a system's view of the evolution of life

REVIEW

doi:10.1098/rsif.2007.0225

Published online 17 April 2007

*bob.williams

Received 20 DAccepted 19 F

A system’s view of the evolution of life

Robert J. P. Williams*

Inorganic Chemistry Laboratory, University of Oxford, South Parks Road,Oxford OX1 3QR, UK

Previous treatments of biological evolution have concentrated upon either the generalappearance or habits of organisms or the sequences of molecules, such as their proteins andDNA (RNA), within species. There is no consideration of the changing relationship of thechemistry of organisms to the elements and energy available from the environment. Inessence, organisms at all times had to accumulate certain elements while rejecting others.Central to accumulation were C, N, H, P, S, K, Mg and Fe while, as ions, Na, Cl, Ca and otherheavy metals were largely rejected. In order to form the vital biopolymers, C and H, fromCO2 and H2O, had to be combined generating oxygen. The oxygen then slowly oxidized theenvironment over long periods of time. These environmental changes were relatively rapid,unconstrained and continuous, and they imposed a necessary sequential adaptation byorganisms while increasing the use of energy. Then, evolution has a chemical direction in acombined organism/environment ecosystem. Joint organization of the initial reductivechemistry of cells and the later need to handle oxidative chemistry has also forced thecomplexity of chemistry of organism in compartments. The complexity increased to take fulladvantage of the environment from bacteria to humans in a logical, physical, compartmentaland chemical sequence of the whole system. In one sense, rejected material can be lookedupon as waste and, in the context of this article, leads to the consideration of the importanceof waste from the activities of humankind.

Keywords: systems: chemical; evolution: chemical; chemistry of evolution;organisms: evolution; biological chemistry; compartments of cells

1. INTRODUCTION

Evolution of our whole system from the gross level ofthe Universe to very local happenings has to be seen as aconsequence of either initial local inevitable andgeneralizable events traceable in a time sequence fromthe Big Bang or local ‘accidents’, chance one-off events,which occur at a given time and in a given place andwhich are not open to a logical treatment. There arethree major events in the evolution of the Universe,which have this ‘one-off’ nature. The first is the BigBang itself for which we can offer only a veryspeculative ‘explanation’. The second is the formationof Earth with the Sun’s other planets. Here, we can givea possible physical explanation of an accident 4.5 Gyrago, but we do not know the chance of a very closelysimilar event. Exploration may be possible here, butany definite evidence about another Earth/Suncreation in the Universe has not yet been found and itis not likely to be easily obtained. The third case is theorigin of life, critically dependent on the Earth/Sunrelationship. We have no evidence except a probabletime, 3.5–4.0 Gyr ago, for this happening and there is

@chem.ox.ac.uk

ecember 2006ebruary 2007 1049

no parallel system. The nature of these three singularevents is certainly outside the scope of this article forthe further very good reason that I have no ability tosay anything useful about them. However, a logicalanalysis has been given for the evolution over all time ofthe first two, the material and energy of the Universeand those of Earth. Physical/chemical studies havegiven rise to collections of observable materials andobservations of changes in them and then to rationalexplanation. The way forward is usually termedreductive analysis, a seeking for the basic ingredientsof today’s material and its energies from given origins inthe Universe and on Earth. This has led to concepts ofvariables, such as pressure and temperature, and adescription of them in terms of the properties of basicmaterials in phases. The materials have been brokendown into particles, atoms in the Periodic Table inchemical studies (e.g. figure 1), together with thedescription of the energy of their interactions incompounds and their movements at all levels. Mean-while, energy has been analysed in a somewhat different‘particulate’ analysis of quanta with a duality of massand wave characteristics. By contrast, the evolution ofliving objects has frequently been treated as if there issome principle operative, which is outside the usual run

J. R. Soc. Interface (2007) 4, 1049–1070

This journal is q 2007 The Royal Society

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

H

Li

Na Mg

Be

K

Rb Sr

Cs Ba Ln Hf Ta W Re Os

UFr Ra Ac Th Pa

Y Zr Nb Mo Tc Ru Rh Pd

PtIr

Ag Cd

Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga

SnIn Sb Te Xe

RnAtPoBiPb

I

TiHgAu

Al Si P S Cl

BrSeAsGe

bulk biologicalelements

trace elements believedto be essential for bacteria,plants or animals

possibly essentialtrace elements forsome species

He

Ne

Ar

Kr

B C N O F

Figure 1. The Periodic Table showing the elements required by all life. Note how almost the whole possible variety of chemistry iscovered, in that there are representative elements from 15 of the 17 chemically active groups in cells.

present

100 million

500 million

1 billion

2 billion

3 billion

4 billion

5 billion

(years ago)the origin of the solar system

earth

earliest cells

mitochondriachloroplastsblue-green algae

seed fernsplants

arthropodsmolluscs

floweringplants bivalves

insectscrabs

cephalopods

starfishsea urchins

fish

echinoderms

vertebrates

amphibians reptiles

birdswhales

elephantshominidsmonkeys

culturetools

warm bloodwalkers

today's freeoxygen

multicellularsystems

some free oxygen

eukaryotesnucleated cells

photochemistryDNA

no free oxygen

animals fungi bacteria

mammals

Homo sapiens

Figure 2. A standard evolutionary tree based on the characteristics of organisms or their DNA which appears to indicate anindependence of different branches of life.

1050 Review. A system’s view of the evolution of life R. J. P. Williams

of physics and chemistry. There is a clash with religionsand beliefs outside experimental tests, and also even thescientific approaches of biologists’ analyses are not onthe same basis as those used in the study of the Universeand Earth. Organisms are said to have evolved asspecies by chance improvement of survival, and thepossibility of a logical description of their evolution,even in large classes based on chemistry and physics,has not been examined. Species are described as having

J. R. Soc. Interface (2007)

arisen in a set of material bodies either with shapes andbehaviours (classical biology) or with these and othercharacteristics related to molecule sequences (molecu-lar biology). The observed similarities in these proper-ties have allowed the development of evolutionary treesof seemingly independent organisms (figure 2). Thetrees can be made extremely detailed beyond the levelof classes to that of individual species of organisms. Thechanges of the environment of organisms in the

Review. A system’s view of the evolution of life R. J. P. Williams 1051

branches of trees are not considered when they aredescribed. The whole is then a driven branching growthfor the success of particular organisms in a struggle forsurvival. These views put forward by Darwin have beenreaffirmed recently in a book by Maynard-Smith &Szathmary (1995) and in the proceedings of a recentRoyal Society Discussion (Cavalier-Smith et al. 2006).Maynard-Smith & Szathmary conclude, in agreementwith many biologists, that although organisms increasein complexity, this is neither ‘universal nor inevitable’.Although features of neo-Darwinism have someelement of environmental determination, there is nophysical/chemical analysis following the style of thoseof the nature of today’s Universe and Earth. Here, asstated, the examination and experimentation reachback to, in fact beyond, the level of atoms in materialsand their energy. As all biological materials are madefrom atoms in and energy from the environment, thesurface of Earth and the Sun, it seems appropriate hereto go back to the same features and their knownchanges in time to see if we can work forward in themanner of a physical/chemical examination in a searchfor a rational physical/chemical explanation of theevolution of living systems (Morowitz 1992, 2002; deDuve 2002). We start from an analysis of the energyinputs to the environment and organisms treating themas one system.

2. ENERGY FROM THE ENVIRONMENT

The energy driving evolution on Earth, both ofgeological and biological objects, is in two parts. (i)Energy moving from the high-temperature interior tothe surface at a lower temperature of 300 K. This flowitself is only sufficient to maintain a surface tempera-ture of approximately 250 K. It has been able to do sofor all the period of Earth’s existence, since the mainlyoxidic rocks gave Earth a hard heat-insulating mantlewith water covering it around 4.0 Gyr ago. The deepinterior of Earth, temperature greater than 5000 K duein part to radioactive decay of thorium, uranium andpotassium, maintains this heat flow, but there are alsoenergy transfers from the decomposition of unstableminerals on or near the surface, especially in oceanvents, for example black smokers. This surface heatinghas been augmented by (ii) energy from the Sun whichis absorbed at the solid/liquid surface of Earth and inthe atmosphere. Together, the two raise the surfacetemperature from 250 K, mentioned above, to theaverage ambient temperature of approximately 300 K.The loss of heat from Earth has fallen somewhat overtime due to loss of some of the greenhouse gases, whilethe Sun has gained in radiative strength with the resultthat the surface temperature of Earth has remainedroughly constant for all the period from ca 4.0 Gyr agoto date with fluctuations of some G25 K in certainperiods of millions of years. We shall assume thereforethat material evolution has taken place effectively in athermostat at 300 K (Cavalier-Smith et al. 2006). Thethermostat kept water as a liquid on the surface, whichpermits much of all the material flow.

The chemicals mentioned so far are minerals,including water, so-called inorganic compounds, but


the effect of the energy flow has also allowed theformation and loss of unstable organic chemicals insynthesis/degradative cycles in cells.

energy

environmentalelements

organic systems,

heat

The organic systems are not just based on H, C, N, O, Sand P, but, as we shall see, they contain a considerablenumber of mineral elements. The energy trapping insuch a system from high-energy chemicals or the Suncan create unstable ‘organic’ chemicals either of high-energy content, for example in the reaction

CO2 C2H2O $$%energy

CH4 CO2;

or in the form of physical gradients of concentration ofcharge or particles, inorganic or organic, acrossboundaries. It is important to remember that only certainelements can be energized chemically for considerableperiods of time as their chemical bonds have sufficientkinetic stability and so can give rise to particular organiccompounds of long life. We shall categorize thesecompounds and also analyse the way in which theenergized materials can be trapped physically in isolatedvolumes of various sizes, which could also have aconsiderable lifetime. The total system has increased inits ability to absorbenergy, as the environment/organismsystem on Earth’s surface has evolved.

In summary, evolution is driven by energy flow anddegradation as numbers of high-energy quanta (light forexample) are degraded to larger numbers of low-energyquanta, heat (entropy gain), while environmentalmaterial goes in the above cycle through life and largelyreturns to the environment (but see waste below). Thematerial cycle increases the rate of energy degradation.We expect the system as a whole to increase its energyabsorption, so that energy and material flux increases asthe system increases in complexity. In effect, if there hadbeen no material loss, once the cycle was in steady-stateflow, the only change would have been entropy pro-duction and there would have been no evolution. Weillustrate the general principles with simple non-organicsystems before we consider the important case of systemswhich cycle in part but create waste.

