Boolean matrix logic programming for active learning of gene functions in genome-scale metabolic network models

Techniques to autonomously drive research have been prominent in Computational Scientific Discovery, while Synthetic Biology is a field of science that focuses on designing and constructing new biological systems for useful purposes. Here we seek to apply logic-based machine learning techniques to facilitate cellular engineering and drive biological discovery. Comprehensive databases of metabolic processes called genome-scale metabolic network models (GEMs) are often used to evaluate cellular engineering strategies to optimise target compound production. However, predicted host behaviours are not always correctly described by GEMs, often due to errors in the models. The task of learning the intricate genetic interactions within GEMs presents computational and empirical challenges. To address these, we describe a novel approach called Boolean Matrix Logic Programming (BMLP) by leveraging boolean matrices to evaluate large logic programs. We introduce a new system, BMLP₀₂ₓ₈ₕ₄, which efficiently explores the genomic hypothesis space by guiding informative experimentation through active learning. In contrast to sub-symbolic methods, BMLP₀₂ₓ₈ₕ₄ encodes a state-of-the-art GEM of a widely accepted bacterial host in an interpretable and logical representation using datalog logic programs. Notably, BMLP₀₂ₓ₈ₕ₄ can successfully learn the interaction between a gene pair with fewer training examples than random experimentation, overcoming the increase in experimental design space. BMLP₀₂ₓ₈ₕ₄ enables rapid optimisation of metabolic models to reliably engineer biological systems for producing useful compounds. It offers a realistic approach to creating a self-driving lab for microbial engineering.