Commentary pubs.acs.org/accounts
Giving Rise to Life: Transition from Prebiotic Chemistry to Protobiology Published as part of the Accounts of Chemical Research special issue “Holy Grails in Chemistry”. Ramanarayanan Krishnamurthy* The Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States ABSTRACT: The challenge of a chemical approach to the origins of life problem involves comprehending the transition from prebiotic chemistry to protobiology. This endeavor demands demonstrating the metamorphosis of a diverse pool of prebiotic building blocks (heterogeneous heterogeneity) into a conglomerate self-assembling system (homogeneous heterogeneity) capable of evolution.
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which may seem utopian and presumptuous, namely to know why nature is such and not otherwise”.2 Looking at the origins of life scenario, one has to come to terms with the most difficult and central aspect of the problem: how does a heterogeneous and diverse mixture of source chemicals and building blocks come together in specific ways (prebiotic chemistry) to give rise to more complex chemical entities, which then transform themselves into homogeneous polymers that function and evolve through heterogeneous interaction with other small and macromolecules (protobiology)? How do the heterogeneous interactions of a diverse collection of heterogeneous molecules (“heterogeneous heterogeneity”: amino acids, sugars, nucleobases, phosphates, fatty acids, small molecules, and metal ions) metamorphose to heterogeneous interactions of a collection of homogeneous supramolecular entities (“homogeneous heterogeneity”: proteins, polysaccharides, nucleic acids, and bilayer lipids) capable of function and evolution? Historically, each of the heterogeneous heterogeneity interactions have been simplified experimentally to deal with the formation of only one class of compounds.3 Prebiotic formation of amino acids and oligopeptides were addressed separately from the formation of the building blocks of nucleic acids and oligonucleotides, while formation of sugars was investigated separately, as was the formation of fatty acids (Figure 1), and most of the time isolated from early earth environmental constraints. While these “clean and isolated” approaches allowed for straightforward hypotheses and
ow life arose on Earth is one of the most enduring puzzle that embraces all fields and disciplines and can be considered a “Holy Grail”. It is a challenge, particularly to the chemical scientific community, to decipher the fundamental secrets that are locked in the nature of the building blocks of life: atoms, molecules, their reactions, and the details of the transition that led to that emergent property called life. While an exact historical account of how life originated on Earth is not a realistic goal, due to the lack of “chemical fossils” and uncertainties associated with details of early Earth’s physicochemical environment, the origins of life studies have benefited enormously from the systematic scientific investigations that have given rise to wide variety of possible solutions for the prebiotic origins of various classes of biological building blocks and their respective biopolymers.1 This has allowed the scientific community to move forward and approach the problem from a different viewpoint, which is the central challenge: to provide experimental demonstrations that “life” can emerge from the self-assembly of molecules and networks of chemical transformations. Implicit in this challenge are the following questions: (a) can we define what life is, and (b) can we create artificial chemical life? While a consensus on the operational definition of “life” is yet to be achieved, the experimental demonstration of “synthetic life” is an achievable goal. Creation of artificial chemical life would be in itself a grand achievement; moreover, it will allow a comparison with natural life that can lead to an in-depth understanding that would not be accessible from studying natural-life alone. Albert Einstein aptly summed it up using nature as a proxy for life: “We not only want to know how nature is (and how her transactions are carried through), but also want to reach, if possible, a goal © 2017 American Chemical Society
Received: September 18, 2016 Published: March 21, 2017 455
DOI: 10.1021/acs.accounts.6b00470 Acc. Chem. Res. 2017, 50, 455−459
Commentary
Accounts of Chemical Research
Figure 1. Worlds apart. Historically, the prebiotic generation of the different classes of biomolecules has been dealt separately from each other. Reliance on extrapolating extant biological pathways backward, based on the principle of parsimony, leads to some of these “worlds” inventing the other classes of molecules, which are lacking in their own respective worlds. The ‘?’ refers to other satellites that may be needed to help these worlds exist and to “evolve”.
