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The Origins Divide: ReconcilingViews on How Life Began

MELISSA LEE PHILLIPS

Did life begin in heat or cold, in a reducing or oxidizing atmosphere, at the ocean

surface or in the deepest sea, with a membrane-enclosed genetic molecule or as a flat

collection of chemical reactions on a rock?

F our and a half billion years ago, theplanet Earth coalesced out of thegas and dust left over from the forma-tion of the sun. For the next severalhundred million years, the youngplanet was bombarded by comets andmeteorites, volcanic eruptions ragedacross its surface, and its heat boiledthe nascent oceans. But within abouta billion years-and perhaps muchearlier-life had arisen.

How nonliving chemicals trans-formed into living molecules is one ofthe biggest mysteries in science, andwe might never know for sure howit happened. Deep divides in opin-ion are found in almost all areas oforigin-of-life research. Did life beginin extreme heat or relative cold? Wereits essential molecules synthesized inthe prebiotic ocean, at the mouthsof churning deep-sea vents, or didthey rain down from space? Did thefirst life-form get its energy from thesun or from the chemical energy ofminerals? Were inherited genetic mol-ecules essential to the first life-form,or could life simply have been a chainof chemical reactions taking place ona rock?

"If we're going to make any prog-ress, we really have to be critically

honest about what we don't know,"says geochemist George Cody, of theCarnegie Institution for Science inWashington, DC. "And that's just abouteverything."

The questions surrounding life'sorigins are indeed vast and, for themost part, unanswered. A compre-hensive explanation of the origin oflife will require pinning down thebeginnings of DNA (deoxyribonucleicacid) and RNA (ribonucleic acid), ofproteins and lipid membranes, of ge-netic coding and metabolic machinery.In modern life, all of these moleculesand processes are so intertwined thatit's difficult to imagine how any ofthem could have arisen without theothers already in place. Chicken-and-egg problems abound.

But new technologies, hypotheses,and experiments are constantly surfac-ing, and each step reveals a bit moreof the way the inanimate chemistry ofEarth's beginnings may have morphedinto the remarkable variety of life wesee today.

BeginningsThe basis of origin-of-life thoughtlies perhaps with Louis Pasteur's dis-proof of spontaneous generation: If

life couldn't arise out of nothing, thenwhere did it come from? A few yearslater, Darwin speculated about chemi-cal reactions in a "warm little pond"and Alexander Oparin and J. B. S.Haldane independently took that ideaa step further by proposing that lifebegan in a primordial ocean of organicmolecules.

Origin-of-life research didn't get itsexperimental start, however, until thefamed chemical synthesis experimentsof Stanley Miller and Harold Urey, ofthe University of Chicago, were pub-lished in 1953. By sending an electricalcurrent through a mixture of water,methane, ammonia, and hydrogen, theysimulated what might have happenedwhen lightning struck the oceans andatmosphere of ancient Earth. What theygot-a mixture of key amino acids andother organic molecules-profoundlychanged views of the origin of life. Theorigin of biology was now experimen-tally approachable.

Other groups soon conductedsimilar experiments, and in thefollowing years, researchers managedto synthesize not only additionalamino acids but also other essentialbiomolecules, including sugars,metabolic acids, and lipids.

BioScinae 60: 675-680.() 2010 Melissa Lee Phillips. ISSN 0006-3568, electronic ISSN 1525-3244. All rights reserved. doi:10.1525/bio.2010.60.9.3

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By sending an electrical current through a mixture of water, methane,ammonia, and hydrogen, Stanley Miller and Harold Urey simulated whatmight have happened when lightning struck the oceans and atmosphere ofancient Earth. The resulting mixture of key amino acids and other organic

molecules profoundly changed views of the origin of life. Graphic: User: Carny(he.wikipedia.org), User: Yassine Mrabet (en.wikipedia.org).