3. BASIC MATERIAL FLOW, PHYSICAL ANDCHEMICAL, ON EARTH

Energy flow is inevitably from a hot source to a coldsink, but it can go through intermediate stages in whichmaterial that has absorbed energy is physically, in twoways, or chemically transformed. The pattern ofphysical transformations arises from increase in ran-dom motion (temperature) and/or increase in directedflow (momentum). The first appears as a change inequilibrated or steady-state structures, solid/liquid/gas, associated with increased random kinetic energy,while the second appears as directed kinetic energy in


steady-state organized patterns of flow. The second isrelated to the creation of gradients. The two are readilydistinguished. On Earth, there are phases of ice andliquid water in containers of fixed structures and watervapour with apparently unimpeded random thermalmotion in the atmosphere. Both the first two phaseshave ordered physical boundaries, and solids also haveordered internal structure, giving rise to static shapes.A very different picture of water in the atmosphere isobserved in clouds, which are examples of material inorganized flow. The clouds come in many closely, notexactly, reproducible dynamic shapes, so that just ascrystals are given symmetry titles, so clouds are givennames based now on their ill-defined shapes. Cumulusclouds are formed from low-down turbulent flow ofwater droplets falling under gravity but dispersingagain at higher temperature as vapour that rises toreform droplets again at lower temperatures. Dropletsand vapour in high stratus clouds circulate in streamingmotion which is not turbulent. Therefore, clouds areclassified descriptively in a collection of types, but it ishardly possible to classify the huge numbers of kindswithin types, i.e. species or individuals, except bydrawing them. We shall see how, when we replace theenergization flow process of physical condensation andvaporization by chemical flows in which hundreds ofchemicals take part in cyclic energized transformationsfrom the environment to cells and back, it is equallypossible to group large numbers of species andindividuals into types. Here, species and individualswithin types are characterized by small differences inshapes, behaviour or certain chemical molecularsequences, where there may be no clear reason fortheir existence beyond survival strength. We shall thenshow that there are ways of rationalizing the physi-cal/chemical characteristics of these types, largegroups, of organisms, such as those of prokaryotes(bacteria) and eukaryotes (protocysts, fungi), plantsand animals, as they evolved. The environment herewill be both that experienced in the formation of clouds,i.e. physical fields and radiant energy, and thechemicals in it. If, at any time, such a physical/chem-ical system reached a complete steady state, no furtherevolution could arise.

The circulation of water can be described further asclouds fall as rain, forming streamsand rivers inpathwayson land. These shapes are muchmore persistent than theshapes of clouds but are not permanent. River flow iscontained by short-range forces, due to the solidmineralsof riverbanks, while flow in a cloud is only contained bylong-rangefields.Now, as a river flows, it gradually erodestheminerals off its banks and causes themtoflow towardsthe sea whence the water came originally before beingenergized into clouds. The eroded material settles as theriver flow slackens forming new shapes of riverbanks anddeltas by the sea. This is a non-cycling waste product offlow. This finely divided deposited material is referred toas sediment or soil, and its evolution with the continuouswater flows has allowed much organic life on land toevolve. The material flow, apart from the water, is notcyclic and it evolves. Note how geo- and biosciences areintimately connected in an ecosystem and there are verydifferent time-scales of change in both.


We could go on to describe the evolution of Earth’ssurface on a still slower scale, where land masses, indifferent sized units surrounded by the sea, change innovel ways due to ‘organized’ flow of molten mineralsbeneath the surface. We shall not do so, but onlyobserve that the nature of ‘organization’, guided flowand its development can have quite different timeconstants and ill-defined sizes and shapes. Clouds,rivers and land show that organisms are far from theonly systems with the characteristics of developingorganized flow.

The simplest chemical system, illustrating organiz-ation and order, is the formation of the ozone layer dueto the action of sunlight on oxygen, which generatesdifferent ozone depths in different latitudes, so that itslayered depth has shape, organization, while O3 is moreordered than O2. The ozone layer has evolved in the last1 Gyr and it is vital for life on land. It would haveremained in a steady state, but humans have intro-duced chemicals interfering with the flow. There are yetother ‘inorganic’ chemical systems giving such organiz-ation on a small scale.

An important conclusion is that these systems are ingeneral, but not in particular, cases predictable and theyfollow physical/chemical principles (Corning 1995,2001; de Duve 2002; Morowitz 2002). The generalbehaviour is not random but gives rise to a steadystate of flow, which can die but then recur, as theenvironment fluctuates. This steady state is one of themaximum flow and maximum energy degradation. Weshall take this as the final outcome of any energized flownoticing how different it is from an equilibrium state andthat it may take a very long time to reach the finalsteady-state condition (Corning 1995, 2001; Morowitz2002). These examples show that characteristics such asshape can readily arise in steady states due to fieldboundary conditions affecting the flow. We nowapproach the environment/organism ecosystem lookingfor similar physical/chemical characteristics linked toorganic chemical flow. The essence of life is organic—a mixture of energized flows of inorganic and organicatoms and molecules. It is an energized organizedchemical system, with molecular physical boundaries,cells, and is very complicated. (Note that a virus isexcluded from living systems as it is an ordered assemblywithout deployment of energy and without flow.)

As an aside, some authors describe the appearance oforganization with internally ordered units such asmolecules as emergent systems. Order itself can arisethrough an energetically favourable process but orga-nized flow cannot. In the process of energy absorptionbefore its inevitable degradation, an unstable systemwith chemical and physical properties can emerge but itcan degrade with time if new features are introduced.

4. ORGANIC SYSTEMS

We are not yet ready to refer to living organisms whichare reproductive rather than recurrent, for we have tosee the origin of life in principle before it becamereproductive (de Duve 2002; Russell & Hall 2006).There has to be some primitive organization beforereproductive life, since it requires a code that can only

Sun

hv(heat)

hv(heat)

hv (light)

chemicalreactions

burial heat

coreof

earth

volcanicmaterial

materiallosses

earth'scrustand

biosphere

Figure 3. Basic unity of the ecosystems’ energy and material.Chemical reactions here include all organism activity(figure 5).

30

20

10

Ca Mg Mn Fe Co Ni Cu Zn Cd

MS

M(OH)2

– lo

g(s

olub

ility

pro

duct

)

Figure 4. Insolubility of divalent metal ion sulphides andhydroxides at pH 7 shown as solubility products. Continuousline with dots, sulphides; broken line with crosses, hydroxides;two horizontal lines, solubility products which allow a freemetal ion of micromolar concentration. Cu, Zn and Cd arevirtually not available in the sulphide era while all the ions areavailable in water at pH 7, Cu weakly so (see also figure 5).Note Fe2C is not available in oxidizing conditions and life hadto scavenge for Fe3C.


‘code’ some pre-existing system. So what material wasavailable to make an energized beginning? Thisquestion takes us back to Earth’s formation from astar and then farther back to the earliest stars and thento the Big Bang. Running forward quickly, at anintermediate stage some time after the Big Bang, thegiant stars formed and then the chemical elementsarose, 92 of them, which fall in the Periodic Table ofatoms (figure 1). They were formed in a predictablepattern of abundances (Frausto da Silva & Williams2001). It was their dispersal at high temperature thatlater, due to cooling with condensation, gave rise to theplanetary system including Earth around the Sun. Aswe have explained, the energy flow, of interest, is to thesurface of this planet and we shall consider Earth’ssurface as including an irradiated sea with an atmos-phere containing certain elements in particular concen-trations and very basic inorganic combinations(figure 3). Therefore, we need to consider only theelements on the surface which through abundance andchemistry were made available and so were irradiated.These were mainly: (i) in the atmosphere, and some-what dissolved in the sea, C (CO, CO2, CH4), H (H2,H2O, H2S), N (NH3, N2), S (H2S) and (ii) in minerals,which are soluble to some very different degrees(figure 4), giving the following ions also in the sea:NaC; KC; Mg2C; Ca2C; Mn2C; Fe2C; Co2C; Ni2C;CuC; Zn2C; Mo or W (MoO2K

4 or WO2K4 ); Se (H2Se); P

ðHPO2K4 Þ; V(VO2C); and ClK. These elements, with

perhaps one or two others, are the only ones of interestin the possible initial organic systems. Of the almost 20elements listed, there are representatives of some 14 ofthe possible 17 groups of elements with strong chemicaldifferences in the Periodic Table (figure 1). Hence, theycan generate very much of the possibilities of chemistry.It is these 20 elements which we shall show are found tobe essential to life and evolution and much of theecosystem. We call the system in an organization,organic. A feature of the availabilities in the environ-ment is that they have not been constant over time in


either concentrations or chemical forms (Williams &Frausto da Silva 2006). This evolution has occurred inboth the environment and the organisms and both havedeveloped cooperatively through the very nature ofenergization of the system of molecules (see Note (i)).The evolution was immediately directional once theflow became to and from compartment cells and in allprobability prior to coding simply by the energizationof organic material in kinetically stable reduced statesof carbon.

4.1. Basic features of kinetic stabilityand organic energization

A system of irradiated or otherwise energized chemicalshas to have a considerable lifetime if it is to enter into aflow system of any complexity and it must not becomedispersed. Molecules made from H, C, N and O, and to alesser extent including S and P, have the ability to bepersistent. It is doubtful whether any other elementscan build similar water-soluble polymers. All suchchemicals made from these basic building blocks are, infact, thermodynamically unstable but kinetically stableat 300 K and are reduced relative to very simpleenvironmental compounds, such as CO2 and H2O.Therefore, it is extremely probable that the originalconstructs of a living cell were uniquely associated withlarger organic molecules of this kind, which we seetoday, i.e. lipids, proteins, saccharides and nucleicacids, and it may well be that there is no other way tocreate life. Then, it is still the case that there is anessential set of pathways from the elementary startingmaterials of the environment to these biopolymers in allforms of life. A characteristic of this perhaps unique setof organic molecules is that: (i) their elements in thecompounds are reduced relative to CO (CO2) and N2

solar radiation(high quality energy)

inorganic matter

heat

organic matter

heat

heat

debrisdecay

living matter+ waste

stores

heat

Figure 5. Energized cycle of material in cells driven by solar energy, which degrades to heat. Note waste which causes evolution(see §2 for alternative energy sources).

