A great many scenarios of the origin of
life (abiogenesis) have been proposed over the years. I explore
here specific features of an origin of life developing on minerals,
based on the idea that selective steps are essential early on,
and that metabolism originating on minerals is poised to answer
the riddle of selection, as well as the need to make polymers
Following the consistency of the reasoning
of Freeman Dyson in his book Origins
I further show that metabolism must have predated replication
and propose that nucleotides were created by a leak of a nitrogen
fixation process. Furthermore homochirality is a false problem
as maintaining a mixture of stereoisomers would cost much more
information than spontaneous symmetry breaking. Chirality is
not a relevant question: On a road, on must ride either on
the left or on the right, not both. The choice of the side
of the road is often contingent: the reason why continental
Europe chose the right, is just because Napoleon decided so!
In the same way many constraints operate that limit life based
on the chemistry of macromolecules.
The atoms that can be used
to this purpose are limited in number, and it is only sloppy
experiments and media hype that let some to think that arsenic
could be present in the backbone of nucleic acids. At best
it could be included as a "decoration" of the standard phosphodiester
Lecture given in Rio de Janeiro for the 100th Anniversary
of the death of Louis Pasteur (February 1995)
Presentation of the
conference in Rio (in French, autumn 1994)
of the presentation
genomics of extant bacterial genomes unravels a scenario
of the origin of life (2007) . This allowed us to substantiate
some of the hypotheses proposed here. In particular the idea
that metabolism predated template-mediated replication of
nucleic acids becomes an inevitable consequence of what we
know of extant life. This also emphasised the importance
of iron-sulphur clusters at the origin of central metabolic
pathways that must have predated life as we know it today,
and that are conserved in most living organisms, placing
the sulfur atom at
the very heart of life.
Louis Pasteur discovered that an original feature
of organic matter was associated to life: organic molecules
that derived from living processes were optically dissymmetrical.
In contrast, molecules obtained artificially were symmetrical.
Life had therefore to include a specific process to be differentiated
from the usual chemistry. Added to his own philosophical (and
perhaps religious) convictions, this meant to him that it was
hardly conceivable that life could originate from chemical
matter, be it mineral or organic. Life had to proceed from
life. Because it was well known that broth left standing in
the air yielded a variety of clearly living processes, it was
necessary to think that this corresponded to the pre-existence
of living seeds that could multiply in the broth:
la prétention de démontrer avec rigueur que
dans toutes les expériences où l'on a cru reconnaître
l'existence de générations spontanées,
chez les êtres les plus inférieurs, où le
débat se trouve aujourd'hui relégué,
l'observateur a été victime d'illusions ou
de causes d'erreur qu'il n'a pas aperçues ou qu'il
n'a pas su éviter. » *
Because life is so sensitive to high temperature,
it was easy to destroy the seeds in the broth, and, with appropriate
technical constructions, to prevent reinfection of the broth
by living seeds: if this hypothesis reflected truth, then a
broth sterilised by heat would be stable in time, and would
not lead to the de novo creation of life. In contrast, allowing
the broth to be open to the air - where seeds were supposed
to be present - would start the well-known multiplication process.
This created a difficulty raised by Pouchet who showed that
a boiled hay broth reaveled life after some time. This was
in fact caused by heat-resistant spores of the bacterium Bacillus
subtilis (named the "hay bacterium" in many languages).
A further objection could be raised to this approach if the
living principle was immaterial (i.e. had no weight permitting
it to sediment into the broth): but this could be tested by
using vessels open to this immaterial principle, where the
opening could not permit a material seed to reach the broth
(this was the origin of the famous Pasteur's "swan" shaped
vials). This Pasteur carried out, and started both a new conceptual
theoretical trend in the study of the origin of life, and an
industrial process, known as " pasteurisation ".
What is the situation today, and can we predict
the future trends of research in this domain of research? In
spite of the demonstration by Pasteur that no life emerged
from a broth, there is still a dominating model where a " prebiotic
soup " is the prerequisite for life's birth. Many scientists
have however stressed that life had rather to start from a
mineral environment, had we to propose that it started on Earth.
