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Franck Molina, Matthias Dehmer, Paul Perco, Armin Graber, Mark Girolami, Goce Spasovski, Joost P. Schanstra, Antonia Vlahou, Systems biology: opening new avenues in clinical research, Nephrology Dialysis Transplantation, Volume 25, Issue 4, April 2010, Pages 1015–1018, https://doi.org/10.1093/ndt/gfq033
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Systems biology as a paradigm shift in clinical research
The marked increase in research spending and individual efforts over the years on the development of disease biomarkers, therapeutic targets and new drugs has provided a wealth of information on individual molecular changes associated with disease (characteristic examples, among many others, in the case of nephropathies are provided in [1,2]). Nevertheless, these unquestionably highly significant and important findings have not been translated into the expected clinical outcome [3–5]. This may point towards the need for a paradigm shift in the way biomarker and drug discovery is conceived: Identification of an association of individual molecules with a specific phenotype (e.g., presence, recurrence, progression, response of the disease, etc.), even following optimization of all technical parameters involved and initial confirmation of findings, is not sufficient for the establishment of this molecule as a clinically useful test or a potential drug target. The multi-factorial molecular phenotype of disease makes increasingly evident that development of novel therapeutic and disease detection approaches should be based upon the study of the entire ‘System’ simultaneously [3]. This is in contrast to the reductionist approach that focuses on individual molecules, as extensively used in the past two centuries to address those complex questions [6]. The reductionistic approach is based on the principle that complex problems can be solved by reducing them into smaller, simpler units easier to deal with. However, it is obvious that living system behaviour cannot be predicted only by the sum of observations made on its individual parts [7]. This is due to several reasons like inter-dependencies, context sensitivity, dynamics and more. Simply stated, molecules in a living cell are involved in networks of interactions that regulate the cell's basic functions such as proliferation, growth, differentiation and death. Thereby cells can be broken down into smaller biologically relevant entities such as DNA, proteins, amino acids, etc., and on the other end, cells are also part of tissues and organs, all connected and dependent. Disruption of a partner in these interactions does not result in linear and definable effects but rather in global and often unpredicted perturbations of the whole network [3,7].
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