Bioenergetics and Life’s Origins - CSHL Pcshperspectives.cshlp.org/content/2/2/a004929.full.pdf · Bioenergetics and Life’s Origins David Deamer1 and Arthur L. Weber2 1Department

Bioenergetics and Life’s Origins

David Deamer1 and Arthur L. Weber2

1Department of Biomolecular Engineering, Baskin School of Engineering, University of California,Santa Cruz, California 95064

2SETI Institute, NASA Ames Research Center, Mountain View, California 94043

Correspondence: [email protected]

Bioenergetics is central to our understanding of living systems, yet has attracted relativelylittle attention in origins of life research. This article focuses on energy resources availableto drive primitive metabolism and the synthesis of polymers that could be incorporatedinto molecular systems having properties associated with the living state. The compart-mented systems are referred to as protocells, each different from all the rest and representinga kind of natural experiment. The origin of life was marked when a rare few protocells hap-pened to have the ability to capture energy from the environment to initiate catalyzed heter-otrophic growth directed by heritable genetic information in the polymers. This articleexamines potential sources of energy available to protocells, and mechanisms by whichthe energy could be used to drive polymer synthesis.

Previous research on life’s origins has forthe most part focused on the chemistry

and energy sources required to produce thesmall molecules of life—amino acids, nucleo-bases, and amphiphiles—and to a lesser extenton condensation reactions by which the mono-mers can be linked into biologically relevantpolymers. In modern living cells, polymers aresynthesized from activated monomers such asthe nucleoside triphosphates used by DNAand RNA polymerases, and the tRNA-aminoacyl conjugates that supply ribosomes withactivated amino acids. Activated monomersare essential because polymerization reactionsoccur in an aqueous medium and are thereforeenergetically uphill in the absence of activation.

A central problem therefore concerns mech-anisms by which prebiotic monomers could

have been activated to assemble into polymers.Most biopolymers of life are synthesized whenthe equivalent of a water molecule is removedto form the ester bonds of nucleic acids, glyco-side bonds of polysaccharides, and peptidebonds in proteins. In life today, the removal ofwater is performed upstream of the actualbond formation. This process involves the ener-getically downhill transfer of electrons, which iscoupled to either substrate-level oxidation orgeneration of a proton gradient that in turn isthe energy source for the synthesis of anhydridepyrophosphate bonds in ATP. The energy storedin the pyrophosphate bond is then distributedthroughout the cell to drive most other energy-dependent reactions. This is a complex andhighly evolved process, so here we considersimpler ways in which energy could have been

Editors: David Deamer and Jack Szostak

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captured from the environment and made avai-lable for primitive versions of metabolism andpolymer synthesis. Because the atmosphere ofthe primitive Earth did not contain appreciableoxygen, this review of primitive bioenergetics islimited to anaerobic sources of energy.

BACKGROUND

Fundamental Considerations fromThermodynamics and Kinetics

In general, life is characterized by the fact thatthe catalytic and genetic polymers exist in asteady state far from equilibrium. It followsthat the origin of life can be understood in termsof a process in which the flow of energy throughrelatively simple systems of molecules produceda more complex set of polymeric molecules thathad specific physical and chemical properties.The origin of life occurred when a subset ofthese molecules was captured in a compartmentand could interact with one another to producethe properties we associate with the living state.

Energy flow, and the changes it produces,are described by the fundamental laws of ther-modynamics and kinetics. These concepts arefamiliar to most readers, but it is less obvioushow they can be applied to our understandingof the prebiotic environment and the increasein chemical complexity driven by energy flux.We will briefly recapitulate them here in relationto the origin of life.

1. The amount of energy released as a reac-tion proceeds toward equilibrium and is referredto as free energy, which has components of en-thalpy and entropy. Both must be taken into ac-count to understand how systems of moleculescan become more complex. On the prebioticEarth, immense numbers and varieties of chem-ical reactions were taking place because theEarth itself was in a state of thermodynamic dis-equilibrium. To understand the origin of life, it isessential to sort out which of the many energysources were primary factors in driving theincreasing complexity from which life emerged.

2. All reactions in principle are reversibleand can approach equilibrium from eitherdirection. This means that a potentially destruc-tive reaction such as hydrolysis of polymers can

proceed toward polymer synthesis if there is away to remove water molecules so that covalentbonds can form. Their enzyme-catalyzedbiosynthesis requires an input of metabolicenergy, primarily delivered as pyrophosphatebonds of ATP, but the linking bonds are alsothermodynamically unstable, which means thatenzymes can also catalyze spontaneous hydro-lysis of the bonds. The result is that life incorpo-rates a continuous and controlled synthesis andbreakdown of its polymeric components. Simi-lar reactions were presumably occurring in theprebiotic environment, so it is essential to estab-lish plausible mechanisms by which polymerscould be synthesized and accumulate despitehydrolytic back reactions.

3. Because the concentration of reactantsstrongly affects reaction rates, it seems likelythat for a prebiotic reaction to proceed at a usefulrate, there must have been concentrating proc-esses such as evaporation or adsorption. A dilutesolution of activated monomers is unlikely toform polymers because at low concentrationstherateofmonomercondensationis lessthantherate of their hydrolytic deactivation. However,adsorption of activated monomers on mineralsurfaces could enhance their polymerization byincreasing their concentration and possibly ori-enting them in a way that favors condensation.

4. The reactants in a given reaction mustovercome an energy barrier called activationenergy that limits the rate at which the reactioncan occur. Elevated temperatures provide acti-vation energy to a potentially reactive systemof molecules. The global temperature whenlife began is estimated to be in the range of 55and 858C (Kauth and Lowe 2003) but therewould be considerable variability around thismean, ranging from cold polar regions to exten-sive high temperature vulcanism. It is reason-able to consider that thermal activation energywas likely to be abundant, so that the majorhurdles to be overcome in promoting polymer-ization reactions would be to concentrate, orga-nize, and chemically activate monomers.

5. Catalysts reduce the activation energybarrier so that a reaction can proceed morerapidly toward equilibrium. There were no pro-tein enzymes on the prebiotic Earth, so simpler

D. Deamer and A.L. Weber

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catalysts like mineral surfaces, metal ions, andsmall polymers presumably acted as catalystsin primitive metabolic pathways.

