Uncertainty in experts' judgments exposes the vulnerability of research reporting anecdotes on animals' cognitive abilities.

Expertise in science, particularly in animal behaviour, may provide people with the capacity to provide better judgments in contrast to lay people. Here we explore whether experts provide a more objective, accurate and coherent evaluation of a recently reported anecdote on Atlantic puffin (Fratercula arctica) "tool use" (recorded on video) which was published in a major scientific journal but was received with some scepticism. We relied on citizen science and developed a questionnaire to measure whether experts in ethology and ornithology and lay people agree or disagree on (1) the description of the actions that they observe (the bird takes a stick in its beak), (2) the possible goal of the action (nest-building or grooming) and (3) the intentional component of the action (the bird took the stick into its beak in order to scratch itself). We hypothesised that contrary to the lay people, experts are more critical evaluators that is they are more inclined to report alternative actions, like nest building, or are less likely to attributing goal-directedness to the action in the absence of evidence. In contrast, lay people may be more prone to anthropomorphise utilising a teleological and intentional stance. Alternatively, all three groups of subjects may rely on anthropomorphism at similar levels and prior expertise does not play a significant role. We found that no major differences among the evaluators. At the group levels, respondents were relatively uncertain with regard to the action of the bird seen on the video but they showed some individual consistency with regard to the description of the action. Thus, we conclude that paradoxically, with regard to the task our experts are typically not experts in the strict sense of the definition, and suggest that anecdotal reports should not be used to argue about mental processes.

Catalytic promiscuity in the RNA World may have aided the evolution of prebiotic metabolism.

The Metabolically Coupled Replicator System (MCRS) model of early chemical evolution offers a plausible and efficient mechanism for the self-assembly and the maintenance of prebiotic RNA replicator communities, the likely predecessors of all life forms on Earth. The MCRS can keep different replicator species together due to their mandatory metabolic cooperation and limited mobility on mineral surfaces, catalysing reaction steps of a coherent reaction network that produces their own monomers from externally supplied compounds. The complexity of the MCRS chemical engine can be increased by assuming that each replicator species may catalyse more than a single reaction of metabolism, with different catalytic activities of the same RNA sequence being in a trade-off relation: one catalytic activity of a promiscuous ribozyme can increase only at the expense of the others on the same RNA strand. Using extensive spatially explicit computer simulations we have studied the possibility and the conditions of evolving ribozyme promiscuity in an initial community of single-activity replicators attached to a 2D surface, assuming an additional trade-off between replicability and catalytic activity. We conclude that our promiscuous replicators evolve under weak catalytic trade-off, relatively strong activity/replicability trade-off and low surface mobility of the replicators and the metabolites they produce, whereas catalytic specialists benefit from very strong catalytic trade-off, weak activity/replicability trade-off and high mobility. We argue that the combination of conditions for evolving promiscuity are more probable to occur for surface-bound RNA replicators, suggesting that catalytic promiscuity may have been a significant factor in the diversification of prebiotic metabolic reaction networks.

Dynamics and stability in prebiotic information integration: an RNA World model from first principles.

The robust coevolution of catalytically active, metabolically cooperating prebiotic RNA replicators were investigated using an RNA World model of the origin of life based on physically and chemically plausible first principles. The Metabolically Coupled Replicator System assumes RNA replicators to supply metabolically essential catalytic activities indispensable to produce nucleotide monomers for their own template replication. Using external chemicals as the resource and the necessary ribozyme activities, Watson-Crick type replication produces complementary strands burdened by high-rate point mutations (insertions, deletions, substitutions). Metabolic ribozyme activities, replicabilities and decay rates are assigned to certain sequence and/or folding (thermodynamical) properties of single-stranded RNA molecules. Short and loosely folded sequences are given replication advantage, longer and tightly folded ones are better metabolic ribozymes and more resistant to hydrolytic decay. We show that the surface-bound MCRS evolves stable and metabolically functional communities of replicators of almost equal lengths, replicabilities and ribozyme activities. Being highly resistant to the invasion of parasitic (non-functional) replicators, it is also stable in the evolutionary sense. The template replication mechanism selects for catalytic "promiscuity": the two (complementary) strands of the same evolved replicator will often carry more than a single catalytically active motif, thus maximizing functionality in a minimum of genetic information.

Ecology and Evolution in the RNA World Dynamics and Stability of Prebiotic Replicator Systems.

