the origin of modern terrestrial life

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The origin of modern terrestrial life

Patrick Forterre1 and Simonetta Gribaldo2

1

Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris et Universit Paris-Sud, CNRS, UMR 8621,91405, Crsay-Cedex, France2Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France

Received 22 June 2007; accepted 22 June 2007; published online 25 July 2007; corrected 11 March 2008)

The study of the origin of life covers many areas of expertise and requires theinput of various scientific communities. In recent years, this research field hasoften been viewed as part of a broader agenda under the name of exobiology or

astrobiology. In this review, we have somewhat narrowed this agenda, focusingon the origin of modern terrestrial life. The adjective modern here means thatwe did not speculate on different forms of life that could have possibly appearedon our planet, but instead focus on the existing forms cells and viruses. We try

to briefly present the state of the art about alternative hypotheses discussing notonly the origin of life per se, but also how life evolved to produce the modernbiosphere through a succession of steps that we would like to characterize asmuch as possible. [DOI: 10.2976/1.2759103]

CORRESPONDENCE

P. Forterre: for [email protected]

S. Gribaldo: [email protected]

Traditionally, two approaches have

been employed to understand how ter-

restrial life originated (Fig. 1). The

bottom-up approach, exemplified by

Millers experiment, attempts to recon-

struct the conditions of the primitive

Earth in order to imagine how the main

components of living organisms came

into being. This is the realm of astro-

physics, geophysics and chemists. The

top-down approach is favored by biolo-

gists, who try finding in modern organ-

isms the relics of their ancestors in or-

der to reconstruct ancient metabolic

pathways and molecular processes.

Neither of these two approaches can be

successful alone, and the final goal of

any origin-of-life program should be

to bring together all these lines of re-

search to build up a coherent scenarioleading from inorganic chemistry to

Darwinian evolution. In that sense, the

quest of our origin is intrinsically inter-

disciplinary and should bring together

various expertises to deal with the same

issues.

Despite the difficulty of the topic,

great advances have been made during

the last decade in understanding the

origin of modern life. A major issue

that remainsto be solved is the origin of

RNA, since this is where the bottom-up

and top-down approaches meet. We

definitely know, from the resolution of

the ribosome structure, that modern

proteins were invented by RNA

(Steitz and Moore, 2003). This means

that, once upon a time, RNA was themaster of life, covering both the genetic

and catalytic properties today per-

formed by DNA and proteins, respec-

tively. However, the formation of a

bona fide ribonucleotide has so far

never been successfully achieved in the

laboratory, and the formation of oli-

goribonucleotides from monomers is

extremely difficult to achieve. In this

review, keeping in mind that the origin

of RNA is the central issue, we will

briefly review the state of the art and

the recent controversies in the fields,

and we will try to identify the most

promising areas of research for the next

decade.

THE BUILDING UP OF A

HABITABLE PLANET

The formation of the Earth

Plausible mechanisms for the forma-

tion of the solar system have now been

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formulated, especially explaining the accretion mechanism

that could have led to the formation of a terrestrial-like

planet (Montmerle et al., 2006). The formation of Earth is

quite precisely dated at 4 56 Ga ago, based on the dating of a

particular type of meteorites called ordinary chondrites.

The accretion mechanism was probably rapid (about

100 Myr), leading in a first time to a very hot planet with a

magma ocean. The formation of oceans and continents took

place probably more rapidly than previously thought (be-

tween 4.5 and 4.4 Ga) (Hawkesworth and Kemp, 2006). This

is inferred from the study of the oldest rock, a 4.4 Ga old

zircon from Australia that gives evidence for an interaction

between water and rock at temperatures below 100 C

(Wilde et al., 2001). An atmosphere would also have formed

quite early from volatile elements (such as nitrogen) contrib-uted by extraterrestrial material on the surface of the Earth.

Astrophysics has taught us that life is not alien to the uni-

verse, since its fundamental fabricorganic chemistryis a

ubiquitous component of the interstellar space. Complex or-

ganic molecules, as well as silicates, hydrocarbons, and vari-

ous forms of ice have been found in extrasolar clouds (Bern-

stein, 2006). Therefore, as temperature decreased, organics,

either produced on Earth or coming from meteorites or mi-

crometeorites (cosmic dust), could have started accumulat-

ing on the surface. For some authors, the conditions for the

emergence of life (liquid water, continental crust, atmo-

sphere) were already in place at 4.44.3 Ga. However, the

habitability of the early Earth was seriously compromised by

multiple giant impacts. In particular, around 3.9 Ga the

Earth was subjected to an impressive episode of bombard-

ment, called the late heavy bombardment (LHB) (Cohen et

al., 2000).

The Late Heavy Bombardment

The craters observed on the surface of the Moon and other

planets whose surface was not remodeled by erosion, sedi-

mentation, and plate tectonics (Mars, Venus) testify for the

diameter of the giant meteorites (more than 100 km and up

to 5000 km) that hit the Earths surface during the LHB [for a

recent review, see (Claeys and Morbidelli, 2006)]. This dra-matic event could have been triggered by the migration of

giant planets that took place after the dissipation of the gas-

eous circumsolar nebula (Gomes et al., 2005). The LBH may

have lasted from 20 to 200 million years, with a frequency

of impact that is highly debated (from one each 10,000 years

to one every 20 years). Models predict that such impacts

would have almost completely resurfaced our planet, leading

to evaporation of the oceans, melting of the crust down to at

least 1000 ms, and loss of the atmosphere. It might be sig-

nificant that the oldest terrestrial continental crust (Isua,

Figure 1. Schematic of bottom-up and top-down approaches. Major events discussed in the text are highlighted.

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Greenland) dates exactly to the end of the LHB, at 3.8 Ga. In

our opinion, it is unlikely that any forms of life, if already

present, would have survived the devastating impacts of the

LHB. If this view is correct, it implies that the path to mod-

ern life would have (re)started after 3.93.8 Ga. The pres-

ence of sedimentary rocks testifies that oceans had already

reformed by that time. However, putative isotopic traces of

life found in these rocks are now believed to be artifactual

(see below), consistent with the idea that modern life might

have indeed originated after the LHB.