6. Chemical kinetics defines the rates atwhich a given reaction occurs, and allowsthermodynamically unstable molecular struc-tures to exist far from equilibrium. A proteinor nucleic acid in water, for instance, will ulti-mately hydrolyze to its component amino acids.However, in the absence of acatalyst, this is a slowreaction, so that faster catalyzed reactions ofbiosynthesis can keep up with the slower degra-dative rate of hydrolysis. The difference inreaction rates is referred to as a kinetic trap. Onthe early Earth, if there was a relatively fast proc-ess that could produce chemical bonds betweenmonomers, kinetic traps would allow the result-ing polymers to have a transient existence even ifthey were thermodynamically unstable.

Overview of Contemporary Bioenergetics

The bioenergetic pathways of contemporaryanaerobic life are well understood. As depictedin Figure 1, the light energy captured by photo-lithotrophs is used to activate and release elec-trons from inorganic donors like H2S, So, or

H2, thereby producing the electrochemical en-ergy that reduces carbon dioxide and yieldsthe organic molecules required by life. Similarly,chemolithotrophs transfer high energy elec-trons from H2 and H2S to lower energy statesin electron acceptors such as CO2 and NO3

2,and use the derived free energy to reduce carbondioxide to organic molecules. The organic pro-ducts of such reactions are subsequently usedby heterotrophic life as electron donors in theirenergy metabolism based on either anaerobicrespiration or fermentation.

In anaerobic photolithotrophy, chemoli-thotrophy, and respiration, the acquired electro-chemical energy is used to pump protons acrossmembranes in such a way that an electro-chemical proton gradient is produced, equiva-lent to approximately 0.2 volts of electricalpotential. This energy of the proton potentialis coupled to ATP synthesis catalyzed by anATP synthase embedded in the membrane.The pyrophosphate bond energy in the ATP isthen transferred by diffusion to the rest of thecell where it drives a variety of essential meta-bolic reactions, motor molecule functions, iontransport processes, and polymerization reac-tions of biosynthesis.

Pathways of anaerobic energy flow

Majorelectron

donors andacceptors

AutotrophyCarbon source - CO2

Photolithotrophy —

Chemolithotrophy —

e–1 donors: H2O, H2S, So, H2, Fe+2

e–1 acceptors: CO2

HeterotrophyCarbon source - organic substances

Primaryenergy source

Energytransduction

system

Energytransfer

molecules

Biosyntheticproducts

e–1 donors: H2, H25

e–1 acceptors: NO3–1, CO2

Fermentation

Anaerobicrespiration

—

— e–1 donors: organic substancese–1 acceptors: organic substances

e–1 donors: organic substances

e–1 acceptors: NO2–1, SO

4–2, Fe+3, Mn+4

Photochemically generatedhigh-energy electrons or proton gradient

+ + Monomers Polymers Sugars(Energized-carbon

storage)

Membrane electron transportand proton gradient

NADPH(electron-pairredox energy)

ATP(anhydride

bond energy)

+ C, N, P, S

+

Monomers + Polymers + Sugars(Energized-carbon

storage)

Fermentation—Substrate-level oxidation oforganic intermed. drives ATPsynthesis often via thioesters

Anaerobic respiration—membrane electron transportchain and proton gradientdrives ATP synthesis

NADPH(electron-pairredox energy)

+ C, N, P, S

ATP(anhydride

bond energy)

High-energy electrons of carbon substrates

+

Figure 1. Energy sources and processing by anaerobic autotrophs and heterotrophs. See text for discussion.


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In contrast, in fermentation, the electro-chemical energy stored in organic substratesactivates the transfer of high energy electronsfrom carbon groups (electron donors) to lowerenergy states provided by other carbon groups(electron acceptors). This substrate-level elec-tron transfer oxidizes the electron donor tocreate an anhydride intermediate (usually athioester) that in turn drives the synthesis ofATP (Gottschalk 1986)

The coupling of ATP synthesis to electrontransfer and proton gradients is clearly a highlyevolved system. The bioenergetic processes usedby the first forms of cellular life must have beenvery different even though the same sourcesof energy were available, with the exceptionof electron transport to molecular oxygen. Tounderstand the origin of life, we need to estab-lish plausible sources of energy that would drivesynthetic reactions.

Energy Sources on the Prebiotic Earth

Three kinds of energy are considered in thisarticle. As shown in Figure 2, the first is the rel-atively high energy required to synthesize smallmolecules that have the potential to serve asmonomers for polymerization reactions andfeedstock for a primitive metabolism. Theseinclude photochemical energy available inultraviolet light, atmospheric electric discharge,

and geological electrochemical energy. The sec-ond is a series of relatively low energy reactionsthat incorporate condensation processes bywhich monomers are assembled into randompolymers. These include anhydrous heat, min-eral-catalyzed synthesis, and sugar-driven reac-tions. The third is the energy flow in metabolicnetworks in which an energy source in the localenvironment is captured and then transfer-red to standardized energy carriers (like ATPand NAD[P]H). These are catalytically coupledto a series of intracellular reactions that ulti-mately activate monomers required for cata-lyzed polymerization.

Table 1 shows the kinds and relative amountsof energy on today’s Earth. It is a reasonable as-sumption that similar energy sources were avail-able 4 billion years ago at the time of life’s origin.Light energy is by far the most abundant, and infact photochemistry drives virtually all life to-day. Could light have been a primary energysource for the first forms of life? This is an ob-vious possibility, yet there is a major conceptualproblem: In modern life, capturing visible lightrequires a pigment system and a mechanism fortransducing the energy content of photons intochemical energy to be used in metabolism, andthere is as yet no plausible way to do this in aprebiotic scenario.

However, ultraviolet light is clearly a poten-tial source of high energy for small molecule

Prebiotic energy flow

Primaryenergy source

Primaryproducts

Hydrosphereprimaryproducts

Secondaryproducts

Amino acids,thioesters,

N-heterocycles,model protocells

Polypeptides,phosphoanhydrides

Acetic acid thioester

Amino acids,nucleobases

Acetic acid,methanethiol

Neutral Atmos.HCHO, HNO

Reducing Atmos.HCN, RCHO + NH3 H2, H2S, CH4, CO

Photochemical energy

UV light Electric discharge Heat Heat Mineralreducing power

Geochemical energy

Sugars,NO2

–1 Æ NH3

Figure 2. Possible pathways for synthetic prebiotic reactions. See text for discussion.





synthesis, together with the energy released byshock waves generated by impacting cometsand asteroid-sized objects (Chyba and Sagan1992). The electrical discharge used in theoriginal Miller-Urey experiments, and elevatedtemperature and pressures associated with geo-thermal environments (.2008C) can also dochemical work, but these sources represent atiny fraction of the total energy flux. Electricaldischarge is meant to simulate lightning in re-ducing gas mixtures, and Miller (1953) foundthat small amounts of highly reactive HCNand HCHO were produced in the discharge,which afterwards underwent Strecker reactionsto produce several amino acids. This experimentrevolutionized origins of life research, becausefor the first time, biologically relevant moleculeswere synthesized in a simulated prebiotic envi-ronment using a plausible source of energy.

