The RNA World concept posits that there was a period of time in primitive Earth's history - about 4 billion years ago - when the primary living substance was RNA or something chemically similar. In the past 50 years, this idea has gone from speculation to a prevailing idea. In this Review, we summarize the key logic behind the RNA World and describe some of the most important recent advances that have been made to support and expand this logic. We also discuss the ways in which molecular cooperation involving RNAs would facilitate the emergence and early evolution of life. The immediate future of RNA World research should be a very dynamic one.
This article is a response to David Armstrong's recent, revisionist account of the epidemiological transition which he claims replaced earlier discourses of ageing with new discourses of chronic disease. We argue (i) that he misrepresents a key element in Omran's account of the epidemiological transition, namely the decline in infant, child and maternal mortality; (ii) that he fails to acknowledge debates going back centuries in Western medicine over the distinctions between natural and accidental death and between endogenous and extrinsic causes of ageing and (iii) that he misrepresents the growth of medical interest in the everyday illnesses of old age over the course of the 20th century as a discourse of suppression rather than a process of inclusion. While we would acknowledge that the chronic illnesses of today are different from those of the past, this amounts to something more than the changing semantics of senility.
The origin of life requires the emergence of a system of autocatalytic polymers such as RNA. We consider a trans-acting replicase that catalyses replication of a template (either a copy of itself or another sequence). Our model includes alternating plus/minus strand replication where only the plus strand is a catalyst. Prebiotic chemistry generates random sequences and allows for non-catalysed, template-directed synthesis of new strands. These chemical reactions are insufficient to sustain replication, but they provide a background in which the first replicase can arise. In the well-mixed case, the minimum value of the catalytic rate parameter k for which a stable replicating state survives scales as 1/f, where f is the fraction of random sequences that are catalysts. When catalysts are rare (f?0), the replicating state is not stable in for any finite k because the replicases are overrun by parasitic templates already present in the prebiotic system, and by additional parasites created by mutation of the catalyst. In contrast, in 2d spatial simulations, the replicating state is stable for moderate k with appropriate values of the local diffusion constant. We calculate the probability of spread of the replicating state from a single isolated catalyst. This occurs in a parameter range that is narrower than that in which existing replicators are stable. The 2d model uses 'Two?s Company' rules, where two molecules on a site may replicate, but crowding occurs when three molecules are on one site. A mean-field theory is presented which predicts the most important results of the spatial model. Our results emphasize that the origin of replication is a spatially-localized stochastic transition between a 'dead' state controlled by prebiotic chemistry and a 'living' state controlled by autocatalytic replication.
Chronic kidney disease stage 5 is a global health challenge in the context of population ageing across the world. The range of treatment options available to patients at all ages has increased and includes transplantation and dialysis. However, these options are often seen as inappropriate for older frailer patients who are now offered the option of conservative kidney management, which is presented as a non-invasive alternative to dialysis, involving symptom management and addressing psychosocial needs. In this study, we conducted qualitative interviews with 26 close persons caring for someone with chronic kidney disease stage 5 in the United Kingdom to investigate how conservative kidney management interacted with implicit ideas of ageing, in both the experience of conservative kidney management and the understanding of the prognosis and future care of the kidney disease. Our findings highlighted participant confusion about the nature of conservative kidney management, which stems from an initial lack of clarity about how conservative kidney management differed from conventional treatments for chronic kidney disease stage 5. In particular, some respondents were not aware of the implicit palliative nature of the intervention or indeed the inevitable end-of-life issues. Although these findings can be situated within the context of communication failure, we would further argue that they also bring to the surface tensions in the discourses surrounding ageing and old age, drawing on the use of a 'natural' and a 'normal' paradigm of ageing. In the context of chronic kidney disease stage 5, more patients are being dialysed at older ages, but conservative kidney management is being advanced as a better option than dialysis in terms of quality of life and experience. However, in doing so, conservative kidney management implicitly draws on a notion of older age that echoes natural ageing rather than advocate a more interventionist approach. The role of discourses of ageing in the provision of treatments for conservative kidney management has not previously been acknowledged, and this article addresses this gap.