Primitive atmosphere and oceans

It has been accepted for a long time that the atmosphere of

the early Archaean was anoxic and probably weakly reduc-

ing, and dominated by oxidative species such as CO 2, N2,

CO, and H2O, with small amounts of H2, that would have

escaped rapidly to the outer space (Kasting, 1993). Reduced

gases supplied by volcanic outgassing, such as CH4

and

NH3, would have been destroyed by UV (photodissociation),

and may have subsisted only locally around hydrothermal

vents. However, a recent theoretical model has estimated that

the hydrogen escape rates were lower than previously as-

sumed in the early archaean atmosphere, suggesting that hy-

drogen may have been abundant (Tian et al., 2005). This

would be good news for models in which life originated at

the surface of our planet, since a reducing atmosphere would

have favored traditional prebiotic chemistry. However,

these recent estimations have already been criticized

(Catling, 2006), and the debate is ongoing. It was noticed

early on that the early Earth was in danger of freezing due to

the low luminosity of the Sun, which was about 30% lessthan it is today (the faint young Sun paradox) (Sagan and

Chyba, 1997). Several authors have suggested that high CO2concentrations (or a mixture of CO2 and CH4) in the early

atmosphere were required to prevent (via a greenhouse ef-

fect) Earth from freezing (Pavlov et al., 2000). Indeed, the

presence of 3.5 Ga old sedimentary rocks excludes a global-

scale glaciation of the planet at least by that time. The study

of organic carbon isotopes indicates that oxygen concentra-

tions became significant (but still very low) only at 2.7 Ga

and then started to rise steadily (up to 1% of the present

level) from 2.4 Ga, what is called the great oxidation Event

(GOE) (Holland, 2006). Interestingly, this period coincides

with two possible snowball Earth episodes around 2.9 and2.4 Ga, which is assumed to have been triggered by the ac-

cumulation of biologically produced oxygen (and conse-

quently the removal of methane and its greenhouse effect)

following the emergence of oxygenic photosynthesis (Farqu-

haret al., 2000; Holland, 2006; Kasting and Ono, 2006).The

isotopic fractionation of elements such as sulfur in archaean

deposits points to an anoxic ocean during the whole archaean

period and beyond, up to 1.8 Gyr. The oceans would have

then gone through a euxinic phase (hydrogen-sulfide rich)

and finally become fully oxygenated around 0.75 Gyr

(Kump, 2005). Oxygen and silicon isotope data from ar-

chaean cherts indicate that ancient oceans may have been

warmer than today, with temperatures as high as 70 C

around 3.3 Ga (Knauth, 1998; Robert and Chaussidon,

2006). However, the interpretation of isotopic data remains

controversial since this would imply that archaean hot and

acidic rainwater would have produced intense weathering

that is not observed in the paleoweathering record. Further-

more, a hot ocean is difficult to reconcile with a first global

glaciation that could have occurred at 2.9 and 2.4 Ga [for a

critical review of these data, see (Kasting and Howard,

2006)].

The fossil record

The first and now popular descriptions of life traces in the

Archaean regard layered structures very similar to present-

day stromatolites from a 3.4 Ga old Australian Apex chert.

These structures contain putative microfossils presenting

morphological characteristics resembling present-day fila-

mentous bacteria [for a review see (Schopf, 2006)]. How-

ever, their biologic nature remains hotly debated. For in-

stance, it was shown that many of these structures are

produced abiogenically in the laboratory under particular

conditions [reviewed in (Brasieret al., 2006)]. Organic mat-

ter has been detected in these structures by in situ laser Ra-

man spectroscopy (Schopf, 2006), although abiogenic struc-

tures also can absorb organic inclusions that give the typical

Raman spectrum of a microfossil (Brasieret al., 2006). The

earliest stromatolite formations of unambiguous biological

origin thus remain for the time being those from around

2.6 Ga (Schopf, 2006). The question of the biogenic or abio-genic nature of earlier Archaean microfossils will have to

await future methodological developments [for recent re-

views see (Lopez-Garcia et al., 2006; Westall, 2005)].

The isotopic composition of different elements is af-

fected by biological processes and can thus indicate the pres-

ence of particular metabolisms. Isotopic signatures of differ-

ent elements (carbon, sulfur, nitrogen, and more recently

iron) have therefore been extensively studied to search for

life signatures in ancient rocks and to identify specific an-

cient metabolisms (Tice and Lowe, 2004) (Ueno et al.,

2006). In particular, the carbon isotope values from apatites

in Isua banded iron formations 3.8 Ga have often been con-

sidered to be the earliest signatures of life on Earth (Mojzsiset al., 1996). However, all the data obtained remain vigor-

ously debated (Fedo and Whitehouse, 2002; Mojzsis and

Harrison, 2002). Some authors have argued, in particular,

that some results are indeed compatible with an abiotic ori-

gin of isotopic composition from hydrothermal activity [for

an extensive critical and well-balanced review on this topic,

see Lollar and McCollom (2006)].

Finally, molecular fossils (kerogens) derived from the

transformation of lipids have also been used to tentatively

determine the age for the emergence of various life forms.

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However, it is very difficult to extract kerogens from Ar-

chaean rocks, and not all lipids are equally resistant. For ex-

ample, lipids from archaea are very fragile and have not been

found in rocks older than 1.8 Ga (Summons et al., 1988).

The older biomarker record regards the presence of hopanes,

lipids that today are distinctive of cyanobacteria, in 2.7 Ga

old rocks from Australia (Brocks et al., 1999). The presence

of eukaryotic-type steranes in the same ancient rocks

(Brocks et al., 1999) is more controversial since some bacte-

ria can produce sterols as well (Pearson et al., 2003; Tippelt

et al., 1998), although not of the complexity of those found

by Brocks et al. (Summons et al., 2006).

