December 2016 Issue Table of Contents
Paradigm-changing discoveries about stellar and planetary evolution, the survival of organic molecules and microorganisms under extreme conditions, and geochemical environments on early Earth and other planets are sparking a synergistic dialogue between geoscientists, chemists, and biologists to understand how life originated. To achieve this goal, we must (i) explain the non enzymatic synthesis of biologically relevant organic molecules under geologically plausible conditions; (ii) overcome the rigid conceptual dichotomy of the “RNA world” versus the “metabolism-first” hypotheses; and (iii) develop high-throughput analytical systems to sample the myriad possible combinations of environmental conditions to find those that could initiate life. This issue of Elements highlights the roles of minerals and geochemical environments in the emergence of protocells, the cell-like entities that might have preceded the Last Universal Common Ancestor.
Keywords: mineral interfaces, RNA world, iron–sulfur world, RNA–peptide world, origin of life, protocells, metabolism
The Earth formed ~4.56 Ga and was initially a hot planet. But oceans, and perhaps even continental crust, may have existed as early as ~4.3–4.4 Ga (Wilde et al. 2001). During this period, Earth was dominated by intense komatiitic volcanism. The first gases released would have been highly reducing and contained H2, CH4 (methane), and NH3 (ammonia). Once the Earth’s core had formed, CO2, N2, and H2O then became the major volcanic outgases that subsequently formed the Earth’s atmosphere, with practically no CH4 and NH3 (Kasting et al. 1993). Earth’s water inventory may have come from volcanic outgassing and/or been delivered by comets, meteorites, and micrometeorites. Similarly, organic compounds would have been synthesized within the early atmosphere (endogenously) and delivered from space (exogenously). The ~3.8 Ga greenstones in Isua (Greenland) indicate that permanent oceans existed by that time. Primitive oceans are estimated to have been about twice as salty as modern oceans and were slightly acidic (pH ~5–6.5) during the Hadean. The date for the emergence of life is still highly debated. The scarcity of rocks from the Hadean Eon and Eoarchean Era, plus problems associated with post depositional alteration, make it difficult to pin down a precise date. A very early date of ~4.1 Ga for the origin of life is based on light carbon isotope signatures from carbon inclusions in zircons of Jack Hills, Western Australia (Bell et al. 2015). Stromatolite-like structures discovered very recently in Isua have been dated to ~3.7 Ga (Nutman et al. 2016), and bacterial microfossil-like structures have been dated at ~3.43 Ga in the Strelly Pool Sandstone Formation, Western Australia (Brasier et al. 2015). Isotopic evidence for methanotrophy and sulfate appear at the much younger ages of ~2.8 Ga to ~2.7 Ga.
Defining Life and the Protocell
The evidence to date suggests that even the most primitive life, at least as preserved in the rock record, was remarkably complex and similar to modern bacteria. Yet, there must have been some precursor cell-like entities in the pathway from simple inorganic molecules containing C, H, O, N, P, and S to bacterial cells. Discovering this transitional process is at the heart of the origin of life field. In order to simulate this process experimentally, one needs to define the characteristics of a living cell. The search for extraterrestrial life also hinges on defining what exactly life is and what biosignatures one should be looking for. But defining life has proven to be surprisingly difficult. Nevertheless, it is widely accepted that all forms of extant life are characterized by three fundamental features (Fig. 1). First, all cells should possess a lipid bilayer membrane that defines cell boundaries, allows mass- and energy-fluxes across the membrane, facilitates signaling between the cell and its environment, and serves many other essential functions. Second, a universal DNA–RNA-based apparatus acts to transmit genetic information from one generation to the next. This apparatus also has the potential to mutate, thereby allowing evolution by natural selection. Third, all cells need to possess metabolism, which may be described as cycles of enzyme-catalyzed electron-transfer reaction networks to synthesize (anabolize) and to break-down (catabolize) complex molecules (Fig. 2). These processes provide the necessary molecules and energy by which the cell can sustain itself and reproduce. Related to these three characteristic features of life are the corresponding molecular building blocks of life, namely, membrane-building phospholipids, DNA/RNA and proteins, and a variety of critical small molecules such as the adenosine phosphates.