Among them, four major leaders should be considered: Desmond
Bernal, who pointed out the importance of clays in mineral
catalysis of organic matter ; Samuel Granick, who considered
that photosynthesis had to be created on a solid surface, and
use sulphur compounds as redox intermediates, and that we should
analyze extant metabolism to extrapolate back to the origin
; Graham Cairns-Smith, who established clearly that a prebiotic
soup would be poisoned by its very capacity to generate a large
- much too large - variety of organic compounds, and who proposed
the existence of a clay replicating material as predating our
organic life ; and, more recently, Günter Wächtershäuser,
who insisted on the fact that metabolism, at the surface of
solid particles, should be seriously considered as the only
possibility for generating life as we know it today .
I shall not here summarise the famous little
book of Schrödinger , nor endeavour to define the laws
of life, but place in the limelight four processes that must
be intimately associated in all living entities. They are:
metabolism, compartmentalisation, memory and manipulation .
The two former processes are organized by small molecules (a
few tens of atoms at most), whereas the two latter are controlled
by macromolecules (nucleic acids and proteins), associated
via processes that are considered as transferring
Thus, two spatial scales are intertwined in living processes,
that develop at a mesoscopic scale.
It has been thought to be so difficult to reconcile
all these processes together that a physicist like Freeman
Dyson has even proposed that life originated twice . This
explains why most molecular biologists have simply forgotten
to take into account metabolism and compartmentalisation as
questions posed to all models of the origin of life, and have
only considered proteins and nucleic acids. In recent years,
the concept of "chassis" proposed by Synthetic Biology, is
remarkably adapted to take into account both processes. At
the conceptual level also, when comparisons have been made
between life and Turing machines, the general principles for
the construction of a self-replicating machine (the chassis)
have nearly always overlooked the need for compartmentalisation
In contrast - and this should come out as a
surprising conceptual defect in scientific thought - scientists
get often very excited when one discovers yet another organic
molecule in the cosmos, be it only an amino-acid, as if this
gave us a clue for the origin of life! Following another trend
the recent discovery of ribozymes  has been perceived as
allowing us to solve the famous vicious circle, who is the
first, the chicken or the egg, nucleic acids or proteins ?
As a consequence life is now seen as having originated in an " RNA
world " endowed of the metabolic functions that are displayed
today by protein enzymes. In this context it is amusing to
illustrate the scientific debate by two quotations expressing
the most opposite views. In an argument similar to that of
Cairns-Smith in his Genetic Takeover, Steven Benner
for example wrote « arguments
that attempt to extrapolate from modern biochemistry back
to the origin of life are futile », , whereas
described his own approach  as « a reconstruction
of precursor pathways by retrodiction from extant pathways »,
as was proposed by Granick** in
a scenario inspired by photosynthesis . While the former
hypothesis makes that it is more or less impossible to guess
what happened at the origin, the latter can be used as a heuristic
approach. Of course we do no know which is right, and it is
likely that the present metabolism is both an archive and a
palimpsest. A major question remains however, for all models
involving an RNA world, that of the origin of nucleotides,
and - this is not of minor importance either - that of the
origin of membranes. This places us back to the question of
metabolism, and to another chicken and egg paradox: which is
the first, RNA or small precursors? Granick's and Wächtershäuser's
models are meant to solve this issue, by placing metabolism
of small molecules at the origin, using the selective power
of solid surfaces, this, without requiring as Cairns-Smith
did, the need for an ancestral mineral genetic replication
The important line of reasoning when thinking about life is
to consider two main processes, reproduction of the
cell machinery, with its compartments (what synthetic biologists
name the chassis) and its metabolism, and replication of
the genetic program. In his book Origins of Life, Dyson has
convincingly shown that this means that in any scenario of
origins, reproduction must have predated replication. In Synthetic
Biology efforts most investigators are interested in the program,
not in the machine. Yet efforts by some, such as Doron Lancet
or Pier Luigi Luisi, aim at understanding the reproduction
phase, by constructing mathematical and experimental models
of what could have happened in the past.
