CAUSATION AND THE ORIGIN OF LIFE. METABOLISM OR
Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva, 84105, Israel
(Received 7 January 2003; accepted in revised form 27 January 2003)
Abstract. The conceptual gulf that separates the ‘metabolism first’ and ‘replication first’ mechan-
isms for the emergence of life continues to cloud the origin of life debate. In the present paper we
analyze this aspect of the origin of life problem and offer arguments in favor of the ‘replication first’
school. Utilizing Wicken’s two-tier approach to causation we argue that a causal connection between
replicationand metabolismcan onlybedemonstrated ifreplicationwould havepreceded metabolism.
In conjunction with existing empirical evidence and theoretical reasoning, our analysis concludes
that there is no substantive evidence for a ‘metabolism first’ mechanism for life’s emergence, while a
coherent case can be made for the ‘replication first’ group of mechanisms. The analysis reaffirms our
conviction that life is an extreme expression of kinetic control, and that the emergence of metabolic
pathways can be understood by considering life as a manifestation of ‘replicative chemistry’.
Keywords: causation, chemical evolution, metabolism first, molecular replication, origin of life,
replication first, teleology, teleonomy
The resurgence of interest in the origin of life on earth that began early in the 20th
century has been largely driven by the conviction that all living beings evolved
from inanimate matter, and that life is no more than a complex set of physico-
chemical processes (for recent reviews see: Fry, 2000; Lahav, 1999; Orgel, 1998,
1992; Lifson, 1997; Wächtershäuser, 1997; Miller and Lazcano, 1996; Maynard
Smith and Szathmáry, 1995; Chyba and McDonald, 1995; Elitzur, 1994; Eigen,
1992). However, even a cursory look at existing theories reveals a major concern.
Many of the evolutionary hypotheses are quite different to one another and often
based on quite different premises. For example, where on the planet did life emerge
– on the earth’s surface in a prebiotic soup (Oparin, 1957), or in hydrothermal
vents under the seas (Wächtershäuser, 1992)? Or did early life arrive here from
some extraterrestrial source (Melosh, 1988)? What was the composition of the
early atmosphere that led to life’s emergence – a reducing atmosphere of methane,
hydrogen, ammonia and water, or a neutral one containing mainly carbon dioxide,
nitrogen and water (Kasting, 1993)? Did life initially emerge from a prebiotic
aqueous environment, as was widely believed till quite recently, or did it derive
from two-dimensional metabolic organization – possibly on iron sulfide (Wächter-
shäuser, 1997), or clay surfaces (Cairns-Smith, 1985)? And given that life systems
Origins of Life and Evolution of the Biosphere 34: 307–321, 2004.
© 2004 Kluwer Academic Publishers. Printed in the Netherlands.
are primarily characterized by a metabolism and the ability to reproduce, which
came first – metabolism or replication? The issue of ‘metabolism first’ or ‘replic-
ation first’ is a particularly fundamental one since it bears on the very nature of
biological complexification. The uncertainty surrounding this issue effectively de-
clares that the physico-chemical principles that were responsible for the process of
complexification remain unclear. So it is not just historic questions such as, where
on earth did life originate, that await more definitive answers. Even the general
principles by which animate matter emerged remain unresolved and in dispute.
The purpose of this paper is therefore to address the issue of ‘metabolism first’
or ‘replication first’ in order to help clarify an ahistoric aspect of emergence – to
better understand the physico-chemical principles that enabled matter to undergo
a process of biological complexification, that eventually led to simple life forms.
By applying Wicken’s (1985) two-tier approach to causation, we believe a sound
causal argument can be made that life began with replication, not metabolism.
As noted above the current scientific confusion associated with the emergence of
life debate appears to stem from both historic and ahistoric uncertainties. Consider
historic uncertainty first. As the conditions that existed on the prebiotic earth are
very uncertain, there are enormous practical difficulties in assessing life’s mech-
anistic beginnings. The elucidation of a reaction mechanism is often problematical
evenwhen thereaction parameters and conditions (reactant concentrations, solvent,
pH, temperature, pressure, catalysts, etc.) are all specified. Yet in addressing the
question of life’s emergence, we have to acknowledge the fact that there is almost
nothing we know about that primordial process with any degree of certainty; we
are unable to identify the initial reactants, nor the reaction conditions for the pro-
cess that initiated that evolutionary transition from inanimate to animate. Clearly
then, attempts to formulate a reaction mechanism for a process whose key reagents
and reaction conditions are largely unknown, necessarily becomes a speculative
But we would argue that in a fundamental sense the precise evolutionary path-
way by which life emerged is actually a secondary one, and needs to be addressed
within the context of a more basic ahistoric question: what is the nature of the
physical and chemical laws that governed that evolutionary process of emergence?
