Path to improving the life cycle and quality of genome-scale models of metabolism

Genome-scale models of metabolism (GEMs) are key computational tools for the systems-level study of metabolic networks. Here, we describe the "GEM life cycle," which we subdivide into four stages: inception, maturation, specialization, and amalgamation. We show how different types of GEM reconstruction workflows fit in each stage and proceed to highlight two fundamental bottlenecks for GEM quality improvement: GEM maturation and content removal. We identify common characteristics contributing to increasing quality of maturing GEMs drawing from past independent GEM maturation efforts. We then shed some much-needed light on the latent and unrecognized but pervasive issue of content removal, demonstrating the substantial effects of model pruning on its solution space. Finally, we propose a novel framework for content removal and associated confidence-level assignment which will help guide future GEM development efforts, reduce duplication of effort across groups, potentially aid automated reconstruction platforms, and boost the reproducibility of model development.