Although it is difficult to define life, it is widely assumed that self-replicating, cell-like entities called protocells possessed all the main characteristics of cells and preceded the Last Universal Common Ancestor (aka “LUCA” – the organism from which all living organisms today descend). Today, most prokaryotes live in biofilm communities attached to mineral surfaces, so it is reasonable to assume that the mineral–water interface would have provided a nursery for protocells and that minerals played a role in the synthesis and self-assembly of the earliest protocells. Specific minerals can even be shown to play the role of certain enzymes (Fig. 1).
DNA/RNA and proteins are polymers of nucleotide monomers and of amino acids. The production of these genetic molecules involves enzymatically catalyzed polymerization of nucleotide monomers. However, the synthesis of the enzymes (catalytic proteins) and of all proteins requires DNA/RNA. The production of membrane-forming phospholipids is also enzymatically catalyzed. Thus, the origin of life is a prime example of a chicken-and-egg problem, because enzymes are needed to produce DNA/RNA, yet DNA/RNA are needed to produce proteins, including enzymes. Thus, before life originated, what molecules and minerals could have served as prebiotic catalysts for the polymerization of nucleotides and amino acids into DNA/RNA and proteins, respectively?
It is not only the polymerization of nucleotides and amino acids that is problematic. Even the preceding step involving the synthesis of monomers from much simpler starting compounds—such as N2, CO2, H2O, HCN, SO2 and H2S, which would have been present in the Hadean and early Archean atmospheres—presents an equally difficult challenge. The difficulties arise from multiple causes. First, carbon is generally in the reduced form in organic compounds, whereas it was the oxidized form of carbon in CO2 that was most likely the stable form of carbon on early Earth. Achieving sufficient reactant concentrations of reduced carbon to yield products in viable quantities under plausible geological conditions and without enzymes is difficult. Many synthesis reactions, as well as the subsequent polymerization reactions, involve condensation reactions. Another major concern is how to drive such reactions forward in aqueous solutions while preventing the degradation of the organics formed by hydrolysis in these aqueous environments. Even when polymerization has been achieved, selecting functional molecules from the huge combinatorial space of polymers to form self-sustaining and reproducing entities is daunting and is yet to be fully experimentally addressed.
Geological Processes and Geochemical Environments
The difficulty of synthesizing monomers from simple starting compounds and subsequently polymerizing them to achieve some type of functionality increases tremendously when attempting to achieve these processes under plausible early Earth geochemical environments and geological processes. For example, some chemical syntheses require very high concentrations of starting compounds and may involve several steps, such as separation and purification. What were the corresponding analogous geological processes? Evaporation, sublimation, rehydration, and others, have all been proposed. But then these processes would need to have occurred in just the right sequence and needed just the right environmental conditions that were used in the experiments (temperature, pressure, pH, etc.). Thus, it is important to consider synthetic scenarios that would be geologically plausible to capture at least a slightly more realistic situation for the origin of life.
Estimating conditions that existed on early Earth relies on the rock record from the Hadean and early Archean. But this is sparse, not least because plate tectonics recycles the crust efficiently. Nonetheless, despite much debate among geoscientists about the ranges of early Earth’s atmospheric composition, there are certain generally accepted conditions. The high partial pressure of CO2 gas on Hadean Earth would result in an acidic pH (~5–6) for surface waters. Alkaline solutions (pH ~10) would be formed in regions where peridotitic mantle was being serpentinized. Estimates for inorganic ion concentrations in such scenarios may be obtained based on thermodynamic calculations of atmosphere–water–rock interactions (Schoonen and Smirnoff 2016 this issue).