Feline hyperthyroidism is commonly diagnosed in general practice. This study assessed the opinions and experiences of UK general practitioners (GPs) regarding the management of feline hyperthyroidism. This included an evaluation of preferred treatment modalities and the monitoring of medically treated cats in relation to thyroxine (T4) level, co-morbid disease and adverse drug reactions. Six hundred and three GPs completed an online questionnaire comprising 34 questions. Oral medication was the most commonly preferred treatment option (65.7% of respondents), followed by thyroidectomy (27.5%) and then radioiodine (5.5%). When cost of treatment was eliminated as a consideration factor, significantly more respondents selected radioiodine (40.5%, P <0.001). Concerning target total T4 levels during medical management, 48.4% aimed for the lower half of the reference interval (RI), 32.3% anywhere within RI, 13.1% within the top half of RI and 0.5% above the RI; 3.4% evaluated efficacy by physical assessment only. In the presence of chronic kidney disease (CKD) respondents were significantly more likely to target total T4 levels within the upper half of the RI (40.3%) or above it (9.8%) when compared with targets for routine cases (P <0.001). Assessment for unmasking of CKD after initiating treatment or for hypertension was not consistently performed. Variability in monitoring strategies may result in CKD and hypertension remaining undetected, inadequate suppression of T4 levels in cats with concurrent CKD and delayed recognition of potentially significant haematological abnormalities.
This paper explores the idea of the fourth age as a form of social imaginary. During the latter half of the twentieth century and beyond, the cultural framing of old age and its modern institutionalisation within society began to lose some of its former chronological coherence. The pre-modern distinction made between the status of the elder and the state of senility has re-emerged in the late modern distinction between the third and the fourth age. The centuries-old distaste for and fear of old age as senility has been compounded by the growing medicalization of later life, the emergence and expansion of competing narratives associated with the third age, and the progressive densification of the disabilities within the older institutionalised population. The result can be seen as the emergence of a late modern social imaginary deemed as the fourth age. This paper outlines the theoretical evolution of the concept of a social imaginary and demonstrates its relevance to aging studies and its applicability to the fourth age.
Ribozymes that act as polymerases and nucleotide synthases are known experimentally, even though no fully self-replicating system has yet been found. If the RNA World hypothesis is true, ribozymes must have arisen initially from within a random abiotic polymerization system. To investigate the origin of the RNA world, we studied a mathematical model of a chemical reaction system describing RNA polymerization. It is supposed that, in absence of ribozymes, polymerization occurs at a small spontaneous rate, and that in the presence of polymerase ribozymes, polymerization occurs at a faster rate that is proportional to the ribozyme concentration. Chains must be longer than a minimum threshold length in order to have the possibility of acting as ribozymes. The reaction system has two stable states that we term dead and living. The dead state is controlled by the small spontaneous rate and has negligible concentration of ribozymes. The living state has high concentration of ribozymes, and the reaction rates are determined by the ribozymes; thus, the system is autocatalytic. Concentration fluctuations in a finite volume can cause a transition to occur from the dead to the living state, that is, an origin of life occurs within this model. We also consider ribozymes that catalyze nucleotide synthesis. We show that living and dead states arise in the presence of synthase ribozymes in the same way as for polymerases. It has been proposed that recombination reactions are a way of generating long RNA chains in the early stages of life. We show that if the possibility of random reversible recombination reactions is added to our model, this does not lead to an increase in long polymer concentration. Thus, if recombination is fully reversible, there is no autocatalytic state controlled by recombination. Nevertheless, recombination can play an important role in ribozyme synthesis if there is an additional process that keeps the recombination reactions out of equilibrium. We modeled a case studied experimentally in which building block strands of moderate length associate due to RNA secondary structure formation. A recombination reaction then occurs between these strands to form a longer sequence that catalyzes its own formation via the recombination reaction. This system has an autocatalytic state, and it is possible for it to arise within our random polymerization system. If complexes formed by associations of shorter strands can act as catalysts without the requirement that the strands be covalently linked, this would alleviate the need for synthesis of very long strands; hence, it makes the emergence of an autocatalytic system from an abiotic random polymerization system much more likely.
