Setting the stage: the history, chemistry, and geobiology behind RNA

No community-accepted scientific methods are available today to guide studies on what role RNA played in the origin and early evolution of life on Earth. Further, a definition-theory for life is needed to develop hypotheses relating to the "RNA First" model for the origin of life. Four approaches are currently at various stages of development of such a definition-theory to guide these studies. These are (a) paleogenetics, in which inferences about the structure of past life are drawn from the structure of present life; (b) prebiotic chemistry, in which hypotheses with experimental support are sought that get RNA from organic and inorganic species possibly present on early Earth; (c) exploration, hoping to encounter life independent of terran life, which might contain RNA; and (d) synthetic biology, in which laboratories attempt to reproduce biological behavior with unnatural chemical systems.     

Origins of Life: Chemical and Philosophical Approaches

In this article we address selected important milestones of chemical evolution that led to life. The first such milestone could be achieved by Oparin’s model, which accounts for the early stages of chemical evolution. These occurred at the dawn of development of primitive chemical systems that were pre-RNA. Oparin’s model consists of spontaneous formation of coacervates that encapsulate chemical matter, undergo primitive self-replication, and provide a pathway to a primitive metabolism. We review the experimental updates of his model from our laboratory and discuss types of selection that could have occurred in these primitive systems. Another major milestone in chemical evolution is the transition from abiotic to biotic. This has occurred later, after the RNA world evolved. A controversy of what life is interferes with the efforts to elucidate this transition. Thus, we present various definitions of life, some of which specifically include the requirements and mechanisms for this transition. Self-replication is one of the major requirements for life. In this context we re-examine the question if viruses, which do not have capability to self-replicate, are alive. We draw on philosophy of Hegel, Aristotle, Rescher, Priest, and Fry to guide us in our endeavors. Specifically, we apply Hegel’s law on quantity-to-quality transition to abiotic-to-biotic transition, Aristotle’s philosophy to the definition of life, Priest’s dialetheism to the question if viruses are alive or not, Fry’s philosophy to the beginning of natural selection in chemical evolution, and Rescher’s philosophy to the possible cognitive bias toward simple definitions of life.     

Modern mRNA proofreading and repair: clues that the last universal common ancestor possessed an RNA genome?

RNA repair has now been demonstrated to be a genuine biological process and appears to be present in all three domains of life. In this article, we consider what this might mean for the transition from an early RNA-dominated world to modern cells possessing genetically encoded proteins and DNA. There are significant gaps in our understanding of how the modern protein-DNA world could have evolved from a simpler system, and it is currently uncertain whether DNA genomes evolved once or twice. Against this backdrop, the discovery of RNA repair in modern cells is timely food for thought and brings us conceptually one step closer to understanding how RNA genomes were replaced by DNA genomes. We have examined the available literature on multisubunit RNA polymerase structure and function and conclude that a strong case can be made that the Last Universal Common Ancestor (LUCA) possessed a repair-competent RNA polymerase, which would have been capable of acting on an RNA genome. However, while this lends credibility to the proposal that the LUCA had an RNA genome, the alternative, that LUCA had a DNA genome, cannot be completely ruled out.     

The roads to and from the RNA world

The historical existence of the RNA world, in which early life used RNA for both genetic information and catalytic ability, is widely accepted. However, there has been little discussion of whether protein synthesis arose before DNA or what preceded the RNA world (i.e. the pre-RNA world). We outline arguments of what route life may have taken out of the RNA world: whether DNA or protein followed. Metabolic arguments favor the possibility that RNA genomes preceded the use of DNA as the informational macromolecule. However, the opposite can also be argued based on the enhanced stability, reactivity, and solubility of 2-deoxyribose as compared to ribose. The possibility that DNA may have come before RNA is discussed, although it is a less parsimonious explanation than DNA following RNA.     

The RNA worlds in context

There are two RNA worlds. The first is the primordial RNA world, a hypothetical era when RNA served as both information and function, both genotype and phenotype. The second RNA world is that of today's biological systems, where RNA plays active roles in catalyzing biochemical reactions, in translating mRNA into proteins, in regulating gene expression, and in the constant battle between infectious agents trying to subvert host defense systems and host cells protecting themselves from infection. This second RNA world is not at all hypothetical, and although we do not have all the answers about how it works, we have the tools to continue our interrogation of this world and refine our understanding. The fun comes when we try to use our secure knowledge of the modern RNA world to infer what the primordial RNA world might have looked like.     

