the riddle of “life,” a biologist’s critical view

8/3/2019 The riddle of life, a biologists critical view

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REVIEW

The riddle oflife, a biologists critical view

Heinz Penzlin

Received: 5 March 2007 /Revised: 17 June 2008 /Accepted: 24 June 2008 / Published online: 2 September 2008# Springer-Verlag 2008

Abstract To approach the question of what life is, we first

have to state that life exists exclusively as the being-aliveof discrete spatio-temporal entities. The simplest unit thatcan legitimately be considered to be alive is an intact

prokaryotic cell as a whole. In this review, I discusscritically various aspects of the nature and singularity ofliving beings from the biologists point of view. In spite ofthe enormous richness of forms and performances in the

biotic realm, there is a considerable uniformity in thechemical machinery of life, which powers all organisms.Life represents a dynamic state; it is performance of asystem of singular kind: life-as-action approach. All life-as-things hypotheses are wrong from the beginning. Life is

conditioned by certain substances but not defined by them.Living systems are endowed with a power to maintain theirinherent functional order (organization) permanentlyagainst disruptive influences. The term organization inher-ently involves the aspect of functionality, the teleonomic,

purposeful cooperation of structural and functional ele-ments. Structures in turn require information for theirspecification, and information presupposes a source. Thissource is constituted in living systems by the nucleic acids.Organisms are unique in having a capacity to use, maintain,and replicate internal information, which yields the basisfor their specific organization in its perpetuation. The

existence of a genome is a necessary condition for life and

one of the absolute differences between living and non-livingmatter. Organization includes both what makes life possibleand what is determined by it. It is not something implantedinto the living beings but has its origin and capacity formaintenance within the system itself. It is the essence of life.The property of being alive we can consider as an emergent

property of cells that corresponds to a certain level of self-maintained complex order or organization.

Keywords Living state . Vital organization . Metabolism .

Self-maintenance . Autonomy. Emergence

Introduction

The bondage of biology to the physical sciences haslasted more than half a century. It is now time for

biology to take her right full place as an exactindependent science: to speak her own language andnot that of other sciences. Haldane (1922)

Living matter exists in a wondrous array of emergentproducts, perhaps 10 to 20 million different species or evenmorenobody really knows the exact number. Life is so

ubiquitous in our world, so evident that we fail to evenwonder at its existence. We take it for granted that a human

being composed of an estimated 10 billion (1013!) tissuecells of about 350 different types and another 30 billion

blood cells should develop from a relatively unstructuredseminated egg celland this, fortunately, with a remark-ably low rate of error. And nevertheless, embryogenesisdoubtlessly belongs to the most amazing and puzzling

phenomena to be found in our natural world. What causesall the cells to differentiate in the way that they do so a

Naturwissenschaften (2009) 96:123

DOI 10.1007/s00114-008-0422-8

H. PenzlinInstitut fr Allgemeine Zoologie und TierphysiologieFriedrich-Schiller-Universitt Jena,Erbertstrasse 1,07745 Jena, Germany

H. Penzlin (*)Leo-Sachse-Strasse 10,07749 Jena, Germanye-mail: [email protected]


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healthy child with a head, trunk, arms, and legs, with abrain, heart, and all the other organs comes into being andbegins to speak and to think? There is probably no one whobetter recognizes how remarkable life actually is than thedevelopmental biologist.

Two hundred years ago, Treviranus, Lamarck, and othersintroduced the term biology to describe the science

dealing with living beings. In the light of the multiple andheterogeneous questions it asks and approaches it takes, theterm life sciences is more usual nowadays. Strictlyspeaking, despite generations of trying, the subject matterof life sciences is as yet still undefined. My centralintention in this review therefore is not to try to definelife, which is probably a hopeless undertaking, but toattempt to work out what living entities are and todemonstrate that living beings are distinct from non-livingentities not only in their degree of complexity butfundamentally, in principle. Organisms have propertiesand facilities, which are unique to them and only to them.

Life means being-alive of discrete entities:

organisms

Life exists exclusively as the being-alive of something

To approach to the question of what life is, we first have tostate that life exists exclusively as the being-alive ofdiscrete entities, which we call living creatures ororganisms. No life exists outside and independently oforganisms; no independent agent makes inorganic matter

alive. Life always means being alive. There is no entitylife, which we can make the object of our science.Therefore, biology is not the science of life but thescience of living entities in all their forms, aspects, andhierarchical levels. We can consider the living entities ashighly complex systems and life as the specific perfor-mance of these systems. This underlines the absolutenecessity of systems thinking in General Biology.

The negation of a vital agent independent fromorganisms is not a trivial step by any means. It implicatesa fundamental point of view in the discussion of the

problem of life. Many cultural groups, philosophies, and

religions, for example, believed and believe in a vital agent,which also exists and acts outside of and independentlyfrom organisms. For Plato for instance, as already men-tioned, the soul is a distinct non-material entity, which

bonds to certain objects and induces in them animatebehavior. However, daily experience teaches us that such aduality does not exist. Life existsas already mentionedonly as being-alive of highly complex, dynamic systemswith the fundamental property to autonomously maintainand replicate their internal organization. Each organism

exists as a single, unique, spatiotemporally restricted entitywith a beginning and an end. Under present conditions onEarth, no organism comes into being spontaneously out ofnon-living matter. In every case, living entities derive fromliving entities: omne vivum e vivo (Lorenz Oken). Eachorganism has a unique, non-repeatable history. Becauseorganisms derive from other organisms (ancestors) and

produce yet other organisms (descendents), a continuoussuccession of generations connects each present organismwith lifes origin on earth.

Cells as elementary organisms

Despite the tremendous diversity of living forms in ourworld, scientists in nineteenth century discovered that all

present-day living organisms are made up of one, some,thousands, millions, or billions of cells. The entiremetabolism takes place in cells, and all cells are derivedfrom the division into two of previously existing cells:

Omnis cellula e cellula (Rudolf Virchow). Life is cellactivityits uniqueness is the uniqueness of the cell.

There are only two different types of cells (Fig. 1), the primitive prokaryotic cell (protocyte) of the archaea andbacteria and the essentially more complex eukaryotic cell(eucyte) of all the other organisms (protista, fungi, plants,and animals). The latter is about a thousand-fold morevoluminous and more complex than the protocyte. Nointermediate forms exist between these two types of cellsthat would guide a gradual evolutionary inference betweenthe prokaryotic and eukaryotic state. The protocyte has nomembrane-bounded organelles. Its genome consists in the

minimum case of a single, double-stranded, closed loop ofDNA. In contrast, the eucyte contains organelles surrounded

by double membranes, a nucleus with its contiguousendoplasmatic reticulum, a Golgi apparatus, and flagellawith a 9-+2-pattern of microtubule arrangement. During theinterphase, their hereditary material is concentrated in a setof complex chromosomes inside the cell nucleus.

The whole cell is the most elementary unit that canmaintain life; it is the least complex thing that properlylives. When protozoan cells divide into two halves, onecontaining the nucleus and the other without, only the firstcan maintain life. A nucleus-less Amoeba is still able to eat

and digest for some time. Later on, this capacity disappears,and the protozoan rejects the undigested food. Only cellfragments with an intact nucleus are able to regenerate thelost parts. The physiologist Ernst von Brcke characterizedthe cell as an elementary organism (Brcke 1851), andmany influential biologists (Walter Flemming 1882, E. B.Wilson 1907, Frederick Gowland Hopkins 1913, andothers) agree with him that life should be considered asthe activityor ensemble of activitiesof whole cells andnothing less. This conclusion expresses on the cellular level

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the holistic concept once formulated by Kant for theorganism as a whole. Below the cellular level, noindependent life is possible. Although some organelles,such as mitochondria and chloroplasts, undergo replication,this requires the functioning of the integrated cell. In tryingto define the essence of the living state (not of organisms!)fundamental for all living entities, we may confineourselves to considering life at its cellular level. When thefirst multicellular organisms appeared, life had alreadyexisted approximately 2.8 Ga. About three quarters ofevolution up to now has taken place on a cellular level or,in other words, was cell evolution1.

