FOCUS_The Origin of Life

Elixirs from the primordial soup

In the Bible, the universe was created step by step: first light, then water and land, and finally the terrestrial animals and humankind. However, from a scientific viewpoint, it seems that the building blocks of life might not have come into being successively, but rather at the same time – at least, this is what Hannes Mutschler of the Max Planck Institute of Biochemistry believes. He and his colleagues in Martinsried, near Munich, are researching the role played by RNA molecules in the emergence of life.

TEXT CLAUDIA DOYLE

et us go back on a journey molecules, and the first cells came through time to the begin- into being. Yet how exactly did all this nings of our planet. Around come about? 4.5 billion years ago, the Earth “It goes without saying that we was an extremely inhospita- can’t turn back time. That’s what makes ble place: itsL surface was an incandes- it so hard to find out what really hap- cent sea of molten stone, the sky was pened,” says Hannes Mutschler, who full of meteorites that rained down in- leads the Biomimetic Systems research cessantly from space and ripped deep group at the Max Planck Institute of craters in the Earth, and the atmosphere Biochemistry. “This is why we are try- was a mixture of carbon dioxide, am- ing to recreate the origins of life in the monium and methane. Living organ- lab – in conditions like those that pre- isms? Not a trace – not in this inferno. vailed on Earth at the time.” Over the next billion years, the fi- ery turmoil subsided. The Earth cooled CELLS CREATED BY HUMAN HAND down; oceans and continents formed. And somewhere in the water, life be- He and his colleagues aim to create ar- gan: the elements of carbon, hydrogen tificial systems that behave like living and nitrogen bonded to form complex cells. There are two different ways to go

26 MaxPlanckForschungMaxPlanckResearch 3 2| 18| 18 primordial soup Elixirsfromthe

Photo: Christian Frumolt/Look Foto such as those that feed the Blue Lagoon in chilly Iceland. chilly in Lagoon Blue the feed that those as such springs hot in being into come have may cells first the that shows This vesicles. cell-like in on passed be can that molecules RNA complex produce and can freezing thawing repeated that shown have experiments Laboratory Earth. on life of emergence the to contributed have may cold and heat between Fluctuations 28 Lego set,”saysMutschler. tube. “It’s like working with a gigantic to assemblethemcorrectly in thetest ed foracelltobeviable.Then theyhave tify themolecularbuildingblocks need- velope. First,thescientistshave toiden- nucleic acidcomponents,andacellen- the bareminimumrequired–enzymes, tute partsof simple “protocells”using Mutschler andhisteamaimtoreconsti AS SIMPLEPOSSIBLE from thebottomup. is toreversetheprocessandcreateacell method, adoptedbyHannesMutschler, ing ofthehumangenome.Thesecond contributed significantlytothedecod- at thebeginningofmillennium tist andentrepreneurCraigVenter, who method waschosenbyAmericanscien- parts thatarenotessentialtolife.This ing cellandsuccessivelyremoveallthe about this.Thefirstistotakeanexist- Vay.Libicher, Le Kai Mayr, Kristian Viktoria and right: Wagner to Left Alexander Weise, methods. Laura and research Mutschler modern to Hannes thanks life of stages different, early more the be not could research still can laboratory group’s scientists the working yet Mutschler’s Hannes in those and times prehistoric in Earth on conditions The MaxPlanckResearch 3 MaxPlanckResearch | 18 - proteins. The structure of the ribosome no acidsinthecorrectorder toform tion asatemplateandassembles ami- machine uses the cell’s genetic informa- of this is the ribosome. This molecular which elementsarevital.One example lecular structures,itisoftenunclear to seewhichofthemareirreplaceable. tioning ofthecar, butitisnotsoeasy components areessentialtothefunc tronics,” saysMutschler. Notallofthese of apilesheetmetal,cablesandelec- modern carandbeleftstandinginfront able. “It’s asifyouwouldtakeaparta andwhicharereplace- tial forsurvival which ofthemanyprocessesareessen- ern cell,itisdifficulttodistinguish them. ous processesandinterwoven evolution hasgraduallyrefinednumer order tolive.Overmillionsofyears, exactly whataminimalisticcellneeds The problemisthatnobodyabletosay Even inthecaseofindividualmo- Nowadays, ifwelookinsideamod- in - - and function in free, unprotected form, and function in free, unprotected form, ergy fromprotongradients. metabolic reactionsdoinfact drawen- ic analyseshaveshownthat primal from subterraneanhotsprings. Genet- came intocontactwithalkalinewater er theacidicwaterinearlyoceans proton gradientswerecreatedwherev- atoms, forexample.Theseso-called tion ofpositivelychargedhydrogen plied bydifferencesintheconcentra duction. Energymayhavebeensup- andrepro- use itfortheirownsurvival by theirabilitytoconvertenergyand all, living organisms are characterized After was thebeginningofeverything. lieve that a simple metabolic process the originsoflife.Someresearchers be- body yetknowswhatitis. an easier way? Quite possibly. But no- are involved in its formation. Is there is highlycomplex:morethan100genes But canmetabolicmolecules exist Even today, scientistsdisagreeabout