In conclusion, the fact that the oldest traces of life that are

not controversial are only those from 2.6 Ga (Schopf, 2006)

leaves open a wide window for the origin of modern life be-

tween 3.9 (end of the LHB) and 2.7 Ga. The quest for traces

of life in this time interval is a rapidly expanding research

field. New drilling projects have now started in order to ob-

tain novel samples of archaean rocks. Isotopic and chemicaltechniques are being improved to detect the presence of or-

ganic matter with less ambiguity, and new in situ techniques

start to be applied to the analysis of putative microfossils.

Novel and more performing techniques of lipid extraction

will hopefully push back the limit of detection of biomarkers

to the early Archaean. In parallel, theoretical models for the

early Earth will surely benefit from a better description of

known metabolisms (see below) and metabolic consortia,

and their current distribution in a wide range of environmen-

tal settings.

THE ORIGIN AND EARLY EVOLUTION OF LIFE

Heterotrophic versus autotrophic theories

In the traditional prebiotic soup scenario, organic mol-

ecules would have first accumulated in the ocean or in

smaller water bodies on the early Earth, either delivered by

extraterrestrial sources (micrometeorites, dust) and/or pro-

duced by Millers type experiments (especially if the early

atmosphere was hydrogen rich, see above) (Bada and

Lazcano, 2003). The first living systems would have then

emerged from the gradual complexification of the prebiotic

broth. The authors supporting this heterotrophic theory of-

ten argue that prebiotic chemistry is the prolongation on our

planet of the cosmic chemistry, whose products (e.g., amino

acids) indeed overlap with the building blocks of life. Forthem, the possibility to easily produce in prebiotic conditions

simple amino acids, purines, sugars, fatty acids, and other

small organic molecules essential to modern life is too strik-

ing to be fortuitous (de Duve, 2003). Proponents of the pre-

biotic soup scenario (especially the Bada and Miller school)

have in general argued in favor of a slow (gradual accumula-

tion) and cold origin of life (essential to the long-term stabil-

ity of organic matter).

As an alternative to the heterotrophic theory, 20 years

agoWachtershauser proposed an autotrophic origin of life, in

which an energy flux provided by chemical reactions at

liquidsolid interfaces was used for carbon fixation (Wacht-

ershauser, 1988) (Wachtershauser, 2006). A related model

was proposed later on by Russell and Hall (1997). In this

view, gradual accumulation and complexification of organic

matter occurred either on mineral surfaces (i.e., a two-

dimensional life) or in networks of mineral pores. Instead of

linking cosmic chemistry with biochemistry, the proponents

of an autotrophic origin of life try to link biochemistry with

geochemistry. Wachterhauser specifically suggested that a

primitive metabolism evolved at the surface of pyrite miner-

als from the reduction of carbon dioxide using hydrogen sul-

fide H2S over ferrous sulfide (FeS) as the reducing agent

[pioneer metabolism theory (Wachtershauser, 1988)

(Wachtershauser, 2006) and references therein]. The nega-

tively charged organic molecules synthesized by this reac-

tion would have been stabilized by binding to the positively

charged pyrite surface, thus forming a two-dimensional net-

work. The number and diversity of these molecules wouldhave thus grown autocatalytically in situ by carbon fixation,

leading to the self-organization of cyclic chemical reactions,

producing more and more elaborated products. Russell and

Hall (1997) suggested that carbon fixation first occurred in-

side mineral three-dimensional networks formed by the pre-

cipitation of iron monosulfide from the mixing of sulfide-

rich hydrothermal fluid and the iron-containing water of an

acidic ocean, the system being energetically driven by a natu-

rally occurring geochemical pH gradient. The authors of au-

totrophic scenarios have been strongly influenced by the dis-

covery of hydrothermal vents and hyperthermophiles in the

late 1970s and early 1980s. In contrast to the proponents of

the heterotrophic origin, they usually favor a hot origin of

life, the initial reaction being driven by a geothermal energy

source. In their models, the stability of organic molecules is

no more an issue, since these would have been short lived.

On the contrary, high temperature is supposed to have in-

creased the rate of reactions at the surface of the minerals or

inside mineral structures.

Although the autotrophic models for the origin of life are

in theory experimentally realizable in toto (Huber and

Wachtershauser, 2006), experimental programs designed to

test these theories have succeeded up to now in producing

only simple organic molecules (from C2 to C4). Furthermore,

none of these reactions has been shown to be autocatalytic, acrucial requirement to start real chemical evolution (Orgel,

2000). The controversy between the proponents of het-

erotrophic and autotrophic theories thus remains lively (de

Duve and Miller, 1991) (Bada et al., 2007). However, there is

now a general agreement on the idea that minerals (espe-

cially clays) may have catalyzed prebiotic reactions and that

metal sulfides have been an important source of electrons for

the reduction of organic compounds (Bada and Lazcano,

2002). In particular, proponents of the heterotrophic theory

now often agree that reactions occurring in a hydrothermal




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and/or in a volcanic setting may have enriched the prebiotic

arsenal of organic molecules, or else suggest that the first or-

ganics useful for life were concentrated at mineral-water in-

terfaces and/or into porous minerals. Volcanic activity might

have been especially important for the production of phos-

phoric compounds that are essential for life (Yamagata et al.,1991) (Schwartz, 2006). Indeed, the first source of phosphate

may have been polyphosphates, which are found in volcanic

condensates and hydrothermal vents produced by volcanic

activity (Yamagata et al., 1991). In order to reconcile the re-

quirements of volcanic activity with an environment favor-

ing molecular stability, it is tempting to suggest that life

originated in an Iceland-like setting mixing ice and fire, in

which a geothermal gradient could provide a stable and con-

tinuous energy source over long periods, whereas a cold en-

vironment could provide stability for the accumulation of or-

ganic molecules.

