: We hold these truths to be self-evident: 1) Cellular signaling mechanisms are vitally important regulators of virtually all cellular functions; understanding them in depth is thus a critical aspect of both basic and applied biology and medicine. 2) Biological systems of such importance are spectacularly complex. The complexity of signaling networks is characterized by simultaneous use of multiple distinct biochemical mechanisms, related members of multi- gene families, and splice products of single genes. This apparent redundancy permits a) partitioning of signaling events to distinct subcellular locations, b).distinct controls for inputs that lead to the same endpoint, c) controlled additivity or non-additivity of parallel or similar pathways, d) variably non-linear response functions, e) robustness to disruption by into untoward inputs, f) distinct patterns of response kinetics and/or amplitude, and g) the ability to developmentally or adaptively alter individual ligand-response relationships differentially. And importantly: 3) human minds are incapable of understanding the emergent properties of such systems by inspection of even the most accurately annotated maps of the circuitry. Quantitative models will be necessary, and the development of such models at both the cellular and organismal level will be a legacy of 21st century biomedical science. ? ? Our progress to date points to signaling systems built from modules with measurable degrees of interactions between modules. We are well-positioned to further our knowledge by application and development of a) tools for measuring the """"""""state"""""""" of module, components, b) tools for measuring information flow between components and modules, c) a program underway to collect data and model quantitatively specific modules operating in a limited time frame (the FXM project), and d) approaches for developing and testing quantitative models of more complex processes operating over longer times (e.g., cytokine secretion). ? ? We believe the AfCS is both a scientific and a social success. Our website serves the scientific community as an invaluable source of experimental data that are accessible to and being actively mined by non-AfCS investigators, signaling information (in a database that includes nearly 4000 molecules), useful reagents (including thousands of DNA constructs), lab protocols, and more. These AfCS efforts are being conducted on a scale unprecedented in previous work with vertebrate cells. In the aggregate, these accomplishments reflect success of an initially risky social experiment the attempt to create a transcontinental consortium of biological laboratories collaborating effectively to achieve a common goal. The potentially unwieldy consortium has revealed a surprising capacity to meet difficult challenges. ? ?
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