On the origin of cell functions encoded in the toponome

The fluorescence imaging technology TIS enables the investigator to locate and decipher functional protein networks (the toponome) in a single cell or tissue section. TIS permits optical resolution and simultaneous detection of thousands of protein clusters in situ, composed of different protein species, and their visualization as coloured mosaic structures. Access to this level of protein organization relies on the ability of TIS to break the spectral limit of fluorescence microscopy and co-map a quasi unlimited number of different proteins by using specific tag libraries. The present review outlines the principles of the TIS technology as a fundamental approach to the internal structure, the code and the semantics of any protein system in situ. The review focusses on the discovery of basic coding rules in the toponome, indicating that cells establish functional protein networks on the cell surface by interlocking protein clusters, in which highly dissimilar proteins are topologically assembled (dissimilarity rule), and each cluster exhibits a characteristic geometry on the submicrometer to micrometer scale (geometry rule). The network is hierarchically controlled by a lead protein, whose inhibition leads to disassembly of the network and loss of function. Use of TIS on a proteome-wide scale provides a new way to medical systems biology.