Both heterotrophic and autotrophic theories are faced

with the problem of ending up with a robust protometabo-

lism that could provide the energy and monomers to establish

the RNA world (de Duve, 2003). Ina first step, it is important

to consider how to transfer the energy acquired either from

the outside (heterotrophic theory) or from the reactions in

hydrothermal fluids (autotrophic theory) for further elabora-

tion of the system inside protocells. Ferry and House (2006)

recently proposed an interesting model in which the energy

obtained from a geothermal energy flux is coupled to the for-

mation of phosphorylated compounds. This model combines

both features of the autotrophic and heterotrophic theories

since the mechanism of energy conservation resembles those

of modern heterotrophs that metabolize reduced organiccompounds for the synthesis of adenosine triphosphate

(ATP) by substrate-level phosphorylation. A major question

is indeed whether the protometabolism can be inferred from

the metabolism of modern cells. The proponents of the het-

erotrophic scenario have often considered that the first or-

ganic molecules were produced by reactions completely in-

dependent from modern metabolism. In particular, Orgel

argued that the metabolisms of the RNA world would have

been completely erased by the emergence of a new metabo-

lism based on proteinenzymes (Orgel, 2003). On the con-

trary, the proponents of the autotrophic theory tend to di-

rectly link the protometabolism to modern(hyperthermophilic) proteins via the coevolution of RNA

and peptides. In fact, as suggested by de Duve (2003) a me-

tabolism entirely sustained by RNA catalysts can also be

linked to the modern one, if one reasons in terms of Darwin-

ian evolution (de Duve, 2003) by assuming that a protein en-

zyme could have initially only replaced the function of an

existing ribozyme (i.e., transformation of a given substrate

into a given product). Similarly, if ribozymes themselves re-

placed the function of more ancient catalysts, the metabolism

of the RNA cells couldhave been built upon the more ancient

protometabolism, especially if the RNA world itself origi-

nated in the framework of Darwinian evolution between

competing protocells.

On the way to proto-cells

Some authors have suggested that Darwinian evolution couldhave already occurred prior to the existence of cellular enti-

ties, through the competition of isolated supramolecular as-

semblies concentrated on mineral surfaces or inside mineral

pores (Wachtershauser, 2006) (Russell and Hall, 1997).

However, compelling theoretical and experimental argu-

ments suggest that cell formation occurred early in life evo-

lution [see for instance (de Duve, 2003; Deameret al., 2006)

(Muller, 2006) (Lopez-Garcia et al., 2006; Forterre, 2005)].

The formation of protocells was probably essential for the

evolution of RNA replicators (see below) and the establish-

ment of any sustained energy-driven protometabolism by (i)

keeping together RNA replicators and their corresponding

genomic RNAs (i.e., only catalysts enclosed by membranes

can benefit from their own reaction), (ii) excluding poten-

tially competing external parasitic RNAs, and (iii) prevent-

ing the dilution of molecules and macromolecules. Further-

more, a protometabolism able to synthesize nucleotides for

RNA production would have also been able to produce

simple (amphiphilic) molecules that are rather easy to syn-

thesize prebiotically and could have been abundant on early

Earth [see (Muller, 2006) and references therein]. Lipid

vesicles can be produced quite easily in vitro from fatty acids

or even better from fatty acid glycerol ester. These vesicles

have the ability to undergo several cycles of growth and di-

vision (Hanczyc et al., 2003). Mineral surfaces, such asmontmorillonite, also stimulate the formation of lipid

vesicles (Hanczyc et al., 2007). Interestingly, mineral cata-

lysts are trapped inside vesicles during this process, suggest-

ing that interactions between fatty acids and minerals on

early Earth may have resulted in the enclosure of diverse ar-

rays of mineral particles with catalytic properties.

Most interestingly, Szostak and co-workers have recently

shown that vesicles encapsulating RNA grow preferentially

by lipid capture at the expense of empty vesicles (Chen et al.,

2004; Chen and Szostak, 2004) (Fig. 2). This is explained by

the higher osmotic pressure inside RNA-containing vesicles

due to the counterions screening the negative charges of

RNA. This osmotic pressure is counterbalanced by mem-brane tension, driving the uptake of fatty acids. At an early

stage, this mechanism could have favored vesicles contain-

ing charged molecules, such as ribose phosphate and/or

polyphosphate, over those containing neutral molecules.

Later on, the encapsulation of RNA replicators would have

induced a primitive form of competition between the first

RNA cells, since those containing more efficient replicators

would have grown faster (Chen et al., 2004) (Fig. 2). In these

scenarios, natural selection between competing protocells in

the absence of genetic systems could have been originally

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driven by the physicochemical features of early systems. Fi-nally, vesicle membrane growth generates a transmembrane

pH gradient (Chen and Szostak, 2004), suggesting that some

universal features of the living world could have their origin

in fundamental physicochemical features. The perspective

now would be to use such vesicles (with various mixtures of

putative catalysts, minerals, peptides, or ribozymes) to test if

they could favor to set up some form of protometabolism.

Origin of ribonucleotides

ATP and other NTPs, including many modified bases which

were not included later on in RNA, probably originated first

as energy conveyors in the protometabolism and as coen-zymes of peptide catalysts before the origin of RNA itself (de

Duve, 2003). Unfortunately, despite recent progress (see be-

low) a single consecutive and convincing prebiotic process

has not yet been experimentally demonstrated for their origin

[for recent reviews, see (Joyce, 2002; Muller, 2006; Orgel,

2004) and references therein]. The main problem is the for-

mation of ribose and nucleosides. Many sugars with four to

six carbons can be produced at alkaline pH by the so-called

formose reaction from formaldehyde and catalytic amounts

of glycoaldehyde, two simple precursors that are present in

interstellar space and were probably on early Earth as well.