oligonucleotides6−8 and ester-peptide containing depsipeptides9). Key to this approach is the realization that starting with a heterogeneous-mixture of source chemicals and building blocks need not be a problem. There could be natural interactions (orthogonal or otherwise) and catalysis that can lead to selective reactions or feedback, which in turn would set the next stage for chemical selections. These approaches, while experimentally and analytically demanding, point to the way in which the chemical origins of life research could actually benefit, by challenging the origins of life practitioners to deal with the difficulties posed by the prebiotic clutter of heterogeneous heterogeneity head on. Such an approach also engenders the possibility to allow for the interaction of the end products (supramolecular and oligomeric entities) with their source chemicals and other building blocks in the same pot, enabling further selection and potential chemical coevolutionary pathways, which have been neglected routinely in the “clean and isolated” approaches. Demanding selective reactions, orthogonal transformations, and catalysis in a prebiotic heterogeneous heterogeneity clutter requires the ability to discover or create conditions that would be able to transform one substrate selectively in the presence of its (or a library of) analog(s). While this appears daunting, focusing on RNA as a case-study may illuminate the possibilities and limits of this approach (Figure 2). A demonstration of the selective emergence of one informational system from a heterogeneous clutter of its “peers” would be a great challenge to the chemical community interested in origins of life. For example, among the four pentoses, selectively
tractable experimental setup and verifications, it also led to the speculation and creation of different “worlds” (for example, protein world, lipid world, RNA world, and thio-ester world), which exist separately and are, therefore, “forced” to invent the other classes of compounds that are lacking in their own world (Figure 1). Substantial reliance on extrapolating biology and metabolic pathways backward purely for the sake of parsimony further complicates matters,4,5 unrealistically narrowing and limiting reaction pathways to those which extant biology utilizes. Such considerations may have no bearing on how prebiotic mixtures of chemicals (absent biological “teleology”) would have progressed further by chemical evolution, especially when dictated by prebiotic environments, which are vastly different from where extant biological molecules and entities are (or would have been) able to emerge and function. This illustrates the quandary facing origins of life field research: how far can biological chemistry be extrapolated backward into the realm of prebiotic chemistry or vice versa, without the risk of being not germane? In the origins of life scenarios, realistically, one has to contend with the complications created by the interactions between a heterogeneous mixture of chemicals. Such a consideration may actually offer some breakthrough solutions that have been long overlooked (or avoided) by the reliance on and the investigation of clean, isolated, and homogeneous systems. One such approach in vogue is “Systems Chemistry”, a concept that is not only increasingly applied to prebiotic chemistry1 but also being implemented at the level of supramolecular chemistry (heterogeneous backbone containing 456
DOI: 10.1021/acs.accounts.6b00470 Acc. Chem. Res. 2017, 50, 455−459
Commentary
Accounts of Chemical Research
Figure 2. Heterogeneity to homogeneity. Emergence of a homogeneous-backbone polymer from a diverse pool of building blocks derived (from the structural and chemical neighborhood) via selective and preferential reactions, associations, and interactions at different levels of chemical and structural complexity.
converting ribose to the canonical RNA nucleosides and not the other three pentoses (lyxose, arabinose, and xylose) would be the first challenge. If such a transformation is not possible at the level of the sugar, then one could envision selections at the next level, phosphorylation mechanisms that prefer ribonucleosides over the lyxo-, xylo-, and arabinonucleosides. Even if
selective phosphorylation is not probable, then there could be a bias envisaged during the nonenzymatic oligomerization of these various isomers of nucleotides. For example, it is possible that β-ribonucleotide could oligomerize more efficiently (due to its more nucleophilic cis-disposed 2′,3′-OH groups) over the arabino-, xylo- and lyxo-counterparts; selectivity over the similar 457
DOI: 10.1021/acs.accounts.6b00470 Acc. Chem. Res. 2017, 50, 455−459
Commentary
Accounts of Chemical Research
Figure 3. Disorganized heterogeneity to organized heterogeneity. (top) Emergence of a polypeptide containing only α-amino acids, and (bottom) origination of a cycle of reactions (citric acid cycle components are illustrated as an example), starting from a diverse pool of building blocks derived from similar structural and chemical analogs via selective and preferential reactions, transformations, and interactions at different levels of chemical and structural complexity.
