Synthetic biology holds great promise for addressing global needs. However, most current developments are not immediately translatable to ‘outside-the-lab’ scenarios that differ from controlled laboratory settings. Challenges include enabling long-term storage stability as well as operating in resource-limited and off-the-grid scenarios using autonomous function. Here we analyze recent advances in developing synthetic biological platforms for outside-the-lab scenarios with a focus on three major application spaces: bioproduction, biosensing, and closed-loop therapeutic and probiotic delivery. Across the Perspective, we highlight recent advances, areas for further development, possibilities for future applications, and the needs for innovation at the interface of other disciplines.
Synthetic biology and its applications hold great promise for addressing global humanitarian needs including the goals of sustainable development, zero hunger, health and well-being, reduced inequality, and improved access to responsibly produced goods and services1. Advances in recent years have demonstrated the potential for synthetic biology to revolutionize technologies across disparate applications including biocomputing2,3, living materials4, electronic interfacing5, therapeutic genome editing6, multiplexed diagnostics, and cellular recording7, third-generation biorefineries8, and living biotherapeutics9. Perhaps the most immediately recognized and advanced application of synthetic biology is the ability to alter metabolism to produce high-value products for applications ranging from biofuels and plant natural products10,11 to polymer precursors and bio-inspired materials12. In this regard, the ability to transform microorganisms into chemical factories that compete with organic chemical synthesis is ushering in a new era of biomanufacturing.
Despite these great advances, most current developments are not immediately translatable to “outside-the-lab” application spaces, which are quite diverse and variable compared to the well-controlled conditions available in laboratory settings. We posit that outside-the-lab scenarios encompass three main settings with respect to available resources: (1) resource-accessible, (2) resource-limited, and (3) off-the-grid. Resource-accessible settings include situations whereby technology is deployed with essentially unlimited access to resources and experienced personnel. Such situations (for which large-scale industrial biotechnology settings are a great example), typically entail technology transfer of lab-scale results followed by iterative process optimizations/scale-up and biological re-design cycles. However, successful deployment (even in these most resource-accessible conditions) is not a guarantee due to a number of factors including genetic stability, economics, feasibility, and other technical challenges. Resource-limited settings include scenarios marked by technology deployment in more remote settings that include more limited (but nonzero) access to resources and/or expertise, such as remote military and space missions. The most extreme condition, off-the-grid settings, include situations with minimal or no access to resources, electrical power, communication infrastructure, and expertise, such as deployment in remote areas on the planet or even within the gut microbiome. These applications necessitate that deployed technologies operate autonomously without external resources or intervention.
As opposed to the (comparatively simpler) technology transfer and scale-up considerations typically needed in resource-accessible settings, resource-limited and off-the-grid settings require new synthetic biology paradigms to allow for successful deployment. Inherent in these applications are demanding requirements including the need for a high degree of system flexibility, long-term storage capabilities, intermittent/repeated usage, and an ability to operate with limited equipment and intervention. Many of the major challenges and technological requirements for deploying synthetic biology-based technologies in major outside-the-lab settings (specifically highlighting space missions, developing nations, military missions, and agricultural settings) are listed in Fig. 1. To be successful, outside-the-lab platforms should be genetically and functionally stable over long time periods under variable storage conditions, require minimal equipment and resources to run, and require minimal intervention by experienced professionals. In this regard, synthetic biology is undergoing a shift in paradigm from utilizing biology to deploying biology.
Fig. 1: Overview of major challenges and requirements for deploying synthetic biology-based platforms in outside-the-lab settings.
Outside-the-lab scenarios have wide-ranging challenges and requirements for synthetic biology that are more demanding than typical laboratory settings. This figure provides a basic overview of major challenges and requirements associated with four major outside-the-lab settings including: space missions, developing nations, military missions, and agricultural settings. Challenges and requirements common to all settings are listed in the center, and those specific to certain outside-the-lab settings are listed in their respective boxes.