However, the products of the formose reaction are unstable,

and ribose accounts for only a minor portion. Moreover, at-tempts to combine ribose with bases and/or phosphate in pre-

biotic conditions also produces complex mixtures of nonspe-

cific products, generating many parasitic molecules that

compete with the normal building blocks of a nucleotide in

the assembly reaction. These observations have led many au-

thors to conclude that ribose was not a prebiotic compound,

but was invented by organisms living in a pre-RNA

world, where the scaffold of the genetic material was not

ribose but simple sugars [threofuranose nucleic acids

(TNA)] or amino acids [peptide nucleic acids (PNA)] [for

reviews see (Joyce, 2002; Orgel, 2004; Eschenmoser, 1999)].However, these compounds are also difficult to produce by

prebiotic chemistry and lack some of the interesting proper-

ties of RNA. In particular, PNA lacks the charged groups that

allow RNA to favor the growth of RNA-containing vesicles

versus RNA free vesicles in Szostaks experiments, whereas

TNA lacks an activated oxygen (such as the ribose 2OH),

essential for ribozyme activity.

Whereas the formation of ribose has never been experi-

mentally investigated in the framework of autotrophic theo-

ries, much effort has been done by proponents of the het-

erotrophic theory to increase the yields and specificity of the

formose reaction. It was shown recently that several com-

pounds( Pb+ +), cyanamide, or borate preferentially com-

plex and stabilize aldopentose and/or especially ribose with

respect to other sugars (Ricardo et al., 2004; Springsteen and

Joyce, 2004; Zubay and Mui, 2001). The complex formed

between ribose and boron is especially interesting since bo-

rate occupies the 2 and 3 position of the ribose thus leaving

the 5 position available for reactions such as phosphoryla-

tion (Li et al., 2005). Borate minerals were probably present

in the interstellar space and on early Earth. It was also sug-

gested that ribose, together with purine bases, could have

been synthesized in hydrothermal environments on the sea

floor (favoring the formose reaction) that could be enriched

in borate (Holm et al., 2006). Another recent finding thatcould be of great importance is that ribose permeates both

fatty acid and phospholipid membranes more rapidly than

other aldopentoses (Sacerdote and Szostak, 2005). The for-

mation of nucleosides (ribose+base) is also very difficult to

achieve in any prebiotic condition. Interestingly, the use of

phosphorylated ribose instead of ribose facilitates the asso-

ciation between the base and the sugar, suggesting that phos-

phoribose might have been a major prebiotic intermediate

[(Orgel, 2004) and references therein]. Future effort should

thus be concentrated on the search for catalysts (including

Figure 2. Competition between

vesicles in the early RNA world

adapted from Chen 2006. Lipid

vesicles containing mineral catalysts

hexagons and able to incorporate ribose

R and polyphosphate PP grow by cap-

turing lipids from vesicles containingamino acids AA only. The growth of

vesicles induces a proton gradient H +

that is used to facilitate the transport of

various compounds, followed by the syn-

thesis of small RNA oligomers crosses .

After division, vesicles containing RNA

replicators red crosses grow at the ex-

pense of those containing RNA without

self-replicating activity blue crosses .

These grow further using additional RNA

green barrel to facilitate the transport of

small polar molecules.




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mixtures of minerals, peptides, and amino acids) that could

produce ribonucleotides (and activated ribonucleotides such

as NTP) from phosphorylated ribose and various bases, pos-

sibly inside lipid vesicles.

Origin of ribozymes

The polymerization of ribonucleotides in prebiotic condi-

tions has only been achieved using nucleotide monophos-

phate activated by various amine compounds and using RNA

primers. It has been shown that clays (montmorillonite) cata-

lyze the condensation of such activated substrates to form

RNA oligomers up to 4050 nucleotides long [for recent re-

views see (Muller, 2006) (Ferris, 2006) (Huang and Ferris,

2003)]. Importantly, the mineral catalysts increase the ratio

of 3 to 5 over 2 to 5 phosphodiester bonds. A major prob-

lem for the establishment of a robust RNA world is the insta-

bility of RNA due to the reactive oxygen in 2 of the ribose

(Forterre et al., 1995; Lazcano and Miller, 1996). RNA can

be stabilized by a high concentration of monovalent salts

(Hethke et al., 1999) (Tehei et al., 2002), but most ribozymes

absolutely require millimolar concentrations of divalent salts

(Woodson, 2005) which, in contrast, strongly increase RNA

degradation at high temperatures (Ginoza et al., 1964). To

solve this problem, Vlassov and co-workers have suggested

that RNA occurred first in cold environments, where synthe-

sis would have been favored over degradation, an RNA

world on ice hypothesis (Vlassov et al., 2005). They re-

ported that polymerization of nucleotides, ligation of small

RNAs, and other critical prebiotic chemical reactions are in-

deed stimulated by freezing [(Vlassov et al., 2004) and ref-

erences therein]. Interestingly, a 3 5

linkage between

nucleotides is the major or even the only product formed un-

der freezing conditions. Freezing probably accelerates some

chemical reactions in aqueous solution because of the orga-

nization of frozen water and the concentration of reactants.

In the RNA world on ice scenario, early ribozymes might

have survived transport to more warm and wet environments

by virtue of their synthetic power outpacing degradation

(Vlassov et al., 2004).

The next problem is the production of polymers of suffi-

cient length to harbor catalytic activity (minimal ribozymes).

