This medical textbook is unusual in that it includes a section devoted to the endothelium and “complex systems.” What may at first appear an editorial eccentricity will, upon further inspection, hopefully be seen as a useful addition and perhaps even as a template for future texts in other clinical fields. Indeed, the endothelium presents a compelling case study of the wide and deep potential interconnections between biomedicine and the contemporary study of complexity (1).

What makes a system complex, and not just complicated? The endothelium exemplifies two key features of complex systems (2). First, such systems function over a broad range of time and space scales (3,4) ranging from picoseconds to minutes, months, and longer, and from the quantum to the cellular to the organismic and even up to the level of social networks. Second, such multiscale systems display dynamics that are nonstationary and nonlinear and, therefore, defy analysis using traditional tools used by biostatisticians (1). Nonstationarity refers to the finding that the statistical properties (e.g., the mean and the variance) of fluctuations generated by a system change over time. Nonlinearity means that the components interact in nonadditive ways, so that the output will not be consistently proportional to the input. Indeed, in nonlinear systems, small changes can have huge or anomalous consequences, a phenomenon sometimes referred to as the butterfly effect.

Nonlinear systems cannot be understood by the traditional reductionist strategy of dissecting out their components, studying them in isolation, and then “recompiling” the system. Instead, the nonlinear interactions can lead to qualitatively novel structures and dynamics, so-called emergent properties. Thus, nonlinear systems cannot be characterized using a “modular” type of approach.