cis-disposed 2′,3′-OH groups in lyxose-nucleotide could be achieved based on steric hindrance. At this juncture, there could very well be mixtures of oligomers with heterogeneity not only in their nucleobase sequences, but also in their sugarconfiguration (α, β, furanosyl and pyranosyl), in their chirality (D and L) and in their phosphate backbone connectivity. At the stage of the oligomer, the propensity to form duplexes and tertiary structures, coupled with the hydrolytic stability of duplex versus single strands (thermodynamic and kinetic stabilities) could act as further selection pressures leading to a one-pot-emergence of a homogeneous system (for example, RNA) over its closest, potentially natural, and available library of isomers. Such a “systems chemistry” approach and analysis also reveals that the supramolecular structures used by extant biology need not be the ones that are present from the very beginning of prebiotic chemical pathways but could allow for “sloppy forerunners” (proto-biopolymers) that could have morphed into what is used by extant biology.7 One could speculate about the types and range of physical or chemical process that could drive the conversion of heterogeneity into homogeneity: (a) as pointed above it could be based on chemical (reactive) selection;10 (b) (in)stability in a given environment, such as relative hydrolytic lability of a 2′,5′-linked RNA and single strands versus 3′,5′linked RNA and double strand (duplexes);11,12 (c) a thermal (or pH) gradient in confined spaces that can influence the selection of certain species over the others;13,14 (d) selection of certain molecular structures based on their function as certain emergent properties (and emergent behavior) begin to manifest (self-assembly, catalysis, and self-replication to name a few).15
More explorations and investigations are needed to demonstrate that heterogeneity-to-homogeneity transition is indeed possible. To establish such selections and emergence (“chemical evolution”) for the other classes of biologically relevantcompounds from their respective heterogeneous clutter would represent a formidable challenge (Figure 3). For the oligopeptides, it would entail the demonstration of the emergence and selection of peptides, starting not just from pure α-amino acids but from a mixture of potentially natural analogs (for example, β-amino acids and corresponding α- and β-hydroxy acids), which are also produced within the same prebiotic environment through the same (and similar) chemistries. An equally exacting task would be to demonstrate the emergence or existence of a “cycle” of reactions consisting of a set of compounds that would interact among themselves in a “self-sorting reactive pathway” producing one (or more) of the components, thus resulting in a closed-loop system, which could become self-sustaining, and resembling those of extant metabolic cycles. A similar investigation into the emergence of fatty acids and lipids from their respective heterogeneous prebiotic source molecules and analogs that are available leading to the formation of protocells would indeed be a challenge, which may be relatively manageable.16 Providing experimental demonstration and evidence for the emergence of each individual class of compounds or systems (homogeneity) from a realistically available concoction of potentially natural and related building blocks and source molecules (heterogeneity) would itself be remarkable and a paradigm shift. Such 458
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(13) Morasch, M.; Braun, D.; Mast, C. B. Heat-Flow-Driven oligonucloetide geleation separates single-base differences. Angew. Chem., Int. Ed. 2016, 55, 6676−6679. (14) Kreysing, M.; Keil, L.; Lanzmich, S.; Braun, D. Heat flux across an open pore enables the continuous replication and selection of oligonucleotides towards increasing length. Nat. Chem. 2015, 7, 203− 208. (15) Black, R. A.; Blosser, M. C.; Stottrup, B. L.; Tavakley, R.; Deamer, D. W.; Keller, S. L. Nucleobases bind to and stabilize aggregates of a prebiotic amphiphile, providing a viable mechanism for the emergence of protocells. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 13272−13276. (16) Szostak, J. W. An optimal degree of physical and chemical heterogeneity for the origin of life? Philos. Trans. R. Soc., B 2011, 366, 2894−2901. (17) Quote taken from Eschenmoser, A. Etiology of potentially primordial biomolecular structures: from vitamin B12 to the nucleic acids and an inquiry into the chemistry of life’s origin: a retrospective. Angew. Chem., Int. Ed. 2011, 50, 12412−12472.