The smallest known ribozyme is a 7mer olinucleotide that

can cleave itself at 37 C [for reviews, see (Muller, 2006;

Vlassov et al., 2005)]. A mini-RNA ligase of 29 nucleotideshas also been obtained by in vitro selection (see below)

(Landweber and Pokrovskaya, 1999). This shows that small

ribozymes may support simple reactions of cleavage and li-

gation of other small RNAs. The production of large RNAs

by successive ligation of small RNAs would have opened the

way to the emergence of true ribozymes. The repertoire of

catalytic activities accessible to RNA has been systemati-

cally explored in several laboratories using modern enzymes

to produce libraries of random RNA oligomers. Large artifi-

cial ribozymes selectedin vitro can catalyze a wide range of

reactions such as RNA polymerization, aminoacylation of

transfer RNA, and peptide bond formation [for reviews see

(Brosius, 2005; Joyce, 2002; McGinness and Joyce, 2003;

Muller, 2006)]. It has even been recently shown that RNA

can be used to transport tryptophan across a membrane

vesicle (Janas et al., 2004). A major goal of these approaches

is to produce an RNA polymerase able to synthesize itself by

carrying its own template [for reviews see (Muller, 2006; Or-

gel, 2004)]. However, whereas the most active RNA poly-

merase ribozyme (RPR) is 189 nucleotides long, it can only

replicate a 14 nucleotide long template (Johnston et al.,

2001). The next objectives are to increase the processivity of

present RPRs and to introduce a helicase activity (an essen-

tial component of all modern polymerases). Future work will

probably focus on the possibility of combining various RNA

modules with different activities to produce a truly efficient

RPR. There is no a priori obstacle to this, and workers in the

field argue that powerful evolutionary search procedures us-

ing high throughput methodology should allow reaching thegoal in the next decade (Muller, 2006).

Emergence of the protein-RNA world

At some point, one has to assume that an efficient poly-

merase was not only able to replicate itself, but also to repli-

cate templates producing catalysts (either ribozymes or pep-

tides) useful for the metabolism of the RNA cell [for reviews

and hypotheses on this period see (Jeffares et al., 1998; Poole

et al., 1998)]. It is likely that many different types of

ribozyme-catalyzed peptide synthesis arose, but that only

one survived, leading to the modern translation apparatus

with tRNA and ribosomes. Many authors have suggested thatprotein synthesis first appeared as a by-product of RNA rep-

lication and was later on selected based on the expanding

chaperone and catalytic activities of longer and longer pep-

tides (see below). For instance, by analogy with modern

RNA viruses that contain tRNA-like structures at their 3end used to initiate the replication of viral genomes, Maizels

and Weiner (Maizels and Weiner, 1994) suggested that the

amino-acid module of tRNA with its CCA end first origi-

nated as a tag for genomic RNA replication (functioning

both as a telomer and as a marker for RNA to be replicated).

All modern tRNAs are monophyletic, i.e., they originated

from a single ancestral molecule that would have appeared in

a particular RNA-cell lineage. They are made of two mod-ules, the amino-acid binding module and the module carry-

ing the anticodon. The amino-acid binding module probably

originated first and was later on duplicated to produce the

anticodon module (Maizels and Weiner, 1994). From the

imagination of scientists, a great variety of scenarios have

been proposed to explain the origin of the translation ma-

chinery (Schimmel and Henderson, 1994) (Poole et al.,

1998) (Copley et al., 2005) (Taylor, 2006) (Szathmary, 1999)

(Wolf and Koonin, 2007). A detailed presentation of these

models is beyond the scope of this review. It is usually as-

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8/13

sumed that the primitive genetic code was simpler (for in-

stance with a two-nucleotide codon and less amino acids)

and expanded in the course of evolution. Two main theories

have been proposed, suggesting either that codon choice was

initiated by specific interaction between amino acids and an-

ticodons (stereochemical theories) or that codon choice wasset up parallel with the evolution of the amino acid biosyn-

thetic pathways (historical theories) [for reviews see (Di

Giulio, 2005; Ellington et al., 2000; Wong, 2005; Yarus et

al., 2005) (Knight and Landweber, 2000)]. In any case, the

modern genetic code is probably not a frozen accident, but

seems to be optimized to minimize the deleterious conse-

quences of mutations (Vogel, 1998) [for review see (Freeland

et al., 2003)]. This indicates that the tendency to increase

faithful translation was the major selection pressure that di-

rected the evolution of the genetic code, as suggested early

on by Woese (1965). Goldenfeld and co-workers have re-

cently shown from in silico stimulation that an optimal code

might have become universal in the frame of a communal

evolution pervaded by intense horizontal gene transfer of

coding sequences and coding system components among co-

evolving communities with different codes (Vetsigian et al.,

2006). If correct, this suggests that mechanisms of gene

transfer were operational very early, allowing genetic ex-

change between RNA-protein cells. Theories about the ori-

gin of the genetic code should now also accommodate struc-

tural data obtained for modern amino-acyl tRNA synthetases

and ribosomes. For instance, from comparative structural

analysis, it has been suggested that all modern amino-acyl

tRNA synthetases evolved from two proteins whose initial

role was to chaperone the tRNA (Ribas de Pouplana andSchimmel, 2001).

The first proteins were indeed probably short chaperone-

like proteins that stabilized ribozymes and increased their

catalytic activities. They would also have facilitated the

transport of molecules (including nucleic acids) through the

membranes of the RNA cells, (Jay and Gilbert, 1987).

Longer genes and proteins may have originated by RNA re-

combination producing proteins of increasing size via a mul-

tistep combinatorial mechanism under the control of natural

selection (de Duve, 2003). Starting from a small number of

proteins of small size (corresponding to modern folds), this

mechanism would have allowed the extensive exploration ofthe space sequence at each size level size. This period ended

up with the establishment of all modern protein superfami-

lies by the various combinations of protein folds. Recent ad-

vances in comparative and structural genomics have pro-

vided fascinating insights on this process [see for instance

many recent papers by the group of Koonin (Iyeret al., 2003)

(Iyeret al., 2004)]. Complex protein enzymes, such as large

RNA polymerases, ribonucleotide reductases, and thymydy-

late synthases, all required for the origin of DNA, likely only

originated at the end of this process.

