Seeing the Forest for the Trees.

Although tens, or even hundreds, of molecular or pharmacological interventions have been shown to affect the course of heart failure in animal models, few have translated to clinical therapies. This likely stems from the fact that biological robustness and flexibility are conferred by the evolution of redundant or adaptive signaling and gene expression pathways, which lead to not one, but multiple “master” control nodes in the network, making it difficult to pinpoint the most effective single target intervention. Systems biology tools and approaches are helping to define how the heart is remodeled during stress and to define important control points, even as they further highlight the scope of our ignorance. Applying these analyses to time-dependent changes in heart failure is essential to understand critical thresholds for aberrant nonlinear cellular responses that lead to emergent events, such as sudden cardiac death. Trying to understand the mechanisms behind heart failure often brings to mind the analogy of science as “a hungry furnace that must be fed logs from the forests of ignorance that surrounds us. In the process, the clearing we call knowledge expands, but the more it expands, the longer its perimeter and the more ignorance comes into view.”1 Extending this further, we scientists often act as independent woodcutters in our own little clearings, either focusing our reductionist minds on taking the tree down like a leafcutter ant rather than by chainsaw, or attempting to frame our favorite target as the master key that unlocks the secret to curing the disease (a must to enchant those study section reviewers). From the literature, it seems that there are many such master keys that prevent or reverse cardiac dysfunction related to heart failure (HF) in animal models—fixing various defects in SR Ca2+ uptake, ryanodine receptor leak, repolarization reserve, oxidative stress, nitric …