Viruses are the most abundant biological entities on ourplanet (Breitbart and Rohwer 2005). There are 10311032

virus particles in the biosphere; this is at least one order ofmagnitude more than the number of host cells! Virus

particles (virions) indeed contain genetic information (DNAor RNA), but they are incapable of growth or division bythemselves. They lack the machinery to generate energy orto synthesize their own proteins. They are obligate parasitesand depend on the host cells ribosomes to synthesize their

own proteins. Therefore, extant viruses are not truly alive.They were generally considered to be fragments of livingentities that have lost their capacity for autonomousexistence, but we must own up to the fact that we reallyhave no sound knowledge of how the entire domain ofviruses is organized, what the origins of viruses are, andhow they evolve (Bamford et al. 2005). Recently, Koonin etal. (2006) proposed an alternative hypothesis to thescenarios that describe viruses originating as genes thathave escaped from cellular organisms. In their concept ofan ancient virus world, the principal lineages of virusesand related selfish agents emerged from a primordial pool

of primitive genetic elements, the ancestors of both cellularand viral genes. In the opinion of these authors, theemergence of substantial genetic diversity antedates theadvent of fully fledged cells. To explain the crucial step ofcompartmentalization in the primordial pool, a highlyspeculative model has been elaborated (Koonin and Martin2005). The assumption of a non-cellular last universalcommon ancestor of the three domains Bacteria, Archaea,and Eukaryotes, as favoured in this scenario, remains atopic of controversial discussion (e.g. Gogarten and Taiz1992).

Last vital units below the cell level?life-as-thingshypotheses

The assumption that single substances are the primaryvehicles of life has a long tradition beginning with the pre-Socratic philosophers. In the Middle Ages and earlyRenaissance, life was sometimes identified as a fluidsubstance known as liquor vitae. Felix Dujardins living

jelly orsarcode was later succeeded by the more generalterm protoplasm which was considered by many as the

1

This cell-as-elementary-organism theorem is not inconsistent withthe well-known fact that the totipotency of the zygote gets lost in thedescendants of the zygote during the ontogenesis of a multicellularorganism. The cells become determined and differentiate into specifictypes of cells. This differentiation usually results from the differentialexpression of genes in the cell, i.e., from the differential regulation oftranscription, posttranscriptional events, or translation but not from aloss of DNA or irreversible changes in the genome. It is onlyirreversible in certain types of cells. In many cases, differentiation isreversible under the right environmental circumstances. Transdiffer-entiation of one differentiated cell type into another type has beenshown to occur for instance during regeneration and in cells in tissueculture.

Eukaryotic cell Prokaryotic cellFig. 1 Diagrams of thelarger and more complicatedeukaryotic (animal) cell (left)and the simpler prokaryotic cell(right). Only the eukaryotic cellshave a separate compartment(nucleus) that contains theirDNA (left figure after Storchand Welsch 2005, right figure

after Kaplan 1972)

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material basis of life until well into the twentieth century.In the second half of the nineteenth century under theinfluence of the blossoming discipline of organic chemis-try, the notion oflast units of life below the cellular levelwas widespread among theoretical biologists: physiologicalentities (Spencer), lebendiges Eiwei (Pflger 1875),Bioblasts (O. Hertwig 1906), Biophors (Weismann

1892), Protomers (Heidenhain 1894), or Biogens(Verworn 1903). All these life-as-things hypotheses baseon the effort to explain the specific properties and

performances of living systems in terms of mysterious units,molecules, or aggregates of molecules.

Nowadays, it is clear that no single molecule, no singlecomponent of the cell per se is alive. Chemists have learnedto synthesize any protein or any nucleotide sequence but, indoing so, have never created life. The birth of life onearth did not coincide with the first appearance of a certain

protein molecule as the physicist Pascual Jordan believed.Neither is it true that life began with the appearance of the

first nucleic acid strand in the primeval soup, which was ableto replicate and to mutate and thus became the subject ofselection, as Kuhn and Waser (1982) once stated. If that werethe case, scientists would have succeeded in making artificiallife in a test tube many times over. We have to accept thatlife is the performance of complex internally organizedsystems and as such necessarily began as a minimal integralmultimolecular system. Translation and replication areconsequences of the total functioning of the whole.

The role and importance of DNA is frequently exagger-ated. It is often uncritically elevated to the vital principle,the thread of life. What we must bear in mind, however,

is that the DNA double helix can only fulfill its centralfunction inside a living cell. Replication requires not justenergy but also the presence of several protein enzymes andsome complex precursors. The same is true of thetranscription of information from DNA to RNA and ofthe translation of the RNA sequence into the propersequence of amino acids in the polypeptide chain. Trans-lation requires highly specific aminoacyl synthetases toattach the correct amino acid to the correct transfer RNA(tRNA), thus permitting the synthesis of polypeptide chainswith the right amino acid sequence. This sequencedetermines at a given pH and temperature the three-

dimensional structure (tertiary structure) of the polypeptidechain, which is accountable for the function of this protein.

No one molecule, including DNA, catalyses its ownformation. There is no such thing as a genobiosis (Kaplan1972) on the level of genes! Numerous efforts (Joyce andOrgel 1986; Joyce 1987) to find an enzyme-free polynu-cleotide system able to undergo replication cycles bysequentially and correctly adding the proper nucleotide tothe newly synthesized strand have not yet succeeded(Kaufmann 1996).

Scientists who pretend that the riddle of life has beensolved by modern molecular biology are quite simpledeluded. Claims such as genes have created us body andmind; so when we know exactly what the genes look like,we will know what it is to be human, are absurd, asLowentin (1992) pointed out in his readable polemic. Lifecannot be associated with a single substance. All life-as-

things views or positions are wrong from the beginning.Life is conditioned by certain substances but not defined bythem. It is in no way a thing; on the contrary, it is action,it is dynamic, it is the performance of certain naturalsystems, which we call alive: life-as-action approach.

Minimal cells

Over the last few years, much theoretical and experimentalwork has been done to determine the minimum set of genesnecessary and sufficient to maintain a functioning cellunder ideal conditions, i.e., in the presence of unlimited

amounts of all essential nutrients and in the absence of anyadverse factors, including competition. Morowitz (1967)calculated that the minimal cell may be about one tenthsmaller than Mycoplasma genitalium, the organism with thesmallest known genome size. The wall-less Mycoplasmahas a cell diameter of 250 nm. That means that, in the caseof an intracellular pH value of 7.0, on average, only two

protons can exist simultaneously in its plasma.M. genitalium and Buchnera sp. (Shimkets 1998) do not

represent a type of ancestral cell but evolved from moreconventional progenitors by a process of massive genomereduction in connection with their life style (Islas et al.

2004): M. genitalium is an obligate parasite in the humanurogenital system and Buchnera sp. an endosymbiont.Their life styles permit the direct import of severalmetabolites and essential compounds from the host and,consequently, the withdrawal of some synthesis activities.

It is probably not wrong to suppose that the largelyunredundant genome of M. genitalium comes close to theminimal gene set essential for maintaining life. The genomeof M. genitalium consists of one circular double strand ofDNA and has 580,074 base pairs (580 kb). Out of 487

protein-coding genes, Glass et al. (2006) identified only100 nonessential genes. The remaining 387 protein-coding

genes plus three phosphate-transporting genes and 43RNA-coding genes constitute the set of genes essential forthe existence of this individual. Genes for electron transportand the citrate cycle are missing. Only one gene (enzyme)exists for the synthesis of amino acids. Gil et al. (2004), onthe basis of their work with Buchnera sp. and otherorganisms, proposed a protein-coding gene core of just206 for a minimal bacterial gene set (Table 1). Resultsobtained by other authors are close to those presented byGil and his co-workers. Two hundred to 300 genes are



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broadly accepted as the theoretical fully fledged minimalgenome. Free-living prokaryotes have a significantly largergenome. No example of a free-living prokaryote with agenome of


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far more important, in quantity and quality, than hithertoimagined, early organismal evolution seems more similar towithin-species genealogies than to traditional species trees(Doolittle 1999; Gogarten et al. 2002; Zhaxybayeva et al.2005). In this sense, Woese (2000) hypothesized anundefined progenote community (organisms without atight coupling between geno- and phenotype) experiencing

an extensive lateral gene transfer rather than a singlecommon ancestor was at the root of the tree of life. Forterreand Philippe (1999) placed the root of the tree of life on theeukaryotic branch. They proposed that the ancestors hadeukaryotic features and that prokaryotes are the result ofregressive evolution. Bapteste and Brochier (2004) claimedradically new approaches.

Since the mid-1970s, the endosymbiont hypothesis iswidely accepted (Schwartz and Daydoff 1978; Maier et al.1996). It starts from the assumption that eukaryotic cells areconglomerates (mosaic-cells; Fig. 3): In a first endosym-

biotic event probably occurring between 2.2 and 1.5 Ga

ago, the early Proterozoic archaeal-like host cells incorpo-rate aerobic -proteobacteria (purple non-sulfur bacteria),the precursors of proto-mitochondria. With this pivotalevolutionary event, the first heterotrophic unicellular

eukaryotes appear. A second endosymbiotic event occurs between 1.5 and 1.2 Ga ago. Ancient mitochondria-carrying eukaryotic host cells incorporate coccoid photo-synthetic cyanobacteria-like cells giving rise to the plastids.How the nucleus made its first evolutionary appearance isstill a matter for discussions. Three competing hypothesesexist (Kutschera and Niklas 2005).