In the above scenario it is already very clear that DNA

probably originated much later than RNA, i.e., in the ribo-

nucleoprotein world (also called the second age of the RNA

world(Forterre, 2005)]. Indeed, it has been convincingly ar-

gued that the reduction of ribose is too complex in terms of

chemistry to be catalyzed by a ribozyme (Freeland et al.,

1999). One can safely assume that the first DNA molecules

still contained uracil, because deoxythymidine triphosphate

(dTMP) is produced in modern organisms by a modification

(methylation) of deoxyuridine triphosphate (dUMP), a reac-

tion catalyzed by thymydylate synthase. Interestingly, recent

work has uncovered the existence of two nonhomologous

thymydylate synthases, ThyA and ThyX, suggesting that

modern DNA with thymidine may have been invented twice,

and possibly independently (Myllykallio et al., 2002).

It is usually assumed that DNA replaced RNA because it

is more stable and can be replicated more faithfully (Lazcano

et al., 1988; Poole et al., 2001). As a consequence, DNA ge-

nomes would have become larger, allowing the evolution ofcomplex cells. However, this cannot explain the selection of

the first organisms with DNA because genome stability and

fidelity was probably not a major problem for fast-replicating

RNA cells with small genomes, and the first DNA cells could

not have anticipated that their descendents would benefit

from a larger genome. One of us has thus suggested that

DNA first originated in viruses as a modified form of RNA to

protect the viral genetic material against defense mecha-

nisms of the infected cell (a direct selection pressure) (Fort-

erre, 2002). Cellular RNA genomes would have then been

transformed later on into DNA genomes following the re-

cruitment by RNA cells of viral enzymes to produce and rep-

licate DNA, or by the takeover of RNA cells by DNA viruses

living in a carrier state (Forterre, 2005).

The introduction of viruses in the early evolutionary sce-

nario implies that viruses themselves originated at an early

stage in life evolution. The concept of an ancient viral world

was indeed first proposed by scientists who suggested that

RNA viruses are relics of the RNA world [see, for instance

(Maizels and Weiner, 1994)], and that retroviruses, with their

RNADNA cycles, could give evidence for the transition

from the RNA to the DNA world. This concept is now sup-

ported by the existence of viruses harboring homologous

capsid proteins that infect cells from different domains (Ar-

chaea, Bacteria, Eukarya) (Akita et al., 2007; Bamfordet al.,2005) suggesting that capsid proteins originated prior to the

last universal common ancestor (LUCA). Several models

have thus been recently proposed to explain the origin of vi-

ruses in the RNA world (Forterre, 2006). Interestingly, the

concept of an ancient viral world implies that both modern

RNA and DNA viruses might have preserved ancient mo-

lecular features from the pre-LUCA era. The study of viruses

(especially the extensive exploration of their diversity)

should thus be a major area for research on early life evolu-

tion in the next decade.




9/13

THE ORIGIN OF MODERN CELLS

The last universal common ancestor

A major goal of the top-down approaches in the origin-of-

life field is to reconstruct the common ancestor of all extant

organisms to reach an intermediary stage between the origin

of life and the present biosphere. The basic principle of celldivision and membrane heredity (Cavalier-Smith, 2001) im-

plies that all modern cells derive from a single cell. This his-

torical entity was called the cenancestor (for common ances-

tor in Greek), the progenote, or the LUCA. This last term has

the advantage to be both neutral (unlike the term progenote,

which suggests a very primitive organism) and precise. It

clearly states that LUCA should not be confused with the

first cell, but was the product of a long period of evolution.

Being the last means that LUCA was preceded by a long suc-

cession of older ancestors. In this framework, a plethora of

cellular lineages that have left no descendants today may

have existed before LUCA. It is important to consider that

many of these were probably still present at the time ofLUCA, and some have probably even coexisted for some

time with its descendants, possibly contributing via horizon-

tal gene transfer to some traits present in modern lineages

(Fig. 3).

A consensus on the nature of LUCA is far from reached.

For some authors LUCA was a very simple organism, even

possibly acellular (Woese, 1998) (Russell and Martin, 2004),

whereas others consider that LUCA was a modern-type bac-

terium (Cavalier-Smith, 2002) or even a primitive Eucaryote

with a nucleus (Fuerst, 2005). Thanks to the advances of

comparative genomics, some aspects of these hypotheses can

now be tested. The identification of a set of genes present in

Archaea, Bacteria, and Eukarya has led to the definition of a

minimal gene content for LUCA (Delaye et al., 2005; Harris

et al., 2003; Koonin, 2003). As expected from the universal-

ity of the genetic code, the minimal protein set includes a

core of ribosomal proteins, tRNA synthetases, and transla-

tion factors (for both initiation and elongation) indicating

that the translation apparatus was already well established in

LUCA. Importantly, the minimal set includes the compo-

nents of machineries that are intimately associated with the

membrane, such as the signal recognition particle (SRP) and

the Sec systeminvolved in protein secretionand the

complex ATP synthasesthat function with a transmem-

brane proton gradient. These observations clearly indicate

that LUCA was a cellular organism with a membrane rathersimilar to that of modern organisms (Jekely, 2006; Pereto et

al., 2004). It remains to be explained why modern lipids are

so different in Archaea compared to the classical lipids

found in Bacteria and Eukaryotes (including an opposite po-

larity) [for discussion see (Pereto et al., 2004) (Xu and

Glansdorff, 2002)]. Future experimental work should focus

on the study of vesicles made ofthe two types of lipids and to

the expression in bacteria of enzymes involved in the ar-

chaeal lipid pathway andvice versa.

Another controversial idea is that modern hyperthermo-

philes (i.e., organisms having an optimal growth temperature

above 80 C) could be the direct descendants of a heat-

loving LUCA. Hyperthermophiles indeed appear as early di-

verging lineages in the rRNA universal tree and have rela-

tively short branches (Stetter, 2006). However, this position

might be due to the high guaninecytosine content of their

rRNAs, which could have reduced their rate of evolution

(leading to shorter branches and artifactual grouping) (Fort-

erre, 1996). Several attempts have been made to determine

putative compositional biases in the rRNA, tRNA, or pro-

teins from LUCA in order to determine the temperature at

which these molecules were functional [see, for instance

(Galtieret al., 1999) (Di Giulio, 2003)]. However, these ap-

proaches led to contradictory results and are hampered by

the difficulty of reconstructing ancient phylogenies and un-certainties concerning the root of the tree of life (see below).

