The RNA World: molecular cooperation at the origins of life.

Abstract

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.

Key points

• Research into the RNA World paradigm is active, and new discoveries in synthetic organic chemistry and biochemistry routinely provide new insights.
• The field of prebiotic chemistry is increasingly discovering phenomena that provide solutions to multiple (as opposed to single) problems simultaneously.
• A key issue in RNA World research is how RNAs might have made copies of themselves (that is, how they replicated). There are now several possible mechanisms of this process, and increasing focus is being placed on those that display autocatalytic feedback.
• Cooperation among various molecules was probably a key aspect of the RNA World, and at least three types of molecular cooperation could have been at play during the origins of life.
• Chemical alternatives to RNA per se may have existed at some point in the Earth's earliest history, and many efforts are underway to find and evaluate such structures.
• Network establishment was another process that had a large impact on the organization of the living state, from small molecules to large molecules and cell-like structures.

Introduction

 

The RNA World is the conceptual idea that there was a period in the early history of life on Earth when RNA, or something chemically very similar, carried out most of the information processing and metabolic transformations needed for biology to emerge from chemistry. This scenario, if it indeed existed, took place some 4 billion years ago. By contrast, the realization that RNA is a good candidate for the emergence of life is an idea that is only ~50 years old. It was recognized early on by Crick¹, Orgel² and others that RNA has both a genotype and a phenotype, and that a system based on RNA would be a plausible precursor to the much more complex system of DNA–RNA–proteins on which current life is based. It was also realized that the ribonucleotide coenzymes now used by many proteins may be molecular 'fossils' from an RNA-based metabolism³. Discoveries of naturally occurring ribozyme catalysts, such as self-splicing introns⁴ and the ribonuclease P catalyst⁵, were made in the 1980s and, with the demonstration that ribosomal RNA catalyses peptide bond formation in the ribosome⁶, the credentials of RNA as a catalyst became firmly established.

 

Spiegelman's classic experiments with the bacteriophage Qβ showed how viral RNA could evolve over time in response to selection⁷. This study gave rise to the field of in vitro evolution⁸ by demonstrating that RNA could behave in a Darwinian manner in the absence of cells. Once this realization has been made, pioneers such as Orgel⁹, Eigen¹⁰, Joyce^{11, 12}, Gold¹³ and Szostak¹⁴ fully demonstrated the evolutionary capabilities of RNA and made it difficult to ignore the possibility that life started with RNA. However, additional pieces of data from both new and old angles then became available. The catalytic repertoire of RNA was shown to be diverse¹⁵, RNA riboswitches were detected in bacteria and shown to be widespread in biology¹⁶, and an autocatalytic cycle based on RNA ligases was found¹⁷. Furthermore, polymerase ribozymes that can use another sequence as a template were selected and improved^{18, 19, 20} (see below).

 

Different research questions are gradually being brought together to assemble a complete picture of the emergence of life via the RNA World scenario (Fig. 1). New routes of chemical synthesis of ribonucleotides that could operate prebiotically are being studied, and there are also further experiments to isolate ribozymes from random RNA sequences. These areas are reviewed below. Theoretical models of RNA action are being developed to describe the origin and evolution of replicating systems. A point that emerges both from theoretical work and from laboratory experiments is that cooperation at the molecular level is essential for the survival of replicating sequences. A key aim of this Review is to describe the different senses in which cooperation is relevant in the RNA World. We argue that RNA replication must also fit into a broader thermodynamic and biological context if this were to form the basis of life (Fig. 1). What was the energy source that drove the synthesis of large macromolecules on early Earth? What were the environmental conditions at the location where these molecules were forming? How did RNA replication become associated with growth and division of protocells? Current ideas on some of these questions are considered later in this Review.

 

Figure 1: Research in different fields is coming together to assemble a more complete picture of the way the RNA World began and operated.

a | Progress in organic chemistry helps to show how nucleotides and RNA oligomers could have been synthesized before life. b | In vitro evolution studies discover functional ribozymes in the very large RNA sequence space. c | Theoretic…

 

Figure 2: RNA polymerases as altruistic cooperators.