Formaldehyde can also be synthesized byUVlight interacting with water vapor and carbondioxide in the upper atmosphere, and a plausiblephotochemical reaction was proposed by Pintoet al. (1980). From reasonable assumptions

about UV flux and composition of the earlyatmosphere, these workers calculated that form-aldehyde was added to the oceans at a rate of 1011

moles/year. It has long been known that formal-dehyde (HCHO) in alkaline solutions readily re-acts to form a variety of carbohydrates, as isdiscussed later. Cyanide (HCN) is another com-mon product of UV and electrical energy im-pinging on mixtures containing nitrogen andgases such as CO and CO2, and cyanide readilyreacts with itself to produce other biologicallyrelevant molecules. For instance, a few years afterthe Miller experiment was published, John Oro(1961) discovered that at high concentration,HCN could undergo pentamerization to formadenine.

Elevated pressures and temperatures asso-ciated with geothermal conditions can alsopromote significant chemical reactions. In par-ticular, the Fischer-Tropsch (FT) reaction useselevated temperatures to provide activationenergy for a reaction in which carbon monoxideand hydrogen combine to produce long-chainhydrocarbons. Nooner et al. (1987) were amongthe first to test this reaction as a potential prebi-otic source of hydrocarbon derivatives, usingmeteoritic iron as a catalyst, which lowers theactivation energy of the reaction.

Although it is a reasonable assumption thatthe synthesis of organic compounds requiredfor the origin of life was driven by energy avail-able in the prebiotic environment, anothersource of potential chemical energy was avail-able in organic compounds delivered by cometsand meteoritic infall during late accretion.Chyba, Sagan, and co-workers (1990, 1992) es-timated the total amount of organic carboncompounds that could be delivered in this way,and within an order of magnitude, it was in therange of the amounts estimated to be synthe-sized by Miller-Urey reactions under the mostfavorable conditions. The energy content wouldbe present in the form of reduced carbon com-pounds that could undergo chemical modifica-tion if they were exposed to mineral surfaces ingeological settings of appropriate fugacity (Shock1990) (See also Pizzarello and Shock 2010).This possibility is largely unexplored and is likelyto be a fruitful direction for future research.

Table 1. Most of the energy flux on the early Earth wasin the form of light energy from the sun, just as it istoday.

Energy sources on the early Earth (kilojoulesm22yr21)

Solar radiation(UV,250 nM)

24,000

Shock waves fromimpacts

200

Radioactivity 117Electrical discharges 2.9Volcanoes 5.4Chemical energy Significant for the origin of

life, not yet estimated.The value shown in the table is the energy of

ultraviolet radiation in a wavelength range thatis absorbed by common organic compoundssuch as PAH, and therefore capable of activatingphotochemical reactions. Table adopted fromestimates given by Chyba and Sagan (1992) andMiller and Urey (1959). There is considerableuncertainty in these estimates, which are presentedonly to illustrate order-of-magnitude approxi-mations for energy flux in meter-scale localizedenvironments.





In summary, early investigations, beginningwith Stanley Miller’s experiments, showed thatthe energy available in electrical discharge, UVlight, and elevated temperatures, when imping-ing on simple gas mixtures, can produce reactivecompounds like HCN and HCHO, which inturn react to form amino acids, purine andpyrimidine bases, lipid-like amphiphiles, andcarbohydrates. Assuming that inorganic phos-phate was also available, all of the monomersrequired for the synthesis of major polymersof life would be available for the next stageof increasing complexity in the prebiotic envi-ronment.

Thermal Energy

Moderate heating at temperatures below 2008Cis not a direct source of useful chemical energy.Heat speeds up the rate at which a reactionapproaches chemical equilibrium, but doesnot change the position of equilibrium to favorone side of a reaction. However, heat can movethe equilibrium of a reaction if it changes theconcentration of the reactants by removing sol-vent, or by evaporating (volatilizing) a productof one side of a reaction, such as water froma condensation reaction. Under these condi-tions, net polymer synthesis becomes favorablebecause the monomer concentration is in-creased, and once the solvent water has evapo-rated, continued heating favors polymerizationby removing the water produced by condensa-tion reactions.

Early researchers investigating the origin oflife attempted, with some success, to drive con-densation reactions by drying potential reac-tants such as amino acids and nucleotides atelevated temperatures. The advantage of usinganhydrous heating to drive condensation isthat it is by far the simplest way to produce thepolymers required for life to begin. Althoughthe amino acid polymerization studied byFox and colleagues is a prominent example(Fox and Harada 1958), there were also earlyattempts to drive phosphodiester bond forma-tion under these conditions. For instance,Verlander and Orgel (1974) found that oligo-nucleotides up to six nucleotides long could be

synthesized from cyclic 20,30-AMP when it wasdried and heated. Usher (1977) suggested thatthe presence of a template should promote suchreactions. Earlier McHale and Usher (1976)had shown that 6-mers of adenylic acid couldform a phosphodiester bond to give a 12-mer,if a polyuridylic acid template was present.

Although anhydrous heat would appear tobe a plausible source of energy to drive prebioticcondensation reactions, there are two problemswith this approach. The first is obvious: In a drystate, potential reactants are trapped in a solidand diffusion is minimized, so that bondformation is limited to interactions betweenneighboring molecules. The second problem isthat multiple reactions become activated astemperature increases, with the result that non-specific chemical bonds begin to form, ulti-mately producing polymerized tars. But attemperatures between 608 and 808C, it may bepossible to organize reactants in such a waythat bond formation is more specific. Cyclingbetween hydrated and anhydrous conditionscould then drive the synthesis of specific kindsof polymers. Furthermore, if the dry phase ofa condensation reaction is cycled repeatedlythrough a hydrated phase, the reaction canlead to the accumulation of more complexproducts, as is discussed in the next section.