0

–2

–4

–6

–8

–10

–12

–14

–16

log(

M)

Na K Mg Ca Mn Fe Co Ni Cu Zn

Figure 6. Estimated free monovalent and divalent metal ionconcentrations in all cell cytoplasm. The values from Na to Caare well known (Frausto da Silva & Williams 2001). Valuesfrom Fe to Zn are possibly too low. Free Fe2C may well benearer to micromolar, and free Zn2C nearer to Klog[M]Z10.The literature contains variable data but the trend is clear(Outten & O’Halloran 2001). Note how it compares with theinsolubility of sulphides in figure 4 and that for obviousreasons it matches the inverse of stability constants of modelcomplexes with thiolate donor atoms (see Note (ii)).


by the incorporation of hydrogen and (ii) they aremostly negatively charged to keep many of themsoluble in water. However, some, the lipids, areinsoluble in water and readily form vesicle membraneswhich prevent dispersion of internal contents, thus theycould generate the precursors of cells. These vesicularprotocells are postulated to give rise to the origin of lifefor which we offer no other positive explanation(Russell & Hall 2006). We are only concerned herewith the evolution of the ecosystem. The reductivechemistry, which later produced kinetically stable cells,simultaneously generated oxidized waste and rejectedsome other materials into the environment.

light

environmentalchemicals

organic systems, + environmental waste

heat

(Light is not the only possible source of energy (see §2)but it has become dominant.) The cycles are shown inmore complicated form in figure 5. Here, one waste hadto be oxidized material such as sulphur from H2S oroxygen from H2O, where the amount and availability ofwater made itself the preferred source of hydrogen quiteearly in evolution. Another waste is in energy applied toreject some available elements that would be poisonousto the system. The necessity for selective rejection isalso part of the origin of protocells and life. It is theadaptation to waste which drives evolution allowinggreater use of energy.

The kinetics of compounds made from inorganic ionsin water, here the sea, are usually quite different fromthose of organic compounds in that generally theyequilibrate quickly between free ionic forms, differentoxidation states and between bound conditions inorganic molecules (Frausto da Silva & Williams2001). Even their compounds of high thermodynamicstability are usually of quite low kinetic stability. Weshall treat all the ions NaC, KC, Mg2C, Ca2C, Mn2C,Fe2C, Co2C, Ni2C, CuC (Cu2C), Zn2C and ClK as ineffective but different equilibria with their compoundsin different oxidation states in both protocells (and laterin cells) and the environment even though distribution


to binding sites may require carriers. (There are someexceptions to this statement.) All these ions exist in thesea and cells in controlled amounts to date, though notin the same amounts in all cells and certainly differentlyin the sea and cells at different times during evolution(Frausto da Silva & Williams 2001). In the protocell,they had to be, as they are today, energized in theirconcentrations by pumps as they cannot cross mem-branes. A general rule is that much as one group ofenergized, synthesized organic molecules of the samekind is to be found in the central parts of all cells, thecytoplasm, so certain free concentrations of ions arepresent there in fixed concentrations to the best of ourknowledge (figure 6; Frausto da Silva & Williams 2001;Outten & O’Halloran 2001). (Metal compounds are notpresent equally in all cell cytoplasms, of course.) Theimplication is that in the steady state of all protocellsand cells, the inward/outward pumping to/from thecytoplasm maintains very similar kinetic gradients of

Table 1. Absolute minimal element content of primitive life. (See Williams & Frausto da Silva 2006.)

elementa availability use

H H2S (air), HSK (sea) organic molecules, energy captureC CH4, CO or CO2 (air) organic moleculesN NH3, HCN (sea) organic moleculesO H2O, CO, CO2 (air) organic moleculesNaC, KC, ClK sea salts electrolyte balance, osmotic controlCa2C, Mg2C sea salts structure stabilization, weak acid catalyst (Mg2C)

P(HPO2K4 ) sea salts organic molecules, energy transfer

S H2S (air), HSK (sea) element transfer, energy metabolismFe Fe2C/Fe3C/S2K (sea) catalysis

a These 12 elements were incorporated of necessity into any vesicle formed in the sea in the period around 3–4 Gyr ago to givethe biopolymers of life. Others that were present in reasonable amounts but perhaps not incorporated of necessity initiallywere Al, Si, V, Mn, Co, Ni, Mo, W, and perhaps Se and Br. The primitive organisms we know, such as archaebacteria, haveapproximately 20 elements.


free ions across all outer cell membranes and thisincludes HC. Particular interest lies in the fact thatprotocells, like all cells, had to reject NaC, Ca2C andClK (and perhaps heavy metal ions especially Mn2C) tothe sea so as to reduce osmotic pressure (NaC, ClK)and prevent conglomeration and precipitation oforganic molecules (Ca2C). KC and Mg2C are thenallowed into the cells to balance the mainly negativelycharged soluble organic molecules. There are alsorestrictions, largely outward pumping, upon severalother M2C ion concentrations although these ions inbound states are required for catalytic or structuralfunctions but a switch in evolutionary conditions laterhas made it necessary to pump these ions selectively innew ways either in or out of cells more effectively. Noteespecially a grave problem with the maintenance of ironlevels in cells, since in oxidizing environmental con-ditions, free iron ions are in very low concentrations,10K17 M Fe(III). Finally, we can list the minimalelement requirement of life and element availability asfar as we know them (table 1).

Among non-metal chemistry, there is anotherdominant chemical feature apart from reduction andpumping, which requires energy, namely condensationand removal of water, which leads not only to mostmetabolites from C, H, N and O basic materials but alsoto all biopolymers, nucleotides, proteins, saccharidesand lipids. The removal of water is driven bypyrophosphate hydrolysis in the form of nucleotidetriphosphates. Apart from the fact that pyrophosphatehydrolysis drives these reactions, phosphate is alsoincorporated into all nucleotides and many lipids, andis a component of many metabolites. It requires energyto form all these phosphorylations again, demanding theprior formation of pyrophosphate. Clearly, thischemical was required before any complex biomoleculecould be formed and there is no known alternativepossibility. Pyrophosphate is synthesized from twophosphates using the energy of a proton gradient in thefirst condensation reaction. The proton gradient ismade directly or indirectly from light (Williams 1961),demanding an electron transfer circuit, which also givesrise to reduction. Underlying condensation and theformation of many cellular chemicals are then the needfor phosphate. In the sea, phosphate cannot exceed


approximately 10K6 M due to the presence of calciumions. The cellular requirement for phosphate can onlybe met therefore by pumping it into cells, where freecalcium is reduced in concentration. Here, energy isagain required. A general point can now be maderegarding biological chemistry. The selection of each ofthe 20 chemical elements, phosphorus is one in cells, isone of the necessities where no other available elementhas equal advantageous properties for a particularchemistry. In other words, life as we know is fashionedby chemical limitations in an unavoidable manner in asystem. Is it unique? Consider a second example.

We have already stressed the requirements for manyelements in cells, including especially their functions inreduction and condensation, and in general physicalstability. In the first two of these, we have seen howmany organic elements are incorporated in compoundsby kinetically stable bond formation and/or by bindingat equilibrium after pumping of ions in or out of cells.There is a particular example of incorporation, that ofoxygen, now using oxidation, not yet mentioned, whichwas and is needed in all life. For this purpose, organismsrequire either molybdenum or tungsten as a catalyst.The chemical problem they solve is the incorporation ofoxygen in the formation of, say, carboxylates fromaldehydes. These elements have the special ability ofbeing able to exchange oxygen atoms with water readilyat low oxidation/reduction potential which existedbefore there was oxygen (Williams & Frausto da Silva2002). It is very surprising at first that life depends fromits beginnings upon not just C, H, N, O, S, P andcommon metal ions but on such elements as molyb-denum and tungsten (figure 1). We ask again ‘Is thesystem unique?’

At this stage, we stress that we have not needed tointroduce anything but physical/chemical principlesapplied to both inorganic and organic materials. Weconsider, as shown experimentally, that lipids whenagitated give rise to vesicles and postulate that thesevesicles can concentrate material. We have shown thatshapes, compartments, arise, but we have had no needto refer to codes. A code will become essential onlywhen we come to reproductive life which we shall put onone side as an accident. We shall show by elementanalysis how the system, coded (we say subsequently)

1

10–1

10–2

10–3

el o

xyge

n co

ncen

trat

ion

as f

ract

ion

nt a

tmos

pher

ic le

vel (

21%

vol

.)

stro

mat

olite

s

band

ed ir

on f

orm

atio

ns

red

band

s

land

pla

nts

land

ani

mal

s

mam

mal

s

flow

erin

gpl

ants


for reproduction, which guaranteed continuity pro-vided that the system already had sufficient persistenceto give time for it, could evolve keeping physical/chemical principles for explanations. We can thenenvisage the whole environment/organism ecosystemdevelopment of chemical types in a rational fashion,which includes the impingement of changing organismwaste in the environment upon the organisms them-selves (figure 5).

10– 4

4600

4000

3000

2000

1000 800

600

400

300

200

100

millions of years before present

grou

nd-l

evof

pre

se

Figure 7. Deposition of geological iron oxide bands in time asthe oxygen level rises. Note the ‘coincidence’ of the fall in iron,rise of oxygen, and the introduction of eukaryotes in evolution(figure 10).

4.5 4 3 2 1 today

time (109 years ago)

avai

labi

lity

Fe

Cu

Zn

Na,K,Mg,Ca,C,P,(S),(Mo)

Fe

S2–

Zn

Cu

SO24

SO24

S2

Figure 8. Rise in SO2K4 and Zn2C in organisms with time. Note

the time of the rise from single-cell to multicellular eukaryotesin figure 10.

5. THE MARKERS OF SYSTEM EVOLUTION

This account of the evolution of the environment/organism ecosystem is very different from any previousanalysis, in that the useful markers of change cannot bethe traditional organic chemicals, e.g. DNA, RNA,proteins or complicated metabolites. The break withtradition is forced, since we treat the environment/organism ecosystem as a unity and there are no suchorganic chemical markers in the environment. In fact,there are only the very small carbon molecules, CO2

and CH4, which could be called organic but are usuallycalled inorganic in studies of global atmosphere changesand are not controllable in cells. The evidence for thechanges in cells of these two chemicals over the periodfrom 4.0 Gyr ago to date is complicated and ofindifferent quality. N2, NH3, O2 and the othercompounds related to the dominant non-metalelements S and P, i.e. SO2K

4 and H2POK4 with their

minerals in the environment, are usually also classed asinorganic compounds. Now, the changes of some of thecompounds of these elements and their isotopiccomposition, e.g. O2, H2S and SO2K

4 , are useful long-period markers of evolutionary change in the environ-ment related to cellular evolution. Most importantly,the long-period changes of the metal elements (ions)and the isotopes of non-metals (Holland 2006) can befollowed in sedimentary mineral deposits such as redbands (figure 7) and baryte, BaSO4. The changes in theuse of these and other inorganic elements in cells,mostly bound with successively introduced organicproteins, make certain proteins also strong markers oflong-period evolution in organisms which can bedirectly related to newly expressed parts of the codedDNA. We shall be particularly concerned withfollowing the changes in availability in the environmentand the use of Ca2C, Zn2C, Mn2C, Fe2C, Co2C, Ni2C

and CuC (Cu2C) and their proteins in cells, all withinthe ecosystem as oxidation of the environmentincreases (figure 5) and then cellular content changes.We can follow them against the known background ofO2 increases and the appearance of, for example, SO2K

4

(figure 8) and NOK3 and some other non-metal

compounds. For all these reasons, the changes of the20 available elements and a broad view of them andtheir compounds in cells are the best markers of theorganisms/environment system evolution.