In a nutshell, the model can be summarised as
follows. Appropriate mineral surfaces, carrying an excess of
positive charges, can select from an aqueous environment molecules
that are negatively charged, mainly polycarboxylates and phosphates.
These molecules are able to react together, and only those
that are able to bind on the surface are kept for further chemical
evolution. In this model, entropy-driven processes are important
because, on a surface, they favour polymerisation, especially
when it is caused by elimination of a water molecule (this
is what usually happens in biological polymerisation) [4,11].
Here too, the model goes against the popular trend, the entropy
rise being the positive element that creates the order necessary
for life construction .
Extant metabolism allows one to substantiate
the model by identifying clues for the first steps of a surface
metabolism, stressing the importance of a few autocatalytic
steps (because they provide a self-consistent means to stabilise
the synthesis of those molecules that are further metabolised).
In this model, coenzymes and nucleotides - molecules usually
overlooked by scientists working on the origin of life - are
of prime importance. The core of metabolism is made of triose-phosphates
, and energy is derived from iron and sulphur redox transitions,
leading to formation of a solid which has iron-sulphur clusters
at its core, pyrite . At this point it is necessary to
investigate further the fate of solid particles: organic molecular
species must have substituted for them. Cairns-Smith has proposed
that RNA molecules, as polyelectrolytes that could mimic clays,
are the obvious substitutes of surfaces . Is it possible
to find in present day RNA molecules, a class that could have
played such a role? In 1975, Wong (now at the Hong Kong University
of Science and Technology), describing the structure of a possible
universal genetic code, proposed that transfer RNA molecules
have played the role of a rigid holder allowing for local modification
of substrates . Since then, many examples of metabolic
alterations involving transfer RNA have been discovered (or
I have proposed to name homeotopic transformation
the in situ modification of non nucleotide residues carried
by tRNA molecules. This accounts for the fact that different
chemical groups can often be used to modify a given position
of the molecule held by the tRNA molecule. Several examples
illustrate this process: amidation of glutamic acid on tRNAgln,
first described by Wilcox and Nirenberg , and also found
in chloroplasts , and addition of hydrogen selenide on
an activated tRNASecys, charged with activated serine
for synthesis of proteins containing selenocysteine both in
eukaryotes and prokaryotes [16-18]. Another well-known example
of homeotopic transformation is the formylation of methionine
carried by initiator tRNA in prokaryotes. This illustrates
the involvement of intermediary metabolism in the control of
macromolecular syntheses, as expected if metabolism is historically
intimately associated with translation processes (see below)
. Finally, tRNA is also associated with many other metabolic
processes that are not related to translation. For example
it has been observed that charged lysine tRNA is involved in
the synthesis of lipids , or that charged glutamic tRNA
is necessary for synthesis of the heme precursor aminolevulinate
in chloroplasts and in many bacteria [21-26].
Remarkably, charged tRNA molecules can also
be required in reactions involving peptide bond formation in
the absence of ribosomes. This is the case of synthesis of
cell wall peptides in Staphylococci or Micrococci where tRNAser,
tRNAthr or tRNAgly are involved [27-30].
N-modification of proteins by addition of leucine or phenylalanine
residues has also been demonstrated in Escherichia coli [31,32].
Finally, degradation of ubiquitylated proteins requires, at
least in some cases, the addition of arginine residues provided
by charged tRNAarg [33-35].
added 15th october 2005: the
work of Dieter Söll is strongly substantiating this
Note added 23d february 2007:
analysis of the
core genome of Bacteria supports the present scenario for
the origin of life. A summary of this view has been presented
at the Institute for Systems Biology: Presentation (1.3
Note added 7th july 2007:
In depth analysis of genomes from Bacteria spanning the whole
tree of life is consistent with the scenario described here.
