Nded on experimental basis, represents yet another discontinuity point with respect to

This may lead to models of tissues and organisms with enhanced predictive power [114]. Second, tissue and cytoskeleton/nucleoskeleton architecture, at the same time as mechanical forces (stiffness, shear strain [115], and surface tension), have to be adequately weighted and investigated, a rather uncommon request for any "traditional" biologist [116]. Third, molecular and genetic adjustments, involving each the epithelial plus the stromal cells, ought to thus be investigated in association and linked for the observed modification of the context. While a great deal has been discovered about molecular components and subcellular processes, the integration of information and models across a wide selection of spatial and temporal scales, taking us from observations at the cellular or subcellular level to understand tissue level phenomena, remains an unchartered territory. Additionally, biophysical influences on cell behavior and differentiation may be adequately appreciated only by studying cells in their three-dimensional context and are therefore disregarded by That was licensed and accredited by the Spanish Agency of Medicines existing experimental methodologies almost fully determined by 2D cultures. As pointedly discussed by Noble [120], one cannot comprehend the physiology or the pathology of cardiac rhythm by only referring for the gene expression and for the options of a single cardiomyocite. Similarly a single cannot fully grasp pathologic processes emerging at the cellmicroenvironment level by only referring to "abstract" generegulatory circuits in the isolated cell.5. Microenvironment and Cancer: Methodological IssuesThe term "microenvironment" encompasses discrete, interacting elements, for example extracellular matrix (ECM), stromal cells, molecular diffusible factors, configuration with the cellstroma architecture [104], nonlocal contro.Nded on experimental basis, represents another discontinuity point with respect to SMT which posits that "biologicalinformation" carried out by genes constitutes the only (or the principle) causative aspect in driving cellular fate and behavior.5 levels. This will likely result in models of tissues and organisms with enhanced predictive power [114]. Second, tissue and cytoskeleton/nucleoskeleton architecture, as well as mechanical forces (stiffness, shear stress [115], and surface tension), have to be adequately weighted and investigated, a rather uncommon request for a "traditional" biologist [116]. Third, molecular and genetic modifications, involving each the epithelial plus the stromal cells, need to hence be investigated in association and linked for the observed modification with the context. Even though much has been discovered about molecular elements and subcellular processes, the integration of data and models across a wide range of spatial and temporal scales, taking us from observations in the cellular or subcellular level to understand tissue level phenomena, remains an unchartered territory. Furthermore, biophysical influences on cell behavior and differentiation might be adequately appreciated only by studying cells in their three-dimensional context and are for that reason disregarded by existing experimental methodologies just about fully depending on 2D cultures. General, these considerations highlight a different basic bias of modern day biology, which is, the lack of a basic theory for understanding biological organization. In order to cope using the increasingly appreciated complexity of living organism, implicitly, biologists have adopted a reductive strategy, mostly according to a gene-centric paradigm, where causative processes are modelled based on a simplified, linear dynamics. From molecules to organs, levels are interrelated and interdependent, in order that the organism is capable to conserve and adapt the integrity of its structural and functional organization against a back-drop of continuous changes within the organism and its environment. That feature represents the updated interpretation of homeostasis, a idea formulated a century ago by W.