During the co-evolution of hosts and symbionts thatfollowed, a large part of the symbiontic genome wastransferred into the nucleus of the eukaryotic cell (intracellularhorizontal gene transfer), giving rise to the mosaic

provenance of the eukaryotic genomes. The mitochondriaand plastids therefore no longer have the full geneticinformation for their own reproduction at their disposal.However, the ribosomes of both mitochondria and plastidsstill resemble in their ribosomal RNA (rRNA) sequencesthose found in bacteria and not those in the eukaryotic cells.They are sensitive to tetracycline, just as bacteria are, but notto cycloheximide. The outer membrane of plastids and

mitochondria is not a remnant of the eukaryotic phagosomallayer as earlier supposed but resembles in its ultrastructure andfunction the Gram-negative outer membrane, which agreesstrongly with the endosymbiont hypothesis.

Fig. 3 The symbiotic theoryproposes that the complexeukaryotic cell arose by a seriesof symbiotic events in whichorganisms of different lineagesmerged (after Kutschera 2006)



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Origin of life

Largely as a consequence of Louis Pasteurs famous experi-ments in 1862, which destroyed any belief in contemporaryspontaneous generation, the question arose of how lifeoriginated in the distant past on Earth. Starting with thefamous papers of Oparin (1924) and the independent efforts

of Haldane (1929), much theoretical and experimental workhas been done and several ingenious and not unreasonablehypotheses proposed, but we have honestly to confess thatno biologist or physicist has yet succeeded in coming upwith a convincing and generally accepted theory as to howlife originated on earth, how the primordial cell might haveevolved, and what its structural und functional particular-ities might have been.

Past research on the origin of life was largely based onthe elementary idea of molecular evolution according towhich life originated from inanimate matter via a sponta-neous increase of molecular complexity and specifity:

bottom-up approach. Starting from the classic experimentof Miller (1953), numerous experiments have clearly shownnot only that a wide range of biologically significantorganic compounds can be synthesized under possible

primitive Earth conditions but also that other importantmolecules resist prebiotic synthesis in acceptable quantitiesin a primeval soup. This concerns mainly the formation ofribose (and other sugars) and pyrimidines and polymeriza-tion in an aqueous solution. Ribose has surprisingly shorthalf-times for decomposition at neutral pH (73 min at 100C;Larralde et al. 1995). It also concerns the formation ofmembranogenic lipidslinear fatty acids with a sufficiently

long (more than 1012 C-atoms) hydrophobic chain.To overcome these shortcomings in the primordial soup

hypothesis, Wchterhuser (1988) suggested that theearliest stages of life occurred in a surface-bondedautocatalytic chemical network consisting of polyanionicorganic compounds on the positive charged surface of

pyrite (FeS2): iron-sulfur-world. Under these conditions,the reactants do not drift away but are kept in each others

proximity. This permits not only sufficiently high reactionrates but also the growth of lipid-covered surface areas andsubsequently the building of semi-cellular structures byabstriction (individualization).

The crucial step of spatial segregation in a chemicalenvironment, the formation of a microscopic membrane-covered organic blob around the primeval RNA or DNA(compartmentalization problem) involves, from the point ofview of a biologist at least, three essential events: firstly, theseparation of the first cell from its environment by aselectively permeable plasma membrane, guaranteeing acontrolled exchange of matter and energy with thesurroundings (individualization); secondly, the manifesta-tion of an internal functional that means teleonomic order

(organization); and thirdly, the creation of informationcoding replicative structures guaranteeing the informationalintegrity and invariance of the system (self-maintenance).

The fact is that even the humblest organism must be acoalition of a high number of molecules of differentspecies. It is also a fact that, in living beings, the geneticmessage can only be translated by the products of its own

proper translation and that these products have no futurewithout nucleic acids. To get around this paradoxicalsituation of nucleic acids being needed to encode proteinsand proteins (enzymes) being needed to replicate nucleicacids, Walter Gilbert, Leslie Orgel, and others proposed anRNA world. They believe that the progenitors of moderncells were based entirely on RNA molecules able to act as

both informational molecules and catalysts. Only later didproteins take over the role of enzymes and DNA appears tostore the genetic information, leaving RNA to mediate

between genes and enzymes. This scenario has gained alarge measure of acceptance within the scientific commu-

nity. In this context it is, however, important to point outthat years of careful effort to find an enzyme-free

polynucleotide system able to undergo replication cyclesby sequentially and correctly adding the proper nucleotideto the newly synthesized strand have not yet succeeded(Kaufmann 1996). Another problem is that, under theconditions of the primeval soup, DNA is more likely toaccumulate than RNA because it is more stable than themore reactive RNA. The spontaneous formation of a self-replicating RNA-familythe molecular biologists dream(Joyce and Orgel 1993)is certainly not a trivial process(Luisi 1999).

Despite several brilliant reflections and outstandingexperiments on this subject, we must assume that there isstill an unbridgeable hiatus between the prebiotic organicchemistry and primordial cells. The gap between life andlifeless has actually become wider rather than smaller ascytology, microbiology, biochemistry, and molecular biol-ogy have advanced. Ignoring this fact is both unhelpful anddishonest. With Jacques Monod, we must honestly admitthat here we reach a real sound wall (Monod 1972).

Nowadays, studies on the origin of life have changed froman area dominated by speculation into a field of testablehypotheses.

Life means performance of complex systems:

dynamics

The conclusion we can draw from the text above is: Life isnot substance, it cannot adequately be defined by aninventory of its material constituents. There is no phenom-enon in living systems that is not molecular, but there isnone that is only molecular, either. We must reject all life-



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as-things hypotheses because life is first and foremost aprocessit represents a dynamic activity and it is perfor-mance of a system of singular kind. Living entities must beconsidered as systems with well-defined spatial boundariesand subject to network dynamics in the sense of generalsystems theory and not as bundles of linear chain reactions

programmed with micro-precision.

Living systems actively remain in a state far fromthermodynamic equilibrium. As Erwin Schrdinger (1944)

pointed out: It is by avoiding the rapid decay into the inertstate of equilibrium that an organism appears so enigmatic.Life is a permanent struggle against destruction. This view is

by no means new. Already in the eighteenth century, GeorgErnst Stahl saw life as a conservatio mixtionis corporisagainst the tendency to decompose. Unlike non-living matter,living cells are continually doing something, metabolizing,exchanging material with their surroundings, moving, and soon. They remain in a state of constant flow. When inorganicsystems are placed in a uniform environment, sooner or later

all motion usually comes to a standstill (equilibrium).

Steady state far from equilibrium, entropy

At the temperature of existence, the living state is unstable.Every cell exists in permanent breakdown and resynthesis.To live is to be involved in an uninterrupted process of self-renewal. There is no stagnation; everything is in constantflux. Living systems represent a state of being and a state of

becoming at the same time. This continual process ofrenewal is not one among many attributes of life but thecharacteristic mode of existence of living systems. Life is a

continuous process; life is dynamics. Nothing is excluded,from the superficial plasma membrane to the innercytoplasm and cytoskeleton. Within 17 days, half of the

protein molecules of an adult rat have disappeared and beenreplaced. Most messenger RNA (mRNA) molecules aredestroyed shortly after they are synthesized. Even the DNAmolecules are subject to permanent breakdown, liable asthey are to be damaged by a variety of agents. Only through

permanent restoration is the DNA able to preserve theinformation stored in it.

In order for this permanent cycle of reconstruction to proceed at a sufficient rate at the temperature of existence,

catalysts for the many metabolic reactions are necessary.This central function is filled by special proteins and proteidsknown as enzymes. There are currently more than 2,000known enzymes, and virtually, all metabolic reactionsdepend on these compounds, which speed up reactions in amore or less specific manner. Enzymes cannot change theoverall free energy change of a reaction. They lower thetransition state energy (G) needed to prime the reaction andthus increase the rate of reaction. These increases range from108 to 1020 relative to the uncatalyzed, spontaneous reaction.

Thermodynamically, organisms are open systems, for theymaintain a continuous exchange of matter and energy withtheir environment in order for life to go on, during which

both the chemical composition and the energy content of thesystem remain almost constant. To maintain the appropriatemix and concentration of chemical components, the degra-dative processes must keep pace with synthesis; the input

must balance the output. We call this time-independent statesteady state or Fliegleichgewicht (Ostwald 1926).

With respect to the entropy S of the system, this meansthat the entropy permanently produced inside (diS) thesystem must be exported into the surroundings (deS). Onlyin this way the complete entropy S of the system can befixed at a certain level (dS=0) (Prigogine 1947):

dS diS deS 0

diS deS

This entropy export requires free energy or enthalpy.The free energy taken by the living organisms from theirsurroundings in the form of nutrients or sunlight finallyreturns to the environment as heat and entropy. The order

permanently produced in the living cell is more thancompensated for by the disorder, which living things createin their surroundings.