The genome splits into a paleome,
that recapitulates the scenario of origin, and a cenome,
that allows the cell to occupy a specific niche.
Note added 16th june 2009: The paleome
has to be split into two parts. The part meant to replicate
the genome and the part meant to reproduce the cell machinery
and casings. The latter, in turn, is split into several groups
of genes. Some manage chemical incompatibilities (chemical
while the rest manages energy-dependent degradation of RNAs
and proteins. The corresponding genes behave as coding for
Maxwell's demons, chosing to protect what is young or functional.
there other, more general, traces of homeotopy in present day
metabolism? If one follows the hypotheses of Granick , modified
by Ycas , then more precisely stated by Jensen , that
enzyme specificity evolved by recruiting proteins that already
existed and catalyzed similar reactions, ancestral metabolic
traits should be found in proteins that are grouped as similar
in structure (and most probably in amino-acid sequence). It
follows that in such families one could find traces of ancestral
As time elapses the number of such cases steadily
increases, and their number is growing rapidly as genome programmes
progress. Kaplan and Nichols, in 1983, discovered that synthesis
of para-aminobenzoate and tryptophane was catalyzed by enzymes
coded by genes trpD and pabA derived from a common
ancestor . Goncharoff and Nichols further developed this
observation by showing that syntheses involving chorismate
were performed by enzymes exhibiting a significant degree of
similarity, such as enzymes synthesized from genes papB (para-aminobenzoate
synthase) and trpE (anthranilate synthase) . Further
work by these authors and others showed that glutamine amidotransferase
was involved in synthesis of para-aminobenzoate, tryptophane,
as well as guanine (genes pabA, trpG and guaA)
and derived from a common ancestor [40, 41]. A further substantiation
of the existence of a primitive amidotransferase catalytic
domain comes from analysis of human CTP synthetase, where the
glutamine amide transfer domain is clearly related to the bacterial
Subsequently Parsot, Cohen and their colleagues
discovered that many activities involving pyridoxal phosphate
were strongly related, in particular in synthesis or degradation
of threonine, serine and tryptophane (thrC, dsdA, ilvA and trpB),
as well as in enzymes involved in biosynthesis of methionine
(metB, metC in E. coli, and their counterparts,
in yeast) [45, 46]. In the same way Schoenlein et al. identified
a significant level of similarity between enzymes responsible
for the synthesis of pyridoxal phosphate (pdxB) and
serine (serA) . This is most revealing in view of
Wächtershäuser's hypothesis of early surface metabolism,
where triose-phosphates had to play a major role (and this
contradicts Benner's dismissal of pyridoxamine as involved
in early living processes ). Along the same line, we demonstrated
that cysteine biosynthesis, in E. coli, shares a common
ancestor with tryptophane biosynthesis . This, together
with the observation that cysteine and tryptophane codons are
found in the same box of the genetic code table (in company
with the UGA selenocysteine codon, also derived after homeotopic
transformation from activated serine), substantiates the hypothesis
that serine(-phosphate) was a general precursor of several
amino-acids synthesis and that tRNA was involved in the process.
Another old observation, the significant binding of charged
tRNAleu or tRNAval to E. coli threonine
deaminase, is well in line with this hypothesis . Finally,
we recently discovered that there is a significant kinship
between synthesis of aspartyl-phosphate, glutamyl-phosphate,
carbamyl-phosphate, and uridine-diphosphate in bacteria .
This is revealing when one remembers that aspartate and carbamyl
phosphate are precursors of pyrimidines.
