Biological functions are causes, not effects: A critique of selected effects theories.

The theory of Selected Effects (SE) is currently the most widely accepted etiological account of function in biology. It argues that the function of any trait is the effect that past traits of that type produced that contributed to its current existence. Its proper or etiological function is whatever effect was favoured by natural selection irrespective of the trait's current effects. By defining function with respect to the effects of natural selection, the theory claims to eschew the problem of backwards causality and to ground functional normativity on differential reproduction or differential persistence. Traditionally, many have criticised the theory for its inability to envisage any function talk outside selective reproduction, for failing to account for the introduction of new functions, and for treating function as epiphenomenal. This article unveils four additional critiques of the SE theory that highlight the source of its critical problems. These critiques follow from the fact that natural selection is not a form of work, but a passive filter that merely blocks or permits prior functioning traits to be reproduced. Natural selection necessarily assumes the causal efficacy of prior organism work to produce the excess functional traits and offspring from which only the best fitted will be preserved. This leads to four new incapacities of the SE theory, which will be here analysed: (i) it provides no criterion for determining what distinguishes a proper from an incidental function; (ii) it cannot distinguish between neutral, incidental, and malfunctioning traits, thus treating organism benefit as irrelevant; (iii) it fails to account for the physical work that makes persistence and reproduction possible, and (iv) in so doing, it falls into a vicious regress. We conclude by suggesting that, inspired by Mills and Beatty's propensity interpretation, the aporia of backward causation implicit in anticipatory accounts of function can also be avoided by a dispositional approach that defines function in terms of work that synchronously counters the ubiquitous tendency for organism entropy to increase in the context of far-from-equilibrium thermodynamics.

A thermodynamic basis for teleological causality.

We show how distinct terminally disposed self-organizing processes can be linked together so that they collectively suppress each other's self-undermining tendency despite also potentiating it to occur in a restricted way. In this way, each process produces the supportive and limiting boundary conditions for the other. The production of boundary conditions requires dynamical processes that decrease local entropy and increase local constraints. Only the far-from-equilibrium dissipative dynamics of self-organized processes produce these effects. When two such complementary self-organizing processes are linked by a shared substrate-the waste product of one that is the necessary ingredient for the other-the co-dependent structure that results develops toward a self-sustaining target state that avoids the termination of the whole, and any of its component processes. The result is a perfectly naturalized model of teleological causation that both escapes the threat of backward influences and does not reduce teleology to selection, chemistry or chance. This article is part of the theme issue 'Thermodynamics 2.0: Bridging the natural and social sciences (Part 1)'.

A degenerative process underlying hierarchic transitions in evolution.

This paper describes an evolutionary process likely involved in hierarchic transitions in biological evolution at many levels, from genetics to social organization. It is related to the evolutionary process described as contingent neutral evolution (CNE). It involves a sequence of stages initiated by the spontaneous appearance of functional redundancy. This redundancy can be the result of gene duplication, symbiosis, cell-cell interactions, environmental supports, etc. The availability of redundant sources of biological functionality relaxes purifying selection and allows degenerative changes to accumulate in one or more of the duplicates, potentially degrading or otherwise fractionating its function. This degeneration will be effectively neutral so long as another maintains functional integrity. Sexual recombination can potentially sample different combinations of these sub functional alternatives, with the result that favorable synergistic interactions between independently degenerate duplicates will have a non-negligible probability of being uncovered. The expression of such a synergistic combinatorial effect will result in the irreversible degradation of any remaining autonomous functionality, thereby initiating selection to prevent breakup of co-dependency. This becomes relevant to the evolution of hierarchic transitions when two or more organisms reciprocally duplicate functions that each other requires. If the resulting relaxation of selection reliably persists for an extended evolutionary period it will tend to produce complementary degenerative effects in each organism, leading to their irreversible codependency and purifying selection to avoid loss of integrity of their higher order functional unity. This provides a partial inversion of Darwinian logic that explains how the potential costs of the loss of organism autonomy can be mitigated, enabling the incremental transition to a synergistic higher order unit of evolution.

Abandoning the code metaphor is compatible with semiotic process.

We agree with Brette's assessment that the coding metaphor has become more problematic than helpful for theories of brain and cognitive functioning. In an effort to aid in constructing an alternative, we argue that joining the insights from the dynamical systems approach with the semiotic framework of C. S. Peirce can provide a fruitful perspective.

The transition from constraint to regulation at the origin of life.

The origin of living dynamics required a local evasion of thermodynamic degradation by maintaining critical dynamical and structural constraints. Scenarios for life`s origin that fail to distinguish between constrained chemistry and regulated metabolism do not address the question of how living processes first emerge from simpler constraints on molecular interactions. We describe a molecular model system consisting of coupled reciprocal catalysis and self-assembly in which one of the catalytic bi-products tends to spontaneously self-assemble into a containing shell (analogous to a viral capsule). In this process, which we call autogenesis, self-repair/reconstitution and reproduction are made possible by the fact that each of these linked self-organizing processes generates boundary constraints that promote and limit the other, and because this synergy thereby becomes embodied as a persistent rate-independent substrate-transferrable constraint on the synergy of its component constraint-generating processes. It is proposed that this higher-order formal constraint is necessary and sufficient to constitute regulation as opposed to mere physico-chemical constraint. Two minor elaborations of this model system demonstrate how cybernetic and template-based regulation could emerge from this basic process.

Colloquium paper: a role for relaxed selection in the evolution of the language capacity.

Explaining the extravagant complexity of the human language and our competence to acquire it has long posed challenges for natural selection theory. To answer his critics, Darwin turned to sexual selection to account for the extreme development of language. Many contemporary evolutionary theorists have invoked incredibly lucky mutation or some variant of the assimilation of acquired behaviors to innate predispositions in an effort to explain it. Recent evodevo approaches have identified developmental processes that help to explain how complex functional synergies can evolve by Darwinian means. Interestingly, many of these developmental mechanisms bear a resemblance to aspects of Darwin's mechanism of natural selection, often differing only in one respect (e.g., form of duplication, kind of variation, competition/cooperation). A common feature is an interplay between processes of stabilizing selection and processes of relaxed selection at different levels of organism function. These may play important roles in the many levels of evolutionary process contributing to language. Surprisingly, the relaxation of selection at the organism level may have been a source of many complex synergistic features of the human language capacity, and may help explain why so much language information is "inherited" socially.

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.