A great advantage in following inorganic ions is thattheir connections between the environment and cells aremade using a particular required series of recognizableproteins, including inward pumps, internal carriers(sometimes required), transcription factors for theirprotein partners, the protein partners themselves,


outward pumps, ion channels and homeostatic cellularbuffers (sometimes required). The chemistry of selec-tive equilibrium binding of all the ions is now wellunderstood (Frausto da Silva &Williams 2001) and wecan therefore find and rationalize the most suitable‘signature’ amino acid sequences in the proteins fordifferent metal ions. They were devised in the earliestcells and have been maintained with only some noveladditions. The set of individual time patterns of ion-binding proteins and enzymes can therefore be found inthe genome. Hence, it is possible to give a developmentpattern of both for different ions, which is related to theintroduction of chemotypes, cells evolving with differentelements, and their protein partners, differently orga-nized (Dupont et al. 2006). An example of theconnection to the genome is shown in figure 9 formolybdenum and of the ability to follow an element inevolution by the calcium-binding sites (tables 4 and 6).

Returning to the non-metals H, C, N and P, whichare very much involved in the general chemistry incells, their compounds did not change greatly in kind inthe cytoplasm although there are many changes of

Table 2. Essential primitive roles of metal ions. (Note thatKC/NaC/ClK control osmotic and charge balance whileCa2C, Zn2C and Cu have very little internal role, but theyand their use are all excellent markers of evolution.)

metal ion some roles

Mg2C glycolytic pathway (enolase)all kinases and NTP reactionsa

signalling (transcription factors)DNA/RNA structureslight capture

Fe2C reverse citric acid cycleCO2 incorporationsignalling transcription factorscontrol of protein synthesis (deformylation)light capture

W(Mo) O-atom transfer at low potentialMn O2-releaseNi/Co H2, CH3-metabolismNaC, KC osmotic/electrolyte balanceCa2C stabilizingmembrane andwall, some signalling?

a Almost all synthesis pathways.

periplasm cytoplasmexternaltransport

MOD A

MoO24 MoO2

4 MoO24

enzymes

coenzymes

pumpATP-aseMOD B

carrierMOD C MOD D

DNAtranscription

reversible stepsirreversible steps

Figure 9. Genetic structure of the molybdenum uptake and incorporation of proteins. The labels are for the genes which occur in asequence after a promoter. Mod A protein carries the molybdenum in the extracellular fluids.


detail. This is a consequence of the conservative natureof all life in its essential production of nucleotides,proteins, saccharides and lipids, all products ofconsiderable reduction of the atmospheric compoundsCO, CO2 and N2. The nature of P is almost invariablyin phosphate compounds. The major studies of the Cchemistry in evolution are of isotopic fractionation, andthose of both C and N chemistry are of molecularsequences (Holland 2006). There was however arelatively small change in carbon chemistry afteroxygen increased in the atmosphere, which we shallnote in messengers and some extracellular proteins, inhigher organisms, and a larger change of nitrogen in theenvironment; table 2 shows the essential primitivemetal elements and their activities in life, as far as wecan estimate them from existing anaerobes. They arethe main metal ions which we shall follow as earlymarkers of evolution together with changes of O, N andS, and then later new markers appear, e.g. Cu and Zn.

As our stress is equally on the environment, which ismuch more rapidly affected by oxidation than organ-isms, we turn to its evolution first.

6. THE EFFECT OF OXYGEN ON THEENVIRONMENT

Waste oxygen from biological activity did not accumu-late quickly in the atmosphere, since the largequantities of reduced inorganic materials in theenvironment rapidly equilibrated with it to giveoxidized states of elements. Thus, the O2 pressure wasbuffered for a long time. The major materials con-cerned, which are powerful fast reductants, were theabundant free H2S and Fe2C from sulphides. They wereoxidized to SO2K

4 and Fe3C, respectively. As mentioned,we can follow their conversion in time by theprecipitation of Fe3C iron bands in surface geologicalminerals and changes in isotope ratios of sulphur insulphates (Holland 2006). It took some 2 Gyr for thefree oxygen concentration to rise to a significant degree,say to 1% of present levels (figure 10; Kasting & Siefert2002). Subsequently, the oxidation potential of O2 rosesteadily with its partial pressure, perhaps for some1 Gyr, reaching present levels say 500 Myr ago. In theselater periods, oxidation of metal compounds, especiallythe sulphides of Co, Ni, Cu and Zn gathered pace, but


vast quantities have remained buried and are still beingmade slowly available (Saito et al. 2003). The elementsvanadium and molybdenum are special cases as theywere more readily oxidized from sulphides. The seabecame quite rich in these two elements early inevolution. Now, non-metals other than sulphur wereoxidized too (figures 8 and 11) and especially theoriginal CO and any NO or NH3 (Miyakawa et al. 2002)were replaced by CO2 and NOK

3 , as in our atmosphereand seas today, and we shall have occasion to refer tothe newly formed selenate and iodine. A peculiarity isthat CH4, formed by organic degradation, reacts slowlywith O2 so that some of it became buried, which led tothe formation of oils and coal. However, the majority oforganic debris materials from cell activity wereoxidized by cells. We emphasize that the loss ofavailability of many elements and the gain of manyothers placed great stress on pre-existing chemical flowsin organisms. The early organisms gradually faced amore and more hostile environment, always present inthe form of the NaC, ClK and Ca2C in the sea, butincreasingly from loss of access to C, N, S, Se and Fe2C

and lastly from the directly poisonous increasing

1

0.0001

0.001

0.01

0.1

present atmospheric level of oxygen (21% of atmosphere)

oxyg

en le

vel (

frac

tion

of p

rese

nt a

tmos

pher

ic le

vel)

5 4 3 2 1 0

formationof earth

billions of years before present

oldest rockpreserved

earliestpreserved cells

beginning of Cambrianhigher life evolves

evolutionof shelledinvertebrates

evolution of higher organisms(differentiated cells)

start of ordinaryrespiration

eukaryotes

prokaryotes

start ofphotosynthesis

synthesisof first cells

Figure 10. Rise in oxygen levels and evolution of the groups of chemotype species (compare figures 7 and 8).

non-metalsmetals

oxidationincreases

today

Mo(VI)/Mo(IV)

H+ /H2

Mg2+ /Mg

Na+ / NaK+ /K

oxidationincreases

4 × 109 yearsago

Cl2/HCl

O2/H2O

NO3–/NH4

+

N2/NH4+

H+/H2

Fe3+/Fe2+

VO2+/ V3+

O2 / H2OMnO2 / Mn2+

Cu2+/Cu+(Cu)

SeO/SeH–

HCHO/CH4CO2/CH4

CO2/HCHO

SiO2/SiH4H3PO4 / PH3H3BO3/BH3

I2/HI

S/SH2 ,SO24 /SH2

FeO24 /Fe3+

Figure 11. Redox potentials of the elements at pH 7, where that for HC/H2 isK0.42 and that for O2/H2O isC0.8. The sequentialchange of the sea will follow these redox potentials if the environment is at equilibrium with oxygen. The redox potential of theenvironment reached around C0.1 some 1.5 Gyr ago and is now approaching the O2/H2O line. The dissolution of sulphidesdepends on their solubility products. A sulphide solubility product change of logSPZ10, increased solubility, will move thesulphide equilibrium by C0.30 V.


presence of amounts of O2 and its non-metal productsand several, slowly more available, transition metalions. It is this systematic, close to equilibrated change,in the environment (figure 11) that forced a directionalevolution of types of organism, as we shall show. We


cannot use single species to describe this change butonly large groups of species which are affectedsimultaneously until humans appeared. Since we aredescribing chemical change we shall refer to chemotypesas the classes of species, while genotype relates to the

prokaryotic stagetype II

type IIA

type IIB

type I

type I

ancestor

HKA (animals) H+/K+

NKA (animals) Na+/K+

SCA Ca2+ (ER)modern prokaryotes Ca2+/K+/H+

PMCA plasma Ca2+, Mg2+?

HA (plants and yeast)

heavy metal ATPases Zn2+/Cu+

(prokaryotes and eukaryotes )

Figure 12. Evolution of the metal ion pumps. The variety ofCa2C pumps rose with the coming of eukaryotes and those forNaC/KC rose with the evolution of animals with nerves.Heavy metal ion pumps have been necessary from veryprimitive cell times.


individual species and specific genes define individuals.It is only the change of chemotypes that can be given aphysical/chemical system explanation.

Here, it is convenient todrawattention to the ideas putforward by Lovelock (2000) that Earth has developed inits chemistry as a changing steady state of organicchemicals of carbon as oxygen increased until todaywhena fixed biological steady state has evolved in whichorganic matter production by organisms is an effectivefinal buffer of oxygen pressure. The Earth’s ecosystem isthen given the title ‘Gaia’ with this implication. Wecannot agreewith this interpretation.Ourview is that theorganic chemistry of organisms through its codedcharacter is extremely conservative, so that it is onlydragged unwillingly forward by the oxidation of itsenvironment which is much closer to being in trueequilibrium, not a steady state, than are organisms. Theenvironment also has important inorganic parts notcovered in Gaia. The process of evolution, as we see, is asimple directed external chemical change due to biologi-cal waste, forcing slow adaptive change upon organisms,the whole increasing energy absorption and degradation.Initially, thebufferingof theO2waspurely environmentaland inorganic by fast Fe2C and H2S reactions whenorganisms hardly changed for 2 Gyr, while today theshort-term buffering is indeed largely organic (as statedby Lovelock 2000), but it is now the residual inorganicchanges of minerals which are slower to adjust but willdemand adaptation to them as the environment changes.In addition, there is the ongoing slow oxidation ofmethane, oil and coal. Moreover, humankind’s industryis today on such a scale as to complicate carbon/oxygenbuffering further as recognized in Gaia and by manyauthors. The outcome is quite unclear and most speciesare not at risk (except for their populations), but it hasalways been so and will continue until at some time Gaiacould be reached in theory much though this may not bepossible in practice. Adaptation is a hazardous activityandflexibility of the system is surely limitedbutunknownwhile environmental changes continue. Bacteria canadapt quickly to long-lasting poisons, organic (certainhalogenated compounds) and inorganic (Hg, Pb, Cd,etc.), but it is very doubtful if higher animals can adapt tosuch changes. Global warming is not a threat to anyspecies that can migrate, but it will force readjustmentof all populations in different places. Population andmore general pollution may be worse problems thanglobal warming, great though this threat is, and may beequally immediate. These considerations apply to all lifeand have deep implications for humankind’s activities(mentioned later).