But all this does not tell us directly what
could have been the precursors of these " holder " nucleic
acids that seem to have played an early role in evolution of
metabolism. It is clear that nucleotides are today part of
several coenzymes, as pointed out by many [10, 52, 53]. But
it cannot be surmised whether this reflects a trace of older
structures rather than more recent adaptation of long nucleic
acid precursors to shorter structures. Peptides are far much
easier to synthesise than nucleic acids. On the other hand,
many coenzymes (e.g. glutathione, pantothenate, folic acid
...) are (iso) peptides, or contain peptides, often at their
active center. It is therefore interesting to explore whether
(iso) peptides have not been precursors not only of most coenzymes,
but of nucleotides as well. Many features of extant metabolism
are pointing in this direction, for amino-acids are certainly
present in the biosynthesis of purines and pteridines (glutamine,
glycine, aspartate and serine, through formyltetrahydrofolate),
or pyrimidines (aspartate).
But, as an indispensable self-catalytic step
requires, are (iso) peptides involved in synthesis of peptides?
The example of peptide antibiotics synthesis is a remarkable
illustration of such self-referring catalysis. Biosynthesis
of tyrocidin or gramicidin derives from formation of peptide
bonds, in the absence of ribosomes. In tyrocidin, for instance,
ten individual amino-acid residues are activated by ATP (as
they are in translation) but are then transferred to an active
SH residue of a protein subunit, forming a thioester bond.
Tyrocidin synthesis begins after all ten sites of the enzyme
complex have been esterified with their specific residue. The
first three amino-acid residues react together sequentially,
forming a thioesterified tripeptide. From this step onwards
a phosphopantetheine cofactor transports the growing peptide
chain on each new residue in turn, using its SH end as a carrier,
and forms a new peptide bond following a transthiolation step,
until the end of the process is reached when a decapeptide
is formed (and finally cyclised). This process is highly reminiscent
of synthesis of fatty acids from acetyl coenzyme A (which contains
a phosphopantetheine arm as a reactive center). In this latter
process acetyl-CoA is first transformed by carboxylation into
malonyl-CoA using ATP as an energy source. A phosphopantetheine
arm, bound to a core enzyme makes a succession of transthiolation
reactions that lead to decarboxylation of malonate (this is
the driving energy source) and condensation of two methylene
residues on the growing chain. After six such steps the synthesis
is completed, yielding palmitic acid. Thermal agitation supplies
the only energy required for positioning of the carrier arm.
Analogy between both processes would only be
anecdotal, had it not been discovered that indeed, proteins
involved in tyrocidin, gramicidin and fatty acids synthesis
share a common ancestor , indicating that their origin
is common, and could be very old. This observation has been
substantiated by the study of many other sequences, in particular
from the programmes aiming at sequencing whole genomes .
Several features of these processes must be emphasized: (i)
a peptide is able to carry out synthesis of a peptide; (ii)
the same process permits synthesis of both lipids and peptides;
(iii) the process requires the presence of active SH groups,
essential components of surface metabolism as proposed by Granick
and Wächtershäuser, and shown by De Duve to be of
major importance for the origin of life ; (iv) energy is
essentially derived from the formation of thioesters (and carboxylation
/ decarboxylation in the case of fatty acids); (v) among the
amino-acids that are used, are present both L- and D-amino
acids (as well as a basic amino-acid residue, ornithine, which
cannot be incorporated into proteins during translation, because
it cannot form stable adducts with tRNA).
If then, we accept that peptide formation is
a very ancient process (it could predate the invasion of Earth
by L-amino-acids), synthesis of peptide bond predating translation,
it becomes particularly important to assess the hypothesis
that nucleotides could have been derived from surface metabolites
containing peptides. In this framework translation is a later
invention, when tRNA molecules, instead of simply offering
a general holding device for homeotopic transformation, have
been involved in an RNA-mediated process for peptide-bond formation.
A large number of examples where peptides can react by intramolecular
reaction to form new molecules can be found. This is typical,
for example of the antibiotic nisin or other lantibiotics,
where serine and cysteine react to form lanthionin, a structural
analogue of diaminopimelic acid [56-59]. Another example of
this situation is the case of decarboxylases that use a pyruvoyl
active site, derived from self-processing of a serine-serine
dipeptide in the polypeptide proenzyme .
