Molecular versus systems biological disease. (a) In the molecular, or single-gene disease, a mutation in or around a piece of DNA causes a change in function of the gene product F. F is solely responsible (or the rate limiting step) for the physiological function that is impaired in the disease, or for the pathology itself. (b) In the systems biological or network disease, the biological function that is impaired in the disease, or the new pathological function, depends on many factors (called Z here) at the same time. Factors Z themselves depend on many other factors, on genes and environmental (for example, nutritional, hormonal, age) factors, and ultimately even on the development of the pathology itself. In terms of transcriptomics, changes in any factors shown could correlate somewhat with the disease, in either type of disease. In the molecular disease (a), however, the correlation between the disease and changes in the single causative disease gene should be 100%. When, as in systems biology, the cause-effect relationships are investigated, the correlations should be time-and perturbation-dependent and consistent with the network drawn (for example, a deletion of Y might not affect the disease totally, but should destroy the causal correlation between gene 2 and disease). The systems biology paradigm is not soft, however, as in that case the correlation between disease and network state should be 100%.