Origin of Life

Diversified World: Drive to Life©s Origin?!**Hans Kuhn* and Christoph Kuhn

Keywords:evolution ¥ genetic apparatus ¥ homochirality ¥information emergence ¥ origin of life ¥ self-organization

What is decisive for the origin of life?Here we do not want to delve into thechemical details but attempt to look atthe fundamental motivation which leadsto the remarkable process of self-organ-ization to simplest forms of life. Thatshould be useful to stimulate experi-mentation. It is often assumed that inprinciple life can arise in a homogene-ous medium or at a reactive interface byintrinsic necessity (see, for example,reference [1]). Processes of this typeare known, but is it really possible thatsuch a process can lead to a machine asintricate as the genetic apparatus ofbiosystems? The idea that life arisesslowly in a chaos of lifeless matter isfascinating, but is life×s emergence not aprocess dfferent in principle? Are notquite special highly diversified environ-mental conditions changing periodicallyin a particular way required as thedriving force for the formation of in-creasingly more complex forms, evolv-ing to forms of early life?

Model Pathway

To establish the plausibility of atheory of the origin of life a tangibleand detailed sequence of hypotheticalphysical-chemical processes which leads

to the basic machinery of life must beproposed. Each step would have to be assimple as possible, however, to under-stand the fundamentals of this type ofprocesses. But it cannot be expectedfrom such a way to go that a geneticapparatus as complex as that whichactually exists in the biosystem will beachieved, but a less intricate apparatuswith the same functional properties.Such a model pathway would have tobe constantly improved on the basis ofnew experiments and knowledge. Adescription of the historical pathway isnot aspired. The process should demon-strate how systems with lifelike proper-ties are formed as well as chemicallytotally differently constructed supramo-lecular systems, or systems that couldarise at suitable locations everywhere inthe universe.

The extremely important questionscurrently of special interest in connec-tion with the origin of life (what role doRNA, DNA, peptides, thioesters, pyrite,etc. play? And where did the processtake place, in the depths of the ocean, ata volcano, on Mars, or elsewhere? Howwas the beginning of a replication proc-ess possible? Which enzyme-free meta-bolic processes were required to synthe-size the building blocks of a first replica-producing system and to exploit anenergy source?[2]) are not consideredhere. We attempt to contribute to find-ing answers to questions concerningfurther evolution of a replicating mole-cule toward the genetic machine bydeveloping theoretical models. Whichprinciple requirements, independent ofthe special chemistry, must be fulfilledto initiate and drive forward this proc-ess? What are the demands placed onthe building blocks of the evolvingsystems and the environment? Howcan these demands be fulfilled with the

resources of chemistry? Can in this waya plausible model pathway to systemswith a genetic apparatus be found? In arecent publication[3] some critical stepsof a simple model pathway suggested inreference [4] are simulated on a com-puter. The model pathway assumes thatquite specific external influences arefundamentally important for the originof life. The proposed hypothetical stepslead to a simple translation device, to aplausible explanation of the basic trans-formations (transition from RNA toDNA as carrier of genetic information),and to the development of the geneticcode of biosystems in detail. Here wefocus on general aspects of the process.

The Beginning

It is assumed that amongst theenormous diversity of regions with dif-ferent properties on the prebiotic Earththere exists, by chance, somewhere asmall, singular region with the followingimportant properties:1) the presence of certain, energy-rich

monomers which were formed byfortuitously prevailing conditionsand are continuously replenished.In the thought experiment two mu-tually complementary monomertypes are assumed to be available;

2) unique, temporal-spatial environ-mental properties which allow thecontinual formation of short strandsby condensation of the monomers;

3) occasionally, in a very seldom step, ashort strand is formed by chance inwhich the monomers are connectedin such a waythat the strand can actas a template for the formation ofthe complementary strand;

[*] Prof. Dr. H. KuhnRingoldswilstrasse 50, 3656 Tschingel(Switzerland)Fax: (þ41) -33-251-3379Dr. C. KuhnGruppe BiophysikInstitut f¸r Molekularbiologie undBiophysikEidgenˆssische Technische HochschuleHˆnggerberg, 8093 Z¸rich (Switzerland)

[**] C.K. is grateful to Professor Kurt W¸rthrichfor his hospitality.

