Signal Transduction Codes and Cell Fate

Abstract

In cells in general, regardless of their identity and functional status, the mediators of signal transduction (ST), the classic second messengers, are highly conserved: calcium, cAMP, nitric oxide, phosphorylation cascades, etc. At the same time, they are significantly less numerous than the extracellular signals (or first messengers) they represent, suggesting that this universal conversion of signals into second messengers follows the conventional rules of an organic code. Nevertheless, the way these second messengers are integrated and the con-sequences they trigger change dramatically according to cell organization – its structure and function. Here we examine ST beyond the generation of second messengers, and more as the ability of a cell in its different configurations to assign meaning to signals through discrimination of their context. In metabolism, cell cycle, differentiation, neuronal, and immune function the circuitry operat-ing at cell level will proceed by the creation of conventional links between an increasing number of physiological activities, that is, changes in environment are progressively coupled to: transcription patterns; transcription and replication patterns; transcription, replication, and differentiation patterns; and transcription, replication, differentiation, and functional patterns. The categorial framework [1] consisting of CELL/SELF/SENSE has been previously proposed [2] as an attempt to classify the levels of organization adopted by living systems. Our working hypothesis is that these categories reflect: (i) an improved comprehension of self-organization and the convergent gain of complexity that are crucial traits of biological systems, (ii) the possibility of a research agenda, which aims to identify organic codes at the transitions between levels. In the present work we shall use the CELL/SELF/SENSE categories to analyze the progressive complexity of cell fate control through evolution and through development, showing how it is related to switches in ST codes. The notion of a physical attractor [3] will be introduced to reframe the role of classical ST pathways in cell function. The notions of degeneracy and polisemy will also M. Barbieri (ed.), The Codes of Life: The Rules of Macroevolution. 265 © Springer 2008 266 M. Faria be examined as possible defining resources for the convergent gain of complexity taking place in biological systems. 1 Signal Transduction as a Recognition Science In 2004, the Journal of Biological Chemistry celebrated its centenary with a series of commissioned papers called reflections. There, the eminent neuroscientist Gerald Edelman wrote a contribution entitled " Biochemistry and the Sciences of Recognition " [4] in which he uses the term " recognition " to emphasize some of the crucial features that evolution, embryology, immunology, and the neurobiology of complex brains display in common. Biochemical rules, he claims, have their roots in the precision of organic chemistry and the generality of thermodynamics, but at the same time are constrained by the flexible organization of life's forms and behaviors across many hierarchical levels. It is only when embedded within the complexity of cells, organs, and organisms that biochemical processes acquire their significance. The emergence of biochemical rules arise by selection acting over time on variable populations of molecules, cells, and organisms and it is precisely these two notions, i.e. variation and selection as the substrate for biological interac-tion, that are fully expressed in the four sciences of recognition. Selective processes guide the interaction among variable molecules, cells, and individuals. In each case we can see the deterministic rules of biochemistry being constrained by higher order principles. In fact, whenever variation is a substrate for selection rather than a source of noise that corrupts proper function, one is certainly dealing with a particular kind of complexity, namely, that of biological systems. That is what is insightful about Edelman's categories; they unify four formulations to the same general question as to how living systems become selective rather than instructive when dealing with choices, an essential question that certainly fits all the proposed arenas: evo-lution, development, immunology, and neurobiology. It is easy to see that muta-tion, competition, and differential reproduction in evolution, cell–cell interaction in morphogenesis, antigen recognition in immune response, and network connec-tivity in neurobiology, are all selection-driven recognition processes. Nevertheless, these properties seem too indistinguishable of life itself to have their origin in cell populations (organisms, embryos, immune, or nervous systems) rather than in single cells. Strongly motivated by this hypothesis (that selective recognition has its most basic expression in single cell behavior) we will turn back to signal transduction (ST), the process by which single cells endow environmental change with contex-tual meaning. This process was recently defined as " the ability to sense changing environmental conditions and then implement appropriate responses " [5]. In its original context the quotation talks specifically about how prokaryotic and eukaryo-tic cells react to their environment. This same definition if applied to cell collectives, to species and/or individuals is strikingly similar to the minimal features defining