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Photo: Axel Griesch FOCUS_The Origin of Life

Ribosomes Ribosomes DNA RNA RNA RNA Replicase RNA DNA ribozyme RNA replicase polymerase polymerase

Other ribozymes Other enzymes Other enzymes

RNA-based minimal cell RNA/protein-based minimal cell DNA/RNA/protein-based minimal cell

or do they have to be protected and researchers in Martinsried are investi- held together by envelopes? After all, gating whether simple biopolymers what good is it if the first complex can exist in coacervates without mem- molecules form but drift apart in the brane and whether they are able to cat- open sea? For this reason, some re- alyze reactions. searchers believe that tiny droplets In contrast, other researchers be- consisting of fat molecules acted as lieve that life began with the transfer the precursors of modern cell mem- of information from one generation branes, and it was they that made life to the next. But how did this transfer on Earth possible. take place? Nowadays, this task is performed by MOLECULAR CLUSTERS INSTEAD the molecule deoxyribonucleic acid OF CELL MEMBRANE (DNA). DNA doubles whenever a cell divides. Each daughter cell receives a These membranes have to be stable, copy of the DNA and thus a full set of Top Different cell variants with minimal able to divide, and capable of con- genetic information. components, like those that may have existed when life emerged on Earth: along with trolling which substances are trans- However, many scientists think it is RNA-based protocells (left), which use ribo- ported in and out of the cell. Howev- unlikely that genetic material original- zymes to copy their genetic material, there er, cell membranes of the type found ly consisted of DNA. Instead, some may also have been cells that used proteins in modern-day cells may not have suggest that genetic information was (RNA replicase) and ribosomes to replicate their genome (center). Modern DNA/RNA/ been necessary at first. Small molecu- conveyed by ribonucleic acid (RNA) protein-based cells (right) use DNA as the lar clusters held together by electro- molecules, which cells now use as a me- information carrier for the production of static forces – known as coacervates – diator for the formation of proteins. In proteins with RNA as the mediator. may initially have performed the tasks a sense, these RNA molecules are DNA Below Part of a chromatography structure of cell membranes. One of the goals of copies that migrate from the cell nucle- with which the researchers can separate Mutsch­ler’s research is to prove this us to the ribosomes in the cell plasma, mixtures of substances into their compo- nents. The individual substances can be hypothesis. In cooperation with two where they act as templates for the for- divided into different test tubes with other working groups from the Max mation of proteins. the help of the collector. Planck Institute of Molecular Cell Bi- Originally, however, RNA could

Photo: Axel Griesch Photo: Axel Griesch; graphics: MPI of Biochemistry ology and Genetics in Dresden, the have been more than an intermediate

3 | 18 MaxPlanckResearch 29 FOCUS_The Origin of Life

In the early days of life on Earth, RNA played a central role by storing information » and acting as a biocatalyst. However, RNA molecules probably never acted alone, but were instead supported by other biomolecules.