A ribonucleopeptide world at the origin of life

The structural flexibility of RNA and its ability to store genetic information has led scientists to postulate that RNA could be the key molecule for the development of life on Earth, further leading to formulate the RNA world hypothesis that received a lot of success and acceptance after the discoveries of the last thirty‐five years. Despite its highly structural and functional significance, the difficulty in synthesizing the four nucleobases that form the RNA polymer from the same primordial soup, its low stability, and limited catalytic repertoire, make the RNA world hypothesis less convincing even though it remains the best explanation for the origin of life. An increasing number of scientists are becoming more supportive of a more realistic approach explaining the appearance of life. In this review, I propose an enhanced explanation for the appearance of life supported by recent discoveries and theories. Accordingly, amino acids and peptides associated with RNA (e.g., ribonucleopeptides) might have existed at the onset of RNA and might have played an important role in the continuous development of self‐sustaining biological systems. Therefore, in this review, I cover the most recent and relevant scientific investigations that propose a better understanding of the ribonucleopeptide world hypothesis and the appearance of life. Finally, I propose two hypotheses for a primitive translation machinery (PTM) that might have been formed of either a T box ribozyme or a ribopolymerase.     

RNA catalysis: ribozymes, ribosomes, and riboswitches

The catalytic mechanisms employed by RNA are chemically more diverse than initially suspected. Divalent metal ions, nucleobases, ribosyl hydroxyl groups, and even functional groups on metabolic cofactors all contribute to the various strategies employed by RNA enzymes. This catalytic breadth raises intriguing evolutionary questions about how RNA lost its biological role in some cases, but not in others, and what catalytic roles RNA might still be playing in biology.     

Peptide nucleic acids and the origin of life

The possibilities of pseudo-peptide-DNA mimics like PNA (peptide nucleic acid) having a role for the prebiotic origin of life prior to an RNA world is discussed on the basis of literature data showing that this type of molecules might have formed on the primitive earth (or other places in the universe), as well as data indicating the possibilities of template-directed PNA chemical replication and ligation. In particular, the merits of an achiral prebiotic genetic material is discussed.     

Planetary Organic Chemistry and the Origins of Biomolecules

Organic chemistry on a planetary scale is likely to have transformed carbon dioxide and reduced carbon species delivered to an accreting Earth. According to various models for the origin of life on Earth, biological molecules that jump-started Darwinian evolution arose via this planetary chemistry. The grandest of these models assumes that ribonucleic acid (RNA) arose prebiotically, together with components for compartments that held it and a primitive metabolism that nourished it. Unfortunately, it has been challenging to identify possible prebiotic chemistry that might have created RNA. Organic molecules, given energy, have a well-known propensity to form multiple products, sometimes referred to collectively as “tar” or “tholin.” These mixtures appear to be unsuited to support Darwinian processes, and certainly have never been observed to spontaneously yield a homochiral genetic polymer. To date, proposed solutions to this challenge either involve too much direct human intervention to satisfy many in the community, or generate molecules that are unreactive “dead ends” under standard conditions of temperature and pressure. Carbohydrates, organic species having carbon, hydrogen, and oxygen atoms in a ratio of 1:2:1 and an aldehyde or ketone group, conspicuously embody this challenge. They are components of RNA and their reactivity can support both interesting spontaneous chemistry as part of a “carbohydrate world,” but they also easily form mixtures, polymers and tars. We describe here the latest thoughts on how on this challenge, focusing on how it might be resolved using minerals containing borate, silicate, and molybdate, inter alia.Interesting organic chemistry occurs throughout the cosmos, including in presolar nebulae (see the article in this collection by Pascale Erhrenfreund), asteroidal bodies (see the article in this collection by Sandra Pizzarello) and icy bodies near the outer boundary of our solar system (Bernstein et al. 2002). Although organic molecules made in off-Earth locales almost certainly contributed to the reduced carbon inventory on Earth before life emerged, planetary processing on Earth undoubtedly also contributed to the inventory of prebiotic molecules that were available to life as it originated (assuming that Earth was the site of life''s origin). Indeed, in the RNA first model for the origin of life on Earth (Joyce and Orgel 1999)(Benner 2009), it is often proposed that terran-based chemistry produced RNA in oligomeric form to initiate Darwinian evolution.How are we to constrain models for planetary processing to converge on a model for what actually happened on Earth four billion years ago? Today, atmospheric dioxygen (O₂) readily converts organic materials to carbon dioxide, making it essentially impossible to observe such processing on the surface of Earth. Furthermore, the ubiquity of life on modern Earth means that any organic processing is more likely to reflect biology than prebiology. The closest we may come today to observe organic transformations absent biology on a planetary scale might be on Titan, a moon of Saturn whose atmosphere and surface is rich in reduced carbon.Nevertheless, it is possible to apply a general understanding of organic chemical reactivity to suggest chemical reactions that might have occurred on early Earth and the products that they might have produced. These suggestions are constrained by models for the atmosphere and mineralogy of early Earth, although these constraints might change as models improve.In this article, we assume that the atmosphere of early Earth was less oxidizing than today''s atmosphere, although not as rich in methane as the simulated atmosphere used in the classic experiments of Stanley Miller (Miller 1955). Further, we assume that the atmosphere on early Earth had access to many sources of energy. These include electrical discharge, ultraviolet and visible light (although the Sun was almost certainly dimmer then than now, a Titan-like haze may have prevented high energy photons from reacting the Earth''s surface), volcanism (providing not only heat but also reactive species and mixtures not at thermodynamic equilibrium), ionizing radiation, and impacts. (See Pizzarello and Shock 2010 for a discussion of such energy sources.)We also assume that life emerged after the planet underwent a geological fractionation in which heavier minerals and elemental iron sank towards the core, leaving lighter rocks to form the crust. Open questions concern the inventory of water relative to the surface of early Earth, an inventory that determined whether planetary organic transformations might have occurred on dry land or below water on a planetary surface that was totally submerged.     