an undertaking would necessitate the confluence of a broad spectrum of scientific expertise: analytical, systems, combinatorial, inorganic, bio-, physical, organic, and prebiotic chemistry. The Everest of these challenges would be to combine all the various classes of heterogeneity clutter (heterogeneous heterogeneity) together in a potentially early earth-like environment and to demonstrate the coemergence of all of these (proto)biopolymers, leading to a functioning and evolvable entity (protobiology/life?). If this is not provocative enough for the chemical community to take the plunge, then the statement by Bernal “if life once made itself, it must not be too difficult to make it again”17 could be the enticement!
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ramanarayanan Krishnamurthy: 0000-0001-5238-610X Funding
Funding jointly from the NSF and the NASA Exobiology Program, under the NSF-Center for Chemical Evolution, CHE1504217, and an award from the Simons Foundation (327124) is gratefully acknowledged. Notes
The author declares no competing financial interest.
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ACKNOWLEDGMENTS I am indebted to my group members and Professor Albert Eschenmoser for discussions and feedback. REFERENCES
(1) Ruiz-Mirazo, K.; Briones, C.; de la Escosura, A. Prebiotic systems chemistry: new perspectives for the origins of life. Chem. Rev. 2014, 114, 285−366. (2) Quote translation taken from Eschenmoser, A. Chemical etiology of nucleic acid structure. Science 1999, 284, 2118−2124. (3) Orgel, L. E. The origin of life - a review of facts and speculations. Trends Biochem. Sci. 1998, 23, 491−495. (4) Orgel, L. E. The implausibility of metabolic cycles on the prebiotic earth. PLoS Biol. 2008, 6, e18. (5) Dworkin, J. P.; Lazcano, A.; Miller, S. L. The roads to and from the RNA world. J. Theor. Biol. 2003, 222, 127−34. (6) Trevino, S. G.; Zhang, N.; Elenko, M. P.; Luptak, A.; Szostak, J. W. Evolution of functional nucleic acids in the presence of nonheritable backbone heterogeneity. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 13492−13497. (7) Krishnamurthy, R. On the emergence of RNA. Isr. J. Chem. 2015, 55, 837−850. (8) Engelhart, A. E.; Powner, M. W.; Szostak, J. W. Functional RNAs exhibit tolerance for non-heritable 2′−5′ vs. 3′−5′ backbone heterogeneity. Nat. Chem. 2013, 5, 390−394. (9) Forsythe, J. G.; Yu, S.-S.; Mamajanov, I.; Grover, M. A.; Krishnamurthy, R.; Fernández, F. M.; Hud, N. V. Ester-Mediated amide bond formation driven by wet−dry Cycles: A possible path to polypeptides on the prebiotic earth. Angew. Chem. 2015, 127, 10009− 10013. (10) Bowler, F. R.; Chan, C. K. W.; Duffy, C. D.; Gerland, B.; Islam, S.; Powner, M. W.; Sutherland, J. D.; Xu, J. Prebiotically plausible oligoribonucleotide ligation facilitated by chemoseletive acylation. Nat. Chem. 2013, 5, 383−389. (11) Usher, D. Early chemical evolution of nucleic acids: A Theoretical Model. Science 1977, 196, 311−313. (12) Kierzek, E.; Biala, E.; Kierzek, R. Elements of thermodynamics in RNA evolution. Acta Biochim. Polym. 2001, 48, 485−493. 459
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