Causation and the origin of life. Metabolism or replication first?

Abstract

The conceptual gulf that separates the 'metabolism first' and 'replication first' mechanisms 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 replication and metabolism can only be demonstrated if replication would have preceded 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'.

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CAUSATION AND THE ORIGIN OF LIFE. METABOLISM OR
REPLICATION FIRST?
ADDY PROSS
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
1. Introduction
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.

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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.
2. Discussion
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
endeavor.
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:

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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
emergence.
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

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to his famous comment that there could never be a Newton able to explain ‘a single
blade of grass.’
In line with modern scientific methodology, recent theories regarding the emer-
gence of life tend to be mechanistic in their approach. Most address the mechanistic
how question rather than the ostensibly inappropriate teleological why question.
The why question seems to take us back to that discredited methodological ap-
proach in which purpose played such a dominant role. But the why question can be
asked with a non-teleological intent. It can be asked in the sense of seeking out the
driving force for some phenomenon. As Wicken (1985) has argued, asking the why
question remains an essential component of scientific understanding; a two-tiered
approach tocausation isoften crucial inobtaining aproper understanding ofnatural
phenomena. Understanding whys is no less important to discovering hows and in
fact in many cases may be an important preliminary step before the mechanistic
how can be tackled. To make the point clear and to reaffirm the need for two-tier
causation let us consider two examples – one physical in orientation: how and why
does water flow on a given surface, and one chemical in orientation: how and why
do chemical reactions occur?
Water flow may manifest itself in different ways: as a leaking roof, a small
stream, a winding river, a waterfall, or there may be no flow at all, as in a desert,
a pond, or a lake. Inspection of a physical surface, its slope and composition, and
knowing the volume of water that is directed at that surface may well provide
a reasonable answer to the question: how will water flow? But the basis of any
attempt to answer the question of how water flows requires an understanding of
why water flows. Newton’s generalization regarding the existence of a universal
gravitational force provides a powerful framework for answering the why question
and this understanding then enables the how question to be usefully addressed.
Mayr (1988) has termed such causal explanations (e.g., gravity as the explanation
for water flow) as teleomatic, the term signifying that the consequence of a process
(in the above case a lowering of potential energy) is offered as the reason for its
occurrence.
Let us now move closer to home and consider the question of how and why
chemical reactions occur. In the present context the example is particularly per-
tinent given the modern view that living beings are ultimately nothing more than
complex chemical systems. In posing the above question the how enquires into
the mechanism of a particular reaction – that is, the detailed description of the
individual steps that lead from reactants to products. Forexample, does the reaction
take place in a concerted one-step process, or are intermediates formed along the
way? Is some form of energy input, such as irradiation, required for the reaction to
occur? Is a catalyst involved? Does the reaction take place in solution or on some
catalytic surface? Understanding how a reaction occurs - its mechanism, provides
us with a measure of control over that reaction, suggesting ways to speed it up or
slow it down, or possibly help eliminate unwanted side-reactions.

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But, as in the case of water flow, understanding why the reaction occurs is a
necessary preliminary step to understanding how it occurs, and it is the concep-
tual framework of thermodynamics that provides an answer to this question. The
science ofthermodynamics teaches usthat energy flowhas direction; closed macro-
scopic chemical systems react because there is a driving force that strives to lower
the free energy of the reacting system till it reaches the point of minimum free
energy – the so-called equilibrium state. Of course whether a particular reaction
actually takes place also depends on the potential mechanism of the reaction. Thus
for a macroscopic chemical system to react, both a thermodynamic driving force
and a kinetically feasible mechanism are required. Here again we see that for a
proper understanding of the factors controlling a chemical process, we need to
answer both themechanistic how andthe teleomatic whyquestions. Thermodynam-
ics is the science of the possible; kinetics and mechanism determine whether the
possible will or will not occur. As we will subsequently see, this two-tier approach
to causation may prove beneficial in our attempts to understand the process of life’s
emergence.
2.2. METABOLISM FIRST OR REPLICATION FIRST
The debate between proponents of ‘metabolism first’ and ‘replication first’ con-
tinues unabated with both approaches subject to criticism. The ‘metabolism first’
approach has been criticized by some of the leading workers in the field (Maynard
Smith and Szathmáry, 1995; Orgel, 1992; Eigen, 1971; Lifson, 1997) based on the
assessment that key steps in the building up of such a metabolic system are highly
improbable. The ‘replication first’ approach is questioned based on the view that
the de novo appearance of oligonucleotides is improbable, and that there is no
clear path from an RNA world to the current dual world of proteins and nucleic
acids (Shapiro, 1984, 2000). We wish to address this key issue and in particular to
inquire how the ability ofliving things toboth replicate and metabolize relate toone
another. Within the context of life’s emergence, could there be a causal relation-
ship between these two life characteristics, and, if so, can that causal connection
assist us to deduce which came first? A reasonably definitive answer to the above
question would be a worthwhile step forward as it would significantly narrow the
range of existing mechanistic possibilities for the emergence of life.
In considering the emergence of life problem in the context of replication and
metabolism, one can in principle consider three alternative scenarios: (a) that meta-
bolism preceded replication, (b) that replication preceded metabolism, and (c) that
the process of emergence led to a primal system that was both metabolic and
replicative. Categories (a) and (c) actually belong to the same conceptual class
of ‘metabolism first’ mechanisms since it is the process by which a metabolic
system can emerge (with or without a replicative capability), that characterises
the ‘metabolism first’ grouping. In reality the more widely known ‘metabolism
first’ mechanisms belong to the (c) category, i.e., they propose that the emerging