A Biosemiotic Analysis of Serotonin’s Complex Functionality Argyris Arnellos +, Martien Brands ++, Thomas Spyrou +, John Darzentas + + Dept of Product & Systems Design Engineering, University of the Aegean, Syros, Greece ++ University of Liverpool, Division of Primary Care

Framework of study Serotonin’s functionality in the immune system is quite complex Complexity Self-organisation T-cell memory formation and activation Serotonin Dendritic cells maturation

Serotonin: an example of a self- organization of a complex system Key process: Memorization of immune system through T cell activation by Serotonin signalling on Dendritic cells and T cells

Serotonin signalling Key concepts: Receptor sensitivity Synaptic plasticity Gene manipulation

Reasons for biosemiotic analysis Traditional pharmacology assumes a dose-effect relationship However, many biological processes depend on signals rather than doses. Homeopathic medicines are prepared by serial dilution and agitation (SDA) SDA effects depends on signal reception rather than their dose

Complexity and biosemiotics Adaptation to microbes & trauma by immune memorization Multifactorial process with systemic features: feedback, receptor sensitivity Functionality by signal transduction

Steps to the path of T-cell memory formation Inflammation: Platelets activation: Serotonin (5 HT) production Dendritic cells (DC):5 HT sequestration DC maturation:exocytosis of 5 HT T cell activation:uptake of 5HT

Serotonin production Sources : - Antibodies and IgE --> mastcell degranulation histmamin & serotonin - Platelets: platelet activating factor -->> serotonin - Complement activation factor - Sympathetic nerves (neurotransmitter)

Sequestration ATP Ca2+ Serotonin Measurements: 1. LAMP-1 2. Amperometry of transmitters 3. Mono oxidase A & B

DC maturation ATP Ca2+ Serotonin Exocytosis of 5 HT by lysosomes

T cell activation cAMP Receptor TPH-1 Indicator: Tryptophan -1 Feedback to DC Ligand -> CD 40 and CD 152

The modeling of T-cell formation under a biosemiotic framework Dynamic Object (DO): an activated and fully-functional T cell. Immediate Object (IO): The DO in its semiotically available form. Indicates a range of possible DOs. Establishes conditions of possibility to the DO. It is not the IO. It is an IO. Immediate Interpretant (II): The range of interpretability. It is the possible IOs. Dynamic Interpretant (DI): The actual effect of the sign. The realization of one of all the possibilities that are denoted by the range of interpretability. The effective reconstruction of an IO.

The modeling of T-cell formation under the biosemiotic framework Interpretant: the reconstruction of a form (habit) which was embodied in an Object. Reconstruction: Communication of the form of an activated and fully-functional T cell through Signs in CD by ligands in potency to the next generation of the immune system. The activated T-cell constrains the behavior of the immune system as an interpreter.

Defining the relevant semiotic levels Macro Antigen-antibody formation and memorization of immune system Focal Dendritic Cell maturation through 5HT uptake and release and T cell activation Micro CD 40 and CD 152 production by ligands as negative and positive feedback triggers for DC maturation

The modeling of T-cell formation under the biosemiotic framework Sign: activated platelets (platelets that sequester 5-HT) IO: The CD ligands. The CD ligands is the object expressed (represented) in the specific Sign. The ligands is the DO (the activated and fully- functional T-cell) in its semiotically available form. A CD ligand can indicate a range of possible functional DOs, as a CD ligand will be interpreted in different ways in different contexts. II: The range of interpretability (the set of different instances) of DC maturation. The set of possible mature DCs that can be mediated by the specific activated platelets (platelets + 5-HT). Activated platelets (Sign) DC maturation (II) CD ligands (IO)

The modeling of T-cell formation under the biosemiotic framework Sign: The ligands as feedback on sequestration. IO: DC maturation as an IO of the activated and fully-functional T cell. DC can modulate T cell proliferation and/or differentiation, then, this IO can indicate a range of possible functional DOs. II: The range of SERT expression in the DC. Interpretant constraints the interpreter in further interactions. DI: The realisation of one of the possible IOs, a DC with a certain degree of maturation. DI will play the role of the Sign in the next semiosis. CD ligands – as a feedback on 5-HT sequestration (Sign) SERT expression in the DC (II) DC maturation (IO)

The modeling of T-cell formation under the biosemiotic framework Sign: The DC mature_SERT_expression via 5-HT release. It is the DI of the previous semiosis. IO: An activated and ready for interaction T cell. II: The range of possibilities of IOs, that is, a set of T-cells with a certain level of cAMP. DI: It will be a T cell from the set denoted by the II. This T-cell will be the Sign of the next semiosis. DC mature - SERT expression via 5-HT release (Sign) T cell with a certain level of cAMP (II) An activated and ready for interaction T cell (IO)

The modeling of T-cell formation under the biosemiotic framework Sign: A T-cell with a specific level of cAMP. IO: A T-cell with a level of TPH-1. II: The range of possibilities of the IO. DI: A T-cell with a specific range of TPH-1. T-cell with a specific level of cAMP (Sign) Possibilities of reconstruction of specific IOs (II) T-cell with a TPH-1 (IO)

The modeling T-cell formation under the biosemiotic framework Sign: A T-cell with a specific range of TPH-1 IO: Antigen – Antibody formation II: T-cell derived signals – CD ligands DI: A specific CD ligand. T-cell with a specific TPH- 1 (Sign) T-cell derived signals – CD ligands (II) Antigen – Antibody formation (IO)

T cell memorization CD ligands – (Sign) SERT expression in the DC (II) DC maturation (IO) DC mature - SERT expression via 5-HT release (Sign) T cell with a certain level of cAMP (II) Activated T cell (IO) T-cell with a specific level of cAMP (Sign) Possibilities of reconstruction of specific IOs (II) T-cell with a TPH- 1 (IO) T-cell with a specific TPH- 1 (Sign) T-cell derived signals – CD ligands (II) Antigen – Antibody formation (IO)

Results and Comments An explanatory tool which models the complex phenomenon at the level of emergence. It seems that serotonin is just a sign (not-dependent on dose). It is a signal that triggers the self-organisation of a very complex system that is being respectively informed under the proper context. It engages in information processes based on the presented analysis. Modeling of the phenomenon under semiotic terms abstracted from the level of biochemistry could help us ask different questions to complex problems. Other tools are missing that should be integrated to the biosemiotic framework. Applying biosemiotics modeling to homeopathy gives us the chance to embody biosemiotics in a very diverse and complex testbed.

Further work Integrate with theories and frameworks of self-organisation and general systemic and evolutionary thinking. A detailed biosemiotic analysis of T cell memory formation. Integration with other works of biosemiotics in intra- and extra- cellular signaling. Experimental designs in SDA research, which will provide a way to test and refine certain aspects of the theory.