As of today, the most credible scientific paradigm pertaining to the origin of life on Earth is undoubtedly the RNA World scenario. It is built on the assumption that catalytically active replicators (most probably RNA-like macromolecules) may have been responsible for booting up life almost four billion years ago. The many different incarnations of nucleotide sequence (string) replicator models proposed recently are all attempts to explain on this basis how the genetic information transfer and the functional diversity of prebiotic replicator systems may have emerged, persisted and evolved into the first living cell. We have postulated three necessary conditions for an RNA World model system to be a dynamically feasible representation of prebiotic chemical evolution: (1) it must maintain and transfer a sufficient diversity of information reliably and indefinitely, (2) it must be ecologically stable and (3) it must be evolutionarily stable. In this review, we discuss the best-known prebiotic scenarios and the corresponding models of string-replicator dynamics and assess them against these criteria. We suggest that the most popular of prebiotic replicator systems, the hypercycle, is probably the worst performer in almost all of these respects, whereas a few other model concepts (parabolic replicator, open chaotic flows, stochastic corrector, metabolically coupled replicator system) are promising candidates for development into coherent models that may become experimentally accessible in the future.

Metabolically Coupled Replicator Systems: Overview of an RNA-world model concept of prebiotic evolution on mineral surfaces.

Metabolically Coupled Replicator Systems (MCRS) are a family of models implementing a simple, physico-chemically and ecologically feasible scenario for the first steps of chemical evolution towards life. Evolution in an abiotically produced RNA-population sets in as soon as any one of the RNA molecules become autocatalytic by engaging in template directed self-replication from activated monomers, and starts increasing exponentially. Competition for the finite external supply of monomers ignites selection favouring RNA molecules with catalytic activity helping self-replication by any possible means. One way of providing such autocatalytic help is to become a replicase ribozyme. An additional way is through increasing monomer supply by contributing to monomer synthesis from external resources, i.e., by evolving metabolic enzyme activity. Retroevolution may build up an increasingly autotrophic, cooperating community of metabolic ribozymes running an increasingly complicated and ever more efficient metabolism. Maintaining such a cooperating community of metabolic replicators raises two serious ecological problems: one is keeping the system coexistent in spite of the different replicabilities of the cooperating replicators; the other is constraining parasitism, i.e., keeping "cheaters" in check. Surface-bound MCRS provide an automatic solution to both problems: coexistence and parasite resistance are the consequences of assuming the local nature of metabolic interactions. In this review we present an overview of results published in previous articles, showing that these effects are, indeed, robust in different MCRS implementations, by considering different environmental setups and realistic chemical details in a few different models. We argue that the MCRS model framework naturally offers a suitable starting point for the future modelling of membrane evolution and extending the theory to cover the emergence of the first protocell in a self-consistent manner. The coevolution of metabolic, genetic and membrane functions is hypothesized to follow the progressive sequestration scenario, the conceptual blueprint for the earliest steps of protocell evolution.

In silico ribozyme evolution in a metabolically coupled RNA population.

BACKGROUND: The RNA World hypothesis offers a plausible bridge from no-life to life on prebiotic Earth, by assuming that RNA, the only known molecule type capable of playing genetic and catalytic roles at the same time, could have been the first evolvable entity on the evolutionary path to the first living cell. We have developed the Metabolically Coupled Replicator System (MCRS), a spatially explicit simulation modelling approach to prebiotic RNA-World evolution on mineral surfaces, in which we incorporate the most important experimental facts and theoretical considerations to comply with recent knowledge on RNA and prebiotic evolution. In this paper the MCRS model framework has been extended in order to investigate the dynamical and evolutionary consequences of adding an important physico-chemical detail, namely explicit replicator structure - nucleotide sequence and 2D folding calculated from thermodynamical criteria - and their possible mutational changes, to the assumptions of a previously less detailed toy model. RESULTS: For each mutable nucleotide sequence the corresponding 2D folded structure with minimum free energy is calculated, which in turn is used to determine the fitness components (degradation rate, replicability and metabolic enzyme activity) of the replicator. We show that the community of such replicators providing the monomer supply for their own replication by evolving metabolic enzyme activities features an improved propensity for stable coexistence and structural adaptation. These evolutionary advantages are due to the emergent uniformity of metabolic replicator fitnesses imposed on the community by local group selection and attained through replicator trait convergence, i.e., the tendency of replicator lengths, ribozyme activities and population sizes to become similar between the coevolving replicator species that are otherwise both structurally and functionally different. CONCLUSIONS: In the most general terms it is the surprisingly high extra viability of the metabolic replicator system that the present model adds to the MCRS concept of the origin of life. Surface-bound, metabolically coupled RNA replicators tend to evolve different, enzymatically active sites within thermodynamically stable secondary structures, and the system as a whole evolves towards the robust coexistence of a complete set of such ribozymes driving the metabolism producing monomers for their own replication.

The dynamics of the RNA world: insights and challenges.

