<i>In Vivo</i> Multicellular Feedback Control in Synthetic Microbial Consortia

In this paper, we present a biomolecular control architecture able to guarantee stable and precise regulation of gene expression. Specifically, we engineer a microbial consortium comprising a cellular population, named <i>controllers</i>, that is tasked to regulate the expression of a gene in a second population, termed <i>targets</i>. Traditional biomolecular control strategies, while effective, are predominantly confined to single-cell applications, limiting their complexity and adaptability due to factors such as competition for limited cell resources and incompatible chemical reactions. Our approach overcomes these limitations by employing a distributed multicellular feedback loop between two strains of <i>Escherichia coli</i>, allowing for division of labor across the consortium. <i>In vivo</i> experiments demonstrate that this control system maintains precise and robust gene expression in the target population, even amid variations in consortium composition. Our study fills a critical gap in synthetic biology and paves the way for more complex and reliable applications in the field.