Strictly speaking, the steady state is not a state ofequilibrium but a state of non-equilibrium because it doesnot coincide with the thermodynamic equilibrium charac-terized by a minimum of free energy and a maximum ofentropy. A system in the state of thermodynamic equilib-

rium cannot perform work or organize itself. It is simplyincapable of living. The maintenance of a steady state farfrom thermodynamic equilibrium is a prerequisite to beingalive. This means nothing more than that the cell itself hasto actively maintain non-equilibria against the second lawof thermodynamics.

The extension of thermodynamics to open systems underfar-from-equilibrium conditions beyond the linear domain,where linear relations between the general thermodynamicfluxes and forces no longer exist, by Ilya Prigogine andothers of the last century showed us that, under theseconditions, systems can also arrive at a permanent state, but

one which is no longer characterized by an extreme valueof a certain potential and which thus no longer displays thestable behavior immune to fluctuations we know fromsystems at or around the chemical equilibrium. Glansdorffand Prigogine (1971) termed steady states that are separatedfrom thermodynamic equilibrium by instabilities dissipa-tive structures, as they must be generated and maintained

by dissipative or entropy-producing processes.For the occurrence of dissipative structures, the open

state of the system is a necessary but not sufficient



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condition. Further prerequisites have to be fulfilled, themost important by far of which in chemical systems is self-enhancement or autocatalysis. In biological processes,simple autocatalyses are often based on feedback andfeed-forward phenomena. The multiple types of these

phenomena and the allosteric enzymes that control themetabolism are important causes of the highly nonlinear

kinetics in biochemical systems. In addition, many enzymesare bound to membranes that also yield a highly complexand non-linear behavior. Clear evidence for the existence ofdissipative structures in metabolism are the numerousexamples of periodicities observed in the synthesis or theactivity of enzymes (Hess et al. 1978).

Living systems maintain a high degree of internal order bydissipating entropy into their surroundings, but organisms areunique examples of dissipative structures since their internalorder is self-created, self-maintained, and self-replicated andnot the result of external forces in form of chemical, thermal,or other gradients under strict observance. They are in-

formed dissipative structures. This absolute autonomy ofliving systems operates through informed pathways on the

basis of an internal genetic program. The study of dissipativestructures may be helpful for a better understanding of lifesorigin: order from disorder. The living state and ontogeneticdevelopment, however, is based on quite different principles:order from order. It has little in common with inorganicdissipative structure building.

Energy

In order to understand life properly, it is essential to appreciate

its sheer improbability. Alone, the preservation of the livingstate of internal order requires permanent delivery of energy.In order to prevent the system from decaying to equilibrium,organisms need to take in free energy on a permanent basis.Because cells function at an essentially constant temperatureand pressure, heat flow cannot be a source of energy for them

because heat can only do work as it passes to a zone or objectat a lower temperature.

The energy that cells can and must use is the so-calledGibbs free energy G derived from the breakdown of organicfuel molecules such as carbohydrates and fats. Most bacteria,all protozoan, fungi, and animals find these nutritious

moleculesready-made organic compoundsin their sur-roundings (chemoheterotrophs). Contrary to these organisms,the autotrophs are able to synthesize the carbohydratesthemselves from carbon dioxide. Cyanobacteria, green and

purple sulfur bacteria, algae, and higher plants capture thenecessary energy for synthesis from light (photoautotrophs),the nitrifying bacteria, non-photosynthetic sulfur bacteria,and iron and hydrogen bacteria obtain the energy fromoxidizing simple inorganic substances such as sulfides andnitrites (chemoautotrophs). The non-sulfur purple or green

bacteria, finally, can also use energy from light but requireorganic substances (alcohols, fatty acids, or carbohydrates)as carbon source (photoheterotrophs). Almost all of theenergy entering the biosphere comes from the absorption of

photons and the conservation of photon-absorbed energy bychlorophyll.

Both heterotrophs and autotrophs transform the free

energy delivered step by step in catabolism into ATP(adenosine triphosphate; Fig. 4) and other energy-richcompounds capable of providing energy for biologicalactivity at a constant temperature and pressure. The energyis dedicated chiefly to three processes: firstly, the resynthe-sis of lost compounds (synthesis work); secondly, the activetransport of molecules and ions (osmotic work); and thirdly,mechanical processes inside the cell (motion work).

The energy transfer fundamental to all living systemsoccurs chiefly by means of the adenosine diphosphate(ADP)ATP cycle. The hydrolytic cleavage (Fig. 4) of theterminal phosphoanhydride bond of ATP

ATP4 H2O!

ADP3 P2i H

corresponds to a free energy change of about Go0

30:5 kJ mol1 under standard conditions. The actual freeenergy of hydrolysis of ATP in living cells is much morenegative, ranging from 50 to 65 kJmol1. The ATP turnoverinside the cell is very high (Sabater 2006). The ATP-ADP-system in eukaryotic cells is kept at a level, which differs fromits thermodynamic equilibrium by 108 to 1010. Via the innermitochondrial membrane, a H+-gradient of about 200 mV(Nicholls and Ferguson 1992) is continuously maintained.

Life means functional, teleonomic order: organized

dynamics

The openness of the system in a steady state far fromequilibrium is doubtlessly a necessary condition for theexistence of life but by no means a sufficient one. Theliving state represents organized dynamics, which means afunctional and therefore teleonomic order. Organismsexhibit an admirable regularity and orderliness, unrivalled

by anything we encounter in the realm of non-living matter.Following Oparin (1961), several authors like to char-

acterize organisms by three fundamental properties: metab-olism, self-reproductivity, and mutability. If, however, weattempt to characterize the living state and not the organismitself, only metabolism still applies as a general expressionto describe the self-maintained dynamics of living systems.Metabolism as the entirety of the chemical events in theliving system includes the turnover of substances, energies,and information. It guarantees the permanent self-renewal,self-duplication, and self-reproduction of the living sys-tems. Organisms are still in a living state even if they do not



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propagate or lack mutability. I agree entirely with Monodthat evolution is not a property of living beings, since itstems from the very imperfections of the conservative

mechanism which indeed constitutes their unique privilege(Monod 1972). The same is true for reproduction. Metab-olism is not just an attribute of living systems, itrepresents the living state itself, which is functionallyorganized. The living state persists at all times, at everystage of development. No interruption ever occurs, eitherduring embryological development or in the sequence ofgenerations2. The continuity of life is really a continuity ofinformation (see below).

What organized means

The living state is best characterized by the adjectiveorganized. Living cells are organized wholes. The termorganization is a central and very old concept in biologyintroduced already by Aristotle. For Lamarck, every fact or

phenomenon observed in a living body is at once a physicalfact and phenomenon and a product of organization (cited inHall 1969). In this view, living systems differ from non-living entities not in being non-physical but in beingorganized. At the turn of the nineteenth century, the conceptof organization, that gave living beings the internal lawdetermining the very possibility of their existence (Jacob1993), became the focus of the naturalists interest. Biologyas an autonomous scientific discipline was born. It was no

longer enough to observe and describe in detail theresemblances and differences between organismsthe aimnow was to work out the general principles common to allliving beings: Everything that is generally common to

plants and animals, and all faculties proper to each of thesebeings without exception must constitute the unique and vastsubject of biology, opined Lamarck (1815).

Biology began to look beyond the diversity of organismstoward the unity of the living world, in an attempt todistinguish living beings from non-living matter. From then

2 Some living entitiesspores of microorganisms, seeds of plants, some

lower invertebrates (tardigrades, nematodes etc.)

are able to enter intoan ametabolic state of cryptobiosis or latent life by undergoing a phase of liquid water loss. This process may result directly fromevaporation or arise through vitrification promoted by the synthesis of acarbohydrate matrix accompanied by metabolic depression. Finally,metabolism comes close to being fully arrested. In this actively causedstate of frozen life, the organisms are able to resist extremeenvironmental condition. In the literature, we find several reports ofmicroorganisms being revived after millions of years from Precambrianor Silurian rocks or salt deposits (Dombrowski 1963; Vreeland et al.2000). It is, however, still an open question whether those micro-organisms are truly long-term survivors, or whether artifacts (contam-ination) could explain the revivals (Kennedy et al. 1994).

Fig. 4 Metabolism representsa unity of energy-releasingcatabolism and energy-requiringanabolism. The primary cou-

pling agent between downhilland uphill reactions in livingcells from bacteria to humans isadenosine triphosphate (ATP)



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on, only two realms were distinguished: the inorganic, non-living, inanimate, inert things on the one hand and theorganic, living, metabolizing, and reproducing beings onthe other, the latter being united through their internal self-maintained organization. The study of living beings couldno longer be treated as an extension of physics andchemistry, but demanded (although this has repeatedly

being called into question over the course of time) newconcepts and its own language. To use the words of RobertRosen (1985): Complexity is not just complication, but awhole new theoretical world with a whole new physicsassociated with it.

