Irene Otero-Murasᵃ , Guillermo Rodrigoᵃ, Alfonso Jaramilloᵃ, Manuel Porcarᵃ, Amparo Pascual-Ahuirᵇ, Diego Orzáezᵇ, Alejandro Vignoniᶜ , Jesús Picóᶜ , Pablo Carbonell ᵃ,ᶜ

ᵃ Institute for Integrative Systems Biology (I2SysBio), Universitat de València-CSIC, 46980 Paterna. ᵇ Institute for Plant Molecular and Cell Biology (IBMCP), UPV-CSIC, Valencia. ᶜ Institute of Industrial Control Systems and Computing (ai2), Universitat Politècnica de València (UPV), 46022 Valencia, Spain.

Abstract
Despite the lively community of synthetic biology and metabolic engineering research labs thriving across Southern Europe, notably the Valencia biohub cluster, the establishment of biofoundries aiming to provide sustainable bio-based solutions for the production of chemical commodities and added-value compounds are still largely lacking. Here, we propose a plan to create a functional biofoundry in Valencia and provide strategies for its long-term sustainability. We follow the scheme laid out by the biofoundry Design-Build-Test-Learn (DBTL) pipeline defined by Carbonell and collaborators (Comm Biol, 2018, doi:10.1038/s42003-018-0076-9) comprising both computational and experimental tools.

Distinctive features of the Valencia Biofoundry include the following:

●  Smart biomanufacturing: a unique approach to the Design-Build-Test-Learn cycle based on the principles of Industry 5.0, including the integration of highly automated laboratory facilities through interconnectivity, interoperability and internet of the things (IoT), with data analysis and artificial intelligence, in order to provide rapid prototyping and response to bio-based demands. This ranges from molecular systems running in vitro to engineered cells/organisms of increasing complexity for industrial, clinical or environmental applications.
●  Plant-based biofactories: going beyond microbial chassis to provide a highly versatile platform, the use of plants for production in those cases where such unique chassis should be advantageous in terms of sustainability and efficiency.
●  Biofoundry digital twins: application of the principles of modeling and simulation in order to have a digitalized real-time virtual representation of the facility, allowing the study of multiple scenarios for the most appropriate combination of genetic parts and optimization of the overall process at every scale.
●  Yeast technology platform for directed evolution: a complete collection of yeast strains and plasmids engineered for directed protein evolution, with optimized features for the production, diversification, and selection of enzymes and antibodies.

The development of the proposed biofoundry will have a significant impact both at the research and industrial levels within the Valencia biohub cluster as well as country-wide, as it will boost innovation through start-ups and spin-offs development; facilitate the industrial scale-up of bio-based products; and will promote new synergies by providing a unique decentralized 
collaborative and highly innovative technological synthetic biology platform across labs, i.e., IBMCP/UPV-CSIC, I2SysBio/UV-CSIC, SB2CL/UPV. We believe that the biofoundry will consolidate Valencia as the leading hub for Synthetic Biology and Metabolic Engineering in Mediterranean Europe and will contribute internationally with unique assets and expertise to the Global Biofoundries Alliance to advance the biomanufacturing field forward in a sustainable, greener world.