More recently, some research hassuggested that Miller's synthesis mightnot have worked after all. Some dataon the likely atmospheric compositionof early Earth have suggested that itactually contained very little methaneor ammonia, and was instead primarilycomposed of nitrogen and carbondioxide-far less reactive gases. Butother work has since countered thatearly Earth could have had a reducingatmosphere full of hydrogen. "Rightnow, you can have it either way, ifyou cite the appropriate papers," saysorganic chemist Jeffrey Bada, of theScripps Institution of Oceanographyin La Jolla, California.

The lack of confidence in the natureof prebiotic Earth's atmosphere holdsback much origins research. Under-standing Earth's early atmosphericcomposition could set rather stringentconstraints on how and where life

might have arisen, but most of thefirst half-billion years of Earth's rockrecord has been recycled back intothe interior of the planet. The earlyatmospheric record "just doesn't exist,"says Jim Cleaves, also of the CarnegieInstitution. "It leaves the whole prob-lem open to speculation."

It's possible, however, that theatmosphere of early Earth may not endup being relevant to the origin of life.Work by Cleaves suggests that importantmolecules could have been synthesizedlocally at gas-belching volcanoes, even ifthe worldwide atmosphere wasn't sup-portive. "I'm not at all convinced thatthe composition of the atmosphere is acentral issue," Bada says. "You can imag-ine local syntheses all over the surfaceof the Earth, so the composition of theglobal atmosphere might not matter:"

Other researchers believe that lifedidn't originate on Earth's surface

at all. Since the 1977 discovery ofelaborate ecosystems near deep-seahydrothermal vents, many scientistshave come to view this environment asperhaps uniquely suitable to nurturingthe beginnings of life. At these vents,hot, mineral-rich water surges fromthe planet's interior into the coolocean above. The chemical and ther-mal disequilibrium between these twowater sources provides the energy thatlocal microorganisms need to survive."In my view, it seems like the mostlikely place to look for somethinginteresting to occur," Cody says.

Miller and his students and colleagueshave expressed doubt about marinevents' role in the beginnings of life,however. They claim that hydrothermaltemperatures are too hot for essen-tial biomolecules to survive, although"ventists" have countered that thesurrounding cold ocean water wouldallow these molecules to remain intact.

Yet another possible origin oflife's important biomolecules liesfar beyond the surface of the Earth.Analyses of carbon-rich meteoritesfound on Earth have revealed aminoacids and other important organicmolecules that appear to have beensynthesized in deep space and thendelivered to Earth. Some scientistshave also criticized this hypothesis,questioning whether significantamounts of organic molecules couldsurvive crashing into the planet. Butwork from Jennifer Blank, of the SETIInstitute in Mountain View, California,has suggested that although violentimpacts may reduce the quantity oforganics delivered to Earth's surface,they can actually induce chemicalreactions that lead to a more diversecollection of biologically relevantmolecules.

Many researchers now believe thatlife's basic building blocks came notfrom one place but from many: theearly ocean and atmosphere, ancientvolcanoes, the crust in the bottom of theocean, and the reaches of deep space.

The origins of geneticsWhile basic building blocks such asamino acids and sugars may have

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Many organic chemists have spent the past few decades trying to figure out how RNA could have spontaneously assembledfrom the simple organic molecules found on early Earth. One theory is that the structure of montmorillonite clay,

diagrammed here, could have acted as a scaffold for the assembly of RNA from its building blocks. Graphic: Andreas Trepte,User: Itub (en.wildpedia.org).

been plentiful on early Earth, thesemolecules are a far cry from proteins,nucleic acids, and cell membranes-life's essential macromolecules. Muchorigins research over the past 50 yearshas focused on how these larger struc-tures assembled themselves.

The question of how DNA andproteins could have arisen at firstseemed intractable: DNA encodesproteins, but protein catalysts arerequired to synthesize DNA. Someresearchers deemed this problem"solved" in the 1980s, when scientistsdiscovered ribozymes, RNA moleculesthat can act as catalysts. Thesemolecules can carry an organism'sgenetic information and also catalyzethe replication of that information.After ribozyines' discovery, manyorigin-of-life scientists converged ona model of life's emergence known asthe RNA world. Before I)NA evolved,they believe, RNA both stored an

organism's genetic code and catalyzedits own reproduction.