The central term organization inherently involves theaspect of functionalitythe teleonomic, purposeful coop-eration of structural, and functional elements. Pittendrigh(1993) once asked the famous mathematician John von

Neumann what he saw as the difference between order andorganization. Von Neumanns short answer was: Organi-zation has purpose, order does not. That is to say:

organization is information-dependent, order is not. Thatwhich is missing from the thermodynamic images oforganization is tied to the concept of function. A systemmay be characterized as organized only when it is able tocarry out certain functions on the basis of cooperation

between its components. Organization is a necessarilyqualitative concept, which needs information for itsspecification. Wicken (1987) defined organization asinformed constraint for functional activity. A system isalways organized with regard to something.

The organization of living systems takes care of self-maintenance and self-reproduction. Therefore, Monod

(1972) speaks quite rightly about the teleonomy oforganization. Jacob (1993), his colleague at the PasteurInstitute in Paris, moves in a similar direction: Organiza-tion is inconceivable without the postulate of a goalidentified with life: a goal no longer imposed from without,

but which has its origin in the organization itself. It is thenotion of organization, of wholeness, which makes finalitynecessary, to the degree that structure is inseparable from its

purpose. Should any part of the cell or organism fail toperform its function properly, the living system will, sooneror later, become handicapped to the point of death.

We can summarize that the concept of organization

integrates all these properties, which characterize living beings as unique in the natural world: wholeness, invari-ance, autonomy, functionality, teleonomy, finality, and

purposeful behavior. In contrast to human artifacts, theorganization of a living being has its origin and capacity formaintenance within itself and is not implanted by thehuman mind. In the words of Jacob (1993): Organizationincludes both what makes life possible and what isdetermined by it. Uexkll (1928) thus defined biology asthe science of organization, and Ludwig von Bertalanffy

(1932) saw with good reasons the basis of life inorganization. In the same vein, Monod (1972) consideredteleonomy an essential property for the definition oforganisms.

Unlike in biology, the term organization is relativelyunknown in physics and chemistry, for good reason.Physicists deal with systems structured by physical forces

rather than those structured for function. When physicists usethe term organization in the context of self-organization,they are mainly dealing with a process, namely the creationof order out of chaos under strict observance of certain

boundary conditions and not with organization in thecommon sense of this word. In nature, the occurrence oforganized systems is restricted to living beings. We knowmany of the parts and many of the processes, which occur inliving systems, but what makes a cell alive is still not clear tous. A definition of the organizational feature common to allliving systems would be tantamount to a definition of theliving state itself. Therefore, this approach should be central

to all Theoretical Biology (Penzlin 1993a).

Proteins as the function bearing molecules

In all organisms, the proteins play the central role inmetabolism. Due to their nearly infinite variety of theirmolecular forms and chemical reactivities, they are thefunction-bearing molecules in organisms. Their spatialstructure gives them the unique ability to recognize andselect their partners and only these partners (ligands,substrates, and receptors) for specific interactions from amost heterogeneous mixture of chemical compounds. Each

protein has its particular, specialized task within the cell.Proteins are indispensable not only as enzymes but also asintra- and intercellular mediators. As structural molecules,they provide much of the cytoskeletal framework of cells.They can perform important transport or movementfunctions. In the plasma membrane, they play an essentialrole as translocators and receptors. Antibodies are highlyspecialized proteins. Last but not least, proteins stabilizeand control the activity of DNA and RNA. It is estimatedthat, in every eukaryotic cell around 4,000 to 5,000,different functional proteins are permanently active asenzymes, transport proteins, receptor proteins, etc. in

maintaining the living state (the so-called house keepingproteins).

The proteins are the intelligent molecules, which bearthe knowledge that maintains the organization of thesystem. In nearly all organisms agreeing, the elementary

building stones of the proteins are the same 20 different-amino acids. We are far from being able to answer thequestion of why only these 20 amino acids and no other,and these furthermore only in the L-form, have been electedto form all the different proteins in organisms. Only a



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minute portion of the potentially possible proteins areindeed realized in living beings. The basis responsible forthe function of a particular protein, or in other words for itsintelligence, is its three-dimensional shape (tertiarystructure), which at a given pH, ionic strength, metal ionconcentration, and temperature, is mainly determined by theamino acid sequence (primary structure) and stabilized

primarily by non-covalent interactions.Proteins make up about two thirds of the organic matter in a

cell. A typical cell requires thousands of different proteins,which have to be synthesized in response to the cells currentneeds. Protein synthesis can account for up to 90% of all thechemical energy needed by a cell for biosynthetic reactions.The proteins are made at exceedingly high rates. A polypep-tide of 100 residues is synthesized in E. coli at 37C in about5 s. In a growing bacterial cell ( E. coli), more than 103

protein molecules and about 104 lipid molecules can besynthesized every second, which demands 2 106 ATPmolecules. The essentially more voluminous and compart-

mented eukaryotic cells need about ten times longer for thesyntheses. Every organelle in a eukaryotic cell performsspecific functions and must therefore contain a certain set of

proteins. Most of them are synthesized in the cytosol.Specific zip codes or signal sequences direct them totheir different final destinations. On the way, many of these

proteins have to traverse at least one membrane or need to beintegrated into a membrane. Thereby, the signal sequencesopen protein-conducting channels.

Metabolism

All living beings differ fundamentally from all non-livingentities in their metabolism. Metabolism is not only therelease of free energy or the turnover of substances but isthe integration of all the chemical processes carried out byliving organisms. It represents in unifying catabolism andanabolism a functional and therefore teleonomic dynamicstate of high order, which we characterize as organized. Itis entirely inadmissible to say that a flame, a growingcrystal in a solution or a machine performs somethingsimilar to metabolism. The sole aim of such statements isto make the gap between living and non-living as small andunessential as possible and in doing so to make the

reductionistic thesis more comprehensible. Even in vitroreplication systems (Mills et al. 1967) consisting of an RNA-strand as a matrix, an RNA-polymerase (Q-replicase), andthe energy-rich building stones (ribonucleoside triphos-

phates) have no metabolism. In contrast to living systems,all these systems lack the feature of permanent self-renewal

by an anabolism in connection with a catabolism. Theyrepresent solely an irreversible downhill catabolism andthus do not differ in any way from other exergonic reactions,which occur in a test tube.

Metabolism is the indispensable basis for the permanentmaintenance of the living state. It is more than the sum ofchemical reactions. It is the concerted action of numerous

processes to pursue the continuity of life. Each of thereactions needs an enzyme, which is itself the result of aseries of synthetic steps and informational transmissions.Thanks to new techniques, scientists are now beginning to

analyze the network of interactions between the chemicalcomponents in the cell (functional genome research) with theultimate goal of understanding the complex interactome(Rual et al. 2005; Stelzl et al. 2005).

Data derived from comparative biochemistry convinc-ingly show that in spite of a great diversity in the structuresand lifestyles of extant organisms, there is an inherent unityof life processes at the molecular level. Only a very fewchemical processes and structures out of many chemically

possible ones have been implemented in living systems.These are the result of natural selection and constitutedspecific biological adaptations. In all living cells, we find

the same or very similar metabolic pathways and energytransfer by adenosine triphosphate. All cells are covered bylipid membranes and use homologous enzymes to generateion gradients across them. All cells use the same 20 aminoacids for the synthesis of their proteins and in all casesexclusively the L-form. All cells use the same fournucleotides for storing and transmitting genetic informationand the same (or a very similar) genetic code. Althoughthere are some differences in the mode of transcription andtranslation, the process is very similar in all cells. Theuniversality of the chart of intermediary metabolism inorganisms doubtlessly counts among the most impressive

discoveries of the past century.It is highly probable that all extant organisms trace back

to a last common ancestor. It is, however, not clear, whetherthis last common ancestor already possessed all the

biochemical pathways we find universally distributed inrecent organisms. We must take into account that some ofthese properties appeared later and spread through horizon-tal gene transfer. In the opinion of Gogarten (1995) andothers, the last common ancestor does not seem to have

been fundamentally different from present-day prokaryotes.To pinpoint events of horizontal gene transfer on the tree oflifeso the author continuesa more extensive sam-

pling of species for slowly evolving molecular markers isneeded.

Metabolism in cells is carried out in aqueous solution orat water interfaces. Water is not only an essential solvent forlife on earth but also an important metabolite. The structureof all biomolecules results from their interaction with water.But under no circumstances should we consider thecytoplasm as a homogeneous aqueous space in whichchemical reactions occur in the sense of MichaelisMentenkinetics. Singular conditions exist in living cells, which can



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cause considerable deviations from kinetics as observed intest tubes.