In addition to organic molecules being synthesized on Earth, organics may also have been delivered from space by meteorites and cosmic dust particles, where the synthesis would have occurred under very different environmental conditions from those on early Earth. Extreme cold temperatures, vacuum-like pressures, and high UV radiation conditions would have been present in space. And, organic molecule synthesis may also be possible under conditions on other planets and their satellites, such as Enceladus and Titan (two moons of Saturn).
RNA World versus Metabolism-first Theories
There are several “origin of life hypotheses” currently being researched, and it is worth briefly reviewing them.
Some researchers in the origin of life field believe that the synthesis of DNA is too complex to have occurred without the input of enzymes. The molecule RNA is an information-carrier, and, thus, the discovery that some RNAs can act as enzymes led to a hypothesis that early life was RNA-based (Gilbert 1986). This is the well-known “RNA world” hypothesis (Box 1).
Others have argued that even the synthesis of RNA is difficult and that prebiotic catalytic molecules must have evolved first to create reaction networks for the synthesis of the molecular building blocks. This is called the “metabolism-first” theory. The role of iron sulfide minerals and thioacids in the emergence of the earliest metabolic cycles before RNA is called the “iron–sulfur world” hypothesis (Wächtershäuser 1990). Another model proposes that the acetyl coenzyme A (acetyl-CoA) pathway linked to a chemiosmotic membrane potential provided the earliest metabolisms (Sousa et al. 2013; Russell et al. 2014; Lane 2015).
The RNA world versus metabolism-first debate has been raging for the past seven decades (Lazcano 2008). However, recent advances suggest that neither hypothesis is exclusively correct. Both RNA and other catalytic molecules may have evolved contemporaneously and, potentially, even cooperatively (Kaddour and Sahai 2014).
In this issue, three main themes are highlighted. First, the critical importance of using geochemically relevant environmental conditions plausible on early Earth for designing experiments that model the emergence and early evolution of life (Schoonen and Smirnov 2016 this issue). Second, the potential role that minerals, dissolved inorganic ions, and ion-clusters (acting as catalysts or as reactants) play in the prebiotic synthesis of the molecular building blocks of life. This complex process of going from inorganic molecules to protocells will be presented in stages. The reactions of inorganic molecules to form simple organic compounds (such as amino acids, nucleotides, sugars, single chain fatty acids, and small molecules used in metabolism) is covered in Dalai et al. (2016 this issue); Maurel and Leclerc (2016 this issue) and Belmonte and Mansy (2016 this issue) consider the next step, which involves the formation of polymers and complexes of nucleotides and peptides; and Kee and Monnard (2016 this issue) provide a perspective on the importance of encapsulation by a lipid membrane to form a protocell. Third, the need for new ways of thinking about the origin of life problem, possibly by considering that genetic and metabolic molecules evolved cooperatively and synergistically.
In general, addressing these three broad themes is essential to bridging the considerable gap that currently exists in origin of life studies between biochemists/organic chemists on the one hand and geochemists/mineralogists on the other.
Geochemical Evolution of Aqueous Solutions on Early Earth
Life has been found in almost every environmental niche on Earth. Therefore, is it possible that life could have flourished under early Earth environmental conditions as well. What were the potential aqueous solution compositions and temperatures on early Earth? The weathering of different rock types under Hadean/Archaean atmospheric compositions and the variety of ocean vent chemistries would have controlled the types of aqueous solution chemistries and the suite of secondary minerals that formed in the geological settings of the time. Particular solution chemistries and species of minerals present would have provided different environmental niches for the origin and sustainability of life. Similar conceptual approaches can be envisioned for environments on Mars and other rocky planets. When discussing the origin of life in terrestrial environments, most studies focus on subaerial and subaqueous environments; but subsurface environments and the interface between the two is often not considered. For example, the interface between the open and closed carbonate systems, provided by the hydrologic water table, is such an environment across which a chemical gradient can be maintained. Schoonen and Smirnov (2016 this issue) address these themes using equilibrium thermodynamics speciation calculations to determine aqueous solution compositions and secondary mineral assemblages under a range of environmental conditions and rock types on early Earth.
