Cancer: Towards a general theory of the target

General theories (GT) are reductionist explications of apparently independent facts. Here, in reviewing the literature, I develop a GT to simplify the cluttered landscape of cancer therapy targets by revealing they cluster parsimoniously according to only a few underlying principles. The first principle is that targets can be only exploited by either or both of two fundamentally different approaches: causality‐inhibition, and ‘acausal’ recognition of some marker or signature. Nonetheless, each approach must achieve both of two separate goals, efficacy (reduction in cancer burden) and selectivity (sparing of normal cells); if the mechanisms are known, this provides a definition of rational treatment. The second principle is target fragmentation, whereby the target may perform up to three categoric functions (cytoreduction, modulation, cytoprotection), potentially mediated by physically different target molecules, even on different cell types, or circulating freely. This GT remains incomplete until the minimal requirements for cure, or alternatively, proof that cure is impossible, become predictable.     

Towards a general theory of adaptive walks on rugged landscapes

Adaptive evolution, to a large extent, is a complex combinatorial optimization process. In this article we take beginning steps towards developing a general theory of adaptive "walks" via fitter variants in such optimization processes. We introduce the basic idea of a space of entities, each a 1-mutant neighbor of many other entities in the space, and the idea of a fitness ascribed to each entity. Adaptive walks proceed from an initial entity, via fitter neighbors, to locally or globally optimal entities that are fitter than their neighbors. We develop a general theory for the number of local optima, lengths of adaptive walks, and the number of alternative local optima accessible from any given initial entity, for the baseline case of an uncorrelated fitness landscape. Most fitness landscapes are correlated, however. Therefore we develop parts of a universal theory of adaptation on correlated landscapes by adaptive processes that have sufficient numbers of mutations per individual to "jump beyond" the correlation lengths in the underlying landscape. In addition, we explore the statistical character of adaptive walks in two independent complex combinatorial optimization problems, that of evolving a specific cell type in model genetic networks, and that of finding good solutions to the traveling salesman problem. Surprisingly, both show similar statistical features, encouraging the hope that a general theory for adaptive walks on correlated and uncorrelated landscapes can be found. In the final section we explore two limits to the efficacy of selection. The first is new, and surprising: for a wide class of systems, as the complexity of the entities under selection increases, the local optima that are attainable fall progressively closer to the mean properties of the underlying space of entities. This may imply that complex biological systems, such as genetic regulatory systems, are "close" to the mean properties of the ensemble of genomic regulatory systems explored by evolution. The second limit shows that with increasing complexity and a fixed mutation rate, selection often becomes unable to pull an adapting population to those local optima to which connected adaptive walks via fitter variants exist. These beginning steps in theory development are applied to maturation of the immune response, and to the problem of radiation and stasis. Despite the limitations of the adaptive landscape metaphor, we believe that further development along the lines begun here will prove useful.     

Towards a general theory of neural computation based on prediction by single neurons

Although there has been tremendous progress in understanding the mechanics of the nervous system, there has not been a general theory of its computational function. Here I present a theory that relates the established biophysical properties of single generic neurons to principles of Bayesian probability theory, reinforcement learning and efficient coding. I suggest that this theory addresses the general computational problem facing the nervous system. Each neuron is proposed to mirror the function of the whole system in learning to predict aspects of the world related to future reward. According to the model, a typical neuron receives current information about the state of the world from a subset of its excitatory synaptic inputs, and prior information from its other inputs. Prior information would be contributed by synaptic inputs representing distinct regions of space, and by different types of non-synaptic, voltage-regulated channels representing distinct periods of the past. The neuron's membrane voltage is proposed to signal the difference between current and prior information ("prediction error" or "surprise"). A neuron would apply a Hebbian plasticity rule to select those excitatory inputs that are the most closely correlated with reward but are the least predictable, since unpredictable inputs provide the neuron with the most "new" information about future reward. To minimize the error in its predictions and to respond only when excitation is "new and surprising," the neuron selects amongst its prior information sources through an anti-Hebbian rule. The unique inputs of a mature neuron would therefore result from learning about spatial and temporal patterns in its local environment, and by extension, the external world. Thus the theory describes how the structure of the mature nervous system could reflect the structure of the external world, and how the complexity and intelligence of the system might develop from a population of undifferentiated neurons, each implementing similar learning algorithms.     

