18. Frank Britto Bisso: Engineering cell fate with adaptive feedback control

Abstract. In multicellular organisms, phenotypical diversity is a direct consequence of decision-making events, where cells in a transient state integrate and process environmental information and respond by committing to a specific fate. By administering external inputs at precise times, a synthetic bias can be introduced to genetically identical cells, such as stem cells, to promote a desired fate. This process, however, involves interfering with native gene regulatory networks through genetic engineering, which requires a deep understanding of the system's dynamics. In this work, we present a biomolecular feedback controller based on an Incoherent Feedforward Loop (IFFL)-like topology that addresses these challenges with its adaptive nature. This synthetic circuit uses sequestration and a delay generated by an intermediate species to produce an output proportional to the approximate discrete temporal derivative of its input. By allowing the controller to act on a target gene involved in decision-making, we achieved a tunable synthetic bias with minimal perturbation to the endogenous network's steady-state equilibrium.
Bio. Frank Britto Bisso is a research assistant at the Cuba-Samaniego Laboratory at Carnegie Mellon University. He received his B.S. in Biomedical Engineering in 2023 from the Joint Program of Pontificia Universidad Católica del Perú and Universidad Peruana Cayetano Heredia (Lima, Perú), where he worked on the principles of resource allocation in E. coli for his undergraduate thesis dissertation. Currently, he works on the design and computational testing of biomolecular controllers, with a particular focus on the Incoherent Feedforward Loop network, and biomolecular neural networks.