It seems reasonable to expect that smallamounts of organic compounds would occurin the prebiotic environment, but they wouldbe present as complex mixtures with inorganicanions and cations. The prebiotic environmentwas likely to have thousands of different organiccompounds dissolved in a global ocean andlacustrine bodies of fresh water that accumu-lated on volcanic land masses rising above theocean. The mixture would contain biologicallyrelevant compounds such as amino acidsand sugars, largely as racemic mixtures of theirD and L enantiomers. Because the organiccompounds would be present as very dilutesolutions, it is essential to discover processesby which such compounds could be concen-trated and organized to participate in intermo-lecular reactions such as polymer synthesisand protocell assembly needed for the originof life.





There are two obvious ways in which dilutesolutions can be concentrated. The simplest isthe input of heat energy to evaporate the solu-tion onto mineral surfaces. For instance, evapo-rating a volume of water containing one micro-mole of an organic solute such as an aminoacid evenly spread onto a mineral surface areaof 100 cm2 will form a film approximately 10molecules thick. During the last stages of eva-poration, the concentration of solutes passthrough molar concentrations, thereby promot-ing any chemical reactions that could not occurspontaneously in dilute solutions. Subsequentwetting cycles would release the products intothe environment for further processing.

The second process, originally proposed byBernal (1951), is that clay surfaces strongly ad-sorb organic compounds from dilute solutionsand thereby concentrate them. Furthermore,the orderly arrangement of charged groups inthe crystal structure of the clay can impose orderon the adsorbed solutes and thereby promotepolymerization reactions. A good example isthe polymerization of activated nucleotides intoshort molecules of RNA, to be discussed later inthis article (for review, see Ferris 1999, 2002).

It is interesting to note that simple freezingis also a process that concentrates potential reac-tants in an otherwise dilute solution. As a solu-tion freezes, the microscopic crystals thatinitially form are nearly pure ice, so that solutesare concentrated into fluid eutectic phasesbetween the crystals. Freezing has been used topromote nucleobase synthesis in frozen cyanidesolutions (Miyakawa et al. 2002) and Kanavar-ioti et al. (2001) found that oligomers of RNAwere synthesized from activated nucleotidesfrozen at 2188C. (See Orgel 2004 for review.)Although extensive ice on a hot early Earthseems unlikely, there is still uncertainty aboutactual temperatures available in specific sites,so ice eutectics cannot be dismissed as a meansto concentrate dilute reactants in solution.

Thermal Energy Storage in PyrophosphateBonds

Most chemical energy in cells today circulates inthe cytoplasm as ATP. Although cells use ATP to

drive synthetic reactions, ATP is not a primaryenergy source, but rather is an energy transfermolecule that picks up energy from an energysource and then delivers it to energy-requiringreactions. This constant resynthesis (cycling)of ATP inside the cell is revealed by estimatesshowing that to synthesize 1 g of cell mass re-quires the energy of about 20–100 g of ATP(Stouthamer 1977). The chemical energy con-tent of ATP is present in the pyrophosphatebonds that link the second and third phosphategroups of ATP. These are anhydride bonds, andtheir chemical energy is released by energeticallydownhill group transfer reactions of the phos-phate group to other molecules, an activatingprocess called phosphorylation. The secondmolecule gains chemical energy and can inturn undergo reactions that otherwise will notoccur. Classic examples include the formationof aminoacyl-tRNA in protein synthesis, oracetyl-CoA in fatty-acid synthesis.

The question is whether pyrophosphatebond energy could have been a significantsource of chemical energy in the reactions lead-ing to the origin of life. In fact, phosphate is suchan integral part of all contemporary life thatphosphorylation reactions must have beenincorporated in primitive metabolic pathways.Baltscheffsky (1996) has argued that this is plau-sible, in part because pyrophosphate and poly-phosphates are readily produced simply byheating inorganic phosphate under anhydrousconditions, a process known to occur undernatural conditions. Pyrophosphate-containingminerals, canaphite and wooldridgeite, havebeen discovered in quarries, albeit in minute qu-antities and in the form of microscopic crystals.Furthermore, Baltscheffsky found that the cou-pling membranes of a photosynthetic bacterialspecies—Rhodospirrilum rubrum—synthesizepyrophosphate instead of ATP. The R. rubrumuse the pyrophosphate as an energy source,much as other organisms use ATP.

Despite the ease of capturing thermal dehy-dration energy as pyrophosphate bonds, a plau-sible pathway for incorporating it as an energysource in early life has not yet been established.This is well worth further study, as is discussedin the last section of this article.





Sunlight and Photochemical Energy

Light only becomes a useful energy sourceif there is a pigment to absorb the photons.When photons are absorbed by a pigment mol-ecule, they interact with the electronic structureof the molecule and add energy to the bonds toproduce an excited state. This seemingly simplephotochemical reaction is the energetic founda-tion of most life on the Earth, because this iswhat happens when a chlorophyll moleculeabsorbs light. Starting with chlorophyll in itsground state, a photon of red light is absorbedand increases the energy content of chlorophyll.The added energy causes it to go to an excitedstate that then donates an electron throughmultiple reactions to carbon dioxide, whichends up after further reactions as a carbohy-drate. In addition, the transfer of the electronto lower energy states is coupled to the genera-tion of a proton gradient across the membranethat is used to drive ATP synthesis. In this way,the original light energy is conserved in theform of chemical energy. After it loses the elec-tron, chlorophyll is positively charged and theelectron is replaced from a water molecule inthe “water splitting reaction,” which releasesoxygen. This is the source of virtually all of theoxygen in the Earth’s atmosphere.

If photochemistry is essential for life today,could it also have provided energy for the originof life? Perhaps, but there is a problem: Whatpigment molecules were available? Certainlynot chlorophyll, which is a very complex mole-cule requiring multiple enzymatic steps for itssynthesis. Furthermore, even if primitive pig-ments were present, the capture of light energywould not be possible unless there were mem-branes available that could contain the pigmentmolecules. To process the absorbed light energy,a primitive cell would also require a system ofelectron transport molecules to transduce thelight energy into chemical energy. Future re-search might someday discover a mechanismby which this seemingly complex series of reac-tions could arise, but until then it seems plausi-ble that an energy source other than light wasused by the first living cells. In other words,the first life was likely to be heterotrophic.