Comparison of complete genomes of Bacteria and Archaea shows that gene content varies considerably and that genomes evolve quite rapidly via gene duplication and deletion and horizontal gene transfer. We analyze a diverse set of 92 Bacteria and 79 Archaea in order to investigate the processes governing the origin and evolution of families of related genes within genomes.
This article explores the characteristics of a newly emergent neuroculture and its relationship to cultures of ageing; in particular, the social meanings associated with active ageing and cognitive health and the discourses and sciences around memory and the ageing brain. The argument proposes a critical perspective on this relationship by looking at the shifting boundaries between standards of normality and abnormality, values of health and illness, practices of therapy and enhancement, and the lines demarcating Third Age (healthy, active and agentic) and Fourth Age (dependency, loss and decline) periods of ageing. Conclusions offer further reflections on the complex questions that arise regarding expectations, hopes and ethics in relation to the promises and perils of a neurocultural future.
Horizontal Gene Transfer (HGT) is beneficial to a cell if the acquired gene confers a useful function, but is detrimental if the gene has no function, if it is incompatible with existing genes, or if it is a selfishly replicating mobile element. If the balance of these effects is beneficial on average, we would expect cells to evolve high rates of acceptance of horizontally transferred genes, whereas if it is detrimental, cells should reduce the rate of HGT as far as possible. It has been proposed that the rate of HGT was very high in the early stages of prokaryotic evolution, and hence there were no separate lineages of organisms. Only when the HGT rate began to fall, would lineages begin to emerge with their own distinct sets of genes. Evolution would then become more tree-like. This phenomenon has been called the Darwinian Threshold.
This article examines the conditions under which epistemological shifts in medicine have shaped the history of apoplexy and stroke. Our intention is to understand how stroke medicine as a distinct branch of bio-medicine has emerged in its current form. In doing so, we draw on aspects of the work of Michel Foucault as they relate to fabrication of biomedical discourses. The past 300 years of the transformation of the condition is examined using Michel Foucaults analysis of medical history as instances of the changing spatialization of disease. While the adoption of this approach helped explain how medical practice was shaped by changing interpretations of the causes of apoplexy and stroke over the past few centuries, we also found that there were certain limitations to such an approach. Overall, however, we hope to show that an examination of the history of stroke medicine through a Foucauldian influenced lens can provide a useful understanding of its current circumstances as well as throw light on gaps in Foucauldian approaches themselves.
Frailty has become a topic of increasing interest in health care. No longer treated as a catch-all term for agedness, decline and disablement it has acquired a more precise definition, applied to those individuals whose aged state is seen to put them at risk of adverse outcomes. This transformation is we argue the outcome of a more general differentiation of terms that were previously used to categorize the weak and marginal within society. Old age re-labelled as later life has become re-articulated as a successful life stage relatively free from impairment. Disability has been re-positioned and its links with impairment attenuated while chronic illness has acquired a new narrative of its own. This has left frailty behind, redolent still with all the old negative attributes of marginality, but now more than ever evacuated of any remaining elements of status or agency. Frailty is defined less by the identities of those who are deemed frail than by what frailty seems to augur in its direction of travel - a journey towards unspecified adverse outcomes. This re-positioning, we suggest, helps lay the foundation of a social imaginary of the fourth age as the new location of old age.
Current UK medical guidance on the management of stroke includes advice on reducing behavioural factors that place people at risk of the disease. This paper explores the historical background to the construction of this risk; it starts by investigating the connections made between individual behaviours and the causation of apoplexy in the medical discourse during the 18(th) and 19(th) centuries described in English medical textbooks from the 1700s. In outlining the emergence of a biomedical discourse around apoplexy and stroke, we note how a number of judgemental and moral concerns are articulated particularly around diet and exercise. While different in emphasis and starting point these discourses have their echo in contemporary approaches to the prevention of stroke. We seek to show that many of the themes common in current health promotion and public health strategies can be seen as continuities of earlier concerns regarding peoples health; albeit now operating against the backdrop of a somatic society rather than a broader sense of moral regulation. We also hope to show how the understanding and prevention of stroke feeds into the moral discourse of the obesity crisis confronting the affluent nations of North America and Europe.