7. THE CHEMOTYPE CLASSIFICATIONOF ORGANISMS

We shall not attempt to follow the changes with time ofthe concentrations of H, C, N and O in their compoundsas the problem in cells is so complicated (Kasting &Ono 2006) and the environment is linked to them onlythrough simple inorganic compounds such as CO2, N2,H2 and H2O which cannot be homeostatically con-trolled. (It is true that the study of small metabolites indifferent cells, metabolomics, is advancing but it is


likely to be species related.) We shall be concerned,however, with the changes in general availability ofthese four elements and some oxidized modifications ofthem and of S, I and Se compounds, as the chemotypeshave diversified. As stated earlier, it is the metal ionconcentrations and components, metallomes, whichhave changed considerably with time and which forman easily seen close link between cells and theenvironment due to the relatively fast reactions inboth compartments. There is then a basic analyticalcontent of both cell and environment compartmentslinked to their free metal ion concentrations throughequilibria, very different in the two, which can be usedto describe evolutionary changes. The best linkage to H,C, N and O chemistry is then via metalloproteins andthen of these proteins to DNA sequences. As stated,these proteins have a homeostatic link to the metal ionsthey bind. We can use the gene to tell us which bindingproteins can be expressed and the metalloproteinconcentration in a compartment to tell us which areformed quantitatively. Often, only the DNA of a celltype has been characterized and we know there aredifferences between DNA and metal/protein charac-teristics of the major types of organisms (Morgan et al.2004; Dupont et al. 2006; Williams & Frausto da Silva2006). For example, in the most primitive single cellanaerobes, unavailable dioxygen and copper cannot beused and their protein partners are absent; in single cellaerobic prokaryotes, there is little, if any, use of calciumand few of its proteins while calcium signalling becomesvaluable for single-cell eukaryotes, in which novelcalcium-binding proteins appear (table 5); multicellularorganisms make use of more extensive Ca, Zn, Cu andFe proteins and many elements outside cells incontrolled fluids, where further regulated novel proteinsoccur. Animals with nerves found a quite new use ofNaC and ClK in these fluids requiring new pumpproteins (figure 12). All these features can be tracedback to new DNA sequences. Simultaneous with thisuse of chemicals in organisms, including humans, cameincreasing use of necessary compartments, cytoplasmic,periplasmic, vesicular, extracellular and then thoseoutside the cell in the environment. These very basicphysicochemical features of an organism/environmentsystem allow us to divide evolution into a few kinds ofchemical organization in a systematic way. We shalldescribe the classes, in turn, noting how they arisethrough adaptations to allow survival value of the sum

Table 3. Major stages of evolution (Alberts et al. 2002).

(a) Prebiotic. They include a variety of energized flow systems of chemicals leading to precursors of the primarychemicals of later stages.

(b) Prokaryotic cells. They came first and are of more than one variety today. There is only one major compartment, thecytoplasm, contained by one major membrane. The cell activities are already coded and concerted. The varietiesof these cells and their metabolism have increased with time, anaerobes and aerobes. Their sensing of theenvironment is not advanced.

(c) Single eukaryotic cells. They have many internal compartments, vesicles and organelles, and many types of such cellsexist. The basic metabolism in the cytoplasm is much like that of prokaryotes. They are all aerobic large cells witha much increased organization internally and an increased ability to recognize environmental factors.

(d) Multicellular eukaryotes. They are often classified as fungi, plants and animals. They are all aerobes. There is a greatincrease in organizational complexity signalling between differentiated cells and organs. They have an increasedability to sense the environment.

(e) Animals with brains. The development of the nervous system with a brain allowed the animal to be informed aboutthe environment and remember experiences. The fast responses were increasingly independent with reference toDNA. Organization in groups is seen in patterns of behaviour.

(f ) Mankind. The further development of the brain led to the understanding of the chemical and physical environmentand many features of organisms. Hence, the environment became usable in constructs independent of inheritancein the DNA. External equipment could perform many desired functions. Information was passed down thegenerations through external and internal recording. Organization expanded enormously externally.


of the random species within them in a graduallychanging environment. However, while the environ-ment links to chemotype changes systematically, thenew element chemistry will be seen to demand alsocompartment separation in organisms giving increasedcompartmental complexity (table 3)—all part of adirected total system. The difficulties of complexity arethen relieved by symbiosis in this total ecosystem.Finally, humankind employs a vast range of newchemical elements outside the organism itself with noDNA connection and creates quite a novel stress forevolution. Table 4 is given here to enable the reader tohave an overview of the connection between the use ofelements as they became available in time andevolution from the earliest prokaryotes to the latereukaryotes as described in the next sections.

7.1. The first chemotypes: anaerobic single cellorganisms, prokaryotes

We wish to relate the organization in organisms tothermodynamic system quantities not simple descrip-tive qualities such as genes. Here, we shall not refer tointensiveDNA sequences, or a description of organisms,except where its organization or expression is controlledby chemical elements. All other cellular components,including proteins, occur as extensive (concentrationdependent) quantities belonging to the thermo-dynamics of system biology in the above cycle. (Doremember, however, that as DNA is destroyed after celldeath, it too cycles.)

Types of anaerobic organisms are generally acceptedto be the most primitive organisms in two groups,bacteria and archaea (Woese 2002). All these cells, thechemistry of which we deduce to have existed fromknowledge of modern anaerobes, have a free concen-tration of KC(10K1 M), Mg2C (10K3 M) and Fe2C

(10K7 M), and they use these elements, Fe2C mostlybound, together with a little Co and Ni but very littleMn and Zn and probably no Cu or Ca ions internally.The archaea appear to differ quite strongly in their use


of Ni, note especially the Ni-porphyrin, F430. All thecells reject NaC (10K3 M), ClK (10K3 M) and Ca2C

(10K6 M) relative to concentrations in the sea. Thecytoplasmic concentrations given are approximate andwe can give only even more uncertain values of free Niand Co ions, while we give maximum levels of Zn andCu ions from knowledge of equilibria with organicsulphides. An outline of the probable free elementcytoplasmic concentrations was given earlier in figure 5.Note that the order of free ion concentration is certainlyin the reverse order to that of the Irving–Williamsstability series of complex ions and observe theconnection to the inverse of sulphide solubility products(figure 4). It can be explained from knowledge ofdissociation constants of metalloproteins and othermodel ligands (Frausto da Silva & Williams 2001). Itwould appear that these concentrations in the cyto-plasm, the only compartment of the earliest cells, areclosely maintained there throughout evolution. Notethat the control of relative concentrations of free ions isvital for otherwise fast exchange would destroy thesystem by poisoning. Hence, any increases in free metalions in the environment can be allowed to give rise tonewmetal-binding proteins but not to change in free ionconcentrations in cells. This emphasizes the uniquecharacter of the cytoplasmic metal ion chemistry of thesystems of all organisms which is also consistent withthe unique pattern of the major organic chemicals inthis compartment of all cells. Cells in steady state musthave concentrations of proteins, including pumps, withbinding side chains limiting free transition metalconcentration in the above fixed free order. While thisdoes not limit the number of different complexes of agiven metal ion and their concentrations, they must allhave similar binding constants if they are in equili-brium. The amounts of binding proteins and moleculesare controlled by feedback from these ion concen-trations to the DNA (Williams & Frausto da Silva2006). For example, it appears that adenosine tripho-sphate (ATP) is always close to 10K3 M, very similar to

free Mg2C concentration, and it is MgATP which is the

Table 4. Involvement of elements in homeostasis during evolution.


active agent in most reactions. This homeostasis alsoapplies to the mobile coenzymes such as NADH andcertainly to the cytoplasmic pH of cells. The freecytoplasmic Ca2C ion concentration is always less than10K6 M and little Ca2C is bound (Carafoli & Klee1999). There are no intracellular Ca2C-binding proteinsin early cells. Certain cellular gradients were thereforeestablished from the beginning of life and they includedthe use of proton gradients to drive many energizedactivities (Mitchell 1961; Williams 1961).

Even before the environment changed, there musthave been development of a few other coenzymes. Inthis article, special interest lies in the four coenzymeslinked to the porphyrin skeleton and metal ions: haem(Fe); coenzyme B12 (Co); chlorophyll (Mg); and factorF430 (Ni). In effect, these four synthesized componentswith non-exchanging metal ions act as if they were fournew elements. Porphyrin may have arisen even beforethere were cells, but in any case these four give new


markers of evolution. Note that F430 (Ni) appears onlyin archaea that do not make chlorophyll (Mg), thusmaking a subchemotype distinction. Another exampleof coenzyme development is that of the dithiolatecomplexes of tungsten (W) and molybdenum (Mo),where the (W) complex is found in archaea. In veryearly times, Mo was precipitated as its sulphide MoS2.There is little further development of Ni, Co and Wchemistry throughout evolution and they are lost frommany higher organisms.

Before going further, we stress again that thisanalysis of chemotype is quite different from that ofgenetic information. Here, we are concerned withexpressed concentrations controlled in a network togive homeostasis in a cell’s steady state. These arecharacteristics of a system and not properties of singlemolecules, such as DNA. Each chemotype system doeshave one set of common genes with many variations,species, which separate it from all other chemotypes.


However, in a general sense, gene development mustfollow chemical change in the environment and giveprotective homeostatic concentrations of free metalions based on unavoidable equilibrium constants whilegenerating novel useful proteins. In so far as theenvironment change is systematic so the organismevolution must be, and we now show that it has been so.

7.2. Aerobic prokaryotes

The bacteria required hydrogen and, as mentionedalready, they discovered water as a source of it, givingwaste oxygen. It is this rejection of oxygen togetherwith that of NaC, Ca2C and ClK (and maybe Mn2C),which created the environmental pressures which droveevolution of the ecosystem in a particular directionchemically. The earliest effect of oxygen is as a poisonespecially through its partially reduced products,superoxide and peroxide. Before the use of oxygen orthese derivatives, protection from excess of them arose.There are enzymes for removing O2 (based on reductionby NADH), O$K

2 (superoxide dismutases based on Feand Mn) and H2O2 (catalases based on Fe or Mn),which occur very early in ‘anaerobes’. Later inevolution, all three products find a use and we shalloften see the progression

Poison/Protective Device/Use of the ‘poison’:

Biological pollution forced adaptative evolution to useself-generated poisons.