Cell metabolism comprises hundreds to thousands ofdifferent reactions occurring simultaneously or successivelyin an orderly manner. All this takes place in an unimagin-ably small space: The volume of the prokaryotic cellreaches about 1015 l, the volume of eukaryotic cells up to

1012 l. This is an order of magnitude, which limits to someextent the unconditional application of the laws ofthermodynamics. The concentrations of the compoundsinvolved in the reactions are very low (between 103 and106 mol/l). In contrast, the concentrations of the enzymesare relatively high and do not differ appreciably from theconcentrations of their substrates. As the molecules are nothomogeneously distributed throughout, the cell summarystatements about concentrations are usually of little indic-ative value.

Regulation of metabolism

The extreme efficiency of the chemical machinery of livingsystems requires extraordinarily precise and efficaciouscoordination between various activities. Metabolism is ahighly sensitive and nevertheless remarkably stable system,which is able to react to disturbances in a sensefulmanner and adapt itself quickly to specific requirements.This is only possible because the diverse chemical reactionsinvolved are controlled by an efficient cybernetic net-work (J. Monod), which guarantees the functional coher-ence of the intracellular chemical machinery. A fullunderstanding of how living organisms function includes

an appreciation of how cells operate at the molecular level.The central regulatory compounds in this network are

the proteins, in particular, the allosteric enzymes, whichcan easily switch on or out (Koshland 1987). Regulatedenzymes are often found at the start point, end, or branch

point of metabolic pathways. Well known is the regulation by negative feedback: The final product of the pathwayinhibits the first enzyme in the pathway. It has long beenknown that metabolic pathways display rate-limitingsteps, which are controlled by specialized key enzymesregulating the flux rate of metabolites at this point. Thereactions in question unlike most other steps occur far from

the chemical equilibrium. They are, therefore, irreversibleand strongly exergonic, which means that they exhibit ahighly negative free enthalpy (G0; Hess and Boitew1971).

In many cases, the control of the flux rate through ametabolic pathway can occur simultaneously at several oreven all steps of the pathway even if with differentefficiencies (distributed metabolic control). The moleculargeneticist Henry Kacser used in this connection the termmolecular democracy (Kacser and Burns 1979). When

yeast cells are placed in conditions, which require a higherenergy turnover, they increase the activity of all glycolyticenzymes.

The metabolic net has both a functional and a structural basis. The extraordinary protein-rich cytoplasm of eukary-otic cells has a submicroscopic architecture, which consistsof a dense network of thin filaments (mainly F-actin; Hou

et al. 1990). For a cell with a diameter of 16 m, the surfaceof this cytomatrix amounts ranges from 40,000 to130,000 m2. Frequently, essential components of meta-

bolic pathways are found united in genetically, structurally,and functionally defined units, which Srere (1993) calledmetabolons (Fig. 5). Many enzymes are combined withstructural elements, metabolites, and ions in loose transientcomplexes. One well-known example is the citric acid cyclein the mitochondrial matrix. The bonds are not so tight thatthe metabolites are prevented from shifting into the freemetabolic pool of the cell, which is of great importance

because several metabolites have multiple functions as

signal molecules, C-sources for other metabolic pathways,or in other way.

Teleonomy and purposiveness

In every organism, structures exist and processes occur,which in general serve certain purposes and are purposefulfor the continued existence of the whole. The componentsof organisms are interrelated one with another to form asystem, which appears to be designed for a particulardirection of activity. In other words: Living systems aredirective and purposive and, in this sense, teleonomic

(Pittendrigh 1958). Nobody can seriously deny that everyunicellular and multicellular organism and their variousorgans (organelles) represent the materialization of func-tions and adaptations, or to put it another way, nothing lessthan the materialization of purposes. Already the philoso-

pher Kant (1790) in his Critique of Judgement veryrightly characterized organisms as Naturzweck in whicheach part is conceived as if exists only through all theothers, thus as if existing for the sake of the others and onaccount of the whole, that means as an organ.

As Monod (1972) emphasized for good reason, objec-tivity obliges us to recognize the teleonomic character of

living organisms, to admit that, in their structure and performance, they act projectivelyrealize and pursue apurpose. The foundation for the teleonomic project inorganisms lies in a certain quantity of information stored inDNA. Anyone who attempts to negate purposes and goals,functions, and adaptations in biological thinking andresearch omits the bios from biology.

Previous to Darwins work, the explanation of thisobvious fact was invariably connected with unbridgeabledifficulties. Many scientists have held and continue to



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nurture a deeply rooted distrust of the acceptance of aimsand purposes in our natural world (Penzlin 1987). Morethan anyone else, Darwin showed us that a natural,objective explanation of purposiveness is a rational possi-

bility and a legitimate scientific goal. What is mostchallenging about Darwin, MacLeod (1957) pronounced,is his reintroduction of purpose into the natural world.Darwin exorcised teleology of its transcendentalism. Onceorganisms are fully conceived in their inherent dynamics as

entities created during a long process of evolution bymutation, recombination, competition, and natural selec-tion, it becomes highly evident that purposiveness cannot

be something grafted onto the living beings but must be anessential immanent peculiarity of them. If the purposefulcooperation of the numerous processes in preserving theliving whole ceases to function correctly, the organism nolonger has a real chance of survival and is excluded fromfurther evolution. I believe Pittendrigh (1993) was rightwhen he said for his own part that he would have beenhappier had The origin of species been called The originof organization: The non-theological explanation of bio-

logical organization (of Pahleys design) was the realDarwinian revolution, much more profound than the originof diversity, which it incidentally entails.

In contrast to the external teleology of certain humanartifacts such as target tracking missiles, the teleology ofliving beings is an internal one because it is inherent to thesystem and self-made and does not originate from theintention of an engineer. Teleonomic in biology meansgoal-directed but by no means goal-intentioned. Teleonomyis directiveness without knowledge of the goal, is perfor-

mance according to a plan. It does not make much sense todiffer between purposeful and teleonomic as proposedMayr (1979). Purposiveness always includes a goal to beachieved. Purposiveness is a relation term. It receives itssignificance only in relation to something else. We can saythat a structure is only considered purposeful when theachievement of a purpose, which is at the same time thegoal, is facilitated or made possible by it. In everyorganism, we notice a hierarchy of purposes (Riedl

1981).The uppermost purpose in every case is to ensure the

realization and perpetuation of the living state with itsspecific performances. All other purposes are subordinatedto this. Throughout the long process of evolution, theorganization of living beings has been perpetually adjustedin such a way that it guarantees their survival andmultiplication.

While in physics the causal connection soon became thedominating form of explanation, biologists cannot renounceteleonomic formulations and explanations because theobjects of biological research are organized and, as such,

are purposive and end-directed. Biologists would lose agreat deal, methodically and heuristically, if they were

prevented from using teleonomic language. That does notmean however that, unlike in physics, causal-analyticresearch in biology is quite inadequate to its task, asRussell (1945) assumed.

Teleonomic and causal-analytic explanations do notcontradict but complement each other. A teleonomicexplanation appeals to the end of the process. It concernsthe function, which the process has to fulfill. The point in

Fig. 5 Supramolecularassociation of glycolyticenzymes to F-actin-troponin(after Bereiter-Hahn et al.1997)



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question is how the process under consideration fits into thegeneral relationships of the whole. A teleonomic explanationdoes not make the causal-analytic explanation superfluous

but invites us to carry out supplemental causal research. Bothforms of explanation have their role and importance in lifesciences. All efforts to translate teleonomic statements into

purely causal ones must fail.

Life means informational integrity and invariance:

self-maintained organized dynamics

Organisms are endowed with a power to maintain theirorganization permanently against disruptive influences.Thus, not only does life represent a highly organizeddynamic; this dynamic is furthermore self-maintained.Organization implies functionality, which in turn requiresstructural relationships, and structures require informationfor their specification. Information in turn presupposes a

source, and this source is constituted in living systems bythe nucleic acids. In this spirit, organisms may beconsidered as information systems, too. Organisms areunique in having a capacity to use information, which isstored in the nucleic acid and yields the basis for theirspecific organization in its perpetuation. A characteristicfeature of this information is that it is historically acquiredduring evolution: Any living cell carries with it theexperiences of a billion years of experimentation by itsancestors (Delbrck). Life is not only able to store butalso to improve its internal programs.

As with other compounds and structures, the intelli-

gent proteins also undergo continuous degradation andmust continuously be built de novo. Up to 90% of thechemical energy used by the cell for biosynthesis can beinvolved in protein synthesis. That means that, in cells, notonly a permanent loss of free energy but also of informationoccurs, which must just as continuously be replaced. Livingorganisms take the necessary energy from their surround-ings in the form of nutrients or sunlight. The source for thenecessary information lies inside the organisms. It is storedin their nucleic acids.

