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"  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 interaction, 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: evolution, development, immunology, and neurobiology. It is easy to see that mutation, competition, and differential reproduction in evolution, cell-cell interaction in morphogenesis, antigen recognition in immune response, and network connectivity 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 contextual meaning. This process was recently defined as "the ability to sense changing environmental conditions and then implement appropriate responses" . 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 the "recognition sciences" proposed by Edelman. This similarity only illustrates that ST in cells does in fact qualify as a selection-driven recognition phenomenon.
Besides variation and selection, Edelman emphasizes that the semantic dimension of biochemical processes is only realized by virtue of their embeddedness in biological systems and their multilevel hierarchical organization. Here, we will approach the subject of ST in cells from an evolutionary perspective fully inspired by Edelman's synthetic efforts; a theoretical background that will consider any biological recognition as a selective process and will take into consideration the organization of the system at the focal level of the interactions described. It is important to note that a large body of work exists that considers the cell as a semi-otic structure and ST as a "meaning-making" process and they will be brought into our discussion where suitable [6,7,8]. The contribution of the present work is in line with these previous efforts, but goes further by introducing categories for considering how living systems increase their complexity through evolution, development, and function. Most importantly, by dissecting the semiotic structure, biological function, and evolved form associated with each of the categories we hope to illuminate some general principles of their organization in biological systems through layers of complexity.
As we have mentioned in the Abstract, the scope of ST that we will explore goes beyond the traditional textbook definition, which is the conversion of the so-called first messengers into second messengers. It has been proposed by Marcello Barbieri that this conversion clearly follows an organic code  that allows for the transformation of a multitude of agents (the various sorts of growth factors, hormones, cytokines, neurofactors, etc.) into a many fewer number of charged molecules (calcium, cAMP, nitric oxide, phosphorylation cascades), the second messengers. But as stated by Barbieri himself there is more to ST codes than that "The effects that external signals have on cells (...) do not depend on the energy and information they carry, but on the meanings that cells give them with rules that can be called ST codes."
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