In our opinion, a mesophilic LUCA fits better with the obser-

vation that hyperthermophiles are sophisticated organisms

that have evolved specific mechanisms to thrive at very high

temperatures [for a review see (Forterre and Philippe, 1999a;

Xu and Glansdorff, 2002)]. In particular, phylogenomics

analyses indeed suggest that reverse gyrase, an atypical DNA

topoisomerase present in all hyperthermophiles, was absent

in LUCA (Brochier-Armanet and Forterre, 2006; Forterre et

al., 2000) whereas hot-temperature-adapted lipids are not

Figure 3. LUCA was the last bottleneck in a long series of an-

cestors to the three present-day cellular domains: Archaea,

Bacteria, and Eukarya. Extinct lineages may have coexisted for

some time with the descendants of LUCA, and transferred some

features to them yellow arrows . The emergence of a universal

code in an earlier bottleneck organism may have been favored by

preferential transfer between organisms sharing the same genetic

code.

HFSP Journal



10/13

homologous in Archaea and Bacteria, suggesting a second-

ary adaptation that occurred independently in each of these

domains (Forterre and Philippe, 1999a; Xu and Glansdorff,

2002).

The minimal set of universal proteins includes a surpris-

ingly small number of proteins that function in DNA replica-

tion, lacking in particular a DNA replicase, a primase, and a

helicase. This is not due to unrecognized homology since the

proteins performing these functions in Bacteria on one side,

and ArcheaEukaryotes on the other, belong to different pro-

tein superfamilies (Bailey et al., 2006; Leipe et al., 1999).To

explain this observation, Koonin and colleagues have sug-

gested that LUCA had an RNA genome, but used DNA as a

replication intermediate (much like a retrovirus) (Leipe et

al., 1999). Alternatively, if LUCA had a DNA genome, the

ancestral system might have been replaced in one lineage

(probably in Bacteria) by a new system of viral origin (Fort-

erre, 1999). Finally, if LUCA still had a bona fide RNA ge-

nome, Forterre suggested that the few universal proteins in-volved in DNA metabolism were independently introduced

by DNA viruses in the three cellular domains (Forterre,

2006).The idea that LUCA still had a RNA genome has been

recently boosted by the discovery of mechanisms for the re-

pair of RNA damages and for enhancing the fidelity of RNA

transcription and replication. These findings have suggested

that RNAprotein cells may have reached a level of sophisti-

cation much more important than previously thought (Fort-

erre, 2005; Poole and Logan, 2005).

Most authors assume that LUCA was identical to the last

common ancestor of Archaea and Bacteria, either because it

is commonly believed that the tree of life is rooted between

the ArchaeaEukaryotes on one side and Bacteria on the

other, or because of models where Eukaryotes originated

from some kind of association between Archaea and Bacteria

(Lopez-Garcia and Moreira, 1999; Martin and Muller, 1998;

Rivera and Lake, 2004; Wachtershauser, 2006). However, the

root of the bacterial tree and the origin of Eukaryotes remain

highly controversial (Forterre and Philippe, 1999b; Gribaldo

and Philippe, 2002), (Poole and Penny, 2007). If the root

turned out to be in the eucaryotic branch (Philippe and Fort-

erre, 1999), several features now exclusively present in Eu-

karyotes could already have been present in LUCA, whereas

features common to Archaea and Bacteria might have origi-

nated in a common lineage to these two domains. At the mo-ment, there is no definitive argument to conclude if the

archaealeukaryal or even the unique eucaryotic features

(e.g., the spliceosome and spliceosomal introns) are ances-

tral or derived. The same can be said for the features that are

common to Bacteria and Archaea, such as the superoperons

encoding ribosomal proteins. In any case, many puzzling ob-

servations that are difficult to fit in a single coherent scenario

remain to be explained. The question of the topology of the

universal tree of life is intimately linked to the problem of the

origin of the three domains. The main questions to be solved

are (i) why three canonical versions of the ribosome (or other

universal traits) exist and (ii) how they are now so different

from each other, but so similar inside each domain (Woese,

1987). Many contradictory scenarios have been proposed

and are still actively debated (Lopez-Garcia and Moreira,

1999; Martin and Muller, 1998; Martin and Russell, 2003;

Rivera and Lake, 2004; Woese, 2002) (Cavalier-Smith,

2002) (Forterre, 2006). Much more work has to be done in

comparative biochemistry and molecular biology to test vari-

ous evolutionary scenarios for all possible molecular ma-

chines present in modern organisms. In particular, it will be

critical to analyze in depth the history of all universal mo-

lecular machines (especially the translation apparatus).

PERSPECTIVES

Although dramatic progress has been made these last

20 years concerning all aspects of research on the origin of

life, there are still critical gaps, especially in the RNA world

theory, and no experimental evidence for a consensus sce-nario. We still do not know how life originated on our planet,

and we will possibly never know, since we address here a

historical problem for which critical records may have com-

pletely disappeared. Furthermore, although the study of the

origin of life is a popular subject, the number of laboratories

truly working on the subject is extremely small. On the other

hand, considering recent trends, we should be able in the near

future to understand the physicochemical principles that sup-

ported the early emergence of life, and the particular path of

evolution of the matter that produced life on our planet could

be at least partly revealed by studying modern cells. A major

bottleneck for further advances is that scientists working in

the various origin of life fields are often isolated from eachother either by the borders of their disciplines or by their own

theoretical preferences. Research on the origin of life will

thus surely benefit from interdisciplinary projects gathering

all relevant disciplines to dive into our most distant past.

ACKNOWLEDGMENTS

Work in our laboratory on DNA replication was funded by a

HFSP grant.

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the origin of modern terrestrial life

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