The genome

Proteins cannot be synthesized by enzymes alone since the bonds to be made up between the amino acids in thegrowing polypeptide chain do not differ from each other.Regardless of the amino acid concerned, the bond is alwaysa peptide bond. Therefore, the linkage of the amino acids inthe right sequence requires more than an enzymaticapparatus, it requires a matrix. That in turn means itrequires information, and this information is stored in thegenome of the cell. The capacity for informational

invariance, the maintaining and multiplying of highlyordered information-bearing structures in the form ofnucleic acids, is a further fundamental and unique featureof organisms in addition to their internal functional order(vital organization). Efficient repair mechanisms ensure thatthe stored information does not get lost: preservation ofgenetic integrity. It is estimated that, for instance, in every

human cell about 5,000 DNA letters get lost every day,which must be instantaneously restored.

The existence of a genomethe complete geneticendowment of an organismis a necessary condition forthe living state and one of the absolute differences betweenliving and non-living matter. Organisms represent a new

principle, the order-from-order principle (Schrdinger),which is the clue to understanding life. The importance ofgenomes for the organisms lies in the fact that they containthe instructions for the construction of the peptides and the

program for the control of their synthesis.Human beings do not differ fromE. coli bacteria in a more

efficient chemistry but in more information. Mycoplasma hasabout 500, E. coli approximately 4,000, yeast 7,000, fruitflies 13,000, nematodes 18,000, and man 35,000 genes.However, we still have no idea what the function of mostgenes might be. Although humans evolved relativelyrecently, the human genome is very old. Of 1,278 proteinfamilies identified in one early screen, only 94 were uniqueto vertebrates. Every organism carries with it a lot ofinformation acquired by its ancestors during the past three

billion years.While the number of genes has a 100-fold range, the

amount of DNA ranges from 5106 to nearly 50109 base

pairs (bp). That is a 10,000-fold range! This is due to theincreased non-coding DNA in eukaryotes with a largerDNA content. The non-coding DNA is not only found

between genes (intergenic DNA) but also as so-calledintrons inside the genes interrupting the coding sequences.In some genes of higher eukaryotes, the introns mayoccupy 90% or more of the DNA. The complete sequenceof the human genome published in April 2003 contains 3109 bp. Only about 1.4% of the genome codes for proteins.More than 50% of our genome consists of short repeatedsequences (repeats). About 45% of our genome come fromtransposable elements (transposons). The human genome

contains for instance 1.8 million copies of the transposonshort interspersed element (SINE) and 1.4 million copiesof the transposon long interspersed element (LINE).

Usually, the genome (in man with the single exception ofthe lymphocytes in blood) is the same in all somatic cells.Gene expression can be regulated at the level of genetranscription, nuclear RNA processing, mRNA translationand/or protein modification. Only a fraction of the genes isswitched on at any given time: in a typical bacterial cellabout 25% of the 1,000 genes. Genes that are needed all the



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time are expressed constitutively. These are known ashousekeeper genes. They are required for the fundamen-tal operations of the cell. The majority of genes are onlyneeded (expressed) under certain environmental conditions,in particular tissues, or at certain stages of development.Cell differentiation leads to many different cell types with

particular patterns of gene activity, which determine which

proteins are synthesized. These patterns can be maintainedover long periods of time and can be transmitted to thecells progeny. The expression levels of large numbers ofgenes in a tissue can now be determined simultaneously byDNA microarrays. All these complex processes of generegulation do not occur spontaneously but require thechemical machinery of the living cell in the form ofenzymes, transcription and initiation factors, tRNAs,ribosomes, etc. They are tightly integrated in the generalcell metabolism and need energy.

Every attempt to isolate life from its systemicdependencies and reduce it to the genomic level, as Richard

Dawkins and others have tried, necessarily leads astray. Anautonomous life of genes, a genobiosis (Kaplan), doesnot exist. Genes are neither selfish nor motivated in any

other way. Living systems display an essentially causalcircularity: Proteins (enzymes) require information (DNA)and DNA requires enzymes. The machinery by which thecell translates the codes consists of several components,which are themselves coded in DNA. That means the codecannot be translated except by using certain products of itstranslation. It is fruitless to ask what came first, the proteins

or the nucleic acids. Both are equally necessary. Only fromthis essential basis does the living system draw its typicalcapacity to maintain its vital organization. In this regard,Wicken (1987) once defined an organism as an informedautocatalytic organization.

Nucleic acids as the information-bearingmoleculesthe genetic code

Genetic information is stored in linear molecules, so-calledpolynucleotides. There are the double-helical deoxyribonu-cleic acid (DNA; Fig. 6) and the single-stranded RNA. The

genetic program in nucleic acids is coded by the specificsequence of the different nucleotides. This code transmitsthe maximum amount of information if the same chance for

Fig. 6 The double strandedDNA forms a double helix(after Bruce Alberts et al. 1995).The genetic code: A codonconsisting of three basesdetermines each amino acid to

be added to a growing polypep-tide chain. Three of the codonsact as stop signals. AUGencoding methionine, acts as astart codon



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incorporation exists for each of the four bases at all sites ofthe sequence. It is this physical indeterminacy that producesthe possible information content of a DNA molecule.

The polynucleotides have unique features that predestinethem for their central role in storing and transferring thegenetic information required for assembling the various

proteins essential to the proper functioning of the living

system. Firstly, they are unique in their capacity forreplication, provided some environmental conditions arefulfilled. Secondly, they can exist in an almost infinitenumber of different variants resulting in an inexhaustiblereservoir of different programs, which can code fordifferent proteins. Only a tiny fraction of this reservoirhas been tried out in life so far: The actual is anexceedingly small part of the possible only (Jacob 1982).

DNA molecules store the genetic information but cannotserve as a direct source of instruction for the living cell. Inorder for the cell to be able to use the information, aworking copy of the DNA must be carried on RNA. For

this reason, the double-stranded DNA must temporarily bepulled apart into the template and the coding strand. Onthe template strand, a complementary RNA strand arises.The sequence of the RNA strand is identical to thesequence of the coding strand apart from the replacementof the thymine in DNA with uracil in RNA. This so-calledmRNA subsequently converts the genetic information intothe proteins. The genetic message can do nothing by itself.It requires an intact cell in order to be able to fulfill itsfunction. Outside the cell, the stored genetic programremains inert. Only cells possesses both the program anddirections for use, the plans and the means of carrying them

out by the proteins (Jacob 1993).The mechanism of protein synthesis demands highly

specific chemical correlations, which cannot occur with thenecessary efficiency (in a normal mammalian cell morethan 106peptide bonds can be joined within one second!) infree solution in the plasma. Overall, almost 300 differentmacromoleculesmany of them localized in the complexribonucleoprotein particles, known as ribosomescooperateto synthesize polypeptides. The ribosomes, aggregates of twosub-units consisting of proteins and rRNA, are the cells

protein factories, found in both prokaryotes and eukaryotes.They decode the nucleic acid-encoded information on the

mRNA to make proteins.In nucleic acid molecules, a group of three successive

basesa so-called codoncodes for a specific amino acid(Fig. 6). Several amino acids are specified by more thanone codon (synonym codons). The codons are read in asuccessive, no overlapping fashion. The beginning of a

polypeptide is signaled by an initiation codon (AUG). Itestablishes the reading frame, in which a new codon beginsevery three-nucleotide residues. The so-called stop codonsnormally signal the end of polypeptide synthesis (termina-

tion codons). In the case of eucytes, the coding exons areseparated by non-coding introns, which must be removed

by splicing before the exons can be joined to the mRNA.The genetic code is, with a few exceptions, nearly identicalin all organisms (universality of the genetic code): Rareexceptions are found in some protozoan and mycoplasmasand in the mitochondrial genome of animals and fungi.

Strictly speaking, it is not a code in the customary sense ofthe word but a correlation schedule for the translation of thesequence of bases in the polynucleotide (DNA) into thesequence of amino acids in the polypeptide (protein; Kay2000). All talk of genetic code is metaphorical.

There are, in principle, two explanations for the univer-sality of the code: Either all organisms descend from onesimple ancestor whose more or less accidental code (frozenaccident, Crick 1968) has persisted relatively unchanged todate or there exists an optimal code on which the dif-ferent living forms have converged in the course of evo-lution. Computer simulations show that the susceptibility of

the natural genetic code to mutative changes is considerablylower than in alternative artificial codes. Only one code outof one million tested had a lower susceptibility (Freelandand Hurst 1998). This property of the natural genetic codemakes it particularly suitable for evolutive adaptations(Freeland et al. 2003). We must assume that the geneticcode arose very early in lifes history 3,500 million yearsago, before the division into the three phylogenetic tribes:

bacteria, archaea, and eukarya (Eigen 1987). This does notmean that life must only have originated once, just thatliving beings with the code in question prevailed against allcompetitors with other codesshould they have existed.

