Ideas Lab: Advancing Cell-Free Systems Toward Increased Range of Use-Inspired Applications

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The U.S. National Science Foundation’s Directorate for Technology, Innovation and Partnerships (TIP) is charged with accelerating use-inspiredand translationalresearch and development (R&D) to advance U.S. competitiveness in key technology focus areas . The Advancing Cell-Free Systems Toward Increased Range of Use-Inspired Applications (CFIRE) initiative will accelerate the adoption of cell-free systems, enable new applications of this technology and contribute to the growth of the U.S. bioeconomy. A nascent industry has formed around the ability to carry out biochemical processes, such as DNA transcription/translation, in cell-free in-vitro systems instead of in traditional cell-based in-vivo bio-reactors. This approach has a number of potential advantages, including rapid turn-around, distributed and highly retargetable manufacturing, high-fidelity instrumentation and control of the manufacturing environments – without the constraints of biological growth and the interference caused by cell biomass and cell membranes during product purification. Furthermore, cell-free systems can produce products that are challenging to manufacture in cell-based cultures, such as those inherently toxic to cells or hydrocarbon products that are consumed by the cellular machinery. Despite these advantages, present-day cell-free manufacturing is significantly more expensive than cell-based methods and cell-free systems have a limited range of applications. CFIRE aims to: 1. Reduce the cost of cell-free systems; 2. Increase the range and capabilities of cell-free systems; and 3. Develop and demonstrate cost-effective use-inspired applications. CFIRE will address the key limitations of cell-free technology by identifying technical approaches that can enable ongoing cycles of improvement. The objective is to place cell-free technology on an exponential growth path in which reduced costs lead to increasing adoption which, in turn, generates the learning and investment required to further reduce costs. In order to keep the work focused and to stimulate increasing adoption, efforts funded through this initiative will focus on one or more specific use cases. CFIRE seeks significant breakthroughs that will accelerate the adoption of cell-free systems by: (a) Demonstrating the feasibility and advantages of cell-free systems through use-inspired applications with specific emphasis on applications beyond human therapeutics; (b) Creating infrastructure components, such as tools, protocols, kits, datasets, and characterization services that can readily be accessed by third parties; and (c) Investing in workforce components focused on the training of translational talent with the skills and passion to engage in use-driven cell-free applications. CFIRE will use the Ideas Lab process (see PAPPG Chapter II.F.6), starting with an intensive meeting that brings together multiple diverse perspectives. The primary objectives of this Ideas Lab workshop will be to: identify specific opportunities to significantly reduce the cost of cell-free systems; establish acceptable standards for the fidelity and reproducibility; expand the range of capabilities in order to facilitate broader adoption of the technology; and identify and prioritize use-driven applications beyond human therapeutics.