Prebiotic Sources of Simple Organic Molecules
Organic compounds had to be present before life began. Simple compounds such as N2, CO2, HCN, SO2, and H2S must have been polymerized into larger compounds with complex structures and functionality, eventually leading to their self-assembly into a protocell. What were the sources of the starting organic compounds that ultimately yielded protocells, and how could they have accumulated on early Earth? The total inventory of organics would have included both exogenous sources (cosmic dust, comets, meteorites) and endogenous sources. On Earth, organics would have been formed in the atmosphere, in solution, and at the mineral–water interface in subaerial, subaqueous, and subsurface environments.
A fascinating feature of life is its homochiral nature, and homochirality [“handedness” of molecules: laevorotatory, or L, for left-handed symmetry; dextrorotatory, or D, for right-handed symmetry] has often been assumed to be a biosignature. However, amino acids from carbonaceous chondrite meteorites also show an enrichment of L- over D-isomers, even for those amino-acids not utilized by biology. These results suggest that chiral selection may have occurred before life originated and may not be a biosignature. So, by what processes could homochirality have arisen? Dalai et al. (2016 this issue) provide an overview of the natural prebiotic sources of organics, the results of experiments that attempt to simulate exogenous and endogenous organic synthesis, and the potential mechanisms for chiral selection.
RNA, Peptides, and Minerals
As mentioned above, DNA is considered to be too complex to have been synthesized abiotically, while RNA has proven to be a versatile alternative biomolecule that, since its structural elucidation, has kept on surprising us. Indeed, RNA has characteristics similar to DNA as a genetic molecule. Furthermore, many vital cellular functions, previously thought to be exclusive to proteins, have been found to be achieved by specific types of RNA. For example, ribozymes are small RNA motifs that have catalytic activity; riboswitches are regulatory segments of messenger RNA (mRNA). These discoveries, together with several additional arguments, support the current idea that life may have originated by self-replicating RNA molecules, which preceded the DNA/RNA/protein world (Box 1).
Could minerals have shaped the ancient RNA world? Clays can catalyze the polymerization of nucleotides and amino acids to form RNA oligomers and peptides, respectively. Beyond the RNA world hypothesis, metal sulfides may have played roles such as catalyzing peptide synthesis. Peptide–RNA complexes may have been endowed with special functions, ones that either RNA alone or peptide alone could not have achieved. Maurel and Leclerc (2016 this issue) address the potential role of minerals in the synthesis and self-assembly of RNA and RNA–peptides. These authors also explore the fascinating idea that viroids—short segments of RNA found in nature as plant parasites—are a sort of molecular fossil from a former “RNA world.”
Metal Sulfides and Metallopeptides in Protometabolism
Given the very large number of prebiotic organic molecules, as well as the complexes they potentially made with metals and other organics that might have existed on early Earth, it is theoretically possible that a huge number of reaction networks could have formed. However, Morowitz and coworkers (e.g. Smith and Morowitz 2010) have recognized that modern metabolisms utilize a very small number (~300) of metabolites compared to the vast number of molecules possibly formed from random chemical combinations. Morowitz and coworkers have argued that this “sparse metabolism” reflects selection based on chemical kinetics. In this scenario, specific reactions are selected by small-molecule organocatalysts. These are distinct from transition metal–organic complex catalysts (discussed below). Some small-molecule organocatalysts are even capable of enantioselectivity [choosing between L and D molecular forms]. The reductive citric acid cycle was proposed as a core metabolism that could produce all the building blocks of life. A different perspective was offered by Virgo and Ikegami (2013) based on the results of computer algorithms of abstract model reactions. These authors showed that intersecting, branching, autocatalytic reaction networks form easily without the need for an initial catalytic molecule to be present. Virgo and Ikegami (2013) argued that the earliest metabolisms were “maximal” and that the reductive citric acid cycle, or other minimal metabolic systems, were derived by later evolution. Whereas many hypothetical schemes modeling metabolic reactions exist in the literature, experiments that simulate metabolic reactions or that couple more than one reaction into a cycle is a major challenge.