Certain prokaryotes have developed new metabolicpathways to use the poisons derived from oxygenincluding new states of non-metals, such as SO2K

4 andNOK

3 , and increasingly, newly available metals such asZn and Cu. Zinc was used in novel extracellulardegradative enzymes and copper in oxidation outsidethe cytoplasm (Williams & Frausto da Silva 2006).Nitrogen fixation from N2 needed quite novel enzymestoo, but we do not know the time of appearance of theknown vanadium (first?) and molybdenum enzymes.The order of oxidation from sulphide is V before Mo.Some new subclasses of aerobic chemotypes appearedincluding sulphate-, nitrogen- and nitrate-dependentbacteria. There was also separation of cell chemotypeswhich used a primary source of energy, light, giving outoxygen from those using only secondary energy sourcessuch as oxidation of reduced debris by oxygen oroxidized compounds. This separation led much later tothe evolution of plants and animals as very distinctsubclasses of chemotypes among multicellular eukar-yotes. The second group (animals) are totally depen-dent on the first for sources of reduced carbon andnitrogen. The divisions of labour in unconnected cellsamong prokaryotes reduce complexity (genetic load) ineach chemotype in a total ecosystem, but it is clearlynot a very effective organization. Competition forsurvival is largely internal to species of very similarchemistry, though clearly the most independent organ-isms (bacteria) can challenge even the most sophis-ticated but later organisms (humans).

As a consequence of oxidation, Fe(II) in the seawas replaced by Fe(III), very largely precipitated


(figures 7 and 8). The devised scavenging agents,siderophiles, for Fe(III) are oxidized organic moleculesand the complexity of this system evolves in higher andhigher organisms (Frausto da Silva & Williams 2001),but all the time theymust seek a balance in an ecosystem.

There are some examples of extravesicular compart-ments in bacteria. A striking case is that of thethylakoid, where localized proton production occursas part of a vastly complex weaving vesicle membranesystem for light capture (Williams 1961). This enablesits internal pH locally to be below 5.0, while maintain-ing the pH of the cytoplasm slightly above 7.0. Thelater device for oxidative phosphorylation uses an outermembrane potential rather than a pH gradient to avoidthe pH problem (Mitchell 1961). A second example is inthe bacteria anammox which oxidizes toxic ammoniawith nitric oxide within a separate vesicle. In the nextsections, we shall see how development of compart-ments had to be a major feature of new chemotypes allthe way to humans.

Furthermore, there are observed small pieces ofcircular DNA, plasmids, separate from the main DNA,to which we shall have occasion to refer again. Theplasmids have the novel genes for combating newpoisons, e.g. drugs and heavy metal ions. Why are theyseparate? They are a new code compartment reducingcomplexity.

7.3. The coming of unicellular eukaryotes

Around 2 Gyr ago, the first truly complex multi-compartment single cells arose apparently simul-taneously in all the lines of development from earlyaerobic bacteria and archaea leading later to plants(light using), fungi and animals (Cavalier-Smith et al.2006). Their arrival has no thorough genetic or shapeconnection to previous organisms. Apart from the factthat they now have a central separate nuclearcompartment, they are all large cells with a novelflexible membrane, many new internal filaments,several new vesicular compartments (some of a longweaving character, including organelles; see below)and new signalling methods. The flexibility of theirouter membrane, due to the inclusion of cholesterol(Summons et al. 2006), allowed them to digestprokaryotes, hence the need to synthesize the chemicalsessential to both was unnecessary. This led increasinglyto symbiosis in which the higher organism was a sourceof certain basic foods required by the lower organism,and the lower organism often supplied the higherorganism with more complicated molecules, coen-zymes, e.g. flavin or materials such as ammonia whichwere difficult to make from N2. The uptake of bacteriainto eukaryotes also led to the creation of organelles, inthe form of new compartments (stripped-downbacteria) capable of generating cell energy in achemically transformed compound, ATP (Margulis1998; Andersson et al. 2003). The organelles take upcertain material from the higher organism’s cytoplasmto aid photosynthesis or oxidative phosphorylation.Now, there is DNA in three different compartments insome organisms. Other compartments were for (i)digestion of bacteria and large molecules, lysosomes,

external calcium

filaments

exitentry

exdoplasmicreticulum

Ca2+ mitochondria

Ca2+

pool

ATP

ATP

ATP

ATPATPnucleus

metabolism

ATP

chloroplast

vesicles

Figure 13. Calcium ion signalling system of eukaryotes. Anexternal event triggers calcium entry which activates simul-taneously a wide variety of physical, shape and metabolicchanges. The time of activation can be as short as 1 ms and norecord of the changes need to be retained by the cell and thereis no interaction with DNA.


(ii) synthesis of large glycosylated and sulphatedmolecules often for export through the flexible mem-brane in the Golgi, (iii) synthesis of minerals for exportin microcrystalline form to give protective outer shells,and (iv) oxidation by enzymes for special metabolism ofcertain organic molecules in peroxisomes or in signal-ling vesicles. As the organic chemical complexity ofthese cells increased, we can readily distinguish theirchemotypical changes. The organelles contained highlevels of Mg2C and Mn2C (in chloroplasts), Fe and Cu(in both organelles) and mitochondria synthesized notonly ATP, but also haem, chlorophyll and Fe/Scofactors; the lysosomes are of unusual acidity (HC);the Golgi has high concentrations of Mn2C and SO2K

4 ;the mineral synthesis vesicles have high amountsvariously of Ca2C, Sr2C, Fe3C, CO2K

3 and sometimesBa2C with SO2K

4 ; the peroxisomes have high quantitiesof haem (Fe). The high concentration of Ca2C inendoplasmic vesicles is used in a messenger system,while zinc has increased in novel transcription proteinsand Cu enzymes are largely periplasmic. The inorganicchemistry is quite different from that of prokaryotes.

Symbiotic internal cooperativity gave increasingefficiency, while still relying on some external symbioticactivity. Now, all the compartmental separations,including internal organelles, had to be coordinatedby internal messages and it was also to the advantage ofthese large long-lived eukaryotic cells to have knowl-edge of the dangers and advantages of the environmentthrough message systems. In prokaryotes (bacteria),there were already internal controls through feedbacklinks to DNA to give homeostasis of cytoplasmicactivity. The messengers here were small moleculesand ions in this single compartment connected toprotein receptor transcription factors bound to DNA.Apart from the many organic molecules of themetabolomes, especially phosphates, there was strongcontrol signalling from Fe2C and Mg2C (Williams &Frausto da Silva 2006). All of these links had to bemaintained in eukaryotes. The rejected elements NaC,ClK and Ca2C played little or no part in signalling inprokaryotes, but we shall see how their use increased ineukaryotes. As stated, the prokaryotes were forced tocreate a steep gradient in Ca2C from approximately10K3 M external to less than 10K6 M internal. Ineukaryotes, the Ca2C ion was allowed to be 10K3 M inthe endoplasmic reticulum vesicles, but the samecytoplasm/environment gradient had to be kept(Carafoli & Klee 1999). These huge gradients areideal for conversion to use in new signalling devices(table 6), especially when coupled to the internalcytoplasmic signalling, for example, by phosphates.We observe that eukaryotic cells obtained knowledge ofthe changes of the external environment, advantageousor disadvantageous, by the opening of Ca2C inputchannels to the cytoplasm (figure 13). Followingcytoplasmic diffusion, this input released additionalCa2C from the reticulae, which acted as an amplifier.Together, the Ca2C ions activated responses ofmetabolism and filament tension, which changedshape, and they also activated the organelles to increaseusable forms of energy, ATP. Thus, both the feedingneeds and protection of the eukaryotes were then met


by Ca2C signalling and consequential responses. Afascinating novel chemical feature had thereforeappeared in organisms. While the rigid cells ofprokaryotes had some knowledge of the changes oftheir outside environment, their major response, apartfrom chemotaxis, had remained by relatively slowmutation and development of their genes. The flexiblecells of eukaryotes evolved with a very fast response toexternal events. Their changes are independent ofchanges of genes so that they could change shape andmetabolism rapidly and reversibly. We shall see thatthis is part of a gradually developing greater environ-ment/organism integration, which increases inevolution. It is a way to increase energy capture whilenot requiring short-time involvement of DNA.

There were also other element changes, in that newZn2C-dependent transcription factor proteins evolved(Klug 2005) and a new protective superoxide dismutaseenzyme based on Cu and Zn appeared. (The free zinc incells is still somewhat below 10K10 M and free copperremained at some 10K15 M of necessity.) Note thatprokaryote superoxide dismutases were and are stillbased largely on Fe or Mn even in organelles. We shallturn to more extensive uses of both copper and zincenzymes in the section on multicellular eukaryotes.Before doing so, we stress the dramatic effect that theexposure to and use of the poisonous element pro-duction in environment had on the evolution oforganisms. There is the use, especially of oxygen andnon-metal oxides, the heavy metal ions that oxygengenerated, and calcium, all poisonous elements orcompounds rejected of necessity from the cytoplasmat first, some even from the beginning of life. The nextchanges are then further adaptation to unavoidable


enforced changes of the chemical element content of theenvironment. It was this that drove the evolution ofeukaryotes and prokaryotes as organisms improved theoverall total rate of energy use and degradation, withstrong survival due to compartmental coordinateddevelopment and symbiosis. The changes in genes orof the linked shapes and sizes of cells in species offer bythemselves no rational explanation for development asthey are said to be random, only coupled to a generalstrengthening of survival. Note that, in part, speciesgene size and load increased, but it is observed that itdecreased in some ways. No more striking examples ofthe reduction of genetic load can be found than therelationship of eukaryotes to bacteria. The eukaryotescame to depend on bacteria for the element as essentialas carbon for life, namely nitrogen. Eukaryotes cannotobtain nitrogen from N2 and many cannot carry outdenitrification from nitrate. Again as noted earlier, thesynthesis of porphyrin and Fe/S proteins occurs inmitochondria. As mitochondria are really internalbacteria, it is not only the transduction of energy(ATP) from oxygen or in chloroplasts from light, whichare in separate cell compartments, but also that ofseveral essential cofactors for the eukaryote cytoplasm.In essence, these cofactors are similar to the laterso-called vitamins, since, for example, many of thevitamins, essential chemicals for humans, are coen-zymes made externally or internally to this organism byprokaryotes. There is no sense of competition herebetween prokaryotes and eukaryotes, but only co-operation, although some bacteria can attack eukar-yotes. Later in this article, we shall stress the greatdependence of the highest organisms upon lowerorganisms for other essential (to all life) chemicalsand note that the lower organisms also gained insymbiosis with higher organisms, in that, for example,the higher plants supply reduced carbon to lowerorganisms, fungi, that do not photosynthesize butscavenge so effectively in their soil environment. Aswe stressed before, the whole is a greater system formaterial and energy uptake and degradation than theparts, a feature of evolution not visible in figure 2. Notethat throughout the above, we are describing physical/chemical pressures driving evolutionary chemotypechange which can only be achieved by DNA changesin species to discover the code for advance in adirection.

Clearly, single cell eukaryotes are quite new majorchemotypes with vast numbers of probably randomspecies in a few subclasses. They are quite distinct fromprokaryotic anaerobes and aerobes in chemical elementuse. While they could not have appeared de nouveau,there is not good evidence for intermediate cases whichmust have existed. The intermediates must have hadsufficient stability to give continuity (see Cavalier-Smith et al. 2006 for an extensive analysis).