Geological Electrochemical Energy

The electrochemical reactions used by aerobiclife today require oxygen produced by plants.In mitochondria and aerobic bacteria, an elec-tron transfer from reduced substrates to mo-lecular oxygen produces 0.2 volts and enoughprotonic current to synthesize ATP. It is im-probable that a complete chemiosmotic systemwas available to the first forms of life, butsimpler electrochemical reactions are still con-ceivable mechanisms in which donors and ac-ceptors of electrons provide an energy source.Several potential donors were likely to be avail-able in the prebiotic environment. Perhaps themost plausible is hydrogen gas itself, as well ashydrogen sulfide (H2S) and methane. A varietyof microorganisms today use these gases as asource of electrons, a good example being theabundant bacteria present in hydrothermalvents. There is a consensus that little or no oxy-gen was present in the early atmosphere, so whatelectron acceptors might have served instead ofoxygen? A useful list of potential anaerobicdonors and acceptors was presented by Gaidoset al. (1999), who considered the interestingquestion of energy sources that might be avail-able in a putative ocean beneath Europa’s icysurface. Terrestrial anaerobes use sulfate, nitrate,iron (III), and manganese (IV) as electronacceptors, with CO, nitrite, and hydrogen sul-fide as electron donors. Sulfate would be abun-dant on the early Earth, as it is today. Nitrateand nitrite could have been made on the prebi-otic Earth from nitrogen gas by photochemicalsynthesis and aqueous processes (Summers andKhare 2007) and in high pressure geochemicalprocesses (Brandes et al. 1998). In addition,Cody et al. (2000, 2004) have shown how sulfideminerals could have been involved in primitivemetabolic pathways.

Energy and Sulfur Chemistry

Sulfur chemistry is of particular relevance tothe origin of life, because the minimal amountof molecular oxygen in the prebiotic environ-ment would allow sulfur to be abundant as anelement, as a reduced gas (hydrogen sulfide),





and as iron sulfide minerals. Taking into consid-eration this prebiotic context, Wachtershauser(1988) proposed that life did not arise by assem-bly of pre-existing organic compounds, butinstead as two-dimensional synthetic chemistryon an iron sulfide mineral surface called pyrite.According to this idea, when hydrogen sulfidereacts with iron in solution to produce insolubleiron sulfide mineral, the reaction generateselectrons that can be donated to the bound com-pounds and thereby drive a series of energeti-cally uphill chemical reactions that otherwisecannot take place in solution. Wachtershausersees these reactions as the beginning metabo-lism, which occurred on a mineral surface ratherthan in the volume of a cell. To test this idea,Huber and Wachtershauser (1997) heated a dis-persion of iron and nickel sulfides together witha source of carbon and analyzed the products.There was no evidence of a long chain of inte-grated reactions, but using CO and H2S, aceticacid was produced, and from CO and CH3SHthe thioester CH3-CO-SCH3 was synthesized.In later work in which amino acids were addedto the simulation (Huber and Wachtershauser1998; Huber et al. 2003), the amino acids wereobserved to be chemically activated and formedpeptide bonds.

DeDuve (1991) has proposed another ver-sion of sulfur chemistry as a source of chemicalenergy related to the origin of life, which in-volves thioesters that could have served to acti-vate energy-dependent steps in primitivemetabolic pathways before the advent of ATP.Thioesters are synthesized when a water mole-cule is lost during the reaction of an organicacid and a thiol: R-COOHþR’-SH – .

R-CO-SR’. Unlike the relatively low-energy con-tent of an ester bond, the thioester bond has anenergy content equivalent to the pyrophosphatebond of ATP. Earlier Weber (1984, 1998) hadshown that a-hydroxy acid and a-amino acidthioesters could be synthesized by reacting sug-ars (or sugar precursors) with ammonia and athiol under plausible prebiotic conditions.

Several investigators have incorporated sul-fur chemistry in their research. Wieland (1953)originally showed that amino acid thioestersspontaneously form peptide bonds in aqueous

solution, and Maurel and Orgel (2000) showedthe elongation of a decapeptide of oligoglutamicacid up to 15 mers in the presence of thiogluta-mic acid. Zepik et al. (2006) extended this reac-tion to protocells by encapsulating decaglutamicacid in liposomes composed of dimyristoyl-phosphatidylcholine, and found that externallyadded thioglutamic acid was able to permeatethe vesicle membrane at a rate sufficient tosupport elongation of the decapeptide withinthe vesicles. It is clear that sulfur chemistry hasconsiderable potential for expanding our under-standing of early bioenergetic processes.

Chemiosmotic Energy Conversion toAnhydride Energy

Life today uses either chemiosmosis or sub-strate-level phosphorylation to convert electro-chemical energy to anhydride chemical energyof ATP (Mitchell 1961, 1966). Was chemios-mosis an ancient process used by the first cells,or a later discovery? Arthur Koch (1985) first ad-dressed this question and speculated that chem-iosmosis may have arisen in the first forms ofprimitive cellular life, and this conjecture isworth considering here. Three relevant postu-lates of chemiosmosis are listed below:

† Coupling membranes maintain a protongradient, and the gradient must be of suffi-cient magnitude to drive ATP synthesis.

† Coupling membranes pump protons by elec-tron transport using either light or electron-transfer as an energy source.

† Coupling membranes contain an ATPasethat is also a proton pump.

The lipid composition of biological membranestoday contains specific lipids that are productsof highly evolved metabolic pathways. A stablehydrophobic lipid bilayer barrier composed ofhydrocarbon chains 16–18 carbons in length isrequired to maintain ionic concentrationgradients, particularly protons in the case of cou-pling membranes. Lipid bilayers are notoriouslyleaky to protons (Nichols and Deamer 1980;Paula et al. 1996), so the first self-assembledmembranes composed of relatively short-chain





amphiphiles would be unable to maintain signif-icant proton gradients, as recently shown byChen and Szostak (2004). Mansy (2010) dis-cusses the role of membrane permeability inprimitive cellular systems. Even if a plausibleprimitive barrier membrane can be discovered,an electron transport system and ATP synthasewould need to be incorporated in the bilayerfor chemiosmosis to be a source of chemicalenergy. In our judgment, the complex require-ments for a functioning chemiosmotic systemweighs against the proposition that primitivelife used chemiosmosis for converting electro-chemical energy to the anhydride energy of ATP.

