Computational and systems biology in trauma and sepsis: current state and future perspectives.

Trauma, often accompanied by hemorrhage, is a leading cause of death worldwide, often leading to inflammation-related late complications that include sepsis and multiple organ failure. These secondary complications are a manifestation of the complexity of biological responses elicited by trauma/hemorrhage, responses that span most, if not all, cell types, tissues, and organ systems. This daunting complexity at the patient level is manifest by the near total dearth of available therapeutics, and we suggest that this dire condition is due in large part to the lack of a rational, systems-oriented framework for drug development, clinical trial design, in-hospital diagnostics, and post-hospital care. We have further suggested that mechanistic computational modeling can form the basis of such a rational framework, given the maturity of systems biology/computational biology. Herein, we briefly summarize the state of the art of these approaches, and highlight the biological insights and novel hypotheses derived from these approaches. We propose a rational framework for transitioning through the currently fragmented process from identification of biological networks that are potential therapeutic targets, through clinical trial design, to personalized diagnosis and care. Insights derived from systems and computational biology in trauma and sepsis include the centrality of Damage-Associated Molecular Pattern molecules as drivers of both beneficial and detrimental inflammation, along with a novel view of multiple organ dysfunction as a cascade of containment failures with distinct implications for therapy. Finally, we suggest how these insights might be best implemented to drive transformational change in the fields of trauma and sepsis.