With this view of life's beginnings,many organic chemists have spent thepast few decades trying to figure outhow RNA could have spontaneouslyassembled from the simple organicmolecules found on early Earth. Workby James Ferris, of the Rensselaer Poly-technic Institute in Troy, New York, hasshown that clays, especially one calledmontmorillonite, could have acted asscaffolds for the assembly of RNA fromits building blocks, ribonucleotides.In a subsequent step, Jack Szostak,of Harvard University in Cambridge,Massachusetts, and his colleagueshave illustrated how ribozymes mighthave evolved from short, noncatalyticstretches of RNA.

But proponents of the RNA worldhave long been plagued by a fundamen-tal problem: Although they have foundplausible pathways to string together

ribonucleotide subunits into RNAand then to "evolve" catalytic RNA,they couldn't explain the presence ofthe original ribonucleotides. Organicchemists have spent decades trying tosynthesize ribonucleotides from theirprecursors of sugars, nucleobases,and phosphate groups. They've hadremarkably little luck with this syn-thesis, which has prompted criticismof the idea that life really started withRNA.

In 2009, however, work from JohnSutherland, of the University of Man-chester, United Kingdom, presented apotential solution. His group managedto synthesize two of RNA's ribonucleo-tides by combining the componentsin a different way than had been donebefore. Instead of trying to attach thebases directly to the sugars, they setup the synthesis so that the mixturewent through.a series of hybrid inter-mediates before the final nucleotides

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emerged. "We spent 14 years exploringall that potential assembly chemistry,and we were largely extremelyunsuccessful' Sutherland says. "But wediscovered eventually that there was away through."

Not everyone is convinced, though.Sutherland's work shows "absolutelybeautiful organic chemistry," saysCody, but the conditions under whichthey performed their experiments werelikely not realistic representations ofwhat early Earth looked like, he says."There really isn't anything plausibleabout the scenario."

Elaborate experimental setups are acommon problem in organic synthesisresearch into the origin of life, Cleavessays. Whenever researchers manageto synthesize an interesting molecule,"it's such a complex and kind of con-trived experiment, it's hard to reallyswallow."

Some researchers have suggestedthat a different genetic molecule camebefore RNA-something easier toassemble from small-molecule compo-nents. RNA is "much too complicatedto have appeared out of the prebioticsoup,' Bada says. One possibility thatchemists have toyed with is a moleculecalled peptide nucleic acid, or PNA.Instead of the sugar-phosphate back-bone of RNA, this synthetic moleculehas a backbone made of the aminoacids found in proteins. Many chem-ists believe PNA would be far easier toput together from precursors.

Assembling any of these geneticmolecules under plausible geo-chemical conditions is "the ultimatechallenge in synthetic organic chem-istry," Bada says. "It's not that it's anintractable problem, it's just that we'reignorant of all of the potential chem-istry that can take place under naturalconditions."

Whether the first genetic mole-cule was RNA or a simpler analog,researchers continue to disagreeabout the likelihood of such a mol-ecule emerging from the prebioticsoup. "There have been some littlesuccesses here and there," Cleavessays, "but I think the field is gettingsplit now, between people who think

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there is going to be some miraculousdiscovery of how you make RNA pre-biotically and people who look at thatand think, it's just too complex."

Among scientists who believe thatnucleic acids could not have arisenspontaneously from organic precur-sors, many have aligned themselveswith a drastically different idea of howlife emerged.

Metabolism firstAt the same time the RNA worldhypothesis was gaining ground, a radi-cally alternative concept of life's originssurfaced-an idea that today underlieswhat many researchers consider to bethe most fundamental divide in origin-of-life theories. "If we could answerthis question one way or the other, itwould put grounding under the wholefield," says Robert Shapiro, of New YorkUniversity in New York City.

In 1988, a German chemist and patentlawyer named Gonter W5chtersh5userpublished a groundbreaking paper onthe origins of metabolism. In Wdchter-

sh5user's view, life began not with agenetic molecule synthesized fromorganic precursors in the environmentbut with a simple network of small-molecule chemical interactions capableof catalyzing its own replication.

