How physiology solves the gene-centric impasse.

The criteria for distinguishing between association and causation in studies of genes and function are clarified. Genomic association scores alone cannot satisfy those criteria, which is why treatment of common diseases has not benefitted from the cures expected when the Human Genome Project was launched. Instead, causal understanding of function and disease requires detailed experimental data at the relevant levels of organization in the organism, from which quantitative physiological modelling then enables causal processes to be measured accurately. They can then be compared with association scores. An example shows how this process works in the heart and how that work led to the identification of a useful medication. Another major field of clinical importance is the nervous system, because nervous diseases were also expected to yield to genomics-driven discoveries of genetic cures. That expectation also has not been fulfilled. It is now necessary to investigate causation at functional physiological levels of organization in order to develop strategies that can identify cures for multifactorial diseases.