Most transfer RNAs (tRNAs) can translate more than one synonymous codon, and most codons can be translated by more than one isoacceptor tRNA. The rates of translation of synonymous codons are dependent on the concentrations of the tRNAs and on the rates of pairing of each anticodon-codon combination. Translational selection causes a significant bias in codon frequencies in highly expressed genes in most bacteria. By comparing codon frequencies in high and low-expression genes, we determine which codons are preferred for each amino acid in a large sample of bacterial genomes. We relate this to the number of copies of each tRNA gene in each genome. In two-codon families, preferred codons have Watson-Crick pairs (GC and AU) between the third codon base and the wobble base of the anticodon rather than GU pairs. This suggests that these combinations are more rapidly recognized by the ribosome. In contrast, in four-codon families, preferred codons do not correspond to Watson-Crick rules. In some cases, a wobble-U tRNA can pair with all four codons. In these cases, A and U codons are preferred over G and C. This indicates that the nonstandard UU combination appears to be translated surprisingly well. Differences in modified bases at the wobble position of the anticodon appear to be responsible for the differences in behavior of tRNAs in two- and four-codon families. We discuss the way changes in the bases in the anticodon influence both the speed and the accuracy of translation. The number of tRNA gene copies and the strength of translational selection correlate with the growth rate of the organism, as we would expect if the primary cause of translational selection in bacteria is the requirement to optimize the speed of protein production.
Improvements in health and longevity in countries such as the UK and USA have radically destabilised notions of ageing and old age. From the 19th century onwards the idea of a natural lifecourse following normatively understood stages ending in infirmity and death has been challenged by social and bio-medical developments. Breakthroughs in bio-gerontology and in bio-medicine have created the possibility of an increasingly differentiated idea of normal ageing. The potential to overcome or significantly reduce the age-associated effects of bodies growing older has led many social gerontologists to argue for a return to a more normatively based conception of ageing and old age. This paper examines and outlines the tensions between these different discourses and points out that our understanding of the norm is also fast changing as it intersects with the somatic diversity inherent in contemporary consumer society. Drawing on the theoretical work of Ulrich Beck and Zygmunt Bauman, this paper argues that the normalization of diversity leads to a reworking of the idea of normativity which in turn is reflected in profound transformations at the level of institutional arrangements and legal systems. Such changes not only lead to more discussion of what is legally and socially acceptable but also potentially lead to greater calls for regulation concerning outcomes. In this paper we argue that we need to distinguish between the newly reconfigured domains of the natural, the normal and the normative now being utilised in the understanding of ageing if we are to understand this important field of health.
The last 40 years have witnessed substantial changes to the experience of later life. Health and life expectancy have improved and the emergence of a putative third age has allowed post-working life to move beyond being a residual social category to become an arena in which later life lifestyles can be constructed. Greater emphasis is now placed on expectations of self-agency and choice. Allied to this is the growing role of consumerism as a way of organizing key aspects of social life. Not only do these changes place increased emphasis on individual responsibility for health, but they also engage individuals in various forms of health consumerism.This study draws on these aspects of contemporary society to provide an explanatory framework for understanding older peoples engagement with, and consumption of non-prescription medicines. We present a qualitative study in which we interviewed 22 men and women aged 60 plus who were purchasing or interested in purchasing non-prescription medicines, including complementary and alternative medicines. Our findings suggest that the use of non-prescription medicines is both pluralistic and makeshift. Moreover, while this pluralism led to tensions with conventional bio-medicine, conventional bio-medicine still maintained the legitimacy of its knowledge base. Self-care using non-prescription medicines appeared more governed by hope than by evidence or knowledge of the treatments concerned.We conclude that such pluralism of approach reflects the growing consumerism in health and self-care and that older people may in fact be similar to other age groups in terms of their approach to such commodification.
