Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm

TLDR

Drug combinations are often more effective than single agents, but identifying potent mixtures is difficult due to the vast combinatorial space and biological complexity. The study aims to demonstrate that a closed‑loop optimization modality can effectively search for potent drug combinations to control cellular functions. The authors employ an iterative closed‑loop optimization that tests drug mixtures across a large parametric space. Only tens of iterations out of one hundred thousand possible trials were needed to identify a potent drug combination that inhibited vesicular stomatitis virus infection in NIH 3T3 fibroblasts, reduced the required dosage by ~10‑fold, and identified a potent cytokine mixture in thirty iterations out of a million combinations that regulated NF‑κB activity in 293T cells, demonstrating the approach’s potential for manipulating diverse biological systems.

Abstract

A mixture of drugs is often more effective than using a single effector. However, it is extremely challenging to identify potent drug combinations by trial and error because of the large number of possible combinations and the inherent complexity of the underlying biological network. With a closed-loop optimization modality, we experimentally demonstrate effective searching for potent drug combinations for controlling cellular functions through a large parametric space. Only tens of iterations out of one hundred thousand possible trials were needed to determine a potent combination of drugs for inhibiting vesicular stomatitis virus infection of NIH 3T3 fibroblasts. In addition, the drug combination reduced the required dosage by approximately 10-fold compared with individual drugs. In another example, a potent mixture was identified in thirty iterations out of a possible million combinations of six cytokines that regulate the activity of nuclear factor kappa B in 293T cells. The closed-loop optimization approach possesses the potential of being an effective approach for manipulating a wide class of biological systems.