Giving Rise to Life: Transition from Prebiotic Chemistry toProtobiologyPublished 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, UnitedStates

ABSTRACT: The challenge of a chemical approach to the origins of life problem involvescomprehending the transition from prebiotic chemistry to protobiology. This endeavordemands demonstrating the metamorphosis of a diverse pool of prebiotic building blocks(heterogeneous heterogeneity) into a conglomerate self-assembling system (homogeneousheterogeneity) capable of evolution.

How life arose on Earth is one of the most enduring puzzlethat embraces all fields and disciplines and can be

considered a “Holy Grail”. It is a challenge, particularly to thechemical scientific community, to decipher the fundamentalsecrets that are locked in the nature of the building blocks oflife: atoms, molecules, their reactions, and the details of thetransition that led to that emergent property called life. Whilean exact historical account of how life originated on Earth is nota realistic goal, due to the lack of “chemical fossils” anduncertainties associated with details of early Earth’s phys-icochemical environment, the origins of life studies havebenefited enormously from the systematic scientific inves-tigations that have given rise to wide variety of possiblesolutions for the prebiotic origins of various classes of biologicalbuilding blocks and their respective biopolymers.1 This hasallowed the scientific community to move forward andapproach the problem from a different viewpoint, which isthe central challenge: to provide experimental demonstrationsthat “life” can emerge from the self-assembly of molecules andnetworks of chemical transformations. Implicit in this challengeare the following questions: (a) can we define what life is, and(b) can we create artificial chemical life? While a consensus onthe operational definition of “life” is yet to be achieved, theexperimental demonstration of “synthetic life” is an achievablegoal. Creation of artificial chemical life would be in itself agrand achievement; moreover, it will allow a comparison withnatural life that can lead to an in-depth understanding thatwould not be accessible from studying natural-life alone. AlbertEinstein aptly summed it up using nature as a proxy for life: “Wenot only want to know how nature is (and how her transactionsare carried through), but also want to reach, if possible, a goal

which may seem utopian and presumptuous, namely to knowwhy nature is such and not otherwise”.2

Looking at the origins of life scenario, one has to come toterms with the most difficult and central aspect of the problem:how does a heterogeneous and diverse mixture of sourcechemicals and building blocks come together in specific ways(prebiotic chemistry) to give rise to more complex chemicalentities, which then transform themselves into homogeneouspolymers that function and evolve through heterogeneousinteraction with other small and macromolecules (protobiol-ogy)? How do the heterogeneous interactions of a diversecollection of heterogeneous molecules (“heterogeneous hetero-geneity”: amino acids, sugars, nucleobases, phosphates, fattyacids, small molecules, and metal ions) metamorphose toheterogeneous interactions of a collection of homogeneoussupramolecular entities (“homogeneous heterogeneity”: pro-teins, polysaccharides, nucleic acids, and bilayer lipids) capableof function and evolution?Historically, each of the heterogeneous heterogeneity

interactions have been simplified experimentally to deal withthe formation of only one class of compounds.3 Prebioticformation of amino acids and oligopeptides were addressedseparately from the formation of the building blocks of nucleicacids and oligonucleotides, while formation of sugars wasinvestigated separately, as was the formation of fatty acids(Figure 1), and most of the time isolated from early earthenvironmental constraints. While these “clean and isolated”approaches allowed for straightforward hypotheses and

Received: September 18, 2016Published: March 21, 2017

Commentary

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© 2017 American Chemical Society 455 DOI: 10.1021/acs.accounts.6b00470Acc. Chem. Res. 2017, 50, 455−459

tractable experimental setup and verifications, it also led to thespeculation 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 theother classes of compounds that are lacking in their own world(Figure 1). Substantial reliance on extrapolating biology andmetabolic pathways backward purely for the sake of parsimonyfurther complicates matters,4,5 unrealistically narrowing andlimiting reaction pathways to those which extant biologyutilizes. Such considerations may have no bearing on howprebiotic mixtures of chemicals (absent biological “teleology”)would have progressed further by chemical evolution, especiallywhen dictated by prebiotic environments, which are vastlydifferent from where extant biological molecules and entitiesare (or would have been) able to emerge and function. Thisillustrates the quandary facing origins of life field research: howfar can biological chemistry be extrapolated backward into therealm of prebiotic chemistry or vice versa, without the risk ofbeing not germane?In the origins of life scenarios, realistically, one has to

contend with the complications created by the interactionsbetween a heterogeneous mixture of chemicals. Such aconsideration may actually offer some breakthrough solutionsthat have been long overlooked (or avoided) by the reliance onand the investigation of clean, isolated, and homogeneoussystems. One such approach in vogue is “Systems Chemistry”, aconcept that is not only increasingly applied to prebioticchemistry1 but also being implemented at the level ofsupramolecular chemistry (heterogeneous backbone containing

oligonucleotides6−8 and ester-peptide containing depsipepti-des9). Key to this approach is the realization that starting with aheterogeneous-mixture of source chemicals and building blocksneed not be a problem. There could be natural interactions(orthogonal or otherwise) and catalysis that can lead toselective reactions or feedback, which in turn would set the nextstage for chemical selections. These approaches, whileexperimentally and analytically demanding, point to the wayin which the chemical origins of life research could actuallybenefit, by challenging the origins of life practitioners to dealwith the difficulties posed by the prebiotic clutter ofheterogeneous heterogeneity head on. Such an approach alsoengenders the possibility to allow for the interaction of the endproducts (supramolecular and oligomeric entities) with theirsource chemicals and other building blocks in the same pot,enabling further selection and potential chemical coevolu-tionary pathways, which have been neglected routinely in the“clean and isolated” approaches.Demanding selective reactions, orthogonal transformations,

and catalysis in a prebiotic heterogeneous heterogeneity clutterrequires the ability to discover or create conditions that wouldbe able to transform one substrate selectively in the presence ofits (or a library of) analog(s). While this appears daunting,focusing on RNA as a case-study may illuminate thepossibilities and limits of this approach (Figure 2). Ademonstration of the selective emergence of one informationalsystem from a heterogeneous clutter of its “peers” would be agreat challenge to the chemical community interested in originsof life. For example, among the four pentoses, selectively

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 theother classes of molecules, which are lacking in their own respective worlds. The ‘?’ refers to other satellites that may be needed to help these worldsexist and to “evolve”.