Chemical Energy of Organic Substrates:Carbohydrates

The environment of the prebiotic Earth was farfrom equilibrium, so that a variety of chemicalreactions were occurring simultaneously. Theproblem is to gain some understanding of whichof these was relevant to the origin of life, andhow they were incorporated. Living systemstoday use chemical reactions to release energyin small steps called metabolism, which can bedefined as a series of chemical reactions linkedin a molecular system that provides energy andsmall molecules required for growth. Each stepis catalyzed by a specific enzyme, and the reac-tion rates are controlled by feedback loops inwhich a product is an allosteric inhibitor ofthe enzyme to be regulated. If the first life washeterotrophic, what nutrients might have beenavailable as a source of chemical energy?

Of all the organic substrates, sugars are byfar the most attractive organic energy substrateof primitive anaerobic life, because they areable to provide all the energy and carbon neededfor the growth and maintenance of a fermenta-tive metabolism. In fact, the sugars that are thefirst substrates of the glycolytic pathway can beconsidered to be optimal biosynthetic sub-strates because they contain mainly alcoholgroups that have maximum self-transformationenergy, and a single carbonyl group (aldehydeor ketone) that makes them reactive and ableto form covalent adducts to enzyme active sites(Weber 2004). Moreover, in fermentation, the

energy content of sugars is converted to theanhydride energy of ATP by substrate-level oxi-dation phosphorylation, a process that does notrequire the organized membrane structures ofphosphorylation coupled to electron transfer.As discussed later, the energy content and reac-tivity of sugars also allows them to act as sub-strates for chemically spontaneous syntheticprocesses that yield many of the molecularproducts required for the origin of life. Suchsugar-driven syntheses require no externalsource of chemical energy (Weber 2000).

RECENT EXPERIMENTAL STUDIES

Sugar-driven Prebiotic Synthesis

In addition to being the sole energy and carbonsource of fermentative organisms today, sug-ars have chemical properties that make themvery attractive substrates for synthetic processesneeded for the origin of life. First, sugars canbe synthesized under plausible prebiotic con-ditions from formaldehyde and glycolaldehydeby the formose reaction (Schwartz and deGraaf 1993; See also Benner et al. 2010). Second,sugars are reactive and contain considerable self-transformation energy, properties that allowthem to react with ammonia, yielding manytypes of molecules needed for the origin of life.These sugar-driven syntheses require no addi-tional source of chemical energy (Weber 2000).

The synthetic versatility of sugars is shown bytheir spontaneous reactions in the presence ofammonia that yield catalytic amines, biomono-mers (amino acids), metabolites (pyruvate, gly-colate), energy molecules (hydroxy and aminoacid thioesters), alternative nucleobases (2-pyra-zinones that resemble uracil), heterocyclic mole-cules (furans, pyrroles, imidazoles, pyridines,and pyrazines), polymers (polypyrroles and pol-yfurans), and cell-like organic microspherules(Weber 2001-2008, refs. therein). Sugars havealso been shown to drive the prebiotic synthesisof ammonia from nitrite. Remarkably, these pre-biotic synthetic processes based on sugar chemis-try can evolve directly into modern sugar-drivenbiosynthesis without violating the principle ofevolutionary continuity.





Finally, sugar synthesis from formaldehydeand glycolaldehyde, and the subsequent conver-sion of sugar products to carbonyl-containingproducts can be catalyzed by small molecules(ammonia and amines including amino acidsand peptides). In fact, small L-dipeptides (theisomer found in proteins) stereoselectively cata-lyzed the formation of D-ribose (Pizzarelloand Weber 2010). These ammonia and amine-catalyzed reactions yielded aldotriose (glyceral-dehyde), ketotriose (dihydroxyacetone), aldote-troses (erythrose and threose), ketotetrose(erythrulose), pyruvaldehyde, acetaldehyde,glyoxal, pyruvate, glyoxylate, and several un-identified carbonyl products. The uncatalyzedcontrol reaction yielded no pyruvate or glyoxy-late, and only trace amounts of pyruvaldehyde,acetaldehyde, and glyoxal. With L-alanine, therates of triose and pyruvaldehyde synthesiswere about 15-times and 1200-times faster, re-spectively, than the uncatalyzed reaction (Weber2001). Because amines are also products of sug-ar–ammonia reactions, these studies suggestedthat the sugar–ammonia reaction could be au-tocatalytic. This possibility was tested in a laterstudy, which showed that reaction of the triosesugar (glyceraldehyde) with ammonia yieldeda crude product mixture capable of catalyzinga 10-fold acceleration of the same sugar–am-monia reaction that produced the catalyticproducts (Weber 2007).

Amphiphile Synthesis Using GeothermalEnergy

Franz Fischer and Hans Tropsch discovered inthe 1920s that a gaseous mixture of carbonmonoxide and hydrogen, when passed over ahot iron catalyst, produced excellent yields ofhydrocarbons. Oro and coworkers (Nooneret al. 1987) first showed that the Fischer-Tropschtype synthesis (FTT) also worked with mete-oritic iron-nickel as a catalyst, and proposedthat long-chain fatty acids may have been pro-duced this way on the early Earth. McCollomet al. (1999) and Rushdi et al. (2001) foundthat the FTT reaction also worked simply bytreating oxalic acid to elevated temperatures1508–2508C and corresponding pressures in a

stainless steel chamber, producing a mixtureof fatty acids and alcohols as products. At elev-ated temperatures, oxalic breaks down into amixture of CO, CO2, and H2, the reactive gasesrequired for FTT synthesis. In a later paper,Simoneit et al. (2006) found that if stoichiomet-ric glycerol was present in the mixture alongwith a variety of fatty acids, the same conditionsproduced good yields of monoglycerides.

These results are significant because themajority of membrane-forming lipids todayare glycerol esters. Furthermore, monoglycer-ides by themselves can assemble into lipid bi-layers, and when mixed with fatty acids are ableto form stable membranes (Monnard et al. 2002;Mansy and Szostak 2008). Future research in thisarea should be directed toward characterizingsuch membranes in terms of long-term stabilityand capacity for maintaining ionic concentra-tion gradients of protons and other cations.

Phosphodiester Bond Synthesis Driven byAnhydrous Cycles

Clay mineral is a common example of an organ-izing surface. Clays have a surprisingly largecrystalline surface area, over 100 m2/g, andhave a multilamellar structure that seems likelyto adsorb, concentrate, and organize potentialmonomers on and between the lamellae. Ferrisand coworkers (1996) have made extensivestudies of montmorillonite clay as an organ-izing agent, and established that activatedmonomers of mononucleotides can in factpolymerize on clay surfaces into RNA-like pol-ymers up to 50 nucleotides in length containingboth 30–50 and 20 –50 phosphodiester bonds.However, the resulting polymers are tightlybound to the clay surfaces, and if they are toparticipate in the origin of cellular life, theRNA products must somehow be associatedwith membranous vesicles to form a protocellu-lar system. Significantly, Hanczyc et al. (2003)found that clay particles with bound RNAwere readily encapsulated in fatty-acid vesicles.

