Combining model-based and data-driven models: an application to synthetic biology resource competition

Abstract

This work explores the integration of machine learning (ML) and mechanistic models (MM). While ML has demonstrated remarkable success in data-driven modeling across engineering, biology, and other scientific fields, MM remain essential for their interpretability and capacity to extrapolate beyond observed conditions based on established principles such as chemical kinetics and physiological processes. However, MM can be labor-intensive to construct and often rely on simplifying assumptions that may not fully capture real-world complexity. It is thus desirable to combine MM and ML approaches so as to enable more robust predictions, enhanced system insights, and improved handling of sparse or noisy data. A key challenge when doing so is ensuring that ML components do not disregard mechanistic information, potentially leading to overfitting or reduced interpretability. To address that challenge, this paper introduces the idea of Partially Uncertain Model Structures (PUMS) and investigates conditions that discourage the ML components from ignoring mechanistic constraints. This work also introduces the concept of embedded Physics-Informed Neural Networks (ePINNs), which consist of two loss-sharing neural networks that seamlessly blend ML and MM components. This work arose in the study of the context problem in synthetic biology. Engineered genetic circuits may exhibit unexpected behavior in living cells due to resource sharing. To illustrate the advantages of the ePINNs approach, this paper applies the framework to a gene network model subject to resource competition, demonstrating the effectiveness of this hybrid modeling approach in capturing complex system interactions while maintaining physical consistency.