Pensioner political movements emerged in the interwar years in America and Europe. Documentary and empirical analyses confirm the influential role such movements played in helping shape the postwar social security systems of Western societies. Pensioner movements, qua pensioner movements, have failed to retain their influence, despite that "old age" and its demographic significance have become more salient. We propose three explanations for this: the first concerns the failure of old age to connect with the generational ethos of identity politics; the second reflects the nature of the actors now involved in the governance of old age; and the third concerns the individualization of retirement as a phase of life.
Life is based on biopolymers that have the ability to replicate themselves. Here we consider how a self-replicating RNA system may have originated. We consider a reaction system in which polymerization is possible by the addition of an activated monomer to the end of a chain. We suppose that a small fraction of polymers longer than some minimum length L have the ability to act as polymerase ribozymes. Polymerization can occur spontaneously at a slow rate and can also be catalyzed by polymerase ribozymes, if these ribozymes exist. The system contains autocatalytic feedback: increasing the polymerization rate causes the ribozyme concentration to increase, which causes the polymerization rate to further increase. For an infinite volume, the dynamics are deterministic. There are two stable states: a dead state with a very low concentration of ribozymes and a polymerization rate almost equal to the spontaneous rate, and a living state with a high concentration of ribozymes and a high rate of polymerization occurring via ribozyme catalysis. In a finite volume, such as the interior of a lipid vesicle or other small compartment, the reaction dynamics is stochastic and concentration fluctuations can occur. Using a stochastic simulation, we show that if a small number of ribozymes is initially formed spontaneously, this can be enough to drive the system from the dead to the living state where ribozyme-catalyzed synthesis of large numbers of additional ribozymes occurs. This transition occurs most easily in volumes of intermediate size.
Of the 20 amino acids used in proteins, 10 were formed in Millers atmospheric discharge experiments. The two other major proposed sources of prebiotic amino acid synthesis include formation in hydrothermal vents and delivery to Earth via meteorites. We combine observational and experimental data of amino acid frequencies formed by these diverse mechanisms and show that, regardless of the source, these 10 early amino acids can be ranked in order of decreasing abundance in prebiotic contexts. This order can be predicted by thermodynamics. The relative abundances of the early amino acids were most likely reflected in the composition of the first proteins at the time the genetic code originated. The remaining amino acids were incorporated into proteins after pathways for their biochemical synthesis evolved. This is consistent with theories of the evolution of the genetic code by stepwise addition of new amino acids. These are hints that key aspects of early biochemistry may be universal.
The arrangement of the amino acids in the genetic code is such that neighbouring codons are assigned to amino acids with similar physical properties. Hence, the effects of translational error are minimized with respect to randomly reshuffled codes. Further inspection reveals that it is amino acids in the same column of the code (i.e. same second base) that are similar, whereas those in the same row show no particular similarity. We propose a four-column theory for the origin of the code that explains how the action of selection during the build-up of the code leads to a final code that has the observed properties.
Among bacteria, we have previously shown that species that are capable of rapid growth have stronger selection on codon usage than slow growing species, and possess higher numbers of rRNA and tRNA genes. This suggests that fast-growers are adapted for fast protein synthesis. There is also considerable evidence that codon usage is influenced by accuracy of translation, and some authors have argued that accuracy is more important than speed. Here we compare the strength of the two effects by studying the codon usages in high and low expression genes and on conserved and variable sites within high expression genes. We introduce a simple statistical method that can be used to assess the significance and the strength of the two types of bias in the same sets of sequences. We compare our statistical measure of codon bias to the common used codon adaptation index, and show that the new measure is preferable for three reasons for the purposes of this analysis. Across a large sample of bacterial genomes, both effects from speed and accuracy are clearly visible, although the speed effect appears to be much stronger than the accuracy effect and is found to be significant in a larger proportion of genomes. It is also difficult to explain the correlation of codon bias in the high expression genes with growth rates and numbers of copies of tRNA and rRNA genes on the basis of selection for accuracy. Hence we conclude that selection for translational speed is a dominant effect in driving codon usage bias in fast-growing bacteria, with selection for accuracy playing a small supplementary role.
