How insects protect themselves against combined starvation and pathogen challenges, and the implications for reductionism.

Abstract An explosion of data has provided detailed information about organisms at the molecular level. For some traits, this information can accurately predict phenotype. However, knowledge of the underlying molecular networks often cannot be used to accurately predict higher order phenomena, such as the response to multiple stressors. This failure raises the question of whether methodological reductionism is sufficient to uncover predictable connections between molecules and phenotype. This question is explored in this paper by examining whether our understanding of the molecular responses to food limitation and pathogens in insects can be used to predict their combined effects. The molecular pathways underlying the response to starvation and pathogen attack in insects demonstrates the complexity of real-world physiological networks. Although known intracellular signaling pathways suggest that food restriction should enhance immune function, a reduction in food availability leads to an increase in some immune components, a decrease in others, and a complex effect on disease resistance in insects such as the caterpillar Manduca sexta. However, our inability to predict the effects of food restriction on disease resistance is likely due to our incomplete knowledge of the intra- and extracellular signaling pathways mediating the response to single or multiple stressors. Moving from molecules to organisms will require novel quantitative, integrative and experimental approaches (e.g. single cell RNAseq). Physiological networks are non-linear, dynamic, highly interconnected and replete with alternative pathways. However, that does not make them impossible to predict, given the appropriate experimental and analytical tools. Such tools are still under development. Therefore, given that molecular data sets are incomplete and analytical tools are still under development, it is premature to conclude that methodological reductionism cannot be used to predict phenotype.