Automatic mechanistic inference from large families of Boolean models generated by Monte Carlo tree search

Front Cell Dev Biol. 2023 Aug 25:11:1198359. doi: 10.3389/fcell.2023.1198359. eCollection 2023.

Abstract

Many important processes in biology, such as signaling and gene regulation, can be described using logic models. These logic models are typically built to behaviorally emulate experimentally observed phenotypes, which are assumed to be steady states of a biological system. Most models are built by hand and therefore researchers are only able to consider one or perhaps a few potential mechanisms. We present a method to automatically synthesize Boolean logic models with a specified set of steady states. Our method, called MC-Boomer, is based on Monte Carlo Tree Search an efficient, parallel search method using reinforcement learning. Our approach enables users to constrain the model search space using prior knowledge or biochemical interaction databases, thus leading to generation of biologically plausible mechanistic hypotheses. Our approach can generate very large numbers of data-consistent models. To help develop mechanistic insight from these models, we developed analytical tools for multi-model inference and model selection. These tools reveal the key sets of interactions that govern the behavior of the models. We demonstrate that MC-Boomer works well at reconstructing randomly generated models. Then, using single time point measurements and reasonable biological constraints, our method generates hundreds of thousands of candidate models that match experimentally validated in-vivo behaviors of the Drosophila segment polarity network. Finally we outline how our multi-model analysis procedures elucidate potentially novel biological mechanisms and provide opportunities for model-driven experimental validation.

Keywords: Boolean model; Drosophila development; MCTS algorithm; model inference; multi-model inference; segment polarity network.

Grants and funding

This work was supported by U.S. National Library of Medicine grant number T15LM007450 (BG) and NSF CAREER award MCB1942255, National Institutes of Health (NIH) U01-CA215845 (CL).