The paradigm of self-organization

This self-movement of all living beings (Platon), thiscoming-out-itself, this self-determination may be calledthe vital self-activity of living systems. Often underempha-sized, it is an essential feature of living beings and one,which characterizes them as fundamentally different fromthe rest of nature. Roux (1895) called this phenomenonAutoergie. Outside forces may threaten the existence ofliving beings, but they are totally unable to alter theorganization of living beings, which is exclusively inher-

ently determined.In science, the term self-organization has been broadly

accepted and has become very popular in many differentscientific branches such as physics, astronomy, neurobiol-ogy, psychology, and sociology. It is celebrated as arevolution of our scientific Weltbild, a new paradigm(Kratky 1990) and a principle inherent in the dynamics ofthe universe from the Big Bang to the appearance ofhuman mind (Jantsch 1984). Similar formulations are foundin Cramer (1993): Self-organization of matter to produce



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life may be understood as a physical principle. Since theBig Bang self-organization has been a physical attribute ofmatter, just as mass is a physical attribute of matter. Capra(1988) goes as far as to state: Dissipative chemicalstructures represent a connecting link between living andnon-living matter. Whether one calls them living organismsor not, is ultimately a matter of agreement. Such

unfounded generalizations and inadmissible simplificationslead astray and have led to the term self-organization often

being used nowadays as a meaningless catchword.It is only admissible to speak in this connection of a new

paradigm in science in the sense of Kuhn (1962) if theapplication of this concept of self-organization to the eventunder consideration brings a real and not only a pretended

progress in our knowledge. In the main, this is not the case.When physicists use the concept of self-organization inconnection with dissipative structures, they usually have theformation of order but not of organization in mind: orderfrom disorder. Inorganic dissipative structures, as for

instance, the RaleighBnard convection pattern, thechemical reaction waves in the BelousovZhabotinskysystem or the laser, are at the most metaphors but by nomeans paradigms of biological structure formation pro-cesses (Penzlin 1993b). They appear as the result of acooperative dynamic (Haken) through a certain range ofthermodynamic gradients such as temperature or reactant-

product concentrations, for instance. They disappear imme-diately when the external applied boundary condition nolonger exists. They neither have a teleonomic character norrepresent a functional order, which means that organizationis lacking. For this reason, they do not require information

for their specification either. They lack a self. There isstill a big gap between the dissipative structures of simplenon-living systems and those associated with livingsystems.

In contrast to all artifacts, living organisms display anunrestrained self-determination of forms and perform-ances. Life is not merely a programmed activity butself-programmed activity (Thorpe 1978). Environmentalconditions may modulate events by enhancing or limitingcertain processes, but they cannot determine or change theteleonomic character of the processes themselves. Due to avariety of cellular mechanisms, including negative feed-

back and redundancy, the embryonic development isremarkable consistent and reliable. Practically nothing isleft to chance, unlike in the case of the formation of cloudsin the sky or the turbulence in a jet of water. The decisionsare made; they do not represent accidental symmetry

breakings (Penzlin 1988). The genome contains a programof instructions for making the organism. This program isgenerative, not descriptive (blueprint), one in which nu-merous activitiesgenes and cytoplasmic constituentsare more or less directly integrated in order to produce and

maintain the organizational relationships that form theidentity of that system. In contrast to all inorganic systems,life involves informed replication through transformationalactivities.

It is not true, that the physical concept of synergetics,as developed by Hermann Haken and others, providesalready the basis for a better understanding of organisms

and their relationships with their surroundings (Kelso andHaken 1997). The open character of the system and theremote-from-equilibrium order are doubtless necessaryconditions for the existence of life, but they are by nomeans sufficient. It is an illusion to think that theorganization of living systems can be maintained in thelong run without a genome or would be understandablewithout its genetic-informational foundation.

The term self-organization in physics is a ratherinfelicitous expression because it is erroneous. For dissipa-tive structures, the appellations self and organizationare ambiguous. The terms create associations, which run

counter to the true situation relations. The only systems thatare self-organizing and self-organized in the true senseof the word are only the living entities in our naturalenvironment, for only they represent a state of functionalorder that we can class as autonomously induced andmaintained organization. We can summarize that themaintenance of specific organization is the essence of life.If a working definition of life is to be found anywhere, itmust be found in the distinctive character of vitalorganization (Wicken 1987). This is by no means anentirely new insight. Kants (1790) important Critique ofJudgement contains the extremely modern sounding

sentences that the organisms are self-organizing beingswhose parts altogether and reciprocally create a whole oftheir own causality.

Life as an emergent property

The fundamental laws of physics and chemistry also applyto living beings, but they are not sufficient to explain themost important phenomena of vital organization, such asindividuality of form and behavior, autonomy, functionality,teleonomy, etc. Our world displays a hierarchical structure.We can distinguish various levels of existence starting with

elementary particles, continuing upwards to the level ofatoms, molecules, cells, and finally to the level ofmulticellular organisms and supra-organismic associationssuch as populations and communities. As we go from oneto the next higher level, entirely new properties appear andnew concepts emerge. Each level in the hierarchy has itsown body of laws and constraints and needs its niveauadequate terminology. This statement goes already back toMills (1843) Logic. Having knowledge of the basicconstituents does not permit one to build up an understand-



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ing of the total system. The hydrogen atom has properties,which we neither find in the single electron nor in the single

proton particle, the water molecule has properties possessedneither by single hydrogen nor single oxygen atoms, andwater has properties that we do not find in single watermolecules. Organisms are not just heaps of molecules.They exhibit regularities, which have as much legitimacy as

the fundamental laws analyzed so successfully by theanalysts. Even if we know everything about every singlemolecule in a muscle cell, we cannot derive from this howthe cell works. The appearance of new qualities as we moveupwards from one hierarchical level to the next is calledemergence. Emergent properties result from the particularway in which the parts of a complex system are integratedto form a whole. The concept of emergence, introduced byLewes (1879), claims that the whole is more than the sumof its parts. Being alive is indeed such an emergent

property of cells.Living systemsand this is also true for machinesare

only understandable in context of their functionality, andfunctionality implies structure as a conditio sine qua non.What makes organisms unique is not their deliverance fromthe universal laws of physics and not the possession of a

particular vis vitalis, but the apparent multitude of initialand boundary conditions that must be determined in orderto bring the laws to bear upon them (Rosen 1985).Following the physicist Polanyi (1968), we can considerstructures in the physical sense as a set of boundaryconditions harnessing the physicochemical processes bywhich the organs perform their function. Boundary con-ditions introduce new principles, which we cannot derive

from the physicochemical laws and forces; they are onlyunderstandable in the context of their function. Theyharness the laws of inanimate nature, but are themselvesirreducible to those laws. In living systems, only anextremely small selection of the possible chemical reactionsis realized at any moment. These rules of order, whichrigorously restrain the possibilities, are the feature thatdistinguishes the living state of any organism in fundamen-tal way from the dead state which is characterized by chaosand autolysis.

These higher principles do not interfere with the laws ofphysics and chemistry; they are additional to them. In this

process of so-called downward causation (Campbell 1974),genuinely novel properties and processes emerge, whichcannot be explained by the material properties of thecomponents. Neither the structure of machines nor thestructure of living entities can be defined in terms ofthe laws, which they harness. They transcend the laws of

physics and chemistry. The higher level laws operate asselective systems or restraints on the lower-level processes.The efficient causes are higher level boundary conditions,which are general principles, and the effects are selective

activations of concrete lower level causal processes (vanGulick 1993). Hulswit (2006) remarked that the termdownward causation is somewhat badly chosen becauseit is usually understood in terms of explanation anddetermination rather than in the sense of bringingabout3.

Boundary conditions need information in order to come

into existence. In the case of human artifacts, the source ofthe essential information is outside the machine in the brainof the constructor. In contrast to these human-mademachines, the structures of the wholes and parts of living

beings are not shaped definitively by a constructor duringmorphogenesis but by the transmission of informationstored internally in the genome. The wonderful skeletonsof the radiolarian (Fig. 7), which once fascinated ErnstHaeckel, are not understandable within the framework of

physics and chemistry. They are the manifestation of aninternal program stored in the genome of these organisms.

Nobody will contest that all matter, including organisms,

consists of atoms. Furthermore, nobody will denynoteven the vitalists nowadaysthat all physical laws are fullyvalid in organisms, too. That is not the issue. However, itmost certainly does not follow that organisms are nothingelse but an ensemble of atoms and the interactionsoccurring between them. It is not true that organisms andeverything that living things do can be understood in termsof the jigglings and wigglings of atoms (Feynman et al.1989). This statement does not even apply to humanartifacts: Nobody would try to understand or explain thefunction of a clock, steam engine or computer in terms ofthe jiggling and wiggling of ato

the riddle of “life,” a biologist’s critical view

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