In modern metabolic pathways, the active sites of many enzymes contain organometallic complexes, in particular, iron–sulfur clusters. The metal–sulfur clusters of enzymes are structurally similar to greigite and other sulfide minerals. This similarity in structure has led to suggestions that metabolic pathways developed in the presence of sulfide minerals. The “iron–sulfur world” hypothesis and the acetyl-CoA chemiosmotic potential model propose that metabolic networks developed before RNA. Belmonte and Mansy (2016 this issue) broaden this concept to explore other metals and peptides in a scenario where various simple catalytic metallopeptide complexes may have predated more complex enzymes. By analyzing modern bacteria, these authors identified that specific peptide sequences that contain aspartic acid (aspartate) are important for binding Mg2+, Mn2+, Zn2+, and Ni2+, whereas sequences that contain cysteine (an amino acid that has a –SH side chain) are important for binding Fe2+. The identification of such peptide sequences could provide a guiding light for designing experiments to simulate ancient metabolisms.
Toward a Protocell: Assembling the Components of Life
A membrane boundary composed of amphiphilic compounds [ones that possess both hydrophilic and lipophilic properties] and that is assembled into a vesicle compartment is one of the key elements of life (Figs. 1 and 2). The membrane defines the cell as a distinct entity, separate from the environment, and plays a critical role in the production and maintenance of the chemiosmotic potential (charge and pH gradients) required to drive cellular reactions. Modern cell membranes consist primarily of phospholipid molecules, but their synthesis is enzymatically catalyzed. So, what was the chemical composition of the protocell boundary? The walls of microscopic pores between mineral grains in rocks or channels in zeolites have been proposed by some workers to act as the earliest “membranes” but these ideas haven’t been thoroughly tested experimentally. On the other hand, single-chain amphiphilic molecules have been identified in meteorites and synthesized nonenzymatically, so lipid membranes may have self-assembled in the earliest protocells. What are the physicochemical conditions for the stability of either the pore-wall membranes or amphiphile membranes? The term “stability” here refers to membrane formation and its ability to sustain integrity over some relevant period of time (i.e. membranes needed the right balance of leakiness versus impermeability to allow molecules and electrons to pass across the membrane to generate electrochemical gradients long enough for the relevant metabolic reactions). How would the organics encapsulated within either of these types of membranes have evolved into a complex network to give birth to a sustainable protocell? Could minerals have played a role in all these processes? Kee and Monnard (2016 this issue) address these important questions and discuss the critical need of a protocell boundary to form self-sustaining, replicating, cell-like entities.
Synergism and Mutalism in the Emergence of Life
Significant advances have been made over the past decade in our understanding of the simple organic molecule–mineral interactions that yield more complex organic molecules (Cleaves et al. 2012). We presently also benefit from a much-improved knowledge of early Earth environments (Sleep et al. 2011). In addition, experiments have shown that specific minerals can play some key roles as “prebiotic enzymes.” For example, montmorillonite can catalyze the formation of RNA polymers (Ferris 2005) and of peptides (Rode 1999); sphalerite (ZnS) can photocatalyze parts of the reverse citric acid cycle (Zhang and Martin 2006). Minerals can also enhance the initial assembly rate of amphiphiles into vesicles, ultimately leading to the formation of a protocell membrane (Hanczyc et al. 2003). The latter finding was recently confirmed in our laboratory and we further showed that the rate-enhancement is dependent on the surface charge of the mineral. Additionally, we found that vesicles were not disrupted by high particle loadings and they can even adsorb intact on a mineral surface (Fig. 3; Sahai et al. 2017). Together, these results suggest that minerals should be given more attention in the context of the emergence of life.
That being said, a careful analysis of the literature raises interesting questions. For instance, in the pioneering work of Prof. James P. Ferris (Rensselaer Polytechnic, New York, USA) and colleagues, only chemically pre-activated monomers were used to react and polymerize into RNA oligomers; even though it is unlikely that such activated nucleotides can be spontaneously generated in prebiotically relevant conditions. Moreover, the yields of these RNA oligomers are rather low, barely enough to be characterized by the most sensitive techniques. Recent efforts have showed that nonenzymatic RNA polymerization can be alternatively achieved by using nonactivated monomers (Šponer et al. 2016).