1 product: it may also have served as the lar Biology in Cambridge, Mutschler repositorygetaut for genetic material. The ad- discovered that in the right condi- vantage of RNA: unlike DNA, it can tions, these snippets can themselves fold more easily in three-dimensional bond together to form RNA chains, form. This means that like modern pro- even complex ones. teins, RNA moleculesGefrier form-Tau structures-Zyklen könnten that act as naturalprimitive catalysts andZellzyklen accel- FREEZING AND THAWING erate chemical reactions. Known as ri- 2 bozymes, these RNAangetrieben structures are habennot One. Im particularly promising procedure, usually as efficientgefrorenen as protein enzymes,Zustand which können is conducted several times in

yetgefroren cells contain thousands of active succession, involves freezing and thaw- ribozymes and theylipidbasierte are central to Vesikelthe ing ihrena saline solution containing RNA survival of every cell. The catalytic cen- molecules. To do this, the researcher ter of the ribosome,Inhalt for example, austauschen con- places. So short RNA chains designed at sists entirely of RNA, i.e. it is a ribozyme. the computer into saline water. Then 3 könnten sich einfache RNA- The ribosome may therefore even be a he cools the solution slowly. The liq- relic of a long-goneReplikatoren biological era, theinnerhalb uid beginsvon to freeze. At first, ice crys- so-called RNA world – a world in which tals consisting of almost pure water RNA performed aVesikelpopulationen dual function as a re- form, while the positively and nega- pository of informationausgebreitet and a catalysthaben tively. charged salt ions remain in the for chemical reactions. liquid. The fragile RNA likes this envi-

4 getaut But what triggered the formation ronment: the ions give it stability, help of the longer RNA molecules from it to fold properly, and promote the which the first ribozymes developed? bonding and linking of individual In the Earth’s early days, the individ- RNA fragments. ual building blocks, known as nucleo- Mutschler then thaws the solution. tides, presumably bonded sponta- The RNA strands, which were previous- neously to form very short RNA mol- ly precisely arranged and held together 1 A protocell with (left) catalytic RNA ecules. “Not much can be done with by so-called hydrogen bonds, separate molecules (ribozymes) and without such short snippets; most of the RNA from each other and float about freely ribozymes (right). 2 The cells exchange their content while in a frozen state. molecules found in cells are longer,” again. During the next freezing pro- 3 + 4 The ribozymes replicate themselves says Mutschler. However, for a long cess, they rearrange themselves and in the thawed cells. In prehistoric times, time it was unclear how the long form another bond. Mutschler has to simple cell cycles may also have been chains needed for ribozymes could repeat this procedure about twelve driven by freezing and thawing, allowing RNA molecules with the ability to self- form. During the time he spent as a times until a strand consisting of replicate to spread through the first cells. postdoc at the Laboratory of Molecu- around 200 building blocks is formed. Graphics: MPI of Biochemistry

30 MaxPlanckResearch 3 | 18 A microscope with image analysis software is able to recognize various cell types. This enables Kai Libicher to scan and sort 20,000 artificial model cells per second.

“This process would presumably hap- Mutschler’s experiments in the labora- most probably happened in hot springs pen by itself, but much too slowly. The tory have shown what repeated cycles located in cold environments, like those repeated freezing and thawing accel- of freezing and thawing can achieve. found in Iceland: “Simple molecules erates the bonding considerably,” ex- Now he has to prove that these pro- could easily have formed in the hot sa- plains Mutschler. cesses could also have taken place in line water of these springs and merged However, one long RNA strand is not the environmental conditions that into more complex molecules in the yet enough to transfer information to existed on Earth more than 3.5 billion cold surrounding areas.” the next generation. The RNA also has years ago – the age of the oldest bac- to be able to replicate itself independent- teria fossils yet known. Because con­ PRIMORDIAL EARTH IN THE LAB ly. In modern biology, an enzyme called ditions on Earth were quite chaotic RNA polymerase helps it do this. How- during its early stages, the ecosystems Mutschler and his colleagues now wish ever, this might not always have been that existed were highly diverse. “This to investigate this hypothesis further by the case. Mutschler is therefore current- is both a blessing and a curse,” says conducting experiments. To this end, ly investigating whether repeated freez- Mutschler. Although this means that they are cooperating with Paola Casel- ing and thawing can also produce a ri- scientists can test a wide variety of en- li’s research group at the Max Planck bozyme with a copy function. vironmental influences, the list of these Institute for Extraterrestrial Physics. Moreover, the temperature fluctu- is extremely long, ranging from deep- This institution houses reaction cham- ations have an additional effect: they sea hydrothermal springs to craters left bers in which scientists can research the appear to be able to trigger a basic by meteorites. origin of organic compounds in space. mechanism that transfers genetic ma- Since many chemical reactions also However, they are equally capable of terial between protocells. Tiny droplets require UV light, Mutschler assumes simulating the conditions that pre- of fat filled with genetic material ad- that life is more likely to have started at vailed on the as yet unpopulated Earth. here to each other during freezing and the surface of a body of water rather Environmental conditions such as tem-

