Figure 1. The Pyramid of System Immunology.

Most investigators have adopted a “top-down” approach to build networks that could explain cellular functions in their globality; the function of a given gene is the premise from which its interactions with other genes are deducted to formulate pathways that lead to coordinated cellular functions (a concept similar to the experimental observation of “operons”). Because the process proceeds in the downstream direction, it becomes increasingly speculative. Here, the authors applied a “bottom-up” (inductive) approach and identified operational (transcriptional) units that they called modules through the identification of genes co-coordinately expressed in distinct pathophysiological conditions; this evidence-based reasoning offers two advantages: It provides a road map for biomarker discovery, and it identifies transcriptional networks that may lead the basic scientist toward the identification of upstream events that lead to pathogenic processes and that, therefore, are most probably relevant to human suffering.