7.4. Multicellular eukaryotic evolution

The next development, of multicellular organisms, isnot so difficult to appreciate as much of the in-cellchemistry is only changed in the quantity and divisionin different cells of the already present chemical


components in the unicellular eukaryotes. The bigchemical changes are in extracellular chemistry ofexternal filaments assisting cell/cell space organiz-ation, of communication between cells via the extra-cellular space, and to some degree, in the chemistry ofdifferentiation. This extracellular space is occupied byfluids which became more and more well controlled asthe organisms grew in size within an outermost ‘skin’.Now, there are some general chemical element changeswhich we can list. In the cytoplasm, there are a vastlyincreased number of zinc transcription factors movingtowards 5% of the total number: there is a decreasinguse of nickel, so that higher animals do not have nickelproteins coded in their genome, and cobalt, wherethere is no function for coenzyme B12 in higher plants(replaced by Zn enzymes), and this cobalt compoundhas as a precursor, a vitamin, in higher animals: thereis some doubt about whether there is coding of t-RNAfor selenium amino acids in these eukaryotes. Outsidethe cells, the cross-linking of animal filaments, such ascollagen, is done by oxidation using novel copperenzymes and the breakdown of filaments, necessary forgrowth, is largely due to zinc proteases, much likeearly digestive enzymes. Digestion also uses more zincenzymes in extracellular fluids. Many of the extra-cellular filaments have numbers of oxidized proteinside chains and are glycosylated, and they frequentlybind calcium. Sulphated polysaccharides are alsofound outside cells. Turning again to the extracellularfluids, they gradually developed as fluids very wellcontrolled in free NaC, KC, Mg2C, Ca2C and ClK andin transport proteins for heavy metal ions such asZn2C, Cu2C and Fe3C. In vesicles, one development isnow especially of oxidized organic molecules, e.g.adrenaline and hydroxytryptamine and amidatedpeptides, as fast cell to cell transmitters, many ofwhich are synthesized with the aid of copper enzymes(figure 14). Zinc enzymes often assist later in theexternal hydrolysis of the peptides. Zinc ions fromvesicles in some organisms in external fluids also act asmessengers. All the above organic molecules are fasttransmitters, but there are also the slower-actingextracellular hormones many of which are producedby a vastly increased number of haem (Fe) oxidases,hydroxylases and peroxidases (cytochromes P450 andthe thyroxine producing peroxidase). The reactionstake place in the cytoplasm in such a way that theenzymes do not release the intermediates O†K

2 andH2O2. These hormones such as sterols, thyroxine andretinoic acid have the zinc transcription factors as theirreceptors. Zinc thus became a general factor linked togrowth and metamorphism and is probably an internalhomeostatic connector between these hormone receptorsso that they act together. (Zinc deficiency causes generalgrowth and metamorphic diseases, for example on anextremely zinc-deficient diet, humansbecomediminutiveand do not go through puberty.) Much of the novelorganic molecule communication system is then con-nected to the increasing availability of the twometal ions,zinc and copper (figure 8). The selectivity of the fasttransmitters at receiving cells is largely based onreceptors linked to Ca2C input as before and thenresponses occur much as in single-cell eukaryotes.

Zn enzymes

Ca P

Ca Ca

CaCaCa

connectivetissue

vesiclehydrolysis

Zn

Na+ ,K+, Ca2+

concentrations(sterol hormones)

Cu enzymes

DNAFe Cuvesicleredox

Cu and Znenzymes

peptidehormones

adrenalin

sterolhormone

ZnZn DNA

P

Ca

bone

Figure 14. Simplified diagram showing the involvement of theincreasingly available zinc and copper ions as well as that ofcalcium in multicellular organisms. Note the differencebetween fast transmitters, very new oxidized molecules,made by the action of copper ions in vesicles and thehormonal slow activators, oxidized molecules by the earlierhaem iron enzymes in the cytoplasm.

no. o

f si

gnal

s in

org

anis

ms

200

100

0

0.5 1.5 2.5 3.5 4.5

time since origin of life (× 109 years)

Ca2+

eukaryotes

organicmolecules

prokaryotes

Figure 15. Increase in signalling Ca2C-proteins and that of thekinds of organic signalling molecules with time. All of theseproteins and molecules arose as oxygen increased above thelevel which, with certain novel element uses, gave rise toincreasingly sophisticated eukaryotes.


There is a remarkable increase in Ca2C receptor proteins(figure 15; tables 5 and 6; Morgan et al. 2004). Note thatthese metal ion-based synthesis and novel messengersystems are common to plants, fungi and animals so thatvery distinct families of unrelated chemotypes, includingvast numbers of species, have similar systems based oncopper, calcium and zinc to a large degree.Given that thechanges of all these functional uses of metal ions occuralmost simultaneously in time in all the three branches ofmulticellular organisms, plants, animals and fungi, whichare connectedonlydistantly throughdifferentbranchesofunicellular organisms to bacterial origins, it could hardlybe that randommutation led to simultaneous appearanceof these similar novelties in all of them (tables 7 and 8).The common factor is the environment change, notinghere especially the rise in copper and zinc. How does geneloss (Ni and Co) and addition (Zn, Ca, Cu and Fe) occurwith environmental change while all elements increase inavailability? (The data for the above statements are allto be found with references in Williams & Frausto daSilva 1996.)

If we ask why organization should develop in thisway (tables 4 and 7), then system analysis of theenvironment/organism ecosystem suggests that theplacing of different functions in more controlledconnected relationships, different organs, in spaceallows greater effectiveness. The resultant increase isin the capture of energy and material for synthesis andthe overall degradation of energy, light to heat, withcycling of material (figure 3). It is as if plants strain togain total area for light capture by increase of heightand spread while animals and fungi evolve to be more


effective consumers of plants and plant debris assistingmaterial turnover with heat (entropy) production.They do so by using a wider diversity of elements innew ways, including sensing, within increasing numbersof compartments. It is especially the increased avail-ability of a few elements, note especially Zn and Cu,which allowed the development. But all this complexityis at a price of a heavier need for the lessening of geneticand control function loads. As mentioned previously,this is relieved to a considerable degree by symbiosis.Plants rely on bacteria for nitrogen supply and fungi forminerals, giving to the symbionts carbon compounds inreturn. The life of higher animals depends totally onplants for food and bacteria for digestion and coen-zymes (vitamins) allowing animals to lose severalmetabolic paths. Animal debris in turn feeds plants.Chemical cooperation is the essence of advance inorganization of an effective total ecosystem and itincreases in evolution (but see humans below). Whyotherwise did organisms lose genes so easily?

8. ANIMALS WITH NERVES AND BRAINS

An additional step in communication systems appearedin the larger scavenging animals. In these animals,awareness using refined senses is coupled to thefilamentous and muscular structures for mobility, nowin several separate organs. The coupling is managed, asit should be, by the fastest possible biological com-munication network, which comprises nerve cells.(Note that cellular material does not allow long-rangeelectronic connection.) They have thin long cylindricalextensions able to conduct depolarizing ionic currents,effectively in wires. In this way, biological organismsare enabled to make long-range fast physical, electro-lytic, connections based on the most mobile ions NaC,KC and ClK. The currents arise mostly from inwardmovement of NaC in exchange for KC. These ions bindto very few organic molecules and hence cannot

Table 5. Distribution of different Ca2C-binding protein motifs in organisms. (The table is based on the total number of allproteins in the DNA sequences available in 2004. The activities of calcium proteins are indicated in table 6. Adapted fromMorgan et al. 2004.)

binding proteins

Excalibur EF-hand C-2 annexins calreticulum S-100

archaea — 6a — — — —bacteria 17 68a — — — —yeasts — 38 27 1 4 —fungi — 116 51 4 6 —plants — 499 242 45 40 —animals — 2540 762 160 69 107

a These proteins have single EF-hands and are not signalling proteins; all the remainder are for signalling.

Table 6. Some classes of calcium proteins.

protein location and function

calmodulina cytoplasm, trigger of kinases, etc.calcineurina cytoplasm, trigger of phosphatasesannexins internal, associated with lipids, triggerC-2 domains part of several membrane-linked

enzymesS-100a internal and external: buffer, messenger,

triggerEGF-domains external growth factor but general

protein assembly control, e.g. fibrillinGLA-domains external, associated with bonecadherins cell–cell adhesioncalsequestrin calcium store in reticulaATPases calcium pumps

a EF-hand proteins.

Table 7. Metalloprotein sets in two organisms.

protein set yeastworm(C. elegans) metal

nuclear hormone receptor(Zn)a

0 270 Zn

binuclear GAL cluster (Zn)a 54 0 Znmetalloproteases 0 94 ZnNaC channelsa 0 28 NaMg2C adhesiona 4 43 Mgcalmodulin-like proteinsa 4 36 CaKC channels (voltage

gated)a0 135 Ca

EGF, Ca2C-bindingcysteine-rich repeatsa

0 135 Ca

kinases (tyrosine) 15 63 Mgcytochrome P450 3 73 Fe

a Absent in bacteria (Williams & Frausto da Silva 2006).


activate changes at nerve cell termini. At nerve/muscleor nerve/nerve synapse junctions, it is thereforenecessary to revert to earlier very short rangecommunication using the activity effective ions, Ca2C,and fast organic transmitters, which do bind toreceptors much as described previously. The featureto be noted here is that the nerve cell electrolyticmessage system is based upon the most primitive cellgradients of NaC, KC and ClK, which were necessarilycreated by the earliest prokaryotes for osmotic protec-tion due to the ‘poisonous’ nature of the sea. It is thisdepolarization current which opens the calciumchannels at synapses. A new NaC/KC ATPase pumpis involved in gradient recovery (figure 12), in which weshow how pumps evolved sequentially. We also notehow the use of elements such as Ca, Zn, Na and Mg hasincreased from yeast to worms (table 7). (It is notabsolutely the case that KC ions do not bind to organicmolecules and KC has found some special use in DNAand a few enzymes.)

The scavenging ability of animals was furtherincreased by the organization of the nervous system inthe brain firstly in primitive worms and then increasinglyup to the arrival of humankind. The earliest brain gaveautomatic responses to the searching power for plantmaterial, food, and enable avoidance of predators,mostlyrather similar animal species. The next stage in theprogress of the brain was to organize the nerves to form aunit not only to coordinate many inputs and outputs(automatic response), but also to remember events. Itthen learnt to control appropriately the best actionopposite apreviouslymet experience.This is not a geneticresponse, though genes create the basic framework of thebrain but with poor connectivity. Connectivity nowcomes from experience. Detailed shaping of a retainedmemory has no code.