Graphics: MPI of Biochemistry Photo: Axel Griesch exchange their contents. than deep in the ocean. He believes this perature, light wavelength, and the

3 | 18 MaxPlanckResearch 31 32 MaxPlanckResearch 3 MaxPlanckResearch | 18 prebiotic conditions,andwhether to findouthowstableRNAisunder required. Inthisway, Mutschleraims set withgreatprecisionandvariedas composition oftheatmospherecanbe emergencelife.of the in role central a played molecules RNA certain: is thing one him, for Yet like. looked Earth on cells first the what exactly certainty absolute with know never probably will he why is which time, back turn to unable is Mutschler Hannes necessary forlife. necessary test tubes – but only just as much as is cial inthefuturetoallowchaos inthe to besuccessful,itwillthereforecru biomolecules rightfromthestart.” ed aloneandreceivedhelpfromother ever, I also believe that RNA never act- when life first began. How- repository role asabiocatalystandaninformation pothesis thatRNAperformedacentral also favors this idea.“Isupport the hy- in the researchers’ test tubes. Mutschler in arathermoredisorderlyfashionthan the sametime. cules came into beingat more orless probable thatawiderangeofmole by-products. Consequently, itseems the right amounts of excipients and the reactionmixturecontainsexactly not work.Theyareonlyinitiatedwhen carefully configuredreactionsoftendo veloped successively. However, the the componentsoflifemusthavede- time. Theobviousassumptionisthat of theseelementsevolvedatthesame stead, itseemsprobablethatallthree give riseseparatelytolivingcells.In- metabolism, and cell envelopes cannot to believethatgeneticinformation, and evolution. such conditions can support catalysis ursprung-des-lebens (inGerman) www.mpg.de/podcasts/ Life mayhavethereforeemerged Scientists areincreasinglycoming If research intotheoriginoflifeis

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FOCUS_The Origin of Life

SUMMARY GLOSSARY

l Scientists want to know which components are essen- Coacervates: Aggregates of macromolecules held together by elec- tial for a cell to be viable. They are therefore attempting trostatic forces between oppositely charged molecules. Chemical to reconstitute a cell with the minimum components – reactions can take place inside these structures, where they are proteins, membrane molecules, and DNA or RNA. protected from external influences; the structures range in size from

l By repeatedly freezing and thawing solutions in the lab, a thousandth to a tenth of a millimeter. researchers are able to link 200 building blocks for RNA Ribozymes: Like proteins (enzymes), certain RNA molecules are able molecules and form longer strands. The first longer to accelerate biochemical reactions. In addition to catalytically active RNA molecules on the primordial Earth could therefore RNA molecules, ribozymes of this type also comprise proteins to which have formed in hot springs located in a cold environment. catalytic RNA is bound. As catalysts, ribozymes reduce the activation l The most important building blocks of life – genetic energy of chemical reactions and thus accelerate them many times material, metabolism and cell envelope – may have over. Ribozymes may have been the first self-replicating biological come into being not successively, but more or less at macromolecules on Earth, as they can function as information reposi- the same time. tories and transmitters besides catalyzing chemical reactions.

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