 Given the increasing emphasis on comprehensive multiscale models, systems biology research may have a unique potential for philosophical insights considering the explanatory role of macroscale properties and top-down effects. Systems biologists for instance point to how enzyme activity is constrained by the chemical environment and the cellular context (Hofmeyr 2017), or how the biophysical properties of muscle fibers and cell membranes provide functional constraints on ionic oscillations central to the generation of heart rhythms (Noble 2012). Interpreting top-down effects as constraining relations may exemplify what philosophers of science have called ‘medium downward causation’ (Emmeche et al. 2000), which interprets downward causation as boundary conditions. Noble (2012) explicitly endorses such a view when arguing that downward causation is necessary by pointing out how equations describing the kinetics of ion channels in cardiac modeling cannot be solved without defining the boundary conditions (e.g., the cell voltage). Multi-scale modeling may thus help to give a more concrete mathematical reinterpretation of the controversial notion of downwards causation (see also Ellis et al. 2011; Green 2018). Moreover, discussions of downward causation in systems biology have practical as well as theoretical implications, e.g., for experimental design in cancer research on studies of cancer as a genetic or tissue-based disease (Bertolaso 2011; Soto et al. 2008; see also  Section 5.3).