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converting ribose to the canonical RNA nucleosides and notthe other three pentoses (lyxose, arabinose, and xylose) wouldbe the first challenge. If such a transformation is not possible atthe level of the sugar, then one could envision selections at thenext level, phosphorylation mechanisms that prefer ribonucleo-sides over the lyxo-, xylo-, and arabinonucleosides. Even if

selective phosphorylation is not probable, then there could be abias envisaged during the nonenzymatic oligomerization ofthese various isomers of nucleotides. For example, it is possiblethat β-ribonucleotide could oligomerize more efficiently (dueto its more nucleophilic cis-disposed 2′,3′-OH groups) over thearabino-, xylo- and lyxo-counterparts; selectivity over the similar

Figure 2. Heterogeneity to homogeneity. Emergence of a homogeneous-backbone polymer from a diverse pool of building blocks derived (from thestructural and chemical neighborhood) via selective and preferential reactions, associations, and interactions at different levels of chemical andstructural complexity.

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cis-disposed 2′,3′-OH groups in lyxose-nucleotide could beachieved based on steric hindrance. At this juncture, there couldvery well be mixtures of oligomers with heterogeneity not onlyin their nucleobase sequences, but also in their sugar-configuration (α, β, furanosyl and pyranosyl), in their chirality(D and L) and in their phosphate backbone connectivity. At thestage of the oligomer, the propensity to form duplexes andtertiary structures, coupled with the hydrolytic stability ofduplex versus single strands (thermodynamic and kineticstabilities) could act as further selection pressures leading toa one-pot-emergence of a homogeneous system (for example,RNA) over its closest, potentially natural, and available libraryof isomers. Such a “systems chemistry” approach and analysisalso reveals that the supramolecular structures used by extantbiology need not be the ones that are present from the verybeginning of prebiotic chemical pathways but could allow for“sloppy forerunners” (proto-biopolymers) that could havemorphed into what is used by extant biology.7

One could speculate about the types and range of physical orchemical process that could drive the conversion ofheterogeneity into homogeneity: (a) as pointed above itcould be based on chemical (reactive) selection;10 (b)(in)stability in a given environment, such as relative hydrolyticlability 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 theselection of certain species over the others;13,14 (d) selection ofcertain molecular structures based on their function as certainemergent 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 demon-strate that heterogeneity-to-homogeneity transition is indeedpossible.To establish such selections and emergence (“chemical

evolution”) for the other classes of biologically relevant-compounds from their respective heterogeneous clutterwould represent a formidable challenge (Figure 3). For theoligopeptides, it would entail the demonstration of theemergence and selection of peptides, starting not just frompure α-amino acids but from a mixture of potentially naturalanalogs (for example, β-amino acids and corresponding α- andβ-hydroxy acids), which are also produced within the sameprebiotic environment through the same (and similar)chemistries. An equally exacting task would be to demonstratethe emergence or existence of a “cycle” of reactions consistingof a set of compounds that would interact among themselves ina “self-sorting reactive pathway” producing one (or more) ofthe components, thus resulting in a closed-loop system, whichcould become self-sustaining, and resembling those of extantmetabolic cycles.A similar investigation into the emergence of fatty acids and

lipids from their respective heterogeneous prebiotic sourcemolecules and analogs that are available leading to theformation of protocells would indeed be a challenge, whichmay be relatively manageable.16 Providing experimentaldemonstration and evidence for the emergence of eachindividual class of compounds or systems (homogeneity)from a realistically available concoction of potentially naturaland related building blocks and source molecules (hetero-geneity) would itself be remarkable and a paradigm shift. Such

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 derivedfrom similar structural and chemical analogs via selective and preferential reactions, transformations, and interactions at different levels of chemicaland structural complexity.

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an undertaking would necessitate the confluence of a broadspectrum of scientific expertise: analytical, systems, combina-torial, inorganic, bio-, physical, organic, and prebiotic chemistry.The Everest of these challenges would be to combine all the

various classes of heterogeneity clutter (heterogeneousheterogeneity) together in a potentially early earth-likeenvironment and to demonstrate the coemergence of all ofthese (proto)biopolymers, leading to a functioning andevolvable entity (protobiology/life?). If this is not provocativeenough for the chemical community to take the plunge, thenthe statement by Bernal “if life once made itself, it must not betoo difficult to make it again”17 could be the enticement!

■ AUTHOR INFORMATIONCorresponding Author

*E-mail: rkrishna@scripps.edu.ORCID

Ramanarayanan Krishnamurthy: 0000-0001-5238-610XFunding

Funding jointly from the NSF and the NASA ExobiologyProgram, under the NSF-Center for Chemical Evolution, CHE-1504217, and an award from the Simons Foundation (327124)is gratefully acknowledged.Notes

The author declares no competing financial interest.

■ ACKNOWLEDGMENTSI am indebted to my group members and Professor AlbertEschenmoser for discussions and feedback.

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