In the Beginning was a Mutualism - On the Origin of Translation

The origin of translation is critical for understanding the evolution of life, including the origins of life. The canonical genetic code is one of the most dominant aspects of life on this planet, while the origin of heredity is one of the key evolutionary transitions in living world. Why the translation apparatus evolved is one of the enduring mysteries of molecular biology. Assuming the hypothesis, that during the emergence of life evolution had to first involve autocatalytic systems which only subsequently acquired the capacity of genetic heredity, we propose and discuss possible mechanisms, basic aspects of the emergence and subsequent molecular evolution of translation and ribosomes, as well as enzymes as we know them today. It is possible, in this sense, to view the ribosome as a digital-to-analogue information converter. The proposed mechanism is based on the abilities and tendencies of short RNA and polypeptides to fold and to catalyse biochemical reactions. The proposed mechanism is in concordance with the hypothesis of a possible chemical co-evolution of RNA and proteins in the origin of the genetic code or even more generally at the early evolution of life on Earth. The possible abundance and availability of monomers at prebiotic conditions are considered in the mechanism. The hypothesis that early polypeptides were folding on the RNA scaffold is also considered and mutualism in molecular evolutionary development of RNA and peptides is favoured.     

Question 5: On the Chemical Reality of the RNA World

The discovery of catalytic RNA has revolutionised modern molecular biology and bears important implications for the origin of Life research. Catalytic RNA, in particular self-replicating RNA, prompted the hypothesis of an early “RNA world” where RNA molecules played all major roles such information storage and catalysis. The actual role of RNA as primary actor in the origin of life has been under debate for a long time, with a particular emphasis on possible pathways to the prebiotic synthesis of mononucleotides; their polymerization and the possibility of spontaneous emergence of catalytic RNAs synthesised under plausible prebiotic conditions. However, little emphasis has been put on the chemical reality of an RNA world; in particular concerning the chemical constrains that such scenario should have met to be feasible. This paper intends to address those concerns with regard to the achievement of high local RNA molecules concentration and the aetiology of unique sequence under plausible prebiotic conditions. Presented at: International School of Complexity – 4th Course: Basic Questions on the Origins of Life; “Ettore Majorana” Foundation and Centre for Scientific Culture, Erice, Italy, 1–6 October 2006.     

Riboswitch effectors as protein enzyme cofactors

The recently identified glmS ribozyme revealed that RNA enzymes, like protein enzymes, are capable of using small molecules as catalytic cofactors to promote chemical reactions. Flavin mononucleotide (FMN), S-adenosyl methionine (SAM), adenosyl cobalamin (AdoCbl), and thiamine pyrophosphate (TPP) are known ligands for RNA riboswitches in the control of gene expression, but are also catalytically powerful and ubiquitous cofactors in protein enzymes. If RNA, instead of just binding these molecules, could harness the chemical potential of the cofactor, it would significantly expand the enzymatic repertoire of ribozymes. Here we review the chemistry of AdoCbl, SAM, FMN, and TPP in protein enzymology and speculate on how these cofactors might have been used by ribozymes in the prebiotic RNA World or may still find application in modern biology.     

Viroids

Viroids are small, circular RNA pathogens, which infect several crop plants and can cause diseases of economic importance. They do not code for proteins but they contain a number of RNA structural elements, which interact with factors of the host. The resulting set of sophisticated and specific interactions enables them to use the host machinery for their replication and transport, circumvent its defence reactions and alter its gene expression. Although found in plants, viroids have a distant relative in the animal world: hepatitis delta virus (HDV), a satellite virus of hepatitis B virus, which has a similar rod-like structure and replicates in the nucleus of infected cells. Viroids have also a cellular relative: the retroviroids, found in some plants as independent (non-infectious) RNA replicons with a DNA copy. In this review, we summarize recent progress in understanding viroid biology. We discuss the possible role of recently identified viroid-binding host proteins as well as the recent data on the interaction of viroids with one part of the host's defence machinery, the RNA-mediated gene silencing and how this might be connected to viroid replication and pathogenicity.     

