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Abstract

Recent advances in molecular biology, neurobiology, genetics, and imaging have demonstrated important insights about the nature of neurological diseases. However, a comprehensive understanding of their pathogenesis is still lacking. Although reductionism has been successful in enumerating and characterizing the components of most living organisms, it has failed to generate knowledge on how these components interact in complex arrangements to allow and sustain two of the most fundamental properties of the organism as a whole: its fitness, also termed its robustness, and its capacity to evolve. Systems biology complements the classic reductionist approaches in the biomedical sciences by enabling integration of available molecular, physiological, and clinical information in the context of a quantitative framework typically used by engineers. Systems biology employs tools developed in physics and mathematics such as nonlinear dynamics, control theory, and modeling of dynamic systems. The main goal of a systems approach to biology is to solve questions related to the complexity of living systems such as the brain, which cannot be reconciled solely with the currently available tools of molecular biology and genomics. As an example of the utility of this systems biological approach, network-based analyses of genes involved in hereditary ataxias have demonstrated a set of pathways related to RNA splicing, a novel pathogenic mechanism for these diseases. Network-based analysis is also challenging the current nosology of neurological diseases. This new knowledge will contribute to the development of patient-specific therapeutic approaches, bringing the paradigm of personalized medicine one step closer to reality. Ann Neurol 2009;65:124–139