Life depends on biopolymer sequences as catalysts and as genetic material. A key step in the Origin of Life is the emergence of an autocatalytic system of biopolymers. Here we study computational models that address the way a living autocatalytic system could have emerged from a non-living chemical system, as envisaged in the RNA World hypothesis.
We discuss the origin of life in terms of an RNA World scenario in which the creation of autocatalytic sequences is the key step. Our computational models illustrate that life arises by a rare stochastic event that occurs due to spatially localized concentration fluctuations. This allows the chemical system to jump from a non-living state with very low ribozyme concentration to a living state that is controlled by ribozymes. Once the living state is established locally, it can spread deterministically through the rest of the system. These are generic features also possessed by more complex models with a greater degree of chemical realism.
A key step in the origin of life is the establishment of autocatalytic cycles controlled by biopolymer catalysts. These catalysts (either ribozymes or proteins) are composed of homochiral monomers. Homochirality in living systems is maintained because biopolymers are asymmetric in their catalysis and synthesize molecules of their own handedness. Asymmetric autocatalysis is also possible with small molecules, as demonstrated by the Soai reaction, but it is rare. As far as we know, single nucleotides and amino acids are not autocatalytic. The observation that organic molecules in meteorites can have an enantiomeric excess of a few percent suggests that the prebiotic mixture may have had a partial chiral bias that was caused by external physical influences. Here, we consider the way that such a partial prebiotic bias would influence the origin of ribozymes in an RNA world scenario. We have previously shown how a transition to a living state can occur in a model for RNA polymerization. Here, we add chirality to the problem by considering simultaneous synthesis and polymerization of left- and right-handed monomers. The two chemical synthesis rates may be equal or unequal, due to physical or chemical effects prior to the origin of life. We determine the stationary states of this reaction system. The nonliving state is racemic, or slightly biased. There are two living states that are almost completely homochiral, whether or not the nonliving state is biased. It is a feature of our model that, for some regions of parameter space, living and nonliving states are both found to be stable under the same conditions. The origin of life therefore involves a stochastic transition between the nonliving and living states. Our model extends previous theories by treating the origin of life and the origin of chirality as aspects of the same model.
When groups of related bacterial genomes are compared, the number of core genes found in all genomes is usually much less than the mean genome size, whereas the size of the pangenome (the set of genes found on at least one of the genomes) is much larger than the mean size of one genome. We analyze 172 complete genomes of Bacilli and compare the properties of the pangenomes and core genomes of monophyletic subsets taken from this group. We then assess the capabilities of several evolutionary models to predict these properties. The infinitely many genes (IMG) model is based on the assumption that each new gene can arise only once. The predictions of the model depend on the shape of the evolutionary tree that underlies the divergence of the genomes. We calculate results for coalescent trees, star trees, and arbitrary phylogenetic trees of predefined fixed branch length. On a star tree, the pangenome size increases linearly with the number of genomes, as has been suggested in some previous studies, whereas on a coalescent tree, it increases logarithmically. The coalescent tree gives a better fit to the data, for all the examples we consider. In some cases, a fixed phylogenetic tree proved better than the coalescent tree at reproducing structure in the gene frequency spectrum, but little improvement was gained in predictions of the core and pangenome sizes. Most of the data are well explained by a model with three classes of gene: an essential class that is found in all genomes, a slow class whose rate of origination and deletion is slow compared with the time of divergence of the genomes, and a fast class showing rapid origination and deletion. Although the majority of genes originating in a genome are in the fast class, these genes are not retained for long periods, and the majority of genes present in a genome are in the slow or essential classes. In general, we show that the IMG model is useful for comparison with experimental genome data both for species level and widely divergent taxonomic groups. Software implementing the described formulae is provided at http://github.com/rec3141/pangenome.
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