The RNA world hypothesis of the origin of life, in which RNA emerged as both enzyme and information carrier, is receiving solid experimental support. The prebiotic synthesis of biomolecules, the catalytic aid offered by mineral surfaces, and the vast enzymatic repertoire of ribozymes are only pieces of the origin of life puzzle; the full picture can only emerge if the pieces fit together by either following from one another or coexisting with each other. Here, we review the theory of the origin, maintenance, and enhancement of the RNA world as an evolving population of dynamical systems. The dynamical view of the origin of life allows us to pinpoint the missing and the not fitting pieces: (1) How can the first self-replicating ribozyme emerge in the absence of template-directed information replication? (2) How can nucleotide replicators avoid competitive exclusion despite utilizing the very same resources (nucleobases)? (3) How can the information catastrophe be avoided? (4) How can enough genes integrate into a cohesive system in order to transition to a cellular stage? (5) How can the way information is stored and metabolic complexity coevolve to pave to road leading out of the RNA world to the present protein-DNA world?

Template directed replication supports the maintenance of the metabolically coupled replicator system.

The RNA World scenario of prebiotic chemical evolution is among the most plausible conceptual framework available today for modelling the origin of life. RNA offers genetic and catalytic (metabolic) functionality embodied in a single chemical entity, and a metabolically cooperating community of RNA molecules would constitute a viable infrabiological subsystem with a potential to evolve into proto-cellular life. Our Metabolically Coupled Replicator System (MCRS) model is a spatially explicit computer simulation implementation of the RNA-World scenario, in which replicable ribozymes cooperate in supplying each other with monomers for their own replication. MCRS has been repeatedly demonstrated to be viable and evolvable, with different versions of the model improved in depth (chemical detail of metabolism) or in extension (additional functions of RNA molecules). One of the dynamically relevant extensions of the MCRS approach to prebiotic RNA evolution is the explicit inclusion of template replication into its assumptions, which we have studied in the present version. We found that this modification has not changed the behaviour of the system in the qualitative sense, just the range of the parameter space which is optimal for the coexistence of metabolically cooperating replicators has shifted in terms of metabolite mobility. The system also remains resistant and tolerant to parasitic replicators.

Phenotype/genotype sequence complementarity and prebiotic replicator coexistence in the metabolically coupled replicator system.

BACKGROUND: RNA or RNA-like polymers are the most likely candidates for having played the lead roles on the stage of the origin of life. RNA is known to feature two of the three essential functions of living entities (metabolism, heredity and membrane): it is capable of unlimited heredity and it has a proven capacity for catalysing very different chemical reactions which may form simple metabolic networks. The Metabolically Coupled Replicator System is a class of simulation models built on these two functions to show that an RNA World scenario for the origin of life is ecologically feasible, provided that it is played on mineral surfaces. The fact that RNA templates and their copies are of complementary base sequences has an obvious dynamical relevance: complementary strains may have very different structures and, consequently, functions - one may specialize for increasing enzymatic activity while the other takes the role of the gene of the enzyme. RESULTS: Incorporating the functional divergence of template and copy into the Metabolically Coupled Replicator System model framework we show that sequence complementarity 1) does not ruin the coexistence of a set of metabolically cooperating replicators; 2) the replicator system remains resistant to, but also tolerant with its parasites; 3) opens the way to the evolutionary differentiation of phenotype and genotype through a primitive version of phenotype amplification. CONCLUSIONS: The functional asymmetry of complementary RNA strains results in a shift of phenotype/genotype (enzyme/gene) proportions in MCRS, favouring a slight genotype dominance. This asymmetry is expected to reverse due to the evolved trade-off of high "gene" replicability and high catalytic activity of the corresponding "enzyme" in expense of its replicability. This trade-off is the first evolutionary step towards the "division of labour" among enzymes and genes, which has concluded in the extreme form of phenotype amplification characteristic of our recent DNA-RNA-protein World.

Spatial aspects of prebiotic replicator coexistence and community stability in a surface-bound RNA world model.

BACKGROUND: The coexistence of macromolecular replicators and thus the stability of presumed prebiotic replicator communities have been shown to critically depend on spatially constrained catalytic cooperation among RNA-like modular replicators. The necessary spatial constraints might have been supplied by mineral surfaces initially, preceding the more effective compartmentalization in membrane vesicles which must have been a later development of chemical evolution. RESULTS: Using our surface-bound RNA world model - the Metabolic Replicator Model (MRM) platform - we show that the mobilities on the mineral substrate surface of both the macromolecular replicators and the small molecules of metabolites they produce catalytically are the key factors determining the stable persistence of an evolvable metabolic replicator community. CONCLUSION: The effects of replicator mobility and metabolite diffusion on different aspects of replicator coexistence in MRM are determined, including the maximum attainable size of the metabolic replicator system and its resistance to the invasion of parasitic replicators. We suggest a chemically plausible hypothetical scenario for the evolution of the first protocell starting from the surface-bound MRM system.

Gag-Pol processing during HIV-1 virion maturation: a systems biology approach.

Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for the production of infectious HIV-1, and inhibitors of the viral PR are an integral part of current antiretroviral therapy. The process has several layers of complexity (multiple cleavage sites and substrates; multiple enzyme forms; PR auto-processing), which calls for a systems level approach to identify key vulnerabilities and optimal treatment strategies. Here we present the first full reaction kinetics model of proteolytic processing by HIV-1 PR, taking into account all canonical cleavage sites within Gag and Gag-Pol, intermediate products and enzyme forms, enzyme dimerization, the initial auto-cleavage of full-length Gag-Pol as well as self-cleavage of PR. The model allows us to identify the rate limiting step of virion maturation and the parameters with the strongest effect on maturation kinetics. Using the modelling framework, we predict interactions and compensatory potential between individual cleavage rates and drugs, characterize the time course of the process, explain the steep dose response curves associated with PR inhibitors and gain new insights into drug action. While the results of the model are subject to limitations arising from the simplifying assumptions used and from the uncertainties in the parameter estimates, the developed framework provides an extendable open-access platform to incorporate new data and hypotheses in the future.

Reaction kinetics of catalyzed competitive heteropolymer cleavage.

A theoretical formulation for complete heteropolymer degradation is developed in terms of Michaelis-Menten reaction kinetics under the quasi-steady-state approximation. This allows the concentration of the entire intermediate decomposition cascade to be accounted for as well as each species of emerging final product. The formulation is implemented computationally and results in stable reaction kinetics across a range of orders of magnitude for K(M) and k(cat). The model is compared with experiment, specifically in vitro HIV-1 protease-catalyzed retroviral Gag-polyprotein processing. Using an experimentally determined cleavage-polypeptide parameter set, good qualitative agreement is reached with Gag degradation kinetics, given the difference in experimental conditions. A parameter search within 1 order of magnitude of variation of the experimental set results in the determination of an optimal parameter set in complete agreement with experiment which allows the time evolution of each individual as well as intermediate species in Gag to be accurately followed. Future investigations that determine the required enzymatic parameters to populate such a scheme will allow for the model to be refined in order to track the time for viral maturation and infectivity.

The evolution of enzyme specificity in the metabolic replicator model of prebiotic evolution.

The chemical machinery of life must have been catalytic from the outset. Models of the chemical origins have attempted to explain the ecological mechanisms maintaining a minimum necessary diversity of prebiotic replicator enzymes, but little attention has been paid so far to the evolutionary initiation of that diversity. We propose a possible first step in this direction: based on our previous model of a surface-bound metabolic replicator system we try to explain how the adaptive specialization of enzymatic replicator populations might have led to more diverse and more efficient communities of cooperating replicators with two different enzyme activities. The key assumptions of the model are that mutations in the replicator population can lead towards a) both of the two different enzyme specificities in separate replicators: efficient "specialists" or b) a "generalist" replicator type with both enzyme specificities working at less efficiency, or c) a fast-replicating, non-enzymatic "parasite". We show that under realistic trade-off constraints on the phenotypic effects of these mutations the evolved replicator community will be usually composed of both types of specialists and of a limited abundance of parasites, provided that the replicators can slowly migrate on the mineral surface. It is only at very weak trade-offs that generalists take over in a phase-transition-like manner. The parasites do not seriously harm the system but can freely mutate, therefore they can be considered as pre-adaptations to later, useful functions that the metabolic system can adopt to increase its own fitness.

Prebiotic replicase evolution in a surface-bound metabolic system: parasites as a source of adaptive evolution.

BACKGROUND: The remarkable potential of recent forms of life for reliably passing on genetic information through many generations now depends on the coordinated action of thousands of specialized biochemical "machines" (enzymes) that were obviously absent in prebiotic times. Thus the question how a complicated system like the living cell could have assembled on Earth seems puzzling. In seeking for a scientific explanation one has to search for step-by-step evolutionary changes from prebiotic chemistry to the emergence of the first proto-cell. RESULTS: We try to sketch a plausible scenario for the first steps of prebiotic evolution by exploring the ecological feasibility of a mineral surface-bound replicator system that facilitates a primitive metabolism. Metabolism is a hypothetical network of simple chemical reactions producing monomers for the template-copying of RNA-like replicators, which in turn catalyse metabolic reactions. Using stochastic cellular automata (SCA) simulations we show that the surface-bound metabolic replicator system is viable despite internal competition among the genes and that it also maintains a set of mild "parasitic" sequences which occasionally evolve functions such as that of a replicase. CONCLUSION: Replicase activity is shown to increase even at the expense of slowing down the replication of the evolving ribozyme itself, due to indirect mutualistic benefits in a diffuse form of group selection among neighbouring replicators. We suggest possible paths for further evolutionary changes in the metabolic replicator system leading to increased metabolic efficiency, improved replicase functionality, and membrane production.