Both cell-based and cell-free system approaches have associated advantages and challenges with regard to ease of deployment in outside-the-lab situations. For instance, while whole-cell platforms are typically easier to mass-produce as well as consolidate multiple complex assays or reactions13,14, there are challenges with long-term viability/stability, toxicity of the analytes or reaction components, and time delays due to the need for cell growth and analyte/nutrient transport15. Cell-free platforms can address many of these associated challenges as they bypass the need for viable cells (and thus can be used to detect or produce compounds typically toxic to cells). This feature of an open reaction environment facilitates the manipulation of metabolism, transcription, and translation16, for instance through exogenous addition of non-native substrates. The elimination of the requirement to sustain life also confers the ability to solely focus the system’s resource utilization on a product or reaction of interest15. However, significant batch-to-batch variability has been demonstrated across academic labs in the context of cell-free protein synthesis yields17. Furthermore, the short cell-free reaction durations (typically on the order of hours)15, high reagent costs (particularly for energy sources and nucleotides), as well as difficulties in folding complex protein products18 present limitations in the application spaces for which cell-free platforms are currently viable.
We focus this Perspective on three major application spaces for the outside-the-lab deployment of synthetic biology: bioproduction, biosensing, and closed-loop living therapeutic and probiotic delivery. We open each major section with a brief intro into its applicability for outside-the-lab developments, analyze current work being done in that area, discuss areas where ongoing improvement is required to enable outside-the-lab deployment, and close with some potential scenarios to which outside-the-lab technology could be applicable.
Synthetic biology has begun to enable both on-demand and continuous (or responsive) production of biochemicals, therapeutics, and even food/food-ingredients using a range of host organisms. The contributions of synthetic biology innovations toward the improved industrial production of small molecules have certainly been well-catalogued elsewhere10,11,19,20,21. In contrast, less attention has been given to production technologies applicable for outside-the-lab scenarios such as on-demand production of small molecules and proteins in developing nations, during remote military and space missions, or for other built-environment in situ production applications. Recognizing the demands and challenges associated with outside-the-lab bioproduction, a number of funding initiatives have been established including the DARPA Battlefield Medicine program aiming to overcome obstacles for on-demand manufacturing through Pharmacy on Demand (PoD) and Biologically derived Medicines on Demand (Bio-MOD) initiatives22. Furthermore, NASA’s Translational Research Institute for Space Health (TRISH)23 seeks to support astronaut health and performance on space missions, including on-demand therapeutic manufacturing on-board spacecrafts24.
Efforts using both whole-cell and cell-free technologies as well as synergistic developments with material science have demonstrated proof-of-concept studies of outside-the-lab molecule production applications. At their core, on-demand and continuous production functionalities entail the preservation and maintenance of metabolic activity in diverse settings. This requires field-deployable platforms to be genetically and environmentally stable, both while in long-term storage and metabolically active states. In addition, coupling of enhanced platform stability with user-friendly deployment technologies (such as integrated production and purification modules and liquid handling capacities) is needed for deployment in settings with limited or no access to resources or experienced personnel (Fig. 2).
Fig. 2: Design strategies for outside-the-lab deployment of synthetic biology systems.
This Perspective encompasses design strategies for deploying synthetic biology outside-the-lab, which vary based on the particular system type (whole-cell (blue), cell-free (red), biotic/abiotic interfacing (yellow)) and application space (bioproduction, biosensing, living therapeutics, and probiotic delivery; all in green). Outside-the-lab bioproduction design strategies include whole-cell liquid cultures, cell-free extract reactions, and encapsulation platforms interfacing living cells with materials, with widespread future applications including on-demand production of small molecules and biologic therapeutics as well as regenerable living building materials. Outside-the-lab biosensing design strategies include whole-cell engineered stress-resilient organisms and regenerable biofilms, cell-free CRISPR/Cas-based sensing platforms, as well as interfacing living cells with novel polymer and electronic systems, with broad future applications including continuous health and hazard monitoring. For bioproduction and biosensing, both whole-cell and cell-free systems are typically interfaced with deployment technologies, such as platform automation and microfluidic liquid handling, to facilitate outside-the-lab usability. Outside-the-lab closed-loop living therapeutics and probiotic delivery design strategies include whole-cell engineered microbes and mammalian cells compatible with the gut and soil microbiomes, as well as interfacing living cells with materials and magnetic systems, with future applications ranging from wound healing to continuous food production on earth and in space.