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4) replica formation starts and con-tinues under the prevailing condi-tions, and by accidental copyingerrors strands are formed withdifferent monomer sequenceswhich display different foldingstructures, and selection occurs(for example, by different hydrol-ysis sensitivities of differently fold-ed strands).Despite considerable efforts it has

hitherto not been possible to realize aplausible initial reproduction processexperimentally,[5] although more re-cent approaches [6,7] are encouraging.Very diverse possibilities have beensuggested as the starting point of life×sorigin on Earth, including processes onmineral surfaces. The question is notunder discussion here, but each proposalshould be substantiated by giving aplausible pathway to a system of self-replicating RNA-like chains.[8] Accord-ing to the model[4] such a replicatingsystem presumes the formation of ahomochiral template strand so that thefitting together of template and thedeveloping strand is guaranteed. Sucha template is formed by chance in aracemic solution of monomers. In thisaccidental, initiating process is seen theorigin of the homochirality of biologicalsystems. The formation of such a sym-metry break has been realized experi-mentally in reference [6]. The experi-ments in reference [7] support the ideaof a complex temporal-spatial structureas fundamental already for the initialprocess.

The thought experiment[4] as descri-bed rests on the assumption that anappropriate self-replicating system willbe realized experimentally, since funda-mentally nothing speaks against it. Thereal puzzling feature in the origin of lifeemanates from the subsequent process-es. How can such a system develop intoan entity with a genetic apparatus?

Structural Diversity of theEnvironment:

Stimulus for Continuous ComplexityIncrease

According to the model the criticalfactor in the origin of life is that in thesmall region under consideration where

multiplication of strands and selectiontakes place, a strand is formed fortui-tously by a copying error which cansurvive and multiply in a neighboringregion with slightly different properties,in contrast to the hitherto existingstrands. The process is ongoing (Fig-ure 1); increasingly less favorable re-gions are occupied with replicableforms. This requires the occurrence ofincreasingly more complex and moreintricate systems. In this way the systemsthus formed become increasingly inde-pendent upon the quite special, restric-tive conditions in the region in which theprocess has begun. The fact that anenormous number of regions with differ-ent properties existed on the prebioticEarth plays a central role in the model.The multiformity is the stimulus for thecontinuous increase in complexity. Inthis view of a beginning in a mostparticular region, sequences of verydifferent processes (many kinds ofchemical reactions, concentration andseparation processes) led to buildingblocks for a replicating system. Thisview should stimulate the search formany different possibilities to obtainsuch building blocks.

Periodicity andCompartmentalization

Living systems are complex aggre-gates of mutually compatible molecules.Thus even for the first steps suitableconditions must be found which lead tothe aggregates of mutually compatiblemolecules and to the evolution of in-creasingly more complex and intricate

aggregates. In addition to the structuraldiversity, temporal periodicity and spa-tial compartmentalization (e.g. day±night cycle and small pores in a rock)are fundamentally important conditions.

A periodic change between totallydifferent environmental influences, forexample different temperatures, is im-portant: aggregates must be formedthrough the interdiffusion and interlock-ing of individual molecules: these ag-gregates are subjected to a selectionprocess; the aggregates must then dis-integrate again into individual mole-cules which are replicated; and a newcycle must begin. The process continues,driven by the given periodicity.Com-partmentalization is important to avoidthe individual molecules diffusing apart,enabling the molecules to come togetherfor reconstitution. The compartmentsmust be somewhat porous so that copiesof the newly produced favorable formwithin a compartment can graduallyspread over the whole region.Thesegeneral considerations are important inthe search for a detailed model path-way[4] and for the determination of theparameters for computer simulation[3] .Two fundamental facts should be takeninto account when considering the evo-lution of increasingly complex aggre-gates:1) A prerequisite for aggregates of

interlocking strands to be formed isthat template strand and replicateare antiparallel in the double strand.Only in this case the single strandsobtained after separating templateand replicate can form compactfolding structures required to buildaggregates. Indeed, the postulated

region ofsmall-pore compartmentspopulated by short strands

region ofstill larger-pore compartmentspopulated by aggregates

region oflarger-pore compartmentspopulated by longer strands(short strands lost by diffusion)

longer strandformed by fusion oftwo short strands

aggregate formedby suitable strands

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incipient short strandthat replicates