Towards the theory of pollinator-mediated gene flow

I present a new exposition of a model of gene flow by animal-mediated pollination between a source population and a sink population. The model's parameters describe two elements: (i) the expected portion of the source's paternity that extends to the sink population; and (ii) the dilution of this portion by within-sink pollinations. The model is termed the portion-dilution model (PDM). The PDM is a parametric restatement of the conventional view of animal-mediated pollination. In principle, it can be applied to plant species in general. I formulate a theoretical value of the portion parameter that maximizes gene flow and prescribe this as a benchmark against which to judge the performance of real systems. Existing foraging theory can be used in solving part of the PDM, but a theory for source-to-sink transitions by pollinators is currently elusive.     

Towards a theory of thresholds

Some authors studying feeding or drinking have assumed that the activity starts or stops when causal factors rise or fall to a given point. Apparently non-homeostatic behaviour is then explained by adding more complex control mechanisms. Other authors, studying the interaction between activities, have assumed that activities compete so that one activity effectively sets the threshold for another. The latter view was embodied in a ‘model animal’ described previously. The model animal has now been used to simulate rat feeding and drinking behaviour. Although its feedback loops are over-simple, the model exhibits some of the non-homeostatic behaviour shown by rats and it is argued that the complexities arising from competition between activities need to be understood before further progress can be made in exploring homeostatic mechanisms.     

The quantal theory of immunity

Exactly how the immune system discriminates between all environmental antigens to which it reacts vs. all selfantigens to which it does not, is a principal unanswered question in immunology. As set forth in this review, because of the advances in our understanding of the immune system that have occurred in the last 50 years, for the first time it is possible to formulate a new theory, termed the ＂Quantal Theory of Immunity＂, which reduces the problem from the immune system as a whole, to the individual cells comprising the system, and finally to a molecular explanation as to how the system behaves as it does.     

Towards a molecular theory of the nerve membrane

Ion transport through the nerve membrane is considered in terms of barrier-limited fluxes calculated from absolute reaction rate theory. Equations are developed to describe the conformational transitions of an enzyme embedded in the membrane to provide a low-energy transport site. The enzyme transitions are controlled by binding and hydrolytic release of an acetylcholine-like molecule, which in turn depends on ion association with a single negative charge on the enzyme. Simulation of the equations gives good agreement with typical experimental voltage clamps and action potentials. A steady-state negative resistance is found in isoosmolar potassium, and the model shows excitation by an acetylcholine pulse under conditions mimicking the postsynaptic membrane. The implications of the model for development of a molecular theory of the nerve membrane are considered.     

Towards a theory of insect epidemiology

An attempt is made to consolidate and extend some of our current thoughts on insect epidemiology using graphical reproduction models. Starting with a simple model with a single equilibrium point, the elementary hypothesis is proposed that epidemics erupt when this equilibrium point increases substantially through improvement of the insect's habitat. The extension of this model to more than one coincident equilibria, some of which may be locally stable, is discussed and generalized using the theory of habitat suitability. Use of equilibrium manifolds is suggested to permit greater dimensionality. Lastly, an explanation of insect epidemics, based on the effects of time delays in the response of density-dependent processes, is elaborated and generalized. The influence of spatial dimensions and insect dispersal on the theory is discussed.     

Towards a theory of ethnic separatism

In the decades between 1896 and the mid-1960s it was unusual for the federal government to act to defend or advance Black Americans' interests. In this article two such rare instances are analysed. Both occurred in the 1920s, a decade with a distinctive political complexion. In 1923 Black Americans called upon the federal government's Veterans Bureau [VB] to make good its assurance that African Americans would staff a newly opened hospital in Tuskegee, Alabama, for blacks. At the end of the decade, the Superintendent of Prisons was petitioned to abrogate the new practice at the federal penitentiary in Atlanta, Georgia, of leasing out exclusively Black American prisoners to local governments for contract work. Each case was formulated and justified within the prejudicial framework of segregated race relations, but Black Americans sought fair treatment within its unsalubrious confines. The cases demonstrate the capacity of the federal government to act on racial issues when political circumstances permitted.     

