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Quantitative understanding of cellular processes, such as cell cycle and differentiation, is impeded by various forms of complexity ranging from myriad molecular players and their multilevel regulatory interactions, cellular evolution with multiple intermediate stages, lack of elucidation of cause-effect relationships among the many system players, and the computational complexity associated with the profusion of variables and parameters. In this paper, we present an elegant modeling framework based on the cybernetic concept that biological regulation is inspired by objectives embedding entirely novel strategies for dimension reduction, process stage specification through the system dynamics, and innovative causal association of regulatory events with the ability to predict the evolution of the dynamical system. The elementary step of the modeling strategy involves stage-specific objective functions that are computationally-determined from experiments, augmented with dynamical network computations involving end point objective functions, mutual information, change point detection, and maximal clique centrality. We demonstrate the power of the method through application to the mammalian cell cycle, which involves thousands of biomolecules engaged in signaling, transcription, and regulation. Starting with a fine-grained transcriptional description obtained from RNA sequencing measurements, we develop an initial model, which is then dynamically modeled using the cybernetic-inspired method (CIM), utilizing the strategies described above. The CIM is able to distill the most significant interactions from a multitude of possibilities. In addition to capturing the complexity of regulatory processes in a mechanistically causal and stage-specific manner, we identify the functional network modules, including novel cell cycle stages. Our model is able to predict future cell cycles consistent with experimental measurements. We posit that this state-of-the-art framework has the promise to extend to the dynamics of other biological processes, with a potential to provide novel mechanistic insights.

Cellular response to inflammatory stimuli leads to the production of eicosanoids—prostanoids (PRs) and leukotrienes (LTs)—and signaling molecules—cytokines and chemokines—by macrophages. Quantitative modeling of the inflammatory response is challenging owing to a lack of knowledge of the complex regulatory processes involved. Cybernetic models address these challenges by utilizing a well-defined cybernetic goal and optimizing a coarse-grained model toward this goal. We developed a cybernetic model to study arachidonic acid (AA) metabolism, which included two branches, PRs and LTs. We utilized a priori biological knowledge to define the branch-specific cybernetic goals for PR and LT branches as the maximization of TNFα and CCL2, respectively. We estimated the model parameters by fitting data from three experimental conditions. With these parameters, we were able to capture a novel fourth independent experimental condition as part of the model validation. The cybernetic model enhanced our understanding of enzyme dynamics by predicting their profiles. The success of the model implies that the cell regulates the synthesis and activity of the associated enzymes, through cybernetic control variables, to accomplish the chosen biological goal. The results indicated that the dominant metabolites are PGD2 (a PR) and LTB4 (an LT), aligning with their corresponding known prominent biological roles during inflammation. Using heuristic arguments, we also infer that eicosanoid overproduction can lead to increased secretion of cytokines/chemokines. This novel model integrates mechanistic knowledge, known biological understanding of signaling pathways, and data-driven methods to study the dynamics of eicosanoid metabolism.