Essentially, this "metabolism first"model proposes that life arose whenvery simple molecules such as carbondioxide, hydrogen, and hydrogensulfide reacted with each other onthe common iron-sulfur mineralspyrrhotite and pyrite, probably athydrothermal vents. With chemicalenergy harnessed from the miner-als, the simple molecules combinedinto successively larger species. Someof these products catalyzed newreactions, and eventually, metabolicnetworks appeared, complete withfeedback loops that allowed the net-works to sustain themselves.

Metabolism-first proponents assertthat no genetic mechanism wasrequired for this first life-form, asfaithful duplication of the entiremetabolic network was built into the

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The metabolism-first model proposesthat life probably arose at deep-seahydrothermal vents, like the black

smoker pictured here, when verysimple molecules such as carbon

dioxide, hydrogen, and hydrogensulfide reacted with each other onthe common iron-sulfur minerals

pyrrhotite and pyrite. Photograph:OAR/National Undersea Research

Program (NURP); NOAA.

cycle itself. Because of the mineral com-plexes he envisioned catalyzing the ini-tial chemical reactions, Wichtershi usernamed this conception of life's begin-nings the iron-sulfur world.

Over the past decade or so,researchers swayed by the idea ofmetabolism before genetics havetried to find supporting evidencein the lab. They have found evi-dence that iron sulfide minerals cancatalyze reactions that produce avariety of important organics, includ-ing acetate and pyruvate, both essen-tial metabolic molecules.

Bada, however, echoes a complaintthat has been directed at much of theresearch on genetic molecule synthe-sis: "You can do stuff in the lab, butit's not directly applicable to a naturalprocess," he says. "Also, you might beable to do a reaction here or there, butany sort of comprehensive, sustainedchemistry has never been shown."

The "RNA world" model arose with the discovery of ribozymes--RNAmolecules, such as the self-cleaving hammerhead ribozyme depicted here,

that can act as catalysts. Could these self-replicating molecules have evolvedfrom short, noncatalytic stretches of RNA, or would an autocatalytic networkof chemical reactions have had to come first? The pink spheres are Mg" 'ionsthat stabilize the structure of the ribozyme. Graphic: Kalju Kahn and Esther

Zhuang, University of California, Santa Barbara; created with PyMol

No complete metabolic cycle has yetemerged in the lab from mineral catalysisof small-molecule reactions, admits Har-old Morowitz, of George Mason Univer-sity in Fairfax, Virginia, but he's hopingthat will change. He believes that life'sfirst metabolic cycle may have lookedvery much like one still in existencein some primitive microorganisms: thereverse citric acid cycle. This cycle, whichallows microorganisms to synthesizeessential biomolecules from water andgas, is now helped along by proteinenzymes. But Morowitz believes thatsulfide minerals did the catalytic work inthe beginning.

www. biosciencetnag.or,g

(DeLano Scientific).

He and his colleagues have recentlydevised a hypothesis that extends theideas of Wachtersh5user from ironsulfides to other so-called transitionmetals, including iron, nickel, cobalt,copper, zinc, manganese, and a fewother elements. When small moleculesor ions attach to these transition metals,the resulting complexes become effec-tive catalysts; Morowitz and colleaguespropose that these could have nudgedalong life's very first metabolic reac-tions. Their hypothesis also supportsthe idea of hydrothermal origins, asmany of these metals are found inabundance at deep-sea vents.

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Morowitz believes that evidence forsuch origins lies in current biology:The cores of many modern metabolicenzymes have clusters of atoms thatlook exactly like tiny bits of sulfideminerals. From iron in hemoglobinand cobalt in vitamin B-12 to the zincthat's incorporated in many proteins,these minerals are clearly an important,and perhaps ancient, part of biology.

