From computational modelling of the intrinsic apoptosis pathway to a systems-based analysis of chemotherapy resistance: achievements, perspectives and challenges in systems medicine

Our understanding of the mitochondrial or intrinsic apoptosis pathway and its role in chemotherapy resistance has increased significantly in recent years by a combination of experimental studies and mathematical modelling. This combined approach enhanced the quantitative and kinetic understanding of apoptosis signal transduction, but also provided new insights that systems-emanating functions (i.e., functions that cannot be attributed to individual network components but that are instead established by multi-component interplay) are crucial determinants of cell fate decisions. Among these features are molecular thresholds, cooperative protein functions, feedback loops and functional redundancies that provide systems robustness, and signalling topologies that allow ultrasensitivity or switch-like responses. The successful development of kinetic systems models that recapitulate biological signal transduction observed in living cells have now led to the first translational studies, which have exploited and validated such models in a clinical context. Bottom-up strategies that use pathway models in combination with higher-level modelling at the tissue, organ and whole body-level therefore carry great potential to eventually deliver a new generation of systems-based diagnostic tools that may contribute to the development of personalised and predictive medicine approaches. Here we review major achievements in the systems biology of intrinsic apoptosis signalling, discuss challenges for further model development, perspectives for higher-level integration of apoptosis models and finally discuss requirements for the development of systems medical solutions in the coming years.