Wächtershäuser (1997) termsthe science ofchemistry ‘an ahistoric science striving
for universal laws, independent of space and time or of geography and the calen-
dar’. Accordingly, in agreement with Wächtershäuser we believe the primary (and
more realistic) challenge regarding the origin of life remains to reduce the historic
process of evolution with all its inherent uncertainties, many of which are unlikely
to be ever resolved, to a universal chemical law of evolution, whose validity would
be independent of time and place. So, at least in the first instance, rather than ask:
CAUSATION AND THE ORIGIN OF LIFE
what was the mechanistic path that led inanimate matter to the earliest life forms,
we need to ask what general features would characterize the transition from in-
animate to animate. What characteristics would define that family of mechanisms
that could, in principle at least, lead to the emergence of life? Even though it is
generally acknowledged that all biological systems derived from a process of com-
plexification, the physico-chemical principles that would lead to the emergence
of such highly complex far-from-equilibrium systems remain unclear. A clearer
physico-chemical understanding of the principles underlying the emergence of life
would also go some way toward resolving the long-standing (and fractious) debate
regarding the definition of life. Asrecently discussed by Cleland and Chyba (2002),
the possibility of defining life in an unambiguous manner rests on our ability to
characterize life as a ‘natural kind’ (Putnam, 1973; Schwartz, 1977). However the
ability tocharacterize life asa‘natural kind’ in turn depends on amorefundamental
understanding of the physico-chemical principles that would have governed life’s
The above considerations lead us directly to the question of ‘metabolism first’
or ‘replication first’. Two of life’s most striking characteristics are: (a) its highly
complex metabolic system, and, (b) its replicating capability. So can we, as a first
step in describing the process of life’s emergence, at least in general terms, determ-
ine which of these two characteristics emerged first? In contrast to many aspects
of emergence this question is unlikely to be historical in character, as there may
well be a causal connection between these two key life characteristics, one that is
directly linked to the essence of life itself and indirectly to the nature of matter. In
order therefore to address this question from a causal perspective we make some
preliminary comments regarding causation.
2.1. TWO-TIER CAUSATION – DRIVING FORCE AND MECHANISM
The question as to what causes change and motion in the universe has been the
subject ofscientific enquiry since the timeofAristotle and before. Though Aristotle
outlined the framework for modern scientific thought, the teleological viewpoint
that he helped establish proved unable to adequately explain the design and order
so evident in the world, as manifested most strikingly in living systems. It was only
during the seventeenth century, two thousand years after Aristotle, that the modern
philosophical foundations of the natural sciences were laid down by Descartes,
Bacon and others. The essence of that change was that the deeply entrenched
teleological view of nature, in which purpose underlay natural phenomena (that
is, processes occurred as means to achieve particular ends) was replaced by a
mechanical-mechanistic world view, in which all of nature, including living sys-
tems, behaved according to well-defined laws of nature. The view attributed to van
Helmont (1648): ‘All life is chemistry’, characterised this new way of thinking,
and was reinforced 150 years later by Immanuel Kant (1952), though interestingly,
Kant’s view of living systems as a ‘natural purpose’ remained teleological, and led
Helmont, J. B. van: 1648, Ortus Medicinae, Amsterdam, pp. 108–109; Translated in Great Exper-
iments in Biology, M. L. Gabriel and S. Fogel (eds) p. 155, Englewood Cliffs, N.J., Prentice
Johnston, W. K. et al.: 2001, RNA-catalyzed RNA Polymerization: Accurate and General RNA-
Template Primer Extension, Science 292, 1319–1325.
Joyce, G. F.: 1994, In Vitro Evolution of Nucleic Acids, Curr Opin. Struct. Biol. 4, 331–6.
Joyce, G. F.: 2002, The Antiquity of RNA-Based Evolution, Nature 418, 214–221.
Kant,I.:1952, in:Critiqueof Judgement, R. Hutchins(ed.),Ch. 65. Chicago, Encyclopedia Brittanica
Kasting, J. F.: 1993, Earth’s Early Atmosphere, Science 259, 920–926.
Kauffman, S. A.: 2000, Investigations, Oxford, Oxford U.P.
Kauffman, S. A.: 1993, The Origins of Order. Self-Organization and Selection in Evolution, Oxford,
Lahav, N.: 1999, Biogenisis. Theories of Life’s Origins, Oxford, Oxford U.P.