 

a | A trans-acting RNA polymerase (or replicase) such as the R18 polymerase¹⁸ is a likely mechanism for supporting replication in the RNA World. b | Such a polymerase can use a template that is either another copy of itself (red) or an unrelated sequence (grey). Well-mixed systems of altruistic replicators are destroyed by parasites. There are two ways in which cooperators can resist parasites. c | First, survival of replicases is possible in two-dimensional models on surfaces. A simulation of altruistic replicators (red) diffusing on a surface in the presence of parasites (grey) demonstrates survival of the replicators as a result of spatial clustering⁸². d | Second, when small groups of molecules are packaged in compartments, group selection can occur. Functional RNAs (red and blue) are shown replicating in a protocell compartment in the presence of parasites (grey). Random segregation creates cells of varying composition. Cells with an excess of parasites are unviable, and this prevents parasites from over-running the system, even if the parasites multiply at a higher rate within a cell. Part a reproduced from Ref. 50, Nature Publishing Group. Part c reprinted from J. Theor. Biol., Vol. 364, Shay, J. A., Huynh, C. & Higgs, P. G., The origin and spread of a cooperative replicase in a prebiotic chemical system, 249–259, Copyright (2014), with permission from Elsevier.

 

Figure 3: Different senses of molecular cooperation.

 

a | Cooperation in networks of mutually dependent strands with different functions is shown. An autocatalytic set involves precursor molecules present in the environment (blue circles) and molecules synthesized by the cycle (green circles). Each reaction (red triangles) is catalysed by a molecule that is part of the set (dashed arrows). b | An autocatalytic set composed of two cross-catalytic ligases¹⁷ is shown. RNA A and RNA B are ligated together by ribozyme E′ to create ribozyme E, which can reciprocate and ligate RNA A′ and RNA B′ to create ribozyme E′. c |Cooperation between multiple strands that assemble to perform a single function is shown. Ribozymes, such as the Azoarcus recombinase⁵⁷, can be made from several short strands that assemble as a result of RNA secondary structure formation and information contained in internal guide sequences (IGSs) and complementary targets (grey). d | While strands can cooperate to form ribozymes, these ribozymes can then potentially cooperate at an even higher level to construct an autocatalytic set, such as a three-membered cycle⁶⁰. In this scheme, the Azoarcus ribozyme is fragmented into two pieces in three different ways (that is, at three different junctions). The IGS of the ribozyme in E₁ is adjusted in such a way that it can only covalently assemble the E₂ ribozyme and so on, such that for assembly of all the ribozymes an obligatory cooperative process must (and does) occur. Part b from Lincoln, T. A. & Joyce, G. F. Self-sustained replication of an RNA enzyme. Science 323, 1229–1232 (2009). Reprinted with permission from AAAS. Parts c and d adapted from Ref. 60, Nature Publishing Group.

Conclusions and perspectives

 

Contemporary studies both in the laboratory and by simulation are beginning to reveal the cooperative nature of the RNA World, as well as how various types of cooperation and conflict probably guided the earliest evolutionary processes. The basics of the RNA World concept are well established, but the details continue to evolve. A powerful theme has begun to emerge from many of these new approaches and their results. One way to describe this is systems chemistry¹⁰⁰. By focusing not on single reactions in isolation but on the collective set of processes that must all occur contemporaneously, systems chemistry can lead to the discovery of 'multi-fers' in which the system as a whole can establish itself through the shared use of common conditions, reactants or products. Another way to look at this process, one that we highlighted in this Review, is that of chemical cooperation (Box 1). This newer view, embedded in the broader perspective of intermolecular cooperation and conflict, is pervading other aspects of study of the RNA World, as we explored above.

 

Key questions for the next decade of research include the following. How long were the first ribozymes? In other words, what is the extent of the error threshold problem? How specific were the first ribozymes? Was life sparked by a single polymerase or a random autocatalytic set? How far can the RNA World go without being encapsulated in a cell, or were there cells already at the earliest stage? What was the energy source for the RNA World? Thus, how was it possible to link a stable energy supply to a metabolic synthesis of RNA? The RNA World idea emphasizes replication, but thermodynamic driving force is still needed for synthesis. We anticipate that the answers to many of these questions will not only be within our conceptual reach in the next decade or two, but will also invoke the insights gained from a more systematic appreciation of how conflict and cooperation can influence molecular processes. 

Nature Reviews Genetics | Review
Article series: Non-coding RNA
Paul G. Higgs^1, & Niles Lehman^2,

Year published (2014)