Wecan followthe very fast developmentof the brain inevolution, but as yet the reasons for the rate of changeandfor the inorganic element and organic transmitterdistributions and its many compartments are unknown(Williams 2003). It is both the new uses of NaC, KC andClK together with the stored element and selectedcompound distribution in the brain, and their conse-quences that make these animals a new chemotype. It isnot possible to give an explanation of the brain’s rapidevolution by reference to genes.


The use of the brain nowmade it possible to constructexternally using natural environmental material. Weobserve animals building nests, making barriers instreams and digging holes. Moreover, the animals areable to protect and feed their offspring. Finally, they areable tomap theworld outside themselves.Amootpoint isthe degree to which they have self-recognition and self-consciousness, but they do have suggestive intriguingbehaviour patterns.Many of these additional details help

Table 8. New element biochemistry after the advent of dioxygen.

element biochemistry

copper most oxidases outside higher cells; connective tissue finalization; production of some hormones, dioxygencarrier, N/O metabolism

molybdenum two-electron reactions outside cells; NOK3 , SO

2K4 , aldehyde metabolism

manganese higher oxidation state reactions in vesicles, organelles, and outside cells; lignin oxidation (note especiallyplants); O2 production

nickel virtually disappears from higher organismsvanadium new haloperoxidases outside cellscalcium calmodulin systems; g-carboxyglutamate links; general value outside cells and in cell–cell linkszinc zinc fingers connect to hormones produced by oxidative metabolismselenium detoxification from peroxides, deiodination?halogens new carbon–halogen chemistry, poisons, hormonesirona vast range of especially membrane-bound and/or vesicular oxidases; peroxidases for the production of

hydroxylated and halogenated secondary metabolites; dioxygen carrier and store

a Note that iron can act as an agent responding to the redox potential changes in the cytoplasm.


to define species, but they do not define a new chemotypeas the chemistry has not changed much in this physicalactivity. It was increase in awareness of the nature of thechemical environment that did allow one species to bevery decidedly a quite new chemotype, Homo sapiens.

Now, we may ask what kind of information is storedin the brain. It is clearly very different from that in theone-dimensional chemical sequences of DNA related togenes. It is created from nerve messages originating inthe senses as well as a basic underlying structure ofnerve tissue laid down under genetic control. Thestored image can be recalled and used in activity. Itgives rise to controlled external activity much as DNAinformation gives rise to controlled internal activity.The image is a consequence of initial electrical pulsesfrom the senses, but these pulses are converted intosynaptic chemical and charge stores, e.g. of NaC, KC. Ifthe same senses are stimulated repeatedly, they causesynapse growth and long-term memory. This is theequivalent of a new gene in a bacterium, but it is asystem’s energized property. Now, an image has aboundary zone in the brain (Kull 2000), and inside theboundary there is activity detected as electric waves.The only immediate parallel the author can see is withthe boundaries of clouds and their constant physicalcirculation. Here, the images (or the reality in thecloud) are not coded in a manner related to DNA oreven to digital storage in a computer. They are a steadystate of flow phenomenon.

9. HUMANKIND

While the use of the NaC/KC gradients and the wholeapparatus of the brain allowed animals with brains tobe classified as a separate chemotype, it is very clearthat the evolution of humankind today is to a differentchemical organizational level. While the most sophis-ticated animals use the environment in learnt physicalways, humans use it by rapidly introducing under-standing and to active innovation in chemistry. Thenovel chemistry and physics using empirical methods,starting from around 1600 and extending to date, is theemployment of the whole range of 92 chemical elementsin the Periodic Table and a few synthesized elements,not the 20 or so of which the genome is aware.


The consequences of this knowledge and that ofphysical properties of materials, and the accompanyingunderstanding of them, have led to huge industries. It isthe exploitation of chemicals not only in construction,but also in the necessary novel modes of transport andcommunication which is a vast extension of external‘biological’ activity heading towards a complete controlover energy and all species and minerals on Earth’ssurface and the remote possibility of a final steady state(Gaia?). There is no doubt that this single species hasthe attributes of a vastly different chemotype, whichhas evolved amazingly rapidly with little change ingenetic complement. This chemotype is a strikingwitness to the ever increasingly deep involvement ofthe environment, material and energy, and organismsin one system, which had to be to increase energydegradation. Starting from the origin of life, organismsbased on environmental material and energy haveincreasingly changed the environment and then, ofnecessity, they have become more and more interactivewith that through senses and hence an ability to adaptto and use information gained from that (Kull 2000). Atthe same time, consistent with the systematic increasein organization internally is the systematic reflectiveuse of the extension of symbiosis. The latest product,humans, is the least effective chemical factory depen-dent on supplies of many vitamins, amino acids andsugars from earlier organisms. Through logical thought,humans are making more striking environmentalchanges rapidly. All the time, the environmentalchange reacts back and will force organisms to change(but note that the fastest genetic readjustment lies withprokaryotes alone). Every new chemotype in theenvironment/organism ecosystem forces change on itall (tables 4 and 8), but we must see this as a logicaldevelopment of the pressure to increase energy andmaterial adsorption and energy degradation: life itselfcreates the changes.

Before closing this account, we have to recognize thathumans’ fast developing chemical activities have graverisks. Biological systems are DNA coded and cannotchange as quickly as the DNA-independent functions,which are now linked to the gene-independent activity ofthe brain. Humans must become the caretaker but not

H2S SO24–

O2H2O

Metaln+ Metal(n+1)+

species

time2.0

1.5

1.5

2.0

2.5

3.0

3.5

2.5

3.0

3.5

today

humans

billions of years age

oxidation

chemotypezone

environment

oxidation

use of energy

animals

multi-cell eukaryotes

aerobic prokaryotesanaerobeseukaryotes

Figure 16. Conical figure of the evolution of chemotypes. The axis of the cone indicates the time from the origin to date andsimultaneously the increase of oxidized chemicals in both the organisms and the environment. Circular sections of the cone andits divisions shows the development of chemotypes all increasing in species numbers and chemical variety from the outside of thecone which is associated with anaerobic conditions to the inside which is increasingly in oxidized conditions. The cone thenrepresents the chemical space in which organisms can exist. Outside the cone is a vast range of chemistry which is now beingexplored by humans. Compare the pictures of evolutionary trees (figure 2).


the spoiler of the ecosystem (figure 16) and must beaware not only of physical effects, such as globalwarming, but also of the whole range of chemicalproblems for organisms which is being created. A greatadvance but a great danger is protection of any organismcreating comfort but overpopulation now using chemi-stry not related to genes. The selfish gene cannot lead toabalanced environment/organismecosystem,which hasto be a global tolerance of many species and individualsin harmony. This can only be achieved by humans usingtheir ability to rationalize collectively.

10. ADDENDUM: GENETICS AND THEENVIRONMENT

There is now a puzzle. How do we make a synthesis ofthe logical history of chemotypes (figure 16) andthe notion of the random appearance of species? Theanswer must lie in the interaction between theenvironment and genes or gene products since for


organisms to evolve genes had to change with time asthe organisms caused environmental change. There isno doubt that much change of DNA is random and wecannot see a rationale for the appearance of each of somany different species of similar organisms, for exampleamong four-legged animals. Then, this is not a questionof environmental pressure acting on genes to createsimilar species. However, the major changes inevolution which we have classified under chemotypesclearly arise as a response to earlier environmentalchanges. These changes are in a particular chemicaldirection, oxidation, produced by the very nature of thereductive metabolism of organisms. It is time to lookagain for a directed long-term effect of the environmenton genetic change. One possibility is that the change ofgenes is in localized regions connected to the initialadverse effect of novel environments. Is this whybacteria have separate regions of DNA plasmidswhich carry so much of adaptation? It may be thatcompletely random search by mutation is not general


but constrained to some extent as appears to be thecase in the immune response (Neuberger et al. 2003).We must leave this possibility to experimental test(Jablonka & Lamb 1995; Turner 2001; Caporale 2004).

It could well be that alternatively the gene changesare not affected so directly by the environment but thatrandom variation of DNA, speciation, is the only waythat DNA can find the direction of the drive towardsoptimal energy use and degradation in tune with theecosystem. Such variation can be, in part, misdirectedand individuals (and species) can behave selfishly.However, the overall direction remained inevitableuntil humans appeared. Through chemistry, andincreasingly through control of breeding and genetics,humans have become freed from the development byrandom gene variation matching the environmentalchanges. The use of brain and knowledge obtainedabout the environment has made a quite new chemistrypossible. However, this activity has risks for allorganisms totally dependent on DNA for control overa more limited chemistry. Can humans handle therisks? Humans must see the nature of the whole of theenvironment/organism ecosystem and conform to itsdirection in the search for a cyclic steady state.

The data for the tables and the figures are obtained fromWilliams & Frausto da Silva (2006). Very extensive referencesare given there to all topics in this article. The author isextremely grateful to two referees for their comments and aidin clarification of the text.

NOTES

(i) Environmental element concentrations and time.In order to obtain concentrations in the sea, weassume that all available inorganic ions equili-brate with potential partners and have done so atall times. Included are the oxidation states of theelements. A general proof of these statementsfollows a consideration of complex ion chemistryand the solubility products of the oxides (hydrox-ides), sulphides (figure 4), carbonates and sul-phates. Evidence from iron mineral deposits andisotopes of sulphur dates the rise of oxygenationand loss of hydrogen sulphide (becoming sul-phate) from the oceans. The loss of Fe2C and HSK

then allowed the further oxidation of less readilysoluble transition metal sulphides. We have usedthe oxidation/reduction poise as it changed withtime to estimate the increases of zinc and copperconcentrations with time (Frausto da Silva &Williams 2001).

(ii) The inorganic ions in cells, free and bound, havebeen measured in many cell types representingorganisms from the earliest times to date. Data onfree KC, NaC, Mg2C, Ca2C, Fe2C and Zn2C arenow robust. Recently, a number of bindingproteins for several important elements havebecome available from genetic analysis in thesecells (Dupont et al. 2006). From studies of modelsystems and direct examination of protein metalion exchange, we know that over time periods of afew microseconds to a few minutes the large


majority of sites of ion binding come to equili-brium. All evidence gives rise to the picture of freeion concentrations in figure 5 and tables 1 and 2(Williams & Frausto da Silva 2006). Thechemical composition is partly linked to elementin and out pumping and partly to gene expressioncontrolled by feedback linkage to the free elementconcentration.

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http://dx.doi.org/doi:10.1016/j.bbamcr.2004.09.010

http://dx.doi.org/doi:10.1016/S0968-0004(03)00111-7







http://dx.doi.org/doi:10.1016/0022-5193(61)90023-6

http://dx.doi.org/doi:10.1016/0022-5193(61)90023-6


http://dx.doi.org/doi:10.1006/bbrc.2002.6518


a system's view of the evolution of life

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