Towards a field theory of behaviour

Classical ethology, with its emphasis on separability of parts, has largely failed to do justice to the wholeness of the individual animal, to the integrity of group behaviour and to the continuity between observable behaviour and consciousness. Field theory has potentialities to do better, as illustrated in this paper with reference to morphogenetic and behavioural fields. A behavioural domain is delineated — playlike behaviour — where field theory is particularly relevant. It is shown that the concept of symmetry can suggest new questions as well as explain some generally known phenomena of group behaviour. New interpretations of displacement activities and of etho-ecological adaptations are offered, both of which involve the whole individual animal.This paper is dedicated to W.M.S. Russell at the occasion of his retirement. He and Claire Russell invented most of what is new in ethology years or decades ago.     

Towards a theory of the evolution of modifier genes

The main findings of a study of the evolution of modifier gene frequencies in models of deterministic population genetics are presented. A wide variety of random mating systems are subject to selection with modifiers operating, in different cases, on mutation rates, migration between subpopulations, and linkage between other loci. In all these instances, the modifier frequencies evolve in such a way as to maximize the mean fitness of the population at equilibrium. This is remarkable since, the modifier genes are selectively neutral in the sense that they do not affect the fitness of their individual carriers. In nonrandom mating systems, the mean fitness concept is not well-defined, and there does not appear to be such a simple principle governing the evolution of modifier frequencies. In assortative mating systems, modifiers favoring reduced assortment propensities tend to increase. In contrast, for selfing-outcrossing systems, modifiers favoring increased selfing tend to increase.     

Pivoting plant immunity from theory to the field

<正>Plants live in complex environments and are constantly exposed to potential pathogens with different lifestyles and infection strategies.The evolutionary arms race between plants and their attackers has provided plants with a highly sophisticated and multi-layered defense system,which recognizes pathogen molecules and responds by activating defense pathways in order to resist the invaders.Here,we discuss recent developments in plant immunity,summarize conserved anti-microbial defense outputs and pathways,and     

Towards a general model for protein-substrate stereoselectivity

Protein-substrate interactions in enzymatic, neurological, and immunological systems are typically characterized by a high degree of stereoselectivity towards complex substrates. We propose a novel stereocenter-recognition (SR) model for stereoselectivity of proteins (or receptors in general) towards substrates that have multiple stereocenters, based on the topology of substrate stereocenters. The model provides the minimum number of substrate locations that need to enter into binding, nonbinding, or repulsive interactions with receptor sites, for stereoselectivity to occur. According to this model, a substrate location may interact with multiple receptor sites, or multiple substrate locations may interact with a single receptor site, but a stereoselective receptor has to offer, in the correct geometry, at least as many interactions as the required minimum number of substrate locations. The SR model predicts that stereoselectivity towards an acyclic substrate with N stereocenters distributed along a single chain requires interactions involving a minimum of N + 2 substrate locations, distributed over all stereocenters in the substrate, such that effectively three locations exist per stereocenter. Thus, enantioselective recognition of molecules with one chiral center requires a protein to interact with a minimum of three substrate locations, while stereoselectivity towards substrates with two or three stereocenters requires interactions with a minimum of four or five substrate locations, respectively, and so on. We demonstrate the general applicability of this model to protein-substrate interactions by interpreting several previous experimental observations.     

Local and general immunity in diseases of the nervous system

In normal condition, the nervous system has no local immunity, and general immunity is here very poor. However, in many neuro-immunological diseases, a local immunity appears, i.e.: a local synthesis of immunoglobulins. General immunity may be increased by transudation of blood components into CSF, either separately (inflammatory transudate) or simultaneously (meningitis) with this local synthesis. A mathematical formula is proposed is useful for some reasons: 1) evaluation of local immunity; 2) definition of CSF immunological patterns into 5 types and a neuro-immunological classification of neurological diseases; 3) research of the etiology in some nervous disease; 4) objective analysis of results of immunotherapy. Multiple sclerosis gives a good example of this 4 points of interest.