Figure 1. Highly diversified world: driving force for increase in complexity by colonizing increas-ingly less favorable regions. Only short strands emerge spontaneously, the occurrence of longerreplica-forming strands is much too improbable. After short strands have multiplied, longerstrands can easily occur by fusion. These strands may form folding structures. Aggregate-form-ing strands may appear.

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antiparallelity is realized in livingforms.

2) A basic question is how to overcomethe difficulty that evolution comes toan end at a certain level of complex-ity because of copying errors accu-mulation. This requirement is ach-ieved automatically in the model bythe formation of aggregates of mu-tually compatible molecules: mole-cules which have a changed foldingthrough reproduction errors do not,in general, integrate and disappear.With increasing complexity of theaggregating forms the mechanism isalways determinative and of funda-mental importance in the evolutionof increasingly intricate systems.The first steps resulting from these

considerations are given in Figure 2.They lead to a simple genetic apparatus.

Computer Simulation

Each cycle in this simulation consistsof a1) construction phase (simulation of

the formation of functional aggre-

gates by diffusion and joining to-gether of molecular strands);

2) selection phase (aggregates–ac-cording to a feasibility parameterwhich determines their survivalprobability–are randomly selected.This parameter is held in a library

for each aggregate form which isregarded as a possibility to occur inany phase in the evolution process;

3) Replication phase (aggregates breakdown into individual strands whichserve as tempates for a replica for-mation after which template andreplica strand separate).The calculation results[3] underpin

critical breakthroughs in the first stagesof the hypothetical model (for example,the formation of an aggregate such as inFigure 3 that functions as a simple trans-lation apparatus).

Basic Idea and Procedure

The basic principle of the model(continuous increase in complexity, as-sociated with the colonization of in-creasingly less favorable regions) repre-sents an extension of the Darwin Theoryaccording to which during biologicalevolution increasingly more complexsystems are formed through new eco-logical niches being populated. Previ-ously empty regions are increasinglyoccupied. Later the creation of ecolog-ical niches by gradual expulsion ofcompetitors becomes important.[9] Thebasic procedure (the search for anunbroken chain of hypothetical, phys-ical-chemical process which leads to agenetic apparatus) represents an exten-sion of Darwin×s way to go. In the searchfor the mechanism of the origin of life

Increasing independence from restrictions by increasing complexity coupled withincreasing populated area

Production of an enzyme thatreduces copying-error probability:

Envelope-forming apparatusacts as translation devicefor this incipient enzyme;further enzymes evolve subsequently

How to avoid error-accumulationwith increasing complexity?

Confinement of building blocks: Aggregates produceenvelope-forming molecules

How to get independentof micro-compartments?

Elimination of erroneous copies:

How to avoid error-accumulationwith increasing complexity?

Capacity of adaption: Replication of short molecular strands

Favorable folded strands aggregate;erroneous copies do not fit and disappear

Figure 2. Early stages in the evolution of life in the thought experiment: logical steps, barriers,and their surmounting.

Figure 3. Translation apparatus for a binary code. Important stage in the model pathway in thecomputer simulation: assembler and hairpin strands of R monomers (R1 and R2). Cohesivealignment of hairpins by means of the reading frame. A-monomers (A1 and A2) are bound to theopen end of the hairpins. A binary code relating the sequence of R1 and R2 in the assembler withthe sequence of A1 and A2, which are linking to form the A-oligomer. The A-oligomer acts as anenzyme. R and A are reminiscent of a ribonucleotide and an amino acid in biosystems.

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the method described should be imme-diately plausible by its relation to Dar-win×s basic ideas.