It is not generally realized that lipids alsoform multilamellar structures that have thepotential to organize and concentrate mono-mers. The most common image of lipids is in





the form of microscopic vesicles bounded by alipid bilayer membrane, usually referred to asliposomes. However, in the dry state, lipids arepresent as multilamellar matrices consisting ofstacked bilayers, or less often as hexagonalphases in which the lipids form indefinitelylong tubes that tend to have a hexagonal pack-ing, rather than lamellar (Reiss-Husson andLuzzati 1967; Deamer et al. 1970). Furthermore,if lipid vesicles undergo drying, the bilayers fuseinto the multilamellar phase, and any solutespresent are trapped and concentrated betweenthe lipid head groups of bilayers. Unlike the sol-id matrix of clay surfaces, the bilayers are liquidcrystals, which means that trapped solutes havediffusional mobility.

Rajamani et al. (2008) investigated the possi-bility that the order imposed on mononu-cleotides by multilamellar lipid matrices couldpromote polymerization. The nucleotides usedwere ordinary 50-ribonucleotides that had notbeen chemically activated. Instead, the chemicalpotential for ester bond formation was providedby cycling through anhydrous conditions atmoderately elevated temperatures in the rangeof 608–908C. Thermal cycling of the mononu-cleotides in mass ratios from 2:1 to 1:2 with thephospholipids was shown to yield relativelylong chains of linear RNA-like polymers, rangingfrom 20 to 100 nucleotides in length. The linear-ity was determined by nanopore analysis of theproducts, and the RNA-like character was estab-lished by 32P-end labeling with T7 RNA kinase.A variety of phospholipids could promote thepolymerization, but in the absence of lipids,only short nucleotide oligomers were detected.

These results show that there is sufficientchemical potential available in anhydrous con-ditions to drive phosphate ester synthesis aslong as the nucleotide monomers are concen-trated and organized within a fluid liquid crys-talline matrix that permits diffusional mobility.Furthermore, at the end of the reaction whenthe lipid matrix is rehydrated, the products ofthe reaction are encapsulated in lipid vesicles.This appears to be a plausible pathway to pro-tocells, which could be generated at the edgesof volcanic geothermal pools where wet–drycycles would be common.

Carbonyl Sulfide as a Plausible PrebioticCondensing Agent

At some point, polymerization reactions musthave evolved from simple processes driven byan input of physical energy to a more complexmechanism involving primitive versions of acti-vation occurring in an aqueous environment.For many years, research has focused on discov-ering a plausible condensing agent that can per-form this feat, and recent discoveries suggestthat carbonyl sulfide is a likely candidate. Car-bonyl sulfide (COS) is a reactive compoundthat has been detected in volcanic gas and min-eral ash (Rasmussen et al. 1982), along with itschemical relatives, carbon disulfide and carbondioxide. Leman et al. (2004) found that if COS ispresent in an aqueous solution of amino acids,di- and tripeptides are synthesized with yieldsup to 80%. In a second paper, Leman et al.(2006) reported that amino-acyl phosphate an-hydrides up to 30% yields were synthesized inmixtures of amino acids, phosphate, and COS.

These results offer a strong clue to the man-ner in which phosphate was initially incorpo-rated into primitive metabolic pathways, partic-ularly those leading to peptide bond formationand the synthesis of small oligopeptides thatmay have served as catalysts and structural com-ponents of early life.

Novel Prebiotic Synthesis of Nucleotides

The nucleotide monomers of nucleic acids con-sist of a purine or pyrimidine linked througha nitrogen–carbon bond to a pentose sugar,which in turn is phosphorylated through anester bond on the 50 hydroxyl group. Each of thecomponent molecules of nucleotides was pre-sumably present in organic mixtures on the pre-biotic Earth, but must be linked into the morecomplex molecular structure of nucleotides be-fore they can be incorporated into nucleic acidpolymers. One might imagine that phosphory-lation of a ribose sugar could occur, becauseester bonds are not difficult to synthesize bysimple condensation reactions, but synthesisof the C-N bond between a sugar and a nucleo-base has been much more challenging.





A recent paper by Powner et al. (2009) (seealso Sutherland 2010) reported a remarkablyefficient series of reactions that leads to mono-nucleotide synthesis. Instead of attempting toproduce C-N bonds between an existing pyri-midine such as cytosine and ribose, the reactionuses sequential additions of cyanamide, cya-noacetylene, glycolaldehyde, and glyceralde-hyde, all in the presence of phosphate. Underthese conditions, spontaneous reactions firstform arabinose aminooxazoline and anhy-dronucleoside intermediates, which then addphosphate and condense into cytosine mono-phosphate. Although it is unlikely that such acomplex mixture of reactants and phosphatemight occur in the prebiotic environment, thefact that the reaction can occur at all in aqueoussolution, using only the chemical energy of thereactants, opens a new direction for future in-vestigations that may reveal a simpler process.

CHALLENGES AND FUTURE RESEARCHDIRECTIONS

Identifying a Source of Condensation Energy

In this article, we briefly touched on processesby which certain kinds of energy could havedriven chemical reactions related to the originof life. There is a consensus that electrical dis-charge and ultraviolet light could drive the syn-thesis of reactive molecules like cyanide andformaldehyde, which in turn would react toproduce more complex molecules that couldserve as potential monomers for primitiveforms of life. However, a plausible energy sourcefor polymerization remains an open question.Condensation reactions driven by cycles ofanhydrous conditions and hydration wouldseem to be one obvious possibility, but seemlimited by the lack of specificity of the chemicalbonds that are formed. On the other hand, theremay be conditions yet to be discovered thatorganize monomers in such a way that the for-mation of specific chemical bonds is promoted.The organizing effect of clay mineral surfaces isone well-known example, and incorporation ofmonomers into orderly lipid matrices also pro-motes specific polymerization reactions. Future

studies of conditions that can add order to reac-tive monomers are likely to reveal new clues toplausible polymerization processes that couldoccur in the prebiotic environment.

