Solving the puzzle of Fe homeostasis by integrating molecular, mathematical, and societal models

Highlights

• Recent studies highlight the complexity of cellular responses to iron deficiency.

• Simulation-based inference (SBI) is an approach that can help shed light on stress responses by formally integrating prior knowledge and new data.

• Collaborative application of SBI to biology requires effective communication, which is the cornerstone of inclusion in science and beyond.

Abstract

To ensure optimal utilization and bioavailability, iron uptake, transport, subcellular localization, and assimilation are tightly regulated in plants. Herein, we examine recent advances in our understanding of cellular responses to Fe deficiency. We then use intracellular mechanisms of Fe homeostasis to discuss how formalizing cell biology knowledge via a mathematical model can advance discovery even when quantitative data is limited. Using simulation-based inference to identify plausible systems mechanisms that conform to known emergent phenotypes can yield novel, testable hypotheses to guide targeted experiments. However, this approach relies on the accurate encoding of domain-expert knowledge in exploratory mathematical models. We argue that this would be facilitated by fostering more “systems thinking” life scientists and that diversifying your research team may be a practical path to achieve that goal.

Introduction

Existing in multiple oxidation states and a wide redox potential range, iron (Fe) can readily donate and accept electrons, making it an excellent cofactor for primary metabolic processes, including DNA synthesis and repair, respiration, and photosynthesis. In excess, Fe can react with oxygen, causing the formation of damaging reactive oxygen species [1]. However, deficiency in Fe availability, sensing, and response inhibits growth and development. Decreased Fe availability is perceived initially in the shoot and signaled to the root, inducing epigenetic regulation and massive signaling, transcriptional, metabolic changes that lead to dynamic changes in Fe uptake and transport mechanisms within the root epidermis [2, 3, 4, 5∗, 6∗]. Herein, we discuss recent advances that shed light on these changes and the ongoing challenges associated with making sense of these dynamic, multiscale physiological phenomena. We then address how a subset of relevant regulatory phenomena can be viewed through the lens of a formal modeling framework. This approach allows one to leverage the powerful mathematical approach of simulation-based inference, which can be used to formally test and refine mechanistic hypotheses by integrating heterogeneous data. As this approach requires accurate encoding of domain-expert knowledge in exploratory mathematical models, we close by suggesting that this interdisciplinary work would be facilitated by intentional efforts to cultivate “systems thinking” amongst plant cell biologists. Systems thinking cell biologists are life scientists with an aptitude for translating biological knowledge into clearly delineated agents, organized into well-specified systems, with articulated interactions between parts of the whole. We propose that inclusive lab environments can provide opportunities for serendipitous cross-disciplinary conversations that foster systems-thinking outside the confines of didactic cross-training.