Additionally, Morowitz believes thatthe chemical nature of these metalsmeans that anywhere they're foundin a supportive environment, catalyticnetworks-and therefore life-willemerge. He and his colleagues arecurrently working on lab experimentsto try to show that the catalysis per-formed by these metals could leadto a metabolic system similar to thereverse citric acid cycle. If they canprove this experimentally, "the realexcitement... is that metabolism islurking in the periodic table," he says.And here lies a fundamental, almostphilosophical, divide between thegenetics-first and the metabolism-firstcamps. The assembly of RNA or anyother genetic molecule from the pri-mordial soup was probably a unique,and perhaps unlikely, event. "You'reinvoking chance to an enormousdegree," Shapiro says.

In a metabolism-first world, how-ever, the buildup of larger moleculesfrom simple ones and the eventualemergence of interacting chemicalnetworks could not only have hap-pened many times and in many placeson Earth but also may in fact havebeen a foregone conclusion, simply aresult of the fundamental chemistryof carbon-based molecules, gases, andmetals. If this is life, "the emergence oflife is probably inevitable," Morowitzsays.

This viewpoint has vast implicationsfor the probability of finding life else-where in the universe. Self-replicatinggenetic molecules such as RNA would

likely evolve only on worlds extremelysimilar to Earth, Shapiro says, whereas"metabolism-first people are free toimagine how life might exist on placeslike Titan, which is very different fromus but seems to have a lot of reactivechemicals. Metabolism first is muchmore amenable to the idea that life canbe very diverse."

Some scientists, most notably PaulDavies, of Arizona State Universityin Tempe, have championed the ideathat such diverse life may even existon Earth-a "shadow biosphere" oflife very different from anything wecurrently know, which we haven'trecognized simply because we haven'tbeen looking for it. "We may havebeen so fixated on studying our ownkind of life that we may have missedthat life operating on a differentprinciple has existed right under ournoses," Shapiro says.

Other researchers, especially organicchemists, however, still resist the centralconceit of metabolism-first models: thatself-replicating chemical networks canbe considered to be alive. "I wouldn'tcall that life. It might be interestingchemistry, but it's not alive,' Bada says."In my opinion, our definition of lifeis that it can pass genetic informationfrom one generation to the next."

Others are uncomfortable with astrict divide between the origins ofgenetics and metabolism. "I thinkthat's a false dichotomy," Cody says.An autocatalytic network of chemi-cal reactions "isn't necessarily life,"he says, but, on the other hand, "it'salmost inconceivable that somethinglike ribozymes could spontaneouslyemerge prior to other metabolicfunction. The systems have to becoordinated in some way."

Systems chemistryResearchers on both sides of thegenetics-metabolism divide, as wellas those who are hoping for some sort

of blend of the two ideas, are movingforward with new experiments, tryingto see how far they can push organicsyntheses along a believable road tosimple life-forms.

Many origin-of-life scientists arenow immersed in a fairly new approachthey term "systems chemistry." Insteadof purifying and isolating chemicalsbefore studying their interactions, sys-tems chemists toss dozens or hundredsof chemicals together and see whatemerges. Often, they find reactions andproducts that they couldn't have pre-dicted simply from knowledge of eachindividual component of the mixture.

The Sutherland group usedthis approach to synthesize theirribonucleotides: By mixing togetheringredients simultaneously, the chemi-cals reacted in important ways that theycouldn't when each was added sequen-tially. By allowing complex mixturesof chemicals to interact, "you can getsome tremendous synergies," Suther-land says. "Ultimately, you might startgetting emergent behavior. And that'sreally what interests everybody who'sinvolved in origin of life."

Metabolists are also using this methodto see how catalytic networks mightarise from complex mixtures of chemi-cals that are simply allowed to react overtime. "You're not trying to force anyresults:' Shapiro says. "You take a lookand see what nature wants' "

The emergence of unexpectedbehaviors from complex interac-tions is "an essential quality of life,"Cody says. "If we can study simplechemical systems and understandhow these things emerge and whatthey do, at least we gain some insightinto what probably happened, evenif we can never replicate exactly whatoccurred on the pathway toward lifeas we know it."

Melissa Lee Phillips (mlp@nasw.org) is afreelance science writer in Seattle.

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The Origins Divide: Reconciling Views on How Life Began

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