An alternative to anhydrous heat is a con-densing agent such as carbonyl sulfide, whichcan activate peptide bond and phosphanhy-dride bond synthesis in aqueous solutions.This discovery certainly deserves further atten-tion. So far, only short oligomers have been pro-duced using COS and dilute monomers, butconditions that can concentrate and organizethe reactants are likely to produce much longerpolymers. Related to carbonyl sulfide as acondensation agent is the energy available inthioester bonds (DeDuve 2005). Although mo-lecular oxygen was virtually absent from the pre-biotic atmosphere, its neighbor in the periodictable—sulfur—was abundant, both as an ele-ment and in common gases such as H2S andCOS. Therefore, it seems probable that sulfurwas incorporated into a variety of organic mol-ecules, and further studies of the thioester bondas a plausible intermediate in primitive meta-bolic pathways should be fruitful.

A third source of energy for polymerizationprocesses is the chemical potential of simple car-bohydrates. Sugars, when heated near 708C inthe presence of ammonia or amines, are knownto produce polymers containing furan andpyrrole residues, and cell-like microspherules(Weber 2005, refs. therein). Sugars also drivethe synthesis of a-hydroxyacid thioesters anda-amino acid thioesters that are known to oligo-merize forming polyesters and peptides, respec-tively (Weber 1998, refs. therein). In addition,in his description of the sugar-driven synthesisof uracil-like 2-pyrazinone, Weber (2008) pro-posed that sugars also have the potential to formpyrazinone monomers witha-hydroxycarbonylside-chain groups (CH2OH-CO-CH2-pyrazi-none) that could spontaneously polymerize togive oligomers joined by enol ether linkages ordehydrated aldol linkages. In contrast to otherprebiotic syntheses, the previously cited sugar-driven processes are “one-pot” reactions thatyield reactive monomers capable of spontaneousoligomerization without being coupled to anadditional source of chemical energy, like ATP.





Phosphate Reactions

There are good reasons why phosphate is centralto energy metabolism today. These were de-scribed by Westheimer (1987) in an excellentreview that should be required reading for stu-dents interested in the origins of life. An impor-tant, still unanswered question concerns howphosphate might have first become involved inlife processes. Phosphate today is mostly presentin the form of a mineral called apatite, the samecombination of calcium and phosphate thatcomposes tooth enamel and bones. Apatite hasa very low solubility, so what was the originalsource of a soluble form of phosphate? Thereare no convincing explanations yet, but it is pos-sible that life began in a low pH environmentsimilar to that of volcanic hydrothermal springs.Calcium phosphate readily dissolves at acidic pHranges to release phosphate anions. The presenceof free phosphate insolutionmay havepermittedincorporation into organic compounds as phos-phate esters, followed by a second set of chemicalreactions that initiated primitive metabolicpathways involving phosphate. For instance,Prabahar and Ferris (1997) reported that ade-nine itself is able to activate phosphate undercertain conditions. Identifying a plausible mec-hanism for prebiotic phosphorylation repre-sents an important problem for future research.

Pigments and Photosynthesis

Sunlight drives virtually the entire biospheretoday, but when and how did life first begin tocapture light as an energy source? Althoughtoday’s photosynthetic process seems muchtoo complex to have been a source of energyfor early life, there must have been some sort ofpigment available that could begin capturinglight energy in a useful way and initiate the evo-lutionary path toward modern photosynthesis.Pteridines are examples of relatively simplepigment molecules that can be generated fromamino acids exposed to anhydrous heat. Thisreaction and potential roles of pteridines in theorigin of life have been extensively explored byKritsky and coworkers and deserve further study(for review, see Kritsky and Telegina 2004).

An alternative scenario is that pigmentsexisted in the environment that partitionedinto lipid bilayers of membranes in such a waythat light energy could be transduced intochemical energy. Were organic molecules pre-sent in the prebiotic environment that mightserve as membrane-bound pigments? Polycyclicaromatic hydrocarbons (PAH) are abundantforms of organic carbon, and most PAH speciesabsorb light in the near UV and blue region ofthe spectrum. After accepting photons, theexcited states can act as reducing agents andrelease protons, thereby generating chemios-motic pH gradients (for review, see Deameret al. 1994). Another interesting photochemicalreaction of PAH derivatives is photocarboxy-lation. For instance, when exposed to near UVlight, phenanthrene reacts directly with carbondioxide to produce phenanthrene carboxylicacid, probably the simplest possible exampleof carbon dioxide fixation (Tazuke et al. 1986;See Deamer 1997 for review). These propertiesof PAH compounds have yet to be exploredthoroughly and surely represent a fruitful areafor future research.

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January 13, 20102010; doi: 10.1101/cshperspect.a004929 originally published onlineCold Spring Harb Perspect Biol

David Deamer and Arthur L. Weber Bioenergetics and Life's Origins

Subject Collection The Origins of Life

Constructing Partial Models of Cells

et al.Norikazu Ichihashi, Tomoaki Matsuura, Hiroshi Kita,

The Hadean-Archaean EnvironmentNorman H. Sleep

RibonucleotidesJohn D. Sutherland

An Origin of Life on MarsChristopher P. McKay

Characterize Early Life on EarthHow a Tree Can Help−−Deep Phylogeny

RandallEric A. Gaucher, James T. Kratzer and Ryan N.

Primitive Genetic PolymersAaron E. Engelhart and Nicholas V. Hud

Medium to the Early EarthCosmic Carbon Chemistry: From the Interstellar

Pascale Ehrenfreund and Jan Cami

Membrane Transport in Primitive CellsSheref S. Mansy

Origin and Evolution of the RibosomeGeorge E. Fox

The Origins of Cellular LifeJason P. Schrum, Ting F. Zhu and Jack W. Szostak

BiomoleculesPlanetary Organic Chemistry and the Origins of

Kim, et al.Steven A. Benner, Hyo-Joong Kim, Myung-Jung

From Self-Assembled Vesicles to ProtocellsIrene A. Chen and Peter Walde

the Origins of LifeMineral Surfaces, Geochemical Complexities, and

Robert M. Hazen and Dimitri A. Sverjensky

The Origin of Biological HomochiralityDonna G. Blackmond

Historical Development of Origins ResearchAntonio Lazcano

Earth's Earliest AtmospheresKevin Zahnle, Laura Schaefer and Bruce Fegley

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Bioenergetics and Life’s Origins - CSHL Pcshperspectives.cshlp.org/content/2/2/a004929.full.pdf · Bioenergetics and Life’s Origins David Deamer1 and Arthur L. Weber2 1Department