Ideas Lab: CFIRE: Electricity-Driven Cell-Free Cascades

Electricity-Driven Cell-Free Cascades Today’s bioeconomy largely relies on using living cells to produce chemicals. While effective, this approach is limited— cells are incredibly complex and difficult to control. A promising alternative is cell-free systems that use enzymes to carry out chemical reactions. However, enzymes require many types of chemical energy, which can be hard to supply outside of living cells. This project introduces a groundbreaking solution: using AI to design new enzymes that can be powered directly by electricity instead. As a proof-of-concept, the researchers will design enzymes to convert CO₂—a gas that exists all around us—into methanol, a valuable fuel and industrial chemical. This research has the potential to establish electricity-driven biology as a powerful sustainable biomanufacturing tool. Ultimately, this work could position the U.S. as a global leader in innovation within the emerging bioeconomy—where electricity-powered chemical production expands what is commercially possible. This proposal aims to transform the electrochemical conversion of CO₂ to methanol by developing a highly efficient, cell-free enzymatic cascade system, positioning bioelectrochemistry as a commercially viable technology. Current methods lose over 50% of input energy, making commercial deployment economically challenging. Through a cross-sector collaboration between academia and industry, the project seeks to achieve energy efficiencies exceeding 70% by integrating AI-driven enzyme design, synthetic chemistry, and advanced electrochemical methods. The project will scale up enzyme production, optimize synthetic mediators, improve system stability through electrochemical cofactor regeneration, and integrate these components into high-performance bioelectrodes compatible with existing benchtop electrolyzers. This approach offers a thermodynamically favorable and sustainable pathway for CO₂ valorization, converting a stable waste gas into methanol—a critical fuel and chemical feedstock. If successful, this work will establish cell-free bioelectrochemical systems as a scalable and economically viable platform for chemical production, enabling new routes for carbon utilization and fostering the growth of a next-generation biomanufacturing sector. In addition to producing transformative scientific insights in enzyme engineering and bioelectrochemistry, this project will train the next generation of scientists and contribute to the development of a skilled biotechnology workforce. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.