Lifson, S.: 1997, On the Crucial Stages in the Origin of Animate Matter, J. Mol. Evol. 44, 1–8.
Maynard Smith, J. and Szathmáry, E.: 1995, The Major Transitions in Evolution, Oxford, Freeman.
Mayr, E.: 1988, Toward a New Philosophy of Biology, p. 44, Cambridge, Harvard U.P.
Melosh, H. J.: 1988, The Rocky Road to Panspermia, Nature, 332, 687–8.
Miller, S. L. and Lazcano, A.: 1995, The Origin of Life – Did it Occur at hHgh Temperatures? J.
Mol. Evol. 41, 689–692.
Miller, S. L. and Lazcano, A.: 1996, The Origin and Early Evolution of Life: Prebiotic Chemistry,
the Pre-RNA World, and Time, Cell 85, 793–798.
Mizuno, T. and Weiss, A. H.: 1974, Synthesis and Utilisation of Formose Sugars, Adv. Carbohyd.
Chem. Biochem. 29, 173–227.
Monod, J.: 1972, Chance and Necessity, London, Collins.
New, M. H. and Pohorille, A.: 2000, An Inherited Efficiencies Model of Non-Genomic Evolution,
Simulation Practice Theory 8, 99–108.
Oparin, A. I.:1957, The Origin of Life on Earth, 3rd ed., Edinburgh, Oliver and Boyd.
Orgel, L. E.: 2000, Self-Organizing Biochemical Cycles, Proc. Nat. Acad. Sci. USA 97, 12503–
Orgel, L. E.: 1998, The Origin of Life – A Review of Facts and Speculations, TIBS 23, 491–5.
Orgel, L. E.: 1992, Molecular Replication, Nature 358, 203–209.
Oro, J.: 1961, Mechanism of Synthesis of Adenine from Hydrogen Cyanide under Possible Primitive
Earth Conditions, Nature 191, 1193–4.
Pitsch, S. et al.: 1995, Mineral Induced Formation of Sugar Phosphates, Orig. Life Evol. Biosph. 25,
Pross, A.: 2003, The Driving Force for Life’s Emergence. Kinetic and Thermodynamic Considera-
tions, J. Theor. Biol. 220, 393–406.
Pross, A. and Khodorkovsky, V.: 2004, Extending the Concept of Kinetic Stability: Toward a
Paradigm for Life, J. Phys. Org. Chem., in press.
Putnam, H.: 1973, Meaning and Reference, J. Philos. 70, 699–711.
Rebek, J., Jr.: 1994, A Template for Life, Chem. Ber. 30, 286–90.
Robertson, M. P. and Miller S. L.: 1995, An Efficient Prebiotic Synthesis of Cytosine and Uracil,
Nature 375, 772–4.
Sanchez, R. A. et al.: 1967, Studies in Prebiotic Synthesis. II. Synthesis of Purine Precursors and
Amino Acids from Aqueous Hydrogen Cyanide, J. Mol. Biol. 30, 223–53.
Schwartz, S. P.: 1977, Introduction, in Naming, Necessity and Natural Kinds, S. P. Schwartz (ed.),
Ithaca NY, Cornell U. P.
Segre, D. et al.: 2000, Compositional Genomes: PrebioticInformation Transfer inMutually Catalytic
Noncovalent Assemblies, Proc. Nat. Acad. Sci. USA 97, 4112–7.
CAUSATION AND THE ORIGIN OF LIFE
Shapiro, R.: 1984, The Improbability of Prebiotic Nucleic Acid Synthesis, Origins Life Evol.
Biosphere 14, 565–70.
Shapiro, R.: 2000, A Replicator was not Involved in the Origin of Life, IUBMB Life 49, 173–6.
Sievers, D. and von Kiedrowski, G.: 1994, Self-Replication of Complimentary Nucleotide-Based
Oligomers, Nature 369, 221–4.
Spiegelman, S.: 1967, An In Vitro Analysis of a Replicating Molecule, American Scientist 55, 221–
Stoks, P. G. and Schwartz, A. W.: 1979, Uracil in Carbonaceous Meteorites, Nature 282, 709–10.
Wächtershäuser, G.: 1992, Groundworks for an Evolutionary Biochemistry: The Iron Sulfur World,
Prog. Biophys. Mol. Biol. 58, 85–201.
Wächtershäuser G.: 1997, The Origin of Life and Its Methodological Challenge, J. Theor. Biol. 187,
Wicken, J.S.:1985, Thermodynamics andtheConceptual Structureof EvolutionaryTheory,J. Theor.
Biol. 117, 363–383.