Origin of Life: Self-Organizationby Intrinsic Necessity or by theNecessity to Increase Complexitywith Extending Populated World?

A diversified environment, the driveto life in the present view, plays no rolein the theories which are based on theassumption that the essential process inthe origin of life can be considered, inprinciple, as a self-organization in ahomogeneous phase by intrinsic neces-sity. It is interesting to inquire after thecauses for the great fascination and thebroad acceptance of this idea.Up to thebeginning of the 1970s it was frequentlythought that the origin of life wasinconsistent with thermodynamics, butthen the thermodynamic conditions forprocesses of self-organization in a ho-mogeneous medium in the steady statewere given.[10] Thus the described state-ment was considered to be disproved,the gap between physics and biologybridged, and the basic laws of a theory ofthe origin of life discovered. However,the fact that structures form in a homo-geneous medium by self-organizationdoes not allow one to conclude that thistype of self-organization can actuallylead to living systems.

Thermodynamics and the Originof Life

The idea that the origin of life isinconsistent with thermodynamics can-not be refuted, in our view, withoutgiving a plausible model pathway, andall the more the more detailed thepathway is. The problem of the originof life is therefore finding such a path-way and not a question of thermody-namics since every physical-chemicalprocess is consistent with thermodynam-ics.

Gradual or Sudden Manifestationof Life?

In the conception that within an inprinciple homogeneous phase increas-

ingly more complex forms evolve slowly,life originates gradually. A differentsituation is given if in contrast we startfrom the concept that in a region withsingular properties a clearly orientatedprocess is set in motion: through repli-cation, variation, and selection a devel-opment is instantaneously initiatedwhich (jointly with an increasing expan-sion of the populated region) leads toincreasingly complex forms. In this ex-plosive process a property of matteremerges all of a sudden which was notpreviously manifest. It is useful to definephysical-chemical systems with this sin-gular behavior as living organisms evenlife in common sense appears muchlater. Thus life originates suddenly withthe appearance of the first self-replicat-ing molecule which is variable througherrors in the copying process.

Genetic Information

The special feature of living organ-isms is that they carry information ascertain sequences of building blocks, therecipe for the construction of copies(genetic information). The evolutionaryprocess and therefore the genetic infor-mation can only be seen in connectionwith the given environment. The geneticinformation carried by the evolvingforms should not be confused with theobserver©s information required to char-acterize the environment of these forms.The genetic information, quantified bythe number of bits, is transferred fromone generation to the next. In thedescribed portrayal of a sudden changefrom the lifeless to the living, geneticinformation is produced with the ap-pearance of the first self-replicatingmolecule. The carrier of the information(the recipe for the construction of cop-ies) is the molecule itself. With theadvance of evolution the geneticallytransferred information grows (meas-ured by the number of bits), and thecarrier of the information itself changesat certain stages of evolution.[8] Theinformation grows with the extensionin the information-bearing chain, and itssignificance increases (measured by theminimum number of bits which must beproduced and rejected in order to ach-ieve the observed evolution stage). Asdescribed above, there are very different

conceptions on the nature of the initialinformation carrier, exemplifying thepresented scenario (sudden appearanceof an initial information-carrying, phys-ical object and continuous complexityincrease).[11] Genetic information isclearly defined other than in scenarioswhere the origin of life is considered asgradual change from the lifeless to theliving.

Outlook

The driving forces inducing theemergence of life are sought by theo-retical modeling. It is attempted to seemotivations that lead to this processwhich must also be valid anywhere inthe cosmos under quite different butextremely specific chemical and spatio-temporal conditions. To achieve advan-ces in our understanding of the origin oflife model pathways must be improvedby an increasingly detailed determina-tion of the environmental conditionsand an ever better preparative chemicalunderpinning. The concept that theprocess begins in a particular regionshould stimulate a broad search forexperimental possibilities.

[1] D. Segrÿ, D. Lancet, EMBO Rep. 2000,1, 217 ± 222; A. D. Miller, ChemBio-Chem. 2002, 3, 45 ± 46.

