The Evolution of Systems Biology and Systems Medicine: From Mechanistic Models to Uncertainty Quantification.

Understanding interaction mechanisms within cells, tissues, and organisms is crucial for driving developments across biology and medicine. Mathematical modeling is an essential tool for simulating such biological systems. Building on experiments, mechanistic models are widely used to describe small-scale intracellular networks. The development of sequencing techniques and computational tools has recently enabled multiscale models. Combining such larger scale network modeling with mechanistic modeling provides us with an opportunity to reveal previously unknown disease mechanisms and pharmacological interventions. Here, we review systems biology models from mechanistic models to multiscale models that integrate multiple layers of cellular networks and discuss how they can be used to shed light on disease states and even wellness-related states. Additionally, we introduce several methods that increase the certainty and accuracy of model predictions. Thus, combining mechanistic models with emerging mathematical and computational techniques can provide us with increasingly powerful tools to understand disease states and inspire drug discoveries.