Investigating the Dynamics of Biochemical Systems

Eduardo Sontag

ECE/BioE University Distinguished Professor Eduardo Sontag is the PI of a $305K NSF grant for designing “New Techniques for Analyzing the Long-term Behavior of Intracellular Networks.” This project aims to develop an approach to the computer-aided analysis of biochemical networks and is based on research done in the Sontag Lab by Senior Research Scientist Muhammad Ali Al-Radhawi.

Abstract Source: NSF

Living cells depend on delicate intracellular networks for their correct functioning. These networks are composed of genes, messenger RNA, proteins, metabolites, and other internal and external chemicals. Any alteration of these networks can lead to pathologies in development, cell proliferation, and other functions. The study of how networks change in time (dynamics) is the focus of a sustained research effort by the mathematical biology community. Yet, many fundamental questions remain open. The central goal of this research is to advance our understanding and develop a theoretical and computational framework for the structural analysis of global dynamical properties of intracellular networks. The project will involve the participation of undergraduate, graduate, and postdoctoral students from the mathematical, engineering, and physical sciences. The results of this mathematical work will have scientific relevance much beyond the molecular realm, because the same formalism can be used to model phenomena at different levels of biological and ecological organization, from cells to tissues to organisms to ecological systems and epidemics.

This project aims to develop novel analytical and computational approaches to characterize the behavior of highly nonlinear biological systems. Motivated by a wide variety of applications, it will study core elements of the larger networks that control fundamental cellular processes such as transcription and translation, cell growth and division, migration, and differentiation. These include processes such as gene regulation, protein post-translational modifications by phosphorylation or methylation, kinetic proofreading in T cell receptor activation, ribosome translation elongation processes, and other regulatory and signaling pathways. Questions such as set invariance (when do the dynamics preserve a “safe” set, not violating physiological constraints?), stability (when does the system return to homoeostasis values after, or even during persistent, perturbations?), and robustness of qualitative behavior under parameter changes can be framed and analyzed through a common mathematical language. Specifically, the work will provide computationally explicit “certificates” that guarantee invariance, stability, or robustness, expressed in the formalism of Biological Interaction Networks (BINs), that allow for the verification of system properties just from the stoichiometric structure, even in the face of substantial uncertainty regarding parameters and even the exact form of the reaction kinetics. This project will expand the class of networks that can be analyzed with the technique, proving new theorems, finding more efficient constructions of certificates, introducing additional tools, and analyzing the effect of inputs, such as ligands in receptor systems.

This award reflects NSF’s statutory mission and has been deemed worthy of support through evaluation using the Foundation’s intellectual merit and broader impacts review criteria.

Related Faculty: Eduardo Sontag

Related Departments:Bioengineering, Electrical & Computer Engineering