[2] N. Lahav, Biogenesis: Theories of Life©sOrigin, Oxford University Press, NewYork, 1999 ; A. Brack, The MolecularOrigins of Life: Assembling the Pieces ofthe Puzzle, Cambridge University Press,New York, 1998 ; C. Wills, J. Bada, TheSpark of Life. Darwin and the PrimevalSoup, Oxford University Press, Oxford,2001; G. W‰chtersh‰user, Prog. Bio-phys. Mol. Biol. 1992, 58, 85 ± 201; C.de Duve, Blueprint for a Cell: TheNature and Origin of Life, Patterson,Burlington, 1991; I. Fry, The Emergenceof Life on Earth, Rudgers UniversityPress, New Brunswick, 2000 ; G. F. Joyce,Nature, 2002, 418, 214–221; Frontiers ofLife, Vol. 1, The Origin of Life (Eds.: D.Baltimore, R. Dulbecco, F. Jacob, R.Levi-Motalcini), Academic Press, SanDiego, 2000

[3] C. Kuhn, Proc. Natl. Acad. Sci. USA2001, 98, 8620 ± 8626.

[4] H. Kuhn, H.-D. Fˆrsterling, Principles ofPhysical Chemistry. Understanding Mol-ecules, Molecular Assemblies, Supramo-lecular Machines, Wiley, New York,

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2000 ; H. Kuhn, J. Waser in Lock-and-key principle (Ed.: J.-P. Behr), Wiley,New York, 1994, p. 247 ± 306; H. Kuhn,J. Waser in Biophysics (Eds.: W. HoppeW. Lohmann, H. Markl, H. Ziegler),Springer, Berlin, 1983 p. 830 ± 874; H.Kuhn, Angew. Chem. 1972, 84, 838 ± 862;Angew. Chem. Int. Ed. Engl. 1972, 11,798 ± 820; H. Kuhn, Naturwissenschaften1976, 63, 68 ± 80; H. Kuhn, J. Waser,Angew. Chem. 1981, 93, 495 ± 515; An-gew. Chem. Int. Ed. Engl. 1981, 20, 500 ±520.

[5] L. E. Orgel, Proc. Natl. Acad. Sci. USA2000, 97, 12503 ± 12504.

[6] A. Eschenmoser, Science 1999, 284,2118 ± 2123; M. Bolli, R. Micura, A.Eschenmoser, Chem. Biol. 1997, 4, 309 ±320.

[7] A. Luther, R. Brandsch, G. von Kie-drowski, Nature 1998, 396, 245 ± 248.

[8] For example, the first self-reproducingmolecule can be a short strand similar to

pyranosyl-RNA. In this case base pair-ing is more stable and selective than isthe case with natural furanosyl-RNA.[6]

This is of advantage for the start ofevolution. Later, when a certain degreeof complexity has been achieved thatcorrect fitting together of the compo-nents is guaranteed, a more rapidlyfunctioning machine built up from fur-anosyl-RNA would be more advanta-geous. But how could such a conversioncome about? A genetic apparatus of acertain complexity based upon pyranos-yl-RNA produces an enzyme whichallows the formation of a furanosyl-RNA replica. This leads to a symbiosisuntil the furanosyl-RNA based system isno longer dependent upon pyranosyl-RNA system which then disappears.

[9] Darwin did not suppose, however, thathis theory of the origin of the species isthe way to approach the problem of theorigin of life, as his famous picture of the

start in a ™warm little pond∫, whichstimulated the later concept of an pri-meval soup, shows.

[10] M. Eigen, Naturwissenschaften 1971, 58,465 ± 523; I. Prigogine, D. Glansdorff,Thermodynamic Theory of Structure,Stability and Fluctuations, Wiley-Inter-science, New York, 1971.

[11] The frequenly posed question ™whatfirst, metabolism or genetic apparatus?∫is not relevant in this context. In thegiven model (life beginning in a mostpartcular region where chains of reac-tions lead to a replicating system) theformer case is assumed: metabolismpresent in the beginning, improved anddeveloped during the evolution of thegenetic apparatus by stepwise inclusionof enzymes.

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