing and reduce dependence on foreign pharmaceutical innovation and supply chains. Prioritizing this research would also transform pandemic preparedness infrastructure from centralized, vulnerable systems to resilient, rapid-response networks. In the future, we envision standardized, GMP-compliant CFE units capable of rapidly scaling production for various vaccines and therapeutics within days, rather than months, of pathogen detection. The freeze-dried and shelf-stable nature of CFE extracts also means that these systems can even be poised for autonomous deployment. Importantly, developing bioorthogonal CFE will fundamentally alter the risk calculus by making any potential replicative product incompatible with natural biological systems. Combined with tiered access controls, this approach would rebalance the traditional tradeoff between beneficial innovation and security concerns.
Cell-based production in bacteria, yeast, or mammalian cells requires sterile culture systems, bioreactors, and sustained technical expertise, and struggles to produce toxins. Chemical synthesis is limited to short peptides and demands costly, specialized reagents. CFE works differently: cells are lysed and processed to retain the core transcription and translation machinery (ribosomes, tRNAs, enzymes) while removing genomic DNA and debris. The extract is supplemented with energy substrates, amino acids, and cofactors, then freeze-dried into shelf-stable kits that activate upon rehydration with a DNA template. No living cells, no sterile infrastructure, no specialized expertise required. This is why CFE is the most accessible production route for malicious lone actors.
Past frameworks, including gain-of-function oversight and gene synthesis controls, were established after the technology was already widespread, resulting in contested and unevenly enforced rules. This proposal intervenes before norms have hardened. Additionally, a primary proposed safety mechanism is bioorthogonality, which replaces standard molecular components with synthetic ones incompatible with normal biological systems. These modifications do not constrain CFE performance. They are the same changes required to increase CFE’s competitiveness in its most commercially valuable applications, specifically the bioproduction of pharmaceuticals. Security and competitive advantage are the same investment.
DNA synthesis and export controls remain the primary regulatory safeguards against de novo production of harmful biological agents, yet governance frameworks lack the situational awareness and enforcement capacity to keep pace with rapidly falling technical barriers.
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