Taken together, these findings have led to the idea that synergism between different catalysts might come into play to enhance the nonenzymatic RNA polymerization of nonactivated nucleotides (Fig. 4) (Kaddour and Sahai 2014).
Multicomponent Systems and Predictive Relationships
It is obvious that nature cannot be minimized to a single-component system in a clean test tube. The results of experiments aimed at understanding the prebiotic synthesis and self-assembly of organics would be significantly more relevant in a multicomponent system. Thus, in an ideal experiment, the molecular building blocks of life should be present along with the minerals and dissolved inorganic ions known to exist in specific geological environments on early Earth. Recent attempts towards a one-pot reaction approach have been successful in the synthesis of lipid monomers, amino acids, and nucleotides (Patel et al. 2015). It would also be a remarkable achievement to expand this approach to the emergence of a sustainable protocell. In this regard, researchers have been synthesizing chemical systems where nonenzymatic RNA polymerization occurs in model protocells (Szostak 2012). With these significant advances, evaluating the potential complicating effects of inorganic ions, pH, and temperature in a multicomponent system should now be considered as next steps towards integrating chemistry and biology with geology.
Exploring a wider range of environmental conditions are hampered by difficulties in experimental design and analytical sensitivity. For example, it can be difficult to analyze reactants and products within model protocell membranes (amphiphile vesicles). This is especially the case in experiments involving mineral suspensions, which tend to aggregate and settle, thereby minimizing interactions with the other components. Furthermore, most reactions are done in batch systems, and geological processes such as fluid flow and wave action are hardly ever simulated in the experimental design. High-throughput analytical methods are sorely needed to test the huge combinatorial search space that must be explored in order to more faithfully simulate geological conditions. Careful examination of a wide range of conditions will ultimately allow the development of predictive relationships. For example, the initial rate of vesicle self-assembly at mineral surfaces has been found to be dependent on the isoelectric point (surface-charge) of the mineral and on the degree of aggregation of mineral nanoparticles (Sahai et al. 2017). Such relationships may allow us to predict the plausibility of protocell membrane self-assembly both terrestrially and extraterrestrially.
The ultimate challenge in the origin of life field is to understand how complex, functional organic molecules were produced from simple inorganic molecules and how such molecules self-assembled into self-sustaining, self-replicating cell-like entities under plausible environmental conditions on early Earth. This means understanding the transition from geochemistry to biogeochemistry. Traces of environmental conditions on early Earth are preserved in the isotope and element signatures of rare Hadean- and Eoarchean-age minerals and rocks, but the molecular pathways from simple inorganic compounds to cells cannot be retraced with complete fidelity. Nevertheless, chemical pathways that rigorously satisfy scientific rationale can be reasonably inferred based on the results of models and experiments that are informed by our knowledge of the biochemistry of modern life and of early Earth’s environmental conditions. We hope that the present issue of Elements illuminates the state-of-the-art in the field, indicates challenging areas for future inquiry, and inspires scientists to adopt interdisciplinary approaches towards uncovering one of the most profound questions in philosophy and science.
The authors are grateful to Dr. Min Gao, Liquid Crystal Institute, Kent State University for the cryo-TEM images and to Dr. Weilong Zhao for coloring the banner image. N. S. and H. K. would like to thank the authors of the invited articles in this issue as well as the reviewers of the manuscripts for their invaluable contributions to this issue. Patricia Dove and Jodi Rosso are thanked for their editorial insights. Nita Sahai gratefully acknowledges financial support from the following grants: NSF EAR Geobiology and Low-Temperature Geochemistry #1251479; the Simons Collaboration on the Origins of Life (SCoL) award #290359 from the Simons Foundation, NY; and “startup” funds from the University of Akron.
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