The RNA world hypothesis: the worst theory of the early evolution of life (except for all the others)

ABSTRACT: The problems associated with the RNA world hypothesis are well known. In the following I discuss some of these difficulties, some of the alternative hypotheses that have been proposed, and some of the problems with these alternative models. From a biosynthetic - as well as, arguably, evolutionary - perspective, DNA is a modified RNA, and so the chickenand- egg dilemma of "which came first?" boils down to a choice between RNA and protein. This is not just a question of cause and effect, but also one of statistical likelihood, as the chance of two such different types of macromolecule arising simultaneously would appear unlikely. The RNA world hypothesis is an example of a 'top down' (or should it be 'present back'?) approach to early evolution: how can we simplify modern biological systems to give a plausible evolutionary pathway that preserves continuity of function? The discovery that RNA possesses catalytic ability provides a potential solution: a single macromolecule could have originally carried out both replication and catalysis. RNA - which constitutes the genome of RNA viruses, and catalyzes peptide synthesis on the ribosome - could have been both the chicken and the egg! However, the following objections have been raised to the RNA world hypothesis: (i) RNA is too complex a molecule to have arisen prebiotically; (ii) RNA is inherently unstable; (iii) catalysis is a relatively rare property of long RNA sequences only; and (iv) the catalytic repertoire of RNA is too limited. I will offer some possible responses to these objections in the light of work by our and other labs. Finally, I will critically discuss an alternative theory to the RNA world hypothesis known as 'proteins first', which holds that proteins either preceded RNA in evolution, or - at the very least - that proteins and RNA coevolved. I will argue that, while theoretically possible, such a hypothesis is probably unprovable, and that the RNA world hypothesis, although far from perfect or complete, is the best we currently have to help understand the backstory to contemporary biology. Reviewers This article was reviewed by Eugene Koonin, Anthony Poole and Michael Yarus (nominated by Laura Landweber).     

RNA viruses in the sea

Viruses are ubiquitous in the sea and appear to outnumber all other forms of marine life by at least an order of magnitude. Through selective infection, viruses influence nutrient cycling, community structure, and evolution in the ocean. Over the past 20 years we have learned a great deal about the diversity and ecology of the viruses that constitute the marine virioplankton, but until recently the emphasis has been on DNA viruses. Along with expanding knowledge about RNA viruses that infect important marine animals, recent isolations of RNA viruses that infect single-celled eukaryotes and molecular analyses of the RNA virioplankton have revealed that marine RNA viruses are novel, widespread, and genetically diverse. Discoveries in marine RNA virology are broadening our understanding of the biology, ecology, and evolution of viruses, and the epidemiology of viral diseases, but there is still much that we need to learn about the ecology and diversity of RNA viruses before we can fully appreciate their contributions to the dynamics of marine ecosystems. As a step toward making sense of how RNA viruses contribute to the extraordinary viral diversity in the sea, we summarize in this review what is currently known about RNA viruses that infect marine organisms.     

Niche shift in invasive species: is it a case of “home away from home” or finding a “new home”?

In recent years, there has been a rather acrimonious debate on matters concerning the biology of invasive species, some as fundamental as the definition and what constitutes an invasive species. However, an abiding commonality of all invasive species is the fact that they have all moved away from their native ranges to newer and often non-native ranges. In plants, Lantana camara has shifted from its native South American range distribution to most other parts of the world. In animals, the African giant snail has dispersed from Africa to most parts of Asia. What do such niche shifts signify about the nature and quality of the habitats to which the invasive species have moved? In this paper, using the classical niche paradigm, we analyse if niche shifts of thirty-three of the world’s top invasive species constitute just moving from one habitat to another similar habitat somewhere on the earth (home away from home) or that they have moved to totally new habitats (different from their native home). Surprisingly, our results show that for 90% of the world’s top invasive species, movements have been largely restricted to homes away from home, rather than into alien homes. This clearly indicates the potential inertia that species might face in moving out of their fundamental niche. We discuss these results in the context of the overall debate on invasion biology and how niche conservatism may have played a role in dampening the rates of invasion.

     

On the evolution of cellular senescence

The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age‐related diseases and extends the life span of mice. While efforts proceed to make therapeutic use of such discoveries, it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence, in order better to understand the biology that we might seek to alter. Cellular senescence is often regarded as an anti‐cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. This is difficult to reconcile with the simple idea of an anti‐cancer mechanism. Furthermore, other studies have shown that cellular senescence is involved in wound healing and tissue repair. Here, we bring these findings and ideas together and discuss the possibility that these functions might be the main reason for the evolution of cellular senescence. Furthermore, we discuss the idea that senescent cells might accumulate with age because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).