A Model of the Cellular Iron Homeostasis Network Using Semi-Formal Methods for Parameter Space Exploration

TL;DR

This paper introduces a semi-formal modeling framework for biological networks, specifically applied to the iron homeostasis network in mammalian cells, using formal tools to explore parameter spaces despite knowledge gaps.

Contribution

It develops a novel semi-formal approach combining formal logic and parameter space exploration for biological network modeling, demonstrated on iron regulation.

Findings

Identified parameter sets consistent with biological behavior

Expanded parameter regions to understand network robustness

Applied methodology to complex iron homeostasis network

Abstract

This paper presents a novel framework for the modeling of biological networks. It makes use of recent tools analyzing the robust satisfaction of properties of (hybrid) dynamical systems. The main challenge of this approach as applied to biological systems is to get access to the relevant parameter sets despite gaps in the available knowledge. An initial estimate of useful parameters was sought by formalizing the known behavior of the biological network in the STL logic using the tool Breach. Then, once a set of parameter values consistent with known biological properties was found, we tried to locally expand it into the largest possible valid region. We applied this methodology in an effort to model and better understand the complex network regulating iron homeostasis in mammalian cells. This system plays an important role in many biological functions, including erythropoiesis, resistance against infections, and proliferation of cancer cells.