Organic molecules are usually presented as
derivatives of carbon chemistry. Yet it is clear that the
organic molecules present in living organisms display also
a very high content of nitrogen. This was not thought to
pose a difficult problem 40 years ago, when the models of
the primitive atmosphere considered it to be strongly reducing,
and rich in NH3. This is no longer the case. And
one now considers that 3.8 billions years ago the atmosphere
was mostly rich in CO2 and N2. It is
therefore of the utmost importance for any model of the origin
of life to propose scenarii permitting to understand prebiotic
Following Granick's approach, it may be interesting
to analyze the present day situation of nitrogen scavenging.
In general, the process requires the presence of iron-sulphur
proteins such as ferredoxins as electron transfer intermediates
Ferredoxins are proteins constructed with a limited number
of amino-acid species, and they contain an iron sulphur cluster,
typical of what could be expected for very early proteins.
Molybdenum is a rare metal in today's earth crust, but it
is not clear whether at some stage of earth evolution, or
locally it could not have been abundant. In addition this
metal ion could be replaced by other ions for the electron
transfer process at early stages of nitrogen fixation .
The cofactor molybdopterin is found in further complex oxidation
reactions. Now, molybdopterin is a sulphur containing coenzyme
- that could be therefore be interacting with metal-sulphur
clusters, that is made of a pterin moiety derived from GTP,
by cyclisation following loss of a one-carbon formyl group.
This step is catalyzed by GTP cyclohydrolase, which yields
pteridine triphosphate from guanosine triphosphate with elimination
of a one carbon residue (precisely a residue transported
by pteridine containing coenzymes). Is it possible to consider
that the reverse reaction be a model for the straightforward
synthesis of nucleotides?
PteridineTP + HCOOH -----> GTP + H2O
We could then speculate that an autocatalytic
process permitting synthesis of pteridine (tri) phosphate
could have produced, as a side-product, the synthesis of
GTP. In this frame of thought GTP would have but been a side-product
of on-going nitrogen fixation.
This wild speculation would ask for a process
permitting synthesis of pteridine from peptides. Exploration
of extant microbial metabolism might give clues for the plausibility
of such processes. The fact that many molybdopterin coenzymes
contain nucleotides in their structure is already consistent
with this hypothesis [62-64]....
Conclusion: a future for the origin of life
Several scientists convincingly proposed that
life emerged from a surface metabolism, rather than from a
poisonous broth. Granick's approach extensively used the knowledge
of extant intermediary metabolism. If his main contention is
right, this means that we are much nearer to the origin than
we could think of previously. Analysis of biosynthetic pathways
might therefore provide clues about the original metabolic
pathways and processes. The hypothesis stating that early metabolism
evolved through specification of broad range catalytic activities
can be appreciated using comparison of enzyme structures in
living cells. Among the most prominent processes are those
which use tRNA molecules as carrier for homeotopic transformation
of more or less universal precursors. Among such reactions,
peptide bond formation could have evolved well before translation.
Peptides are therefore placed in the limelight. They could
have evolved before complex coenzymes, allowing their own synthesis.
Synthesis of nucleotides would have been derived from nitrogen
fixation (for purines and ribose) and from condensation of
aspartate to carbamyl-phosphate (for pyrimidine synthesis).
In turn nucleotides would have produced RNA carrier molecules,
thus solving the chicken and egg paradox raised by the generally
accepted hypothesis of an ancestral RNA world.
An interesting consequence of the depth of the
conceptual reflection of scientists is that concepts can not
only be organized to explain reality, but also to act in a
creative way, constructing a new aspect of reality. This has
been put into action for example when physicists have created
Laser beams. Thus, nothing precludes that research in the Origin
of Life results in new prospects: this is already illustrated
by the success of selective combinatorial chemistry.
* Louis Pasteur (1862) "Sur
les corpuscules organisés qui existent dans l'atmosphère.
Examen de la doctrine des générations spontanées" in
: Leçons de chimie et de physique professées en
1861 (à